Intellectual and Developmental 

Disabilities (IDD) Branch

NICHD

Report to the NACHHD Council

September 2009

U.S. Department of Health and Human Services

National Institutes of Health

Eunice Kennedy Shriver National Institute of Child Health and Human Development
The cover of this report features photos from the life of Eunice Kennedy Shriver, who was instrumental in helping 

to establish the NICHD, now named in her honor. Most people are aware of Mrs. Shriver’s efforts related to 

Special Olympics and her championing for the rights of those with disabilities. Less well known and especially 

important to the NICHD, she was equally passionate about the need to study IDD as a way to improve the care 

of and quality-of-life for those with IDD and their families. Both passions were critical to the establishment of the 

NICHD, the IDD Branch and its research mission, and the IDD Research Centers Program, which is also now 

named in her honor. Mrs. Shriver died on August 11, 2009, at the age of 88.

Photos shown are as follows:

1. Mrs. Shriver stands with her arms around two athletes with IDD during a Special Olympics trip to South Africa. 

(Photo courtesy of Special Olympics)

2. On October 17, 1962, President John F. Kennedy hands his sister, Mrs. Shriver, the pen he used to sign 

Public Law 87-838, authorizing the establishment of the NICHD to “encourage imaginative research into the 

complex processes of human development from conception to old age.”

3. The first National Advisory Child Health and Human Development Council poses to commemorate its first 

meeting on November 14, 1963. Mrs. Shriver, fourth from the left in the front row, served a standard tenure on 

the first Council and took part in Institute-sponsored meetings and conferences for some time thereafter.

4. Mrs. Shriver smiles at her son, Timothy, during the March 2008 event in her honor. During the event, 

the NICHD officially became the Eunice Kennedy Shriver National Institute of Child Health and Human 

Development. The Institute also renamed its flagship research program as the Eunice Kennedy Shriver IDD 

Research Centers Program and inducted Mrs. Shriver into the NICHD Hall of Honor.

5. During the Surgeon General’s Conference on Health Disparities and Mental Retardation in 2001, Mrs. Shriver 

poses with a few friends, including (L to R): Dr. Loretta Claiborne, an accomplished and celebrated Special 

Olympics athlete, member of the Special Olympics International Board of Directors, and passionate advocate 

for people with IDD; Dr. Duane Alexander, former NICHD Director; then Surgeon General Dr. David Satcher; 

and Dr. Timothy Shriver, her son and Chairman of Special Olympics. The NICHD played a lead role in the 

conference, which was planned and carried out with full inclusion of persons with IDD. During the event, Dr. 

Satcher presented the Surgeon General Medallion Award to Mrs. Shriver for her public health achievements.

6. During “Camp Shriver”—the precursor to the Special Olympics—Mrs. Shriver helps a child into the swimming 

pool at her Maryland farm, Timberlawn, in 1962. (Photo courtesy of Special Olympics)

7. Mrs. Shriver congratulates an athlete during the 2007 Special Olympics World Games in Shanghai, China. 

(Photo courtesy of Special Olympics)
TABLE OF CONTENTS

EXECUTIVE SUMMARY .......................................................................................................... 1

INTRODUCTION TO THE BRANCH ...................................................................................... 2

EUNICE KENNEDY SHRIVER IDD RESEARCH CENTERS (IDDRCS) .......................... 5

EUNICE KENNEDY SHRIVER IDDRC PROGRAM SCIENCE ADVANCES .......................................... 7

PROGRAM ON FRAGILE X SYNDROME (FXS) AND ASSOCIATED DISORDERS ..... 9

FXS RESEARCH CENTERS (FXSRCS): THE CENTERS-WITHIN-CENTERS MODEL ...................... 10

THE NIH FRAGILE X RESEARCH COORDINATING GROUP (FXRCG)

 AND THE NIH RESEARCH PLAN ON FXS AND ASSOCIATED DISORDERS ................................. 12

COLLABORATIVE EFFORTS ON FXS ............................................................................................ 12

FXS RESEARCH PROGRAM SCIENCE ADVANCES ........................................................................ 13

RARE DISEASES COOPERATIVE RESEARCH CONSORTIA (RDCRC)...................... 14

UREA CYCLE DISORDERS RARE DISEASE CONSORTIUM ............................................................. 15

CONSORTIUM FOR RARE EPIGENETIC DISORDERS ...................................................................... 16

SENATOR PAUL D. WELLSTONE MUSCULAR DYSTROPHY COOPERATIVE 

RESEARCH CENTERS ............................................................................................................ 17

WELLSTONE CENTERS SCIENCE ADVANCES ............................................................................... 18

CHROMOSOME ABNORMALITIES, GENETIC/GENOMIC SYNDROMES, 

AND EPIGENETIC DISORDERS ........................................................................................... 19

DOWN SYNDROME ...................................................................................................................... 19

WILLIAMS SYNDROME ................................................................................................................ 21

SMITH-MAGENIS SYNDROME (SMS) .......................................................................................... 21

DISORDERS WITH A SHARED PATHWAY ...................................................................................... 22

EPIGENETIC DISORDERS ............................................................................................................. 22

BIOCHEMICAL AND METABOLIC RESEARCH .............................................................. 24

HYPOXIA/ISCHEMIA .................................................................................................................... 25

MITOCHONDRIAL DISORDERS ..................................................................................................... 26

UREA CYCLE DISORDERS ........................................................................................................... 27

CHOLESTEROL METABOLIC PATHWAY DISORDERS .................................................................... 28

RESEARCH ON AUTISM SPECTRUM DISORDERS (ASDS) ........................................... 28

AUTISM CENTERS OF EXCELLENCE (ACE) PROGRAM ................................................................ 28

INTERAGENCY AUTISM COORDINATING COMMITTEE (IACC) STRATEGIC 

 PLAN FOR ASD RESEARCH ..................................................................................................... 29

NATIONAL DATABASE FOR AUTISM RESEARCH (NDAR) ........................................................... 30

OTHER ASD-RELATED RESEARCH ACTIVITIES ........................................................................... 30

SCIENCE ADVANCES IN ASD RESEARCH .................................................................................... 31

PLANNED ASD RESEARCH ACTIVITIES: AMERICAN RECOVERY AND REINVESTMENT 

 ACT OF 2009 (ARRA) ............................................................................................................ 34
NEWBORN SCREENING ......................................................................................................... 35

SECRETARY’S ADVISORY COMMITTEE ON HERITABLE DISORDERS IN 

 NEWBORNS AND CHILDREN (ACHDNC)................................................................................ 35

NEWBORN SCREENING SAVES LIVES ACT .................................................................................. 36

ADVANCES IN NEWBORN SCREENING ......................................................................................... 36

RESEARCH RESOURCES ....................................................................................................... 40

REPOSITORY FOR MOUSE MODELS OF CYTOGENETIC DISORDERS .............................................. 40

BRAIN AND TISSUE BANK FOR DEVELOPMENTAL DISORDERS .................................................... 41

BRANCH-SUPPORTED TRAINING INITIATIVES ............................................................ 41

FUTURE DIRECTIONS FOR THE BRANCH....................................................................... 42

RESEARCH ON THERAPEUTIC INTERVENTIONS FOR IDD ............................................................. 43

EARLY IDENTIFICATION AND DIAGNOSIS VIA NEWBORN SCREENING ........................................ 44

RESEARCH ON ADOLESCENT BRAIN DEVELOPMENT ................................................................... 45

HEALTH DISPARITIES AND HEALTH PROMOTION RESEARCH RELATED TO IDD ......................... 46

TRAINING INITIATIVES IN THE IDD FIELD .................................................................................. 47

TOWARD A NEW CONCEPTUALIZATION OF IDD RESEARCH ....................................................... 47

REFERENCES ............................................................................................................................ 49

FIGURES AND TABLES ............................................................... FIGURES AND TABLES-1

APPENDIX A: IDD BRANCH PERSONNEL ............................................... APPENDICES-1

APPENDIX B: BRANCH FUNDING INITIATIVES, FISCAL YEAR 2005 

THROUGH FISCAL YEAR 2008 .................................................................... APPENDICES-3

APPENDIX C: EXPERT PANEL MEMBERS .............................................. APPENDICES-6

APPENDIX D: BRANCH-SPONSORED CONFERENCES 

AND WORKSHOPS .......................................................................................... APPENDICES-7

APPENDIX E: BRANCH-SUPPORTED TRAINING 

AND CAREER DEVELOPMENT GRANTS, FISCAL 

YEAR 2005 THROUGH FISCAL YEAR 2008 ............................................ APPENDICES-12

APPENDIX F: MARRAKECH DECLARATION ....................................... APPENDICES-16

STRENGTHENING NEWBORN SCREENING IN THE MIDDLE EAST 

 AND NORTH AFRICA CONFERENCE ..................................................................... APPENDICES-16
Executive Summary 1 

EXECUTIVE SUMMARY

The Intellectual and Developmental Disabilities (IDD) Branch, formerly the Mental Retardation 

and Developmental Disabilities Branch, within the Center for Developmental Biology and 

Perinatal Medicine of the Eunice Kennedy Shriver National Institute of Child Health and Human 

Development (NICHD), has a longstanding history of providing support for a diverse portfolio of 

research projects, training programs, and research centers dedicated to promoting the well-being 

of individuals with IDD. When the Institute was created at the National Institutes of Health

(NIH) in 1962 at the request of then-President John F. Kennedy and with the support of congress, 

one of its primary charges was to encourage investigations in human development throughout the 

lifespan, with an emphasis on understanding developmental disabilities, including intellectual 

disabilities (historically referred to as mental retardation). The mission of the IDD Branch is to: 

• Develop and support research and research training programs in IDD; 

• Administer a program of support for centers for research in IDD; 

• Coordinate with university-affiliated programs for IDD with respect to integration of 

research, training, and service activities; and 

• Partner with other federal agencies, organizations, and advocacy groups to advance efforts 

toward the prevention, diagnosis, treatment, and management of IDD that will improve the 

quality-of-life for these individuals and their families.

Since its last report to the National Advisory Child Health and Human Development (NACHHD) 

Council, the Branch has continued its mission through a variety of mechanisms, grants, and 

contracts. The Branch has also added breadth to its portfolio by expanding traditional efforts to 

address quality-of-life issues for individuals with IDD, while increasing multidisciplinary and 

translational research to facilitate the movement of basic research from the bench to the clinic 

and beyond. The Branch’s expanded newborn screening program and the growth of certain 

cooperative research centers reflect such efforts. 

This report highlights advances from Branch-sponsored research, emphasizes major Branch 

initiatives from the past four years, and outlines areas of future expansion in the field of IDD

research. 

Branch activities are organized into topical research initiatives, with some areas of programmatic 

overlap. The following initiatives will be the focus of subsequent sections of this report: 

• Eunice Kennedy Shriver IDD Research Centers (IDDRCs)

• Program on Fragile X syndrome (FXS) and associated disorders

• Rare Diseases Cooperative Research Consortia (RDCRC) 

• Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Centers

• Chromosome abnormalities, genetic/genomic syndromes, and epigenetic disorders 

• Biochemical and metabolic research 

• Research on Autism Spectrum Disorders (ASDs) 
2 Introduction to the Branch

• Newborn screening 

• Research resources

• Branch-supported training initiatives

The next several sections focus on major accomplishments within each of the areas listed above, 

with an emphasis on areas for which the Branch has employed collaborative approaches to 

improve coordination and leverage of resources. 

The report concludes with an overview of possible Future Directions for the Branch in IDD 

research. The section describes the discussions of an expert panel of IDD researchers and 

clinicians assembled as part of the Institute’s continued efforts to improve strategic planning and 

transparency for its components. The expert panel and Branch members gathered to discuss the 

Branch’s existing research portfolio as a way to address the following issues: opportunities in 

prenatal, perinatal, and postnatal identification of infants and children at risk for developing

cognitive impairment; areas, such as adolescent brain development, obesity, and health 

disparities, in which IDD research has lagged; and promotion of training initiatives. Branch staff 

and members of the expert panel also discussed a de-emphasis on individual disorders with 

concomitant support for groups of conditions with common pathways or shared elements as a 

way to facilitate the ambitious but necessary goal of developing drugs and other cognitive and 

behavioral interventions to improve the lives of individuals with IDD and their families. The 

potential to guide the IDD field toward translational applications is enormous and potentially 

transformative, making this a very exciting time in IDD research. 

Biosketches of Branch personnel are listed in Appendix A. Funding Opportunity Announcements 

(FOAs), which reflect areas of programmatic emphasis released by the Branch during the last 

four years, are listed in Appendix B. Appendix C lists expert panel members. Appendix D

describes the various conferences and meetings the Branch supported since the Branch’s last 

report to the NACHHD Council. 

INTRODUCTION TO THE BRANCH

Intellectual and developmental disabilities (IDD) represent a significant source of morbidity and 

mortality among the pediatric population. Intellectual disability is characterized by significant 

limitations in intellectual functioning and adaptive behavior as expressed in conceptual, social, 

and practical life skills. These limitations originate before age 18 years. The American 

Association on Intellectual and Developmental Disabilities describes developmental disabilities 

more broadly as severe chronic disabilities that can be cognitive, physical, or both, that generally

appear before age 22 years, and that are likely to be lifelong. The etiology of IDD is complex, 

and more than 500 genetic diseases (most individually rare) contribute to this condition; 

chromosomal disorders, such as Down syndrome, are estimated to account for 5 percent to 

19 percent of all IDD cases (Yeargin-Allsopp et al, 2007). The prevalence of severe intellectual 

disability is estimated as 3 to 4 per 1,000 children and adults, while mild intellectual disability is 

much more common. IDD significantly impacts the physical, emotional, and financial health 
Introduction to the Branch 3 

and well-being of the affected individuals and their families. Approximately 17 percent of 

children in the United States have some type of disability, and about 2 percent of children will 

require lifelong care for their disability; the associated economic costs of these disabilities are 

significant (Boyle and Cordero, 2005). 

Although “mental retardation” and “intellectual disability” are technically synonymous, 

intellectual disability is the preferred term among many professional organizations, advocacy 

groups, and government agencies. This language is considered to be less offensive to persons 

with IDD, to be more consistent with internationally used terminology, and to align with current 

professional practices that focus on supports tailored to enhance individuals’ functioning 

(Schalock et al, 2007). To reflect the field’s move away from the term “mental retardation” and 

toward the broader term IDD, the Eunice Kennedy Shriver National Institute of Child Health and 

Human Development (NICHD) changed the name of the Branch from the Mental Retardation 

and Developmental Disabilities Branch to the IDD Branch. Similarly, this document uses the 

term IDD, not “mental retardation” to describe the relevant conditions. Branch reports and other 

documents published prior to September 2009 use the older Branch name and terminology. 

This change in the Branch name also necessitated a change in its functional statement, now 

revised to better reflect the Branch’s growing number of partnerships with other federal agencies, 

organizations, and advocacy groups. The revised mission of the IDD Branch is to: 

• Develop and support research and research training programs in IDD; 

• Administer a program of support for centers for research in IDD; 

• Coordinate with university-affiliated programs for IDD with respect to integration of 

research, training, and service activities; and 

• Partner with other federal agencies, organizations, and advocacy groups to advance efforts 

toward the prevention, diagnosis, treatment, and management of IDD that will improve the 

quality-of-life for these individuals and their families.

The revised mission also better reflects the Branch’s longstanding goals of prevention, diagnosis, 

treatment, and management of IDD with a focus on improving outcomes for persons with IDD. 

In fiscal year 2008, the Branch supported IDD research with a total budget of $106.4 million, 

which represents a stable investment of approximately $106 million during the four-year 

reporting period, as well as a decrease in actual or constant dollars when corrected for inflation 

for that same time period (Figure 1). Among the 236 total Branch-supported projects for fiscal 

year 2008, most (just less than 50 percent) were research project grants (e.g., R01, R03, R13, 

R15, R21, and R37 mechanisms), the “bread and butter” of National Institutes of Health (NIH) 

awards (see Figure 2 and Table 1). One-quarter of Branch funds supported Research Centers 

grants (P30 and P50 mechanisms), and 13.5 percent of the portfolio supported Program Project 

grants (P01 mechanism) for multi-investigator projects. Another 3 percent of the Branch’s 

portfolio was devoted to training initiatives, including training programs (Ts), fellowships (Fs), 

and research career development program awards (Ks). Small business awards (Small Business 

Innovative Research awards and Small Business Technology Transfer awards), contracts, and 

cooperative research consortia in rare diseases and muscular dystrophy (U54s) comprised the 

remainder of the portfolio. 
4 Introduction to the Branch

The funding of Branch initiatives also reflects some subtle shifts in programmatic emphasis. For 

instance, during the four-year reporting period, allocation of funds remained fairly consistent in

the following categories of research projects: Biomedical, typically considered basic-science 

oriented; Behavioral, related to behavioral research studies; and Biobehavioral, a combination of 

Biomedical and Behavioral (Figure 3). However, when further categorized, a trend of increasing 

support of Biobehavioral projects with concomitant reduction in support for Biomedical research 

is apparent. This trend is especially evident when comparing human projects (Figure 4) and 

animal projects (Figure 5), perhaps reflecting the increased sophistication of testing algorithms to 

dissect complex behaviors in rodent and other animal models of human developmental disorders. 

Another way to evaluate IDD Branch funding trends is to examine the Branch’s support for 

selected disorders during the four-year reporting period. Figure 6 and Figure 7 illustrate these 

trends for nine different conditions or topics within the Branch’s portfolio. The figures indicate 

fairly consistent support for research related to Fragile X syndrome (FXS), metabolic/ 

mitochondrial disorders, and Down syndrome, while also showing a steady increase in support 

for Autism Spectrum Disorders (ASDs), which now represents almost 25 percent of the total 

Branch portfolio (Figure 6). Conditions such as muscular dystrophy and Rett, Williams, and 

Prader-Willi syndromes received fairly stable support, while the Branch’s commitment to 

newborn screening increased six-fold during this reporting period (Figure 7).

The remainder of the report highlights the science advances sponsored by the IDD Branch during 

the past four years. Although there are some areas of programmatic overlap, Branch activities 

are organized into the following topical research initiatives: Eunice Kennedy Shriver IDD

Research Centers (IDDRCs); program on FXS and associated disorders; Rare Diseases 

Cooperative Research Consortia (RDCRC); Senator Paul D. Wellstone Muscular Dystrophy 

Cooperative Research Centers; chromosome abnormalities, genetic/genomic syndromes, and 

epigenetic disorders; biochemical and metabolic research; research on ASDs; newborn 

screening; research resources; and Branch-supported training initiatives. These sections describe 

the Branch’s activities with a focus on major accomplishments of each initiative. The final 

section of this report describes possible Future Directions for the Branch. 

Biosketches of Branch personnel are listed in Appendix A. Funding Opportunity Announcements 

(FOAs), which reflect areas of programmatic emphasis, released by the Branch during the last 

four years are listed in Appendix B. Appendix C lists expert panel members. Appendix D

describes the various conferences and meetings the Branch supported since the Branch’s last 

report to the National Advisory Child Health and Human Development (NACHHD) Council. 
Eunice Kennedy Shriver IDD Research Centers (IDDRCs) 5 

EUNICE KENNEDY SHRIVER IDD RESEARCH CENTERS (IDDRCS) 

Congressional mandate established the IDDRCs (formerly the Mental Retardation and 

Developmental Disabilities Research Centers), the flagship program of the NICHD, one year 

after the Institute’s founding in the early 1960s. These centers were to provide facilities and 

support for research in IDD and to develop university-affiliated programs for training personnel 

to care for individuals with IDD. In 2008, when an Act of Congress changed the name of the 

Institute to the Eunice Kennedy Shriver National Institute of Child Health and Human 

Development, the NICHD’s leadership also renamed its flagship centers program in her honor as 

the Eunice Kennedy Shriver IDDRCs. The focus of the program is to support researchers whose 

goals are to understand the causes of and to develop treatments for IDD. During the last 

40 years, the Centers’ activities have made dramatic strides in achieving these goals. 

Currently, 14 funded sites and one site under a no-cost extension located at universities and 

children’s hospitals throughout the country comprise the Eunice Kennedy Shriver IDDRCs 

(Figure 8). Many of these Centers are at institutions that also support University Centers for 

Excellence in Developmental Disabilities Education, Research, and Service (UCEDDs), which 

represent 67 sites located in every state in the country. Quite a few Centers also overlap with the 

38 Leadership Education in Neurodevelopmental and Related Disabilities (LEND) programs, 

which are funded through the Maternal and Child Health Bureau of the Health Resources and 

Services Administration (HRSA) to provide interdisciplinary leadership training. Thus, these 

three programs—the Eunice Kennedy Shriver IDDRCs, UCEDDs, and LENDs—function 

synergistically at many sites to promote IDD-related research, service, and training. A P30 grant 

mechanism funds the Eunice Kennedy Shriver IDDRCs in the form of core infrastructure that 

supports independently funded, IDD-relevant projects and new program development projects, 

the latter of which represent a small portion of the overall budget expenditure within an 

individual Center. As a result, the IDDRCs primarily provide research support services for 

investigators rather than directly funding research projects.

The Centers differ from each other in many aspects, including their scientific focus, size, 

lifespan, and history. Although these differences impart a unique quality to each Center, the 

Eunice Kennedy Shriver IDDRCs share common features that are discernible and important, 

including their ability to leverage resources from their host institutions, private donors, and other 

sources to facilitate growth. Each Center presently supports between 45 and 166 projects and at 

least 20 to more than 70 principal investigators (PIs), who receive funding from a variety of 

sources. This diversity allows the Centers to support substantially more projects and affiliates 

than would be possible using NICHD support alone. In fact, between fiscal year 2005 and fiscal 

year 2008, the IDDRCs expanded the total number of projects supported by their cores from 

approximately 1,000 to 1,200, in spite of nearly flat funding provided to the program from the 

NICHD during that time period. Many of the additional projects receive funding from other NIH 

Institutes, such as the National Institute of Neurological Disorders and Stroke (NINDS) and the 

National Institute of Mental Health (NIMH), and a number also are supported by nongovernmental sources, such as foundations and private research institutions (Figure 9). In 

addition, IDD Branch staff work closely with the IDDRC directors and/or co-directors at twiceannual meetings and in various one-on-one discussions. 
6 Eunice Kennedy Shriver IDD Research Centers (IDDRCs)

Although it is difficult to summarize the breadth of research supported by the Eunice Kennedy 

Shriver IDDRC Program, a number of accomplishments are worth highlighting: 

• Three Requests for Applications (RFAs), issued in 2005, 2007, and 2008, solicited 

competitive continuation and new grant applications. The RFAs spelled out the goals of 

collaborating, sharing, and translating discoveries in IDD research. These RFAs attracted 

new applicants to the field, and several successfully competed for research funds. 

• The creation, launch, and expansion of a secure Web portal for the Program facilitated 

collaboration among investigators affiliated with the Eunice Kennedy Shriver IDDRCs. This

project lasted three years, ending in 2008. The NICHD funded the work under a subcontract 

to the Association of University Centers on Disabilities, which hosted and updated the 

“public” face of the Web portal. 

• The Centers are making efforts to integrate several patient registries across all the IDDRCs. 

This process began with a Participant Registries Meeting, sponsored by the IDDRCs at the 

University of North Carolina (UNC) and the University of Wisconsin, held at the Waisman 

Center at the University of Wisconsin in June 2007. The meeting attracted representatives 

from most IDDRCs, other IDD centers programs (including UCEDDs and LENDs), the 

Centers for Disease Control and Prevention (CDC), and some advocacy groups (such as the 

Fragile X Research Foundation, called FRAXA). The two sponsoring IDDRCs initiated a 

proof-of-principle test to integrate their patient registries and document the process of 

addressing human-subjects compliance issues and other challenges. Initial efforts will be

focused on registering individuals with FXS; registries of those with other disorders will 

follow. 

• The IDDRCs at the Kennedy Krieger Institute (KKI) in Baltimore and at the Children’s 

Hospitals in Washington, D.C., and Philadelphia, Pennsylvania, initiated a Mid-Atlantic 

Consortium on March 30, 2007, with aims to synergize their efforts on shared research 

interests, develop collaborative projects, and create cross-institutional training opportunities. 

The second meeting of this Consortium, which focused on ASD research, occurred on 

April 27, 2009. 

• Translational Analysis of Chronic Aberrant Behavior across the Life Span, a program project 

with a focus on collaboration, received an outstanding score for funding in fiscal year 2009. 

This program consists of one project at the IDDRCs based at the KKI, the University of 

Kansas, and the University of Massachusetts and will utilize an IDDRC Core at the 

University of Massachusetts. This project will share a unique resource, facilitate 

collaboration among users of three IDDRCs, and translate basic knowledge in behavioral 

science into treatments for difficult behavior. 

• The University of Wisconsin IDDRC organized an interdisciplinary training conference that

gathered representatives of all Branch-funded T32 training programs in IDD. The 

conference’s aim was to enhance training opportunities and facilitate synergy. This effort 

resulted in an R13 application, Interdisciplinary Training Conference in Intellectual 

Disabilities, for support of a mentoring workshop for predoctoral and postdoctoral fellows 

that will be held in conjunction with the annual Gatlinburg Conference on Research and 

Theory in IDD, a seminal meeting for investigators in the field. 
Eunice Kennedy Shriver IDD Research Centers (IDDRCs) 7 

• In 2005, the IDDRC directors catalogued collaborations among IDDRC affiliates. Since 

then, the directors have consciously facilitated collaborations among individual investigators, 

within and across IDDRCs, and with other centers programs, including FXS Centers-withinCenters, to better address research goals. 

The fifth-year hiatus in the competition of the Eunice Kennedy Shriver IDDRCs occurred in 

2006-2007 and provided an opportune time to contemplate change for the Program. NICHD 

leadership and IDD Branch staff established several goals for this process, including: 

encouraging the Centers’ leaders to share unique resources, facilitating collaboration among 

users, and stimulating translation of knowledge about the causes of IDD into interventions; 

soliciting input from IDDRC directors and their colleagues, patient advocacy groups, and 

potential funding partners to facilitate restructuring for the continued vitality of the Program;

considering a formal evaluation of the P30 funding mechanism as a means of defining and 

achieving new Program goals; and updating existing and issuing new guidelines that reflect 

contemporary Program goals. The outcomes of this effort are outlined below: 

• The IDD Branch sponsored a workshop entitled Mental Retardation and Developmental 

Research Centers Program: Planning for the Fiscal Year 2007 Hiatus and Beyond in June 

2006. Three principal recommendations resulting from the meeting were to retain the P30 

funding mechanism, increase monitoring of progress, and make the Program much better 

known to constituencies, congress, and the public. 

• Consequent to the 2006 workshop recommendations, Branch staff organized a meeting on

Community and Public Interest Insights for the Mental Retardation and Developmental 

Research Centers, held on March 25, 2007. The purpose of the meeting was to include 

advocacy groups in Program planning and outreach. Attendees included representatives from 

advocacy organizations and NICHD staff, including the NICHD Director. 

• The steady increase in the number and quality of P30 applications, despite flat funding, is 

also a significant achievement. This trend reflects the growth of IDD research nationally, the 

openness and transparency of the Program, and the recognition of the pivotal role that the 

IDDRC Program plays in promoting and advancing IDD research. 

EUNICE KENNEDY SHRIVER IDDRC PROGRAM SCIENCE ADVANCES

Neural Stem Cells (NSCs) and Induced Pluripotent Stem Cells (iPSCs)

The discovery of NSCs in the adult mammalian brain dramatically changed the view of the 

brain’s regenerative potential and raised the possibility of preempting the development of some 

neurodegenerative (e.g., Alzheimer disease) and neurodevelopmental (e.g., Down syndrome) 

diseases. Despite intense efforts to identify their origin during the last ten years, NSCs’ identity 

had remained elusive. One group of scientists, supported by the IDDRC at University of 

California, Los Angeles (UCLA), provided evidence, based on their demonstrated cell surface 

markers, that the ependymal cells lining the murine brain ventricles are NSCs (Coskun et al, 

2008). Characterizing these cells structurally and functionally will be important for developing 

methods to control their proliferation and differentiation in situ before onset of pathogenesis to 

preempt development of disease.
8 Eunice Kennedy Shriver IDD Research Centers (IDDRCs)

In another development involving stem cells, new technologies are allowing investigators to take 

skin fibroblasts from individuals with neurological disorders and reprogram them to become 

iPSCs, which can then be differentiated into neurological cell types. This cellular 

reprogramming might provide an opportunity to not only understand fundamental disease 

mechanisms, but also to screen drugs and other compounds for their potential therapeutic utility. 

Investigators at the Waisman Center at the University of Wisconsin have generated iPSCs from 

the skin cells of a child with spinal muscular atrophy (SMA), a genetic neurological disorder 

resulting from mutations in the Survival Motor Neuron 1 (SMN1) gene that cause SMN protein 

deficiency and lead to the loss of motor neurons, muscle weakness, paralysis, and death (Ebert et 

al, 2009). This research showed that the iPSCs can be differentiated into expressing markers of 

spinal motor neurons by treating them with neurotrophic and other growth factors, and that the 

cells from the affected child exhibited selective motor neuron degeneration consistent with SMA. 

Moreover, treatment of the cells with drugs to increase the amount of SMN protein showed a 

compensatory improvement. These technologies show potential for investigating disorders that 

affect neurons, which are notoriously difficult to isolate from affected individuals, and the 

promise of developing therapies to treat them. 

Rett Syndrome

Rett syndrome, caused by mutations in the MECP2 gene, occurs almost exclusively in girls, 

causing loss of language, cognitive, and fine motor skills around the time they are learning to 

walk. In boys, who have only one X chromosome compared to girls’ two X chromosomes, this 

deficiency tends to cause death or very severe neurological impairment during infancy. Until 

recently, scientists believed that the MECP2 gene was an “off” switch, or silencer, for other 

genes. But a study performed by IDDRC investigators showed that the gene is an “on” switch 

for a startlingly large number of genes. A team at the Baylor College of Medicine IDDRC 

analyzed gene-activity patterns in the brains of both mice with a MeCP2 deficiency and those 

with an MeCP2 gene duplication, notated as MeCP2+

 (Chahrour et al, 2008). Previous studies 

revealed only subtle differences between the brains of normal and MeCP2-mutant mice, but 

those studies measured gene activity throughout the brain. In this study, the investigators 

focused on the hypothalamus, a region known to produce hormones that influence growth, mood, 

and the sleep-wake cycle—all of which are affected in Rett syndrome. Their analysis revealed 

nearly 2,600 misregulated genes in both mouse models, with opposite patterns. The activity of 

about 2,200 genes decreased in MeCP2-deficientmice and increased in MeCP2+ mice, indicating 

that MeCP2 is an activator for those genes. Among the genes activated by MeCP2, the 

researchers found many that encode neuropeptides; however, about 400 genes showed the 

reverse pattern, indicating that MeCP2 is a repressor for their expression. 

These results dramatize the need for a paradigm shift in research on genetically caused IDD from 

the “one gene-one protein” linear approach to a “gene-protein network” approach. Based on this 

discovery, researchers could design therapies for Rett syndrome and MECP2+ syndrome by 

targeting the downstream genes affected by MeCP2, but first they would have to know which 

target genes and which brain regions are most relevant to neurological function in this condition. 
Program on Fragile X Syndrome (FXS) and Associated Disorders 9 

Cornelia de Lange Syndrome (CdLS)

A team of researchers affiliated with the IDDRC at Children’s Hospital of Philadelphia identified 

two new genes that contribute to CdLS, a multisystem genetic disease affecting an estimated one 

in 10,000 children. Classically, CdLS includes IDD, impaired growth, heart defects, feeding 

problems, deformed upper limbs, and distinctive facial features. In this current study, mutations 

in two genes of interest caused IDD, but resulted in less-pronounced facial features and no limb 

defects, such as missing hands or fingers, that are hallmarks of classic CdLS (Deardorff et al, 

2007). In contrast to mutations in the NIPBL gene, which cause roughly one-half of all known 

CdLS cases, mutations in the new genes, SMC3 and SMC1A, cause only about 5 percent of CdLS 

cases. All three genes (NIPBL, SMC3, and SMC1A) encode cohesin proteins, which are known 

to play an important role in controlling the integrity of chromosome pairs during cell division 

and early development. Mutations seem to have a particular effect on brain development. 

Researchers hope that by studying mutations that give rise to a rare genetic disease, they will be 

able to identify biological pathways that may play broader roles during human development, and 

potentially identify genetic causes of more common forms of intellectual impairment and ASDs. 

Genetics of Myelin Production

Peripheral neuropathies, disorders affecting the nerves outside the brain and spinal cord, are 

often characterized by numbness, weakness, pain, and impaired movement. One of the most 

common genetically inherited disorders, Charcot-Marie-Tooth disease, is a peripheral 

neuropathy characterized by defects in production of myelin, a fatty coating made by Schwann 

cells that covers nerve cells and increases the speed and reliability of their electrical signals. 

Investigators affiliated with the University of Wisconsin IDDRC discovered that the Early 

Growth Response 2 (EGR2) gene produces a protein that serves as a master regulatory gene by 

activating several other genes necessary for myelin production (LeBlanc, Ward & Svaren, 2007). 

Defects in the EGR2 gene affect the normal copy of the gene as well as the functioning of the 

other genes encoding critical myelin proteins, such as peripheral myelin protein 22 (PMP22) and 

myelin protein zero (MPZ). Not only is MPZ the most abundant myelin protein in the peripheral 

nervous system, but the overproduction or underproduction of MPZ and PMP22 accounts for the 

majority of inherited peripheral neuropathies. This discovery enhances understanding of myelin 

production within Schwann cells and may facilitate the development of new therapies for 

peripheral neuropathies. 

PROGRAM ON FRAGILE X SYNDROME (FXS) AND ASSOCIATED DISORDERS

FXS, estimated to occur in 1 in 2,500 births, is the most common inherited form of IDD. FXS 

results from a mutation in the FMR1 gene, on the long arm of the X chromosome, that is

associated with an unstable expansion of a CGG trinucleotide repeat within the gene. The length 

of the trinucleotide repeat determines the severity of the condition, ranging from: 

• Normal (fewer than 55 repeats), to 

• Premutation (between 55 and 200 repeats), to 

• Affected or full mutation (more than 200 repeats). 
10 Program on Fragile X Syndrome (FXS) and Associated Disorders

Because males carry only a single copy of the X chromosome, they tend to be more severely 

affected than females, who have a normal X chromosome to partially compensate. Although the 

full mutation can affect both males and females, premutation and full-mutation females may 

exhibit marked variability of characteristics depending in part on the extent of X-chromosome 

inactivation. Individuals with FXS can exhibit a range of cognitive impairment, with particular 

deficits in visual-spatial perception, speech and language, attention, self-regulation, and shortterm memory. Many individuals with FXS also exhibit symptoms of ASDs, and some have 

seizures. 

In the past several years, researchers have gained a greater understanding of the medical 

consequences of carrying a premutation, such as risks for a Parkinson-like condition 

characterized by tremor and ataxia in older males, called Fragile X-associated Tremor/Ataxia 

Syndrome (FXTAS), and risks for premature ovarian insufficiency, in this case known as Fragile 

X-associated Primary Ovarian Insufficiency (FXPOI), in women of reproductive age. 

FXS RESEARCH CENTERS (FXSRCS): THE CENTERS-WITHIN-CENTERS MODEL

The FXSRC Program, associated with the existing Eunice Kennedy Shriver IDDRC Program, 

supports research that will improve the diagnosis and treatment of FXS and its related 

conditions. The Branch’s three FXSRCs were initially funded in fiscal year 2003 in response to 

the Children’s Health Act of 2000 (P.L. 106-310), which provided for the establishment of at 

least three centers to conduct and support basic and biomedical research into the detection and 

treatment of FXS. The FXSRCs stimulate the formation of multidisciplinary, multi-institutional 

teams with the common goal of facilitating the translation of basic research findings from bench

to bedside to community. The Centers were refunded after a successful recompetition in early 

fiscal year 2008. 

Each FXSRC includes research programs in both basic and clinical science. Several projects 

focus on newborn screening and include studies that assess methods of testing immediate and 

extended family members and the impact of newborn screening on the family. A description 

of the Centers and their affiliates appears below. For a map of the Center locations and their 

affiliate sites, see Figure 10. 

FXSRC at Baylor College of Medicine, Texas 

(IN COLLABORATION WITH EMORY UNIVERSITY, GEORGIA, AND UNIVERSITY OF ILLINOIS AT URBANACHAMPAIGN, ILLINOIS) 

Research at the Baylor FXSRC revolves around a common theme of determining the full 

phenotypic spectrum of humans and mice with genetic alterations in the FMR1 gene and the 

underlying pathological causes, with an aim of discovering and testing effective treatments. The 

four research projects focus on: 

• Using mouse models to understand the developmental timing requirements for Fmr1; 

• Measuring behavioral and electrophysiological responses to genetic alterations in the Fmr1

knockout mouse model; 
Program on Fragile X Syndrome (FXS) and Associated Disorders 11

• Drug treatments in fly models and mouse neurons; and 

• The human male premutation phenotype, which involves late-onset tremor and cognitive 

decline. 

An additional strength of this FXSRC is the Neuronal Imaging Core, which offers expertise in 

neuroimaging at the molecular and cellular levels to support the development of better mousemodel phenotypic definitions and methods to assess treatment outcomes. These projects provide 

improved understanding of the function of the FMR1 gene and its protein product and have the 

potential to inform treatment development that will improve quality-of-life for affected 

individuals. 

FXSRC at UNC, Chapel Hill 

(IN COLLABORATION WITH UNIVERSITY OF KANSAS; UNIVERSITY OF WISCONSIN; RTI INTERNATIONAL,

NORTH CAROLINA; AND THE UNIVERSITY OF CALIFORNIA, DAVIS/ MEDICAL INVESTIGATION OF 

NEURODEVELOPMENTAL DISORDERS [MIND] INSTITUTE) 

This FXSRC focuses on family adaptations to FXS. Currently, 13 investigators from 

11 disciplines (including anthropology, developmental psychology, educational psychology, 

clinical psychology, forensic medicine, social work, law, medical genetics, special education, 

speech and hearing sciences, and psychiatry) collaborate on an integrated and longitudinal set of 

studies, including: Determining Maternal Responsivity and Development of Children with FXS, 

Adaptations of Families of Adolescents and Adults with FXS, and Family Adaptation to 

Newborn Screening for FXS. The projects have direct relevance to public health because they 

identify the specific challenges faced by parents of children with FXS. Findings from these

projects provide information that facilitates development of support and services to maximize 

family well-being and provide important information about the ramifications of newborn 

screening for families. 

FXSRC at University of Washington 

(IN COLLABORATION WITH UNIVERSITY OF CALIFORNIA, DAVIS/MIND INSTITUTE; RUSH UNIVERSITY 

MEDICAL CENTER, ILLINOIS; UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN, ILLINOIS; AND FRED 

HUTCHINSON CANCER RESEARCH CENTER, WASHINGTON) 

The University of Washington FXSRC brings together clinical and laboratory researchers to 

address research projects, such as a multi-institutional effort on newborn screening for the FXS 

full mutation and premutation. The goal of the project is to clarify the developmental 

consequences of the full spectrum of the FXS mutation in infants and to understand FXS-related 

disorders in families. In addition, the researchers are exploring the functional and structural roles 

of the antisense transcript of the FMR1 gene, including possible molecular and clinical 

correlations with FXTAS. Another collaboration addresses the phenotypic consequences of 

restoring partial function to the Fragile X protein in conditional mouse mutants, which vary by 

regional and temporal levels of Fmr1 expression. Finally, investigators are using NIH-approved 

lines of human embryonic stem cells to help understand early developmental processes that lead 

to the variable epigenetic inactivation of FMR1. 
12 Program on Fragile X Syndrome (FXS) and Associated Disorders

THE NIH FRAGILE X RESEARCH COORDINATING GROUP (FXRCG) AND THE NIH RESEARCH 

PLAN ON FXS AND ASSOCIATED DISORDERS

In January 2007, the Director of the NICHD established the FXRCG to encourage coordinated 

FXS research efforts and facilitate collaboration across NIH and with other federal agencies and 

advocacy groups. Led by the IDD Branch, the Group is composed of NIH extramural staff and 

intramural researchers at Institutes that support and conduct research projects related to FXS and 

its associated disorders, FXTAS and FXPOI. In addition to the NICHD, participating Institutes

include the NIMH, the NINDS, the National Institute on Aging (NIA), the National Institute of 

Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institute of General 

Medical Sciences, the National Cancer Institute (NCI), and the National Institute on Deafness 

and Other Communication Disorders (NIDCD). During the past several years, research 

programs with support from across NIH have made significant advances in understanding FXS 

and associated disorders. This Group will help to ensure continued coordination of efforts and 

resources. 

The Senate Committee on Appropriations, in its report for the fiscal year 2008 budget for the 

U.S. Department of Health and Human Services (DHHS), requested that “the NIH, through the 

NICHD and other participating Institutes, convene a scientific session in 2008 to develop 

pathways to new opportunities for collaborative, directed research across Institutes, and to 

produce a blueprint of coordinated research strategies and public-private partnership 

opportunities for Fragile X.” In response, the IDD Branch, via the FXRCG, brought together 

representatives from the research, advocacy, and clinical communities along with other relevant

federal agencies and affected individuals and their families. The Group convened three working 

groups in March 2008 to develop comprehensive recommendations for specific high-priority 

research objectives for each of the primary disorders associated with the FMR1 gene: FXS, 

FXTAS, and FXPOI. The recommendations were designed to be used by the NIH and the FXS, 

FXTAS, and FXPOI research and advocacy communities and to be shared with other federal 

agencies to facilitate coordinated research activities in pursuit of timely detection, diagnosis, 

treatment, and prevention of the targeted disorders. 

The FXRCG completed the NIH Research Plan on FXS and Associated Disorders in September 

2008. The final version of the research plan was published on July 20, 2009, and is available 

through the NICHD Web site at 

http://www.nichd.nih.gov/publications/pubs_details.cfm?from=&pubs_id=5729. 

COLLABORATIVE EFFORTS ON FXS

The Branch continues to collaborate with other NIH Institutes and Centers and to cultivate

public-private partnerships in its efforts related to FXS and associated disorders. Among these 

activities is the annual FXS conference held at Cold Spring Harbor Laboratory’s Banbury 

Conference Center. This cutting-edge meeting has enjoyed continuous primary support from the 

NIMH and joint funding from the NICHD and FRAXA since 2001. 
Program on Fragile X Syndrome (FXS) and Associated Disorders 13

In addition, multiple research efforts currently aim to develop treatments and novel interventions 

for FXS. One such effort seeks to develop metabotropic glutamate receptor (mGluR) antagonists 

as therapeutics for FXS and for ASDs. The project has, as its basis, an ongoing cooperative 

agreement led by the NIMH in partnership with the NICHD, including the Obstetric and 

Pediatric Pharmacology Branch (OPPB) and its congressionally mandated activities as described 

in the Best Pharmaceuticals for Children Act (BPCA), as well as NINDS, FRAXA, and Autism 

Speaks. 

In May 2008, the IDD Branch, in collaboration with the NICHD OPPB and its activities being 

performed under the BPCA, the NIH Office of Rare Diseases Research (ORDR), NINDS, 

NIMH, FRAXA, the National Fragile X Foundation (NFXF), and representatives of the Fragile 

X Clinics Consortium (a body established by the NFXF that includes clinics throughout the 

United States and Canada that treat individuals with FXS), held a two-day scientific meeting to 

discuss challenges related to selecting outcome measures for use in clinical trials involving 

children with FXS. Participants included members of constituency groups, representatives from 

the Food and Drug Administration (FDA), clinicians who treat children with FXS, and 

researchers experienced in clinical trials of pharmaceuticals involving children with FXS. 

Additional participants included researchers with expertise in successful clinical trial design, in 

development of psychometric assessments, and in conduct of behavioral and cognitive studies of 

children with FXS. A second outcomes measures workshop is planned for November 5-6, 2009. 

The Branch’s efforts to understand the relationships between FXS and ASDs also continued 

through the Program Announcement (PA) soliciting research to study the Shared Neurobiology 

of FXS and Autism (PA 06-429/430). This PA, originally issued in 2005 and reissued in 2007, 

represents a public-private partnership led by the NIMH in collaboration with NINDS and 

NICHD that also includes the Canadian Institutes of Health (Institute of Neurosciences, Mental 

Health, and Addiction and the Institute of Genetics), the Health Research Board of Ireland, 

FRAXA, Autism Speaks, and the National Alliance for Autism Research (which is now part of 

Autism Speaks). This mechanism has supported 12 grants (seven with primary NICHD funding) 

since its inception that encompass a broad spectrum of research, ranging from studies of 

language in children with FXS to studies of FXS mouse models that explore the structural 

abnormalities observed in neurons. 

FXS RESEARCH PROGRAM SCIENCE ADVANCES

The mGluR Theory

The mGluR theory of FXS (Bear et al, 2004) posits that long-term depression of glutamate 

receptors in the hippocampus leads to the neurological, cognitive, and behavioral problems in 

FXS. The work presented in the Bear paper, funded in part by NICHD, presented a novel theory 

to explain many of the deficits in FXS. Loss of FMRP, the defect responsible for FXS in 

humans, increases long-term depression in mouse hippocampus. The research presented a theory 

to account for diverse neurological and psychiatric aspects of FXS based on the assumption that 

many of the protein synthesis-dependent functions of metabotropic receptors are exaggerated in 

FXS. The theory suggests new directions for basic research as well as novel therapeutic 
14 Rare Diseases Cooperative Research Consortia (RDCRC)

approaches for individuals with FXS. The field has moved rapidly to preclinical and phase I 

clinical trials using mGluR antagonists as treatments for FXS as a result of this research. 

Mouse Models of FXS

The Fmr1 gene has two paralogs in humans and mice, and researchers hypothesize that one of 

these, Fxr2 (encoding FXR2P), partially compensates for the loss of FMRP in FXS. In one 

Branch-supported study, investigators examined long-lasting synaptic plasticity in Fmr1

knockout, Fxr2 knockout, and Fmr1/Fxr2 double knockout mice (Zhang et al, 2009). Findings 

indicated that the long-term depression of mGluR in the hippocampus was affected in all

knockout mice at young ages (4 to 6 weeks old). In addition, Fmr1/Fxr2 double knockout mice 

showed significant deficiencies in baseline synaptic transmission and short-term presynaptic 

plasticity, suggesting that the gene products may cooperate to regulate presynaptic plasticity. 

These findings indicate that both FMRP and FXR2P function in synaptic plasticity, and that they 

likely operate in related, but independent, pathways. 

Rapid Polymerase Chain Reaction (PCR) Assay for FXS

Current testing for FXS, which employs a combination of Southern blot and PCR techniques, is 

laborious, expensive, and has limited utility for identifying not only female carriers, but also 

those with intermediate repeat sizes. As a result of the absence of an effective screening tool for 

expanded FMR1 allelesin large populations, there are no unbiased estimates of the number of 

full-mutation FMR1 alleles in the general population. Branch-supported researchers have 

described a rapid PCR-based screening tool for expanded FMR1 alleles that would have 

applicability for testing both males and females, and for determining allele sizes throughout the 

premutation and full-mutation ranges (Tassone et al, 2008). The methodology has potential for 

screening large populations of newborns or those at high risk for expanded FMR1 alleles using a 

small sample of blood from a single dried blood spot. Additional efforts could use this low-cost 

method to identify the frequency of premutation alleles on a large scale, and to enhance the 

understanding of family adaptation to newborn screening. 

RARE DISEASES COOPERATIVE RESEARCH CONSORTIA (RDCRC) 

The Rare Diseases Act of 2002 (P.L. 107-280) directed the NIH ORDR to establish a Rare 

Diseases Clinical Research Network—a collaborative, cooperative network of investigators and 

patient groups in partnership with technology leaders that focuses on studying rare diseases to 

enhance communication and resource sharing via a multidisciplinary approach. The resulting 

RDCRC program conducts the following activities:

• Collects clinical information to develop biomarkers and new approaches to diagnosis, 

prevention, and treatment; 

• Provides content for an Internet-based resource site about rare diseases; 

• Trains new clinical investigators in rare diseases research; and
Rare Diseases Cooperative Research Consortia (RDCRC) 15

• Supports a comprehensive and integrated approach to data collection, storage, and 

management and integrates clinical data with other unique data, including genetic, imaging, 

pathologic, and laboratory data through the Data and Technology Coordinating Center. 

The first competition for the RDCRC in 2003 established eight funded consortia using the U54 

mechanism, and the program subsequently expanded to 10 centers. During the past six years, the 

IDD Branch provided scientific management for two Consortia (listed below) and their affiliate 

sites that have made significant progress and research contributions within the field of rare 

diseases research. Recompetition of the entire program, including the Data and Technology 

Coordinating Center, occurred in 2009; both of the IDD Branch-supported Consortia will 

continue for another five years. 

UREA CYCLE DISORDERS RARE DISEASE CONSORTIUM

Primary Site: Children’s National Medical Center (Washington, D.C.) 

AFFILIATED U.S. SITES: CHILDREN’S HOSPITAL, BOSTON; CHILDREN’S HOSPITAL OF PHILADELPHIA;

YALE UNIVERSITY; GEORGETOWN UNIVERSITY; BAYLOR COLLEGE OF MEDICINE; UNIVERSITY 

HOSPITALS OF CLEVELAND/RAINBOW BABIES AND CHILDREN’S HOSPITAL; UCLA; VANDERBILT 

UNIVERSITY; MOUNT SINAI SCHOOL OF MEDICINE; CHILDREN’S HOSPITAL, DENVER; OREGON 

HEALTH AND SCIENCE UNIVERSITY; AND SEATTLE CHILDREN’S HOSPITAL

AFFILIATED INTERNATIONAL SITES: THE HOSPITAL FOR SICK CHILDREN (TORONTO, CANADA) AND 

THE UNIVERSITY CHILDREN’S HOSPITAL (ZURICH, SWITZERLAND) 

This RDCRC is a highly integrated network of investigators with a long history of cooperative 

interactions (see Figure 11 for site locations). With a focus on urea cycle disorders, the 

Consortium’s investigators have established a registry to estimate incidence and prevalence of 

the eight urea cycle disorders they study. In general, this RDCRC conducts the following 

activities: 

• Performs longitudinal natural history studies of urea cycle disorders to understand morbidity, 

mortality, and treatment efficacy; 

• Surveys and promotes newborn screening for urea cycle disorders to aid in identification and 

treatment; 

• Tests new approaches to therapy for these disorders to help bring new drugs to market in 

collaboration with pharmaceutical companies; 

• Develops novel non-invasive methods for assessing changes in urea synthesis, both over time 

and under varying treatment conditions; 

• Performs neuropsychological and neuroimaging studies on affected individuals identified at 

various sites to better understand the effects of hyperammonemia on neurocognitive function; 

• Maintains a Web site, in collaboration with the Data Management Coordinating Center 

(formerly called the Data and Technology Coordinating Center) and the National Urea Cycle 

Disorders Foundation, to provide clinical and research information on urea cycle disorders to 

the public, health care providers, and affected families; and 
16 Rare Diseases Cooperative Research Consortia (RDCRC)

• Promotes the entrance of M.D. and Ph.D. investigators into the study of urea cycle disorders 

through a postdoctoral fellowship training program. 

Additional information about the activities of this Consortium is included in the Urea Cycle 

Disorders Section of this report. 

CONSORTIUM FOR RARE EPIGENETIC DISORDERS

Primary Site: Baylor College of Medicine (Houston, Texas)/University of Alabama,

Birmingham

AFFILIATED SITES: UNIVERSITY OF FLORIDA; CHILDREN’S HOSPITAL, BOSTON; GREENWOOD 

GENETIC CENTER (SOUTH CAROLINA); VANDERBILT UNIVERSITY MEDICAL CENTER; CHILDREN’S 

MERCY HOSPITAL (KANSAS)/UNIVERSITY OF KANSAS MEDICAL CENTER; CHILDREN’S HOSPITAL, SAN 

DIEGO; AND UNIVERSITY OF CALIFORNIA, IRVINE, MEDICAL CENTER

This RDCRC, which had its primary site at the Baylor College of Medicine until August 1, 2009, 

at which time it switched to the University of Alabama, Birmingham, studies a collection of rare 

epigenetic disorders, including Angelman syndrome (AS), Rett syndrome, and Prader-Willi 

syndrome (PWS) (see Figure 12 for site locations). Among its activities, the Consortium focuses 

on new diagnostics and new therapies and seeks to: 

• Establish natural history protocols for the three disorders; 

• Develop new therapeutics for AS; 

• Use microarray comparative genomic hybridization (array-CGH) to search for deletions in 

patients with PWS-like features, or in those with early morbid obesity; 

• Develop new methodologies for detecting large chromosomal deletions in individuals with 

Rett syndrome; 

• Provide prenatal diagnosis of deletion cases of PWS and AS using chromosome microarray 

analysis; and 

• Distinguish between different-sized deletions for PWS and AS with two unique research 

microarrays.

Additional information about the activities of this Consortium is included in the Epigenetic 

Disorders Section of this report. 
Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Centers 17

SENATOR PAUL D. WELLSTONE MUSCULAR DYSTROPHY COOPERATIVE 

RESEARCH CENTERS

The Muscular Dystrophy Community Assistance, Research, and Education Amendments of 2001,

also called the MD-CARE Act (P.L. 107-84), authorized the establishment of the Muscular 

Dystrophy Coordinating Committee (MDCC) to develop a federal plan across NIH and other 

federal agencies and programs on research and education in the various forms of muscular 

dystrophy and authorized NIH to establish centers of excellence for muscular dystrophy 

research. In response to the Act, the MDCC Action Plan for the Muscular Dystrophies was

approved in December 2005, and the NIH established the Senator Paul D. Wellstone Muscular 

Dystrophy Cooperative Research Centers (referred to hereafter as the Wellstone Centers). The 

NIH currently funds six Wellstone Centers through a U54 Cooperative Agreement mechanism, 

permitting significant Institute staff involvement in design and execution of the research 

program. 

The NICHD, NINDS, and the National Institute of Arthritis and Musculoskeletal and Skin 

Diseases (NIAMS) each fund two Wellstone Centers. The NICHD-funded centers are: 

Children’s National Medical Center and the Boston Biomedical Research Institute (BBRI) in 

Watertown, Massachusetts. The NICHD also funded a third Wellstone Center at the University 

of Washington in Seattle through 2008 (see Figure 13 for Wellstone Center locations). 

Each Wellstone Center brings together expertise, infrastructure, and resources focused on major 

questions in muscular dystrophy and provides resources used by national muscle biology and 

neuromuscular research communities. The Wellstone Centers also serve as focal points for 

research collaborations in the muscular dystrophy field and provide training and advice about 

muscle diseases for basic and clinical researchers. To further enhance activities at the Wellstone 

Centers, the NIH funds administrative supplements to promote collaborations and to maximize 

opportunities for career development among junior investigators affiliated with the Centers. The 

NICHD funded one such fellowship at the Children’s National Medical Center. 

Specifically, the NICHD-supported Wellstone Centers address the following topics: 

• The Wellstone Center at the Children’s National Medical Center, in Washington, D.C., 

analyzes genetic and cellular factors that contribute to the progression of a severe form of 

muscle disease, Duchenne muscular dystrophy (DMD), and the response of patients to 

treatments. DMD, found predominantly in males, affects one in every 3,500 males. Females 

can be carriers of the DMD gene, but usually do not show symptoms of the disease. 

• A new Wellstone Center, funded in fiscal year 2008 at the BBRI, investigates 

facioscapulohumeral muscular dystrophy, also called FSHD, a common form of muscular 

dystrophy affecting one in 20,000 individuals and causing progressive weakness of skeletal 

muscles of the face and shoulder region. Although atrophy typically progresses slowly, there 

may be periods of rapid decline and eventual involvement of the pelvic girdle and inability to 

ambulate. The BBRI Wellstone Center identifies biomarkers to evaluate outcomes of clinical 

trials through four research projects and three support cores. 
18 Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Centers

• The third Wellstone Center at the University of Washington, which was funded by NICHD 

until 2008, focused on gene therapy and muscle stem cells as potential therapies for DMD, 

approaches that may also have applications for other forms of muscular dystrophy. 

The NICHD is currently leading the latest round of competition for the Wellstone Centers, to be 

funded in fiscal year 2010. IDD Branch staff anticipate that several current and past Centers will 

compete for the two slots available. 

WELLSTONE CENTERS SCIENCE ADVANCES

The research team at the Wellstone Center at the Children’s National Medical Center recently 

reported an exciting finding. They found that injecting a cocktail of antisense oligonucleotides 

into the bloodstream of dogs with a genetic form of DMD reduced skeletal muscle deterioration 

(Yokota et al, 2009). Using a novel genetic technology, known as “exon skipping,” researchers 

developed a successful treatment for the canine version of DMD, which occurs naturally in dogs 

and affects the same gene affected in the human form of the disease. Using this “exon skipping” 

technology, portions of DNA-like molecules, known as morpholinos, act as “molecular patches” 

to cover mutant DNA sequences of the Dystrophin gene, responsible for DMD. Injecting the 

morpholinos into the dogs’ bloodstream allowed the dogs to make an imperfect—but 

functional—version of the needed protein, significantly slowed their muscle deterioration, and 

improved their muscle functioning. This finding may lay the foundation for human testing of 

gene therapy for this devastating disease. 

The NICHD co-funded two highly successful workshops focused on specific topics in muscular 

dystrophy research through administrative supplements to the Wellstone Centers. The first 

workshop aimed to develop standard operating procedures (SOPs) for clinical trial endpoints in 

the mdx mouse, a mouse model for DMD. A follow-up meeting, sponsored by Treat-NMD, a 

European-based advocacy organization focused on neuromuscular diseases, approved the SOPs 

for clinical trial endpoints in humans (visit http://www.treat-nmd.eu/research/preclinical/SOPs/). 

Adopting these procedures enables standardized toxicity and efficacy studies of investigational 

new drugs, a prerequisite for FDA licensing. Another workshop, Translational Research in 

Muscular Dystrophy, included keynote talks, a case study in therapy development for a rare 

neuromuscular disorder, working group summaries of topics for which consensus was reached 

prior to the meeting, individual talks by selected experts, and feedback by a panel of 

distinguished industry scientists and regulators who work outside of the muscular dystrophy 

community. The number of companies at the Workshop with active muscular dystrophy 

programs and the innovative partnerships that have already formed between academia, 

corporations, advocacy groups, and funding agencies serve as evidence of the potential for new 

therapeutics for muscular dystrophies. 
Chromosome Abnormalities, Genetic/Genomic Syndromes, and Epigenetic Disorders 19

CHROMOSOME ABNORMALITIES, GENETIC/GENOMIC SYNDROMES, AND 

EPIGENETIC DISORDERS

Cytogenetic abnormalities, such as trisomy, mosaicism, or chromosome rearrangements, cause a 

significant proportion of cognitive impairment and morbidity and mortality, especially among 

infants and children. Recent advances in high-resolution cytogenetic analysis and the 

development of the molecular cytogenetics field, mainly through the application of fluorescence 

in situ hybridization and array-CGH, provide opportunities to identify subtle chromosomal 

rearrangements, such as cryptic deletions or duplications, in individuals with IDD or genetic 

syndromes. Other genetic syndromes may be caused by mutations in single genes or by other, as 

yet unknown, genetic or epigenetic (resulting from changes in the regulation of gene activity and 

expression not dependent on gene sequence) mechanisms. Studies of genetics, epigenetics, and 

genomics are a core portion of the IDD Branch portfolio and represent exciting new areas of 

research for the NICHD and the NIH, through the Roadmap initiative 

(http://nihroadmap.nih.gov/epigenomics/). The following section highlights some findings from

Branch-supported research on chromosome abnormalities, genetic syndromes, and epigenetic 

disorders. 

DOWN SYNDROME

Down syndrome is a significant genetic cause of IDD in human populations, occurring in 

approximately one in 800 newborns, an incidence that has remained relatively constant for the 

past century in virtually every ethnic group in the world. More than 95 percent of individuals 

with Down syndrome possess an extra copy of the smallest human chromosome, 

chromosome 21, a situation known as trisomy 21 (Ts21). Of the remaining individuals with 

Down syndrome, 2 percent to 4 percent have an extra copy of the majority of chromosome 21, 

derived from a balanced translocation of chromosome 21 to another chromosome inherited from 

one of the parents (called a Robertsonian translocation); 1 percent to 2 percent of those with 

Down syndrome are mosaic, meaning they have both normal cells and Ts21 cells in their bodies. 

Individuals born with Down syndrome today enjoy a greatly increased life expectancy compared 

with their counterparts from 25 years ago. Approximately 45 percent of individuals with Down 

syndrome survive past the age of 60 years, and about 15 percent live almost to the age of 

70 years. Among Caucasians with Down syndrome, life expectancy is approximately 70 years of 

age, triple the expectancy of several decades ago. The life expectancy of non-Caucasians with 

Down syndrome has risen during the same time frame, from younger than five years of age to 

nearly 35 years of age in Western cultures, but this expectancy is still significantly lower than in 

the Caucasian population. Many older adults with Down syndrome develop Alzheimer-like

dementia, but they do so at younger ages than the general population. 

Science Advances in Down Syndrome Research

In the past decade, one of the goals of the IDD Branch has been to encourage multiple Institutes

to work together to create and implement a matrix for research issues related to Down syndrome. 

A congressional directive in 2005 led to the establishment of the Trans-NIH Taskforce on Down 
20 Chromosome Abnormalities, Genetic/Genomic Syndromes, and Epigenetic Disorders

Syndrome to coordinate NIH efforts on Down syndrome research. IDD Branch staff chair the 

Taskforce, which includes representatives from NIA, NINDS, the National Eye Institute, 

NIDCD, NIAMS, the National Human Genome Research Institute (NHGRI), NCI, the National 

Heart, Lung, and Blood Institute, and the National Institute of Allergy and Infectious Disease, 

among others. The Trans-NIH Taskforce met three times, once with members of the Taskforce 

on Down Syndrome organized by the National Down Syndrome Society. Three additional 

meetings resulted: 

• Gatlinburg Conference, March 2007, Down Syndrome: Genes, Brain and Behavior

• Trans-NIH Taskforce Meeting, July 2007, Down Syndrome and Cognition (funded by the 

NICHD Office of the Director) 

• R13 conference, September 2007, The Biology of Chromosome 21 Genes: Toward 

Genotype/Phenotype Correlations in Down Syndrome 

This effort resulted in the issuance of the NIH Research Plan on Down Syndrome in October 

2007. Table 2 lists the matrix of research objectives from the Plan; the full Plan is available at

http://www.nichd.nih.gov/publications/pubs/upload/NIH_Downsyndrome_plan.pdf. This 

research agenda will address, within the next five to ten years, topics such as: 

• Aging and family dynamics

• Measures of cognitive function in Down syndrome throughout the lifespan 

• Issues involving medications and clinical trial participation

• Use of Alzheimer disease research to inform potential therapeutics

• Transitions to independent or assisted living for adults 

• Comorbid psychiatric and medical conditions throughout the lifespan 

• Improving and expanding availability and studies in animal models

• Health disparities in survival and access to care

In 2009, NICHD issued an RFA, Factors Affecting Cognitive Function in Adults with Down 

Syndrome (RFA HD 09-028). Applications in response to that RFA were reviewed in August 

2009; two R01 grants have been awarded, with co-funding provided by NIA. 

Other advances in the realm of Down syndrome research include: 

• An assessment of gastrointestinal anomalies by sex, race, and ethnicity; 

• Identification of modifier genes located on other chromosomes that impact variability in 

Down syndrome features; 

• Evidence from animal models of specific genes involved in craniofacial and brain 

development and in reduced solid-tumor formation; and 

• Identification of specific genes that are candidates for the constant features of Down 

syndrome. 

There continues to be compelling evidence for the benefit of early intervention programs for 

children with Down syndrome as well as other forms of IDD (Guralnick, 2005). Other ongoing 
Chromosome Abnormalities, Genetic/Genomic Syndromes, and Epigenetic Disorders 21

activities include efforts to develop clinical trials, in humans and animal models, for agents that 

ameliorate or improve intellectual development and cognitive performance and to identify 

biomarkers that predict likelihood of progression to Alzheimer-like dementia in older individuals 

with Down syndrome. In particular, partnerships with the NIA have been fruitful for the latter 

initiative. 

In addition, advances in Down syndrome research have been a direct result of the Branch’s 

establishment and support of the Repository for Mouse Models for Cytogenetic Disorders. 

Initiated in the 1970s, the Repository generates and distributes mice that recapitulate, at least in 

part, human cytogenetic disorders, with a special focus on Down syndrome. Please visit the 

Research Resources section for a more detailed description of this resource. 

WILLIAMS SYNDROME

Williams syndrome, which has a prevalence of between one in 10,000 and one in 20,000, arises 

from deletions in a group of genes, including the Elastin locus, on the long arm of chromosome 7 

at 7q11. Congenital heart defects, as well as distinctive facial features, abnormal calcium 

metabolism, failure to thrive during infancy, unique personality with increased friendliness, and 

moderate levels of intellectual impairment characterize many individuals with Williams 

syndrome. 

One focus of IDD Branch-sponsored research in Williams syndrome is the dissection of the 

unique cognitive and behavioral phenotypes of this condition. Investigators found that concrete 

and relational vocabulary at five to seven years of age is highly predictive of future concrete and 

relational vocabulary, and that relational vocabulary at these ages correlates closely with later 

visuospatial construction ability (Mervis and John, 2008). 

Characterization of the comorbid psychiatric disorders found in Williams syndrome children at 

different ages is also an area of emphasis, as is research on the role of altered neuroanatomical 

pathways identified through specific imaging techniques during social engagement and during 

social and affective language tasks. Additional studies aim to characterize specific phenotypes 

related to the extent of deletion of specific genes in the critical region of chromosome 7, and to 

understand the effects of both inversion and duplication of that region on phenotypic 

characteristics.

SMITH-MAGENIS SYNDROME (SMS)

SMS, a contiguous gene-deletion syndrome associated with missing genetic material on the short 

arm of chromosome 17, has a prevalence of one in 25,000. Individuals with SMS typically 

demonstrate: moderate IDD; speech and motor delays; behavioral abnormalities, including selfinjurious behavior; insensitivity to pain; sleep disturbance; short stature and short fingers; and 

distinctive craniofacial features. Many with SMS are also obese. The minimal critical region of 

chromosome 17 associated with SMS is about 950 kilobases, a region that contains 

approximately 25 genes. 
22 Chromosome Abnormalities, Genetic/Genomic Syndromes, and Epigenetic Disorders

Some individuals with SMS have no obvious large-scale deletions, but they do have novel 

deletions in the retinoic acid induced-1 (RAI1) gene on chromosome 17p that result in shortened 

RAI1, a protein normally localized in the nucleus. RAI1 resembles transcriptional co-activator 

TCF20 and might stimulate transcription by interacting with DNA-binding proteins. Ongoing 

Branch-sponsored research in this field suggests that RAI1 haploinsufficiency correlates 

significantly with many features of SMS. In addition, mice with a single copy of Rai1 vary in 

their craniofacial phenotype depending on differences in their genetic strain of origin, suggesting 

a role for modifier genes. 

Genome-wide expression studies have characterized a variety of metabolic and genetic pathways 

affected in SMS. Ongoing studies seek to understand the highly variable and complex 

duplications and deletions on chromosome 17p that produce distinctive phenotypes in 

individuals with atypical SMS and in a separate syndrome characterized by a duplication of this 

same region—called a reciprocal disorder—or Potocki-Lupski syndrome. 

DISORDERS WITH A SHARED PATHWAY

The IDD Branch also supports research to clarify a role for common pathways in the 

pathogenesis of IDD conditions, such as CdLS. Among the efforts the Branch supports are a 

number of grants that aim to understand the cohesin complex, a protein complex essential for the 

proper mitotic segregation of chromosomes that plays an essential role in gene expression during 

development and is disrupted in CdLS. Common signaling pathways are also the subject of 

research in the FXS portfolio, particularly studies involving mGluR. 

The Branch also supports research to understand disorders, including Costello syndrome, 

Noonan syndrome, Cardiofaciocutaneous syndrome, and Neurofibromatosis 1, that result from 

genetic defects in the molecules that participate in the Ras and mitogen-activated protein kinase 

(MAPK) pathways. The Ras/MAPK pathway is an area of great interest to the Branch because

the shared clinical features of many of these disorders could facilitate understanding of the 

underlying etiology and provide opportunities to identify potential targets for interventions. 

EPIGENETIC DISORDERS

Within the IDD community, increased emphasis on research into the roles of methylation, 

histone modification, imprinting, and other epigenetic factors in the pathogenesis of IDD has 

also led to enhanced support of such research within the Branch’s portfolio. For example, 

Branch staff initiated and led an Epigenetics and Systems Biology Working Group for the 

NICHD during 2008. The Group hosted six seminars featuring area scientists and participated in 

NIH-wide seminars related to these research interests. The Branch is also sponsoring a 

Workshop on the Epigenetic Basis of IDD, which will be held in 2010. 

A number of Branch-supported grants funded during the past four years focus on three specific 

epigenetic disorders—AS, PWS, and Rett syndrome. All three disorders are characterized by 
Chromosome Abnormalities, Genetic/Genomic Syndromes, and Epigenetic Disorders 23

variable degrees of IDD, but the manifestations are quite disparate. Children with AS have 

significant cognitive and speech impairments, often exhibit seizures and an ataxic gait, and have 

a tendency toward inappropriate laughter. Deletions of the maternal copy of a portion of 

chromosome 15q, paternal uniparental disomy for this region, or point mutations in the UBE3A

gene have been implicated as causative. In contrast, deletions of the paternal copy of 

chromosome 15q or imprinting defects of this region cause PWS, characterized by failure to 

thrive and poor feeding in infancy that evolves into insatiable appetite, preoccupation with food, 

and risk of morbid obesity if not treated aggressively. Other compulsive behaviors, such as skinpicking, can also evolve in PWS. Rett syndrome, as described earlier, is associated with loss of 

purposeful hand movements and speech in affected girls in early childhood, problems with 

balance and coordination, and seizures, hang wringing, and other features of ASDs. Most cases 

of Rett syndrome are caused by mutations in the MECP2 gene on the X chromosome. 

Among the research topics addressed by Branch-supported projects are the following: mouse 

models of imprinting defects on chromosome 15 in PWS and AS; a mouse model of AS based on 

an Ube3a point mutation; MECP2 gene regulation in Rett syndrome; and the role of MECP2 in 

chromatin methylation. The Branch also supported an R13 conference proposal establishing a 

multisite clinical network for international studies on Rett syndrome.

As described earlier in this report, the Consortium for Rare Epigenetic Disorders, whose primary 

site was at Baylor College of Medicine but is now at the University of Alabama, Birmingham, 

focuses on AS, PWS, and Rett syndrome and includes longitudinal natural history studies and 

drug treatment interventions aimed at altering aberrant methylation patterns in these disorders. 

Science Advances in AS, PWS, and Rett Syndrome 

Discoveries in AS, PWS, and Rett syndrome include the following: 

• Mice that lack Ube3a, a gene implicated in AS, have altered numbers, length, and spine 

morphology in cerebellar Purkinje cells and in hippocampal and cortical pyramidal cells

(Dindot et al, 2008). 

• Researchers identified four genes (NIPA1, NIPA2, CYFIP1, and GCP5) in the 15q critical 

region that are implicated in the ASD phenotype observed in many children with AS. 

• Branch funding supported the creation of new mouse models of AS that affect the imprinting 

center shared with PWS. 

• Studies demonstrated shared features between several epigenetic disorders, including the 

discovery that altered MECP2 expression often occurs in AS as well as in PWS and Rett 

syndrome (Nagarajan et al, 2006); similarly, researchers found significant deficits of Ube3a

expression in mouse models of Rett syndrome and in the brains of individuals with Rett 

syndrome and ASD (Swanberg et al, 2009). 

• Mouse models of PWS have been hampered by embryonic lethality in the past, but by 

placing a deletion of the chromosome 15 imprinting center on a different genetic strain, 

investigators created mouse pups that survive to birth, providing a valuable new tool for 

research and demonstrating the presence of modifier genes (Chamberlain et al, 2004). 

• To address the problem of excessive food consumption in PWS, investigators developed a 

hyperphagia questionnaire (Dykens et al, 2007). These investigators also detected neural 
24 Biochemical and Metabolic Research

differences in visual responses to food stimuli based on the food’s composition and 

suitability for consumption in different forms of PWS.

• The First International Conference on Hyperphagia explored similarities and differences in 

five syndromes associated with hyperphagia: PWS, Bardet-Biedl syndrome, WAGR 

syndrome (characterized by Wilms tumor, aniridia, genitourinary anomalies, and IDD),

Alström syndrome, and in a subset of individuals with FXS. 

• Researchers examined the relative abnormalities of the perisylvian region of the brain with 

respect to speech and language problems in PWS. Other studies provided an analysis of 

visuospatial processing involved in solving jigsaw puzzles. 

• Branch-funded clinical studies revealed that maladaptive and behavioral problems decreased 

in PWS as age and intelligence quotient (IQ) increased. 

• The Branch supported studies to evaluate clinically available interventions for PWS, 

including those that examine the incidence of sleep apnea after growth hormone treatment. 

These studies also found that treatment with topiramate had a positive effect on reduced skin 

picking, but had no effect on overeating behaviors. 

• Branch-sponsored research on Rett syndrome included support of the creation of InterRett 

and RettBASE—international databases for Rett syndrome that include mutations and 

clinical features for affected girls with this condition (Bebbington et al, 2008). 

• Researchers also developed an understanding of the correlation between clinical severity and 

various mutations in the MECP2 gene, although the impact of X-chromosome inactivation on 

this correlation is now providing an additional challenge. 

• Researchers identified histone modifications and methylation patterns that associate with

specific MECP2 mutations. 

• Ongoing research on Rett syndrome also includes: 

o Studies to demonstrate a correlation between expression of Mecp2 in specific neuronal

populations, in astrocytes, and in feeding behavior, aggression, and stress responses in 

animal models of Rett syndrome (Maezawa et al, 2009)

o Efforts to correlate MECP2 expression with ASD features 

o Studies of a unique syndrome identified in males who have duplications of MECP2; these 

males have neurological delays and increased susceptibility to respiratory infections 

(Velinov et al, 2009) 

BIOCHEMICAL AND METABOLIC RESEARCH

Because biochemical pathways are fundamental to normal body and brain function, changes in 

those pathways can disrupt the processes and functions that rely on the pathway’s products and 

byproducts. The IDD Branch funds research on biochemical processes and metabolism as these 

topics relate to brain functioning, brain injury, and long-term consequences to the brain. A few 

of the Branch’s efforts are described below.
Biochemical and Metabolic Research 25

HYPOXIA/ISCHEMIA

Fetal hypoxia (low oxygen levels) can lead to severe hypoxic ischemic encephalopathy (HIE), a 

major problem worldwide with significant morbidity and mortality. HIE occurs in three to nine 

of every 1,000 term infants; about one-half of these infants die or suffer severe lifelong 

problems, such as IDD or cerebral palsy. Knowing the mechanisms of hypoxic injury could 

enable health care providers to prevent or even reverse the injury, possibly improving 

neurodevelopmental outcomes for affected infants. 

During the last four years, Branch research shifted from an emphasis on very basic animal and in 

vitro studies to more clinical and translational studies, as summarized below: 

• The IDD Branch, in partnership with the NICHD Pregnancy and Perinatology Branch (PPB), 

supports translational research on HIE. The PPB currently funds a study of head cooling in 

newborns, the only intervention for hypoxia/ischemia currently in clinical trials. Although 

efforts to reduce the effects of HIE by hypothermia (cooling) have been hampered by the 

lack of a reliable non-invasive method for monitoring infant brain temperature during the 

treatment, the IDD Branch funded a Small Business Technology Transfer Phase I study that 

demonstrated use of Passive Microwave Radiometry for monitoring intracranial temperature 

in neonates. The Branch is also funding a Phase II study to develop an affordable system for 

reliable and continuous monitoring of intracranial temperature in neonates. 

• Preterm infants are at risk for reduced blood flow and hemorrhage to the periventricular areas 

that surround the fluid-filled spaces of the brain (ventricles). Such lesions can lead to 

unilateral or multi-focal white-matter damage, known as periventricular leukomalacia (PVL). 

Children with PVL are more likely to have cerebral palsy and neurodevelopmental 

disabilities. The goal of one Branch-sponsored study is to relate the degree and patterns of 

white-matter damage from PVL to linguistic and cognitive outcomes. Diffusion-Tensor 

Imaging (DTI) provides detailed voxel-based quantitative information on the integrity of 

white-matter microstructure, and functional Magnetic Resonance Imaging (fMRI) 

characterizes the patterns of neural activity that underlie cognitive skills. The combination of 

these methods allows linkages between brain structure, brain functioning, and behavioral 

outcomes. 

• The Branch funds several research studies on outcomes of HIE in rodent models, including 

the following: 

o One study is following juveniles to adulthood to determine long-term behavioral 

outcomes of HIE in sensory processing and learning, with a focus on electrophysiology 

and neuroanatomy. 

o Another study builds upon a ten-year history of rodent model research resulting in the 

discovery that the delta opioid receptor (DOR) protects cortical neurons from hypoxic 

injury. This study is testing the hypothesis that electro-acupuncture-induced upregulation of DORs is a therapeutic strategy that may protect against hypoxic injury and 

damage to the cortex. 

o Another study aims to capitalize on a decade-long research effort using piglets to test the 

therapeutic benefit of neuronal nitric oxide synthase (nNOS) inhibition in hypoxia. The 

hypothesis for this effort derives from the discovery that the highly selective nNOScatalyzed nitrous oxide mediates neuronal injury in this model. 
26 Biochemical and Metabolic Research

• The Branch funded a new R01 grant to support researchers using erythropoietin and cooling 

to treat HIE in non-human primates. Given the importance of testing therapies in closely 

related species before moving into studies with humans, Branch funding for this project was 

a natural progression from earlier Branch-supported studies in rodents with HIE. 

• In addition, the Branch supports annual meetings of the Society for Inherited Metabolic 

Disorders through an R13 conference grant mechanism.

MITOCHONDRIAL DISORDERS

Mitochondria represent the primary energy-producing organelles in the cell. Approximately one 

in 4,000 children has a mitochondrial cytopathy; although the symptoms can vary in severity and 

distribution, organs with high energy demands, such as central nervous system, kidneys, skeletal 

muscle, heart, liver, eyes, ears, and pancreas, are particularly susceptible. Mitochondrial 

disorders can result from defects of the mitochondrial DNA (mtDNA), which encodes the 

mitochondrial transfer RNAs and ribosomal RNAs comprising the mitochondrial protein 

assembly machinery, and some of the electron transport chain (ETC) subunits that generate 

energy as adenosine triphosphate, or from defects in genes encoded by nuclear DNA (nDNA). 

One of the Branch’s long-standing program project grants focuses on the natural history of a 

large cohort of individuals with MELAS (Mitochondrial Encephalopathy, Lactic Acidosis, and 

Stroke-like Episodes) syndrome. MELAS syndrome is caused by a point mutation in mtDNA 

(A3243G) and is estimated to occur in one out of every 750 individuals; many of those with the 

mutation are asymptomatic. 

Researchers looking for ways to improve quality-of-life for individuals with and reduce 

symptoms of MELAS syndrome found early promise in dichloroacetate (DCA), a compound to 

improve mitochondrial function; unfortunately, a clinical trial of DCA determined that long-term 

treatment was associated with neurotoxicity in the form of peripheral neuropathy. Another 

Branch-supported project is screening for therapeutic compounds that enhance respiratory chain 

function in cultured primary human cortical neurons. The group found that two superoxide 

compounds produced protective effects and reduced reactive oxygen species; one of these 

compounds is currently in a Phase I clinical trial. A third project aims to build an in vitro model 

of the blood-brain barrier to test the ability of compounds, including potential therapeutics, to 

enter the brain parenchyma to treat MELAS symptoms. The final project in this group is 

evaluating gene expression, including expression of genes that encode respiratory chain enzymes 

and tight junction proteins, in the ependymal cells from patients with different mtDNA disorders, 

including MELAS syndrome. 

Many mitochondrial disorders occur because of defects in nDNA genes, which encode proteins 

important in mitochondrial biogenesis. Two studies of these types of disorders involve Leigh’s

disease, a progressive neurometabolic disorder that is usually fatal by age six or seven years. 

The first project studies the French-Canadian variant of Leigh’s disease arising from mutations 

in the LRPPRC gene that seem to cause aberrant regulation of mitochondrial transcription and 

resultant cytochrome c oxidase deficiency. In the second study, investigators created a mouse 
Biochemical and Metabolic Research 27

model for classic Leigh’s disease by knockout of Ndufs4, an accessory subunit of complex I of 

the ETC, with resultant reduced complex I activity.

The diversity of Branch-supported grants examining mitochondrial function has also expanded 

during the past four years to include topics beyond classic mitochondrial disorders associated 

with mitochondrial dysfunction. For example, mitochondrial dysfunction in Down syndrome 

arises, in part, from overexpression of the ETS-2 gene, which is triplicated in most individuals 

with Down syndrome. By releasing apoptosis-inducing factor from the mitochondrion, ETS-2

promotes an apoptotic pathway, which might explain why mitochondria from individuals with 

Down syndrome exhibit persistent energy-production deficits and increased cellular oxidative 

stress. This mitochondrial dysfunction in both neurons and astrocytes of those with Down 

syndrome could cause aberrant amyloid precursor protein metabolism, providing potential clues 

to the dementia seen in older persons with Down syndrome. 

UREA CYCLE DISORDERS

In addition to the general goals of the Urea Cycle Disorders Rare Disease Consortium, which has 

its primary site at the Children’s National Medical Center and focuses on this group of 

conditions (described earlier in this report), the Branch also supports a wide range of ongoing 

studies on these disorders through individual research grants. Branch-supported efforts, 

including those conducted through the Urea Cycle Disorders Rare Disease Consortium, include 

the following: 

• Studies to: 

o Compare intellectual, adaptive, and behavioral functioning in children with urea cycle 

disorders; 

o Determine biomarkers of brain injury in ornithine transcarbamylase deficiency (OTCD) 

using anatomic imaging, fMRI, DTI, and magnetic resonance spectroscopy; 

o Create new animal models that more closely resemble the characteristics of specific urea 

cycle disorders; and

o Examine the pathophysiology of astrocytes in urea cycle disorders. 

• In addition to cross-sectional multicenter studies of patients with urea cycle disorders, 

clinical research efforts are also underway to determine the:

o Role of specific amino acids in the clinical variability of individuals treated with sodium 

phenylbutyrate; 

o Effect of treatment of individuals with urea cycle disorders with N-carbamylglutamate; 

and

o Medical management and nutritional interventions for difficult-to-treat urea cycle 

disorder patients. 

• Gene therapy approaches to urea cycle disorders include creation of new mouse models that

more faithfully represent the typical clinical presentation of specific urea cycle disorders, 

such as OTCD, and creation of conditional knockout mice to permit a better understanding of 

critical developmental time points and cell populations to target with therapeutic 

interventions. 
28 Research on Autism Spectrum Disorders (ASDs)

CHOLESTEROL METABOLIC PATHWAY DISORDERS

The Branch also supported efforts to understand cholesterol metabolic pathway disorders during 

the reporting period. For example, Branch staff organized a symposium titled Smith-Lemli-Opitz 

Syndrome (SLOS) and Inborn Errors of Cholesterol Synthesis, held June 27-29, 2007, in 

Portland, Oregon. This symposium, which was co-organized by staff from the NICHD Division 

of Intramural Research, sought to promote interactions among scientists who have expertise in 

SLOS, cholesterol homeostasis, brain cholesterol metabolism, embryonic development, and 

oxysterol and neurosteroid biology with clinician-scientists who study and treat patients with 

inborn errors of cholesterol biosynthesis, such as SLOS. 

RESEARCH ON AUTISM SPECTRUM DISORDERS (ASDS) 

ASDs are complex neurodevelopmental disorders characterized by social impairments, 

communication difficulties, and restricted, repetitive, or stereotyped patterns of behavior. The 

most recent ASD prevalence estimates from the CDC are nine children per 1,000 children, or one 

child per 110 children (CDC, 2009). During the last decade-and-a-half, the NICHD has 

supported a considerable number of research projects related to ASDs. The NICHD’s past 

efforts included the Collaborative Programs of Excellence in Autism (CPEA) Network on the 

Neurobiology and Genetics of Autism, which was co-funded by the NIDCD, and the Studies to 

Advance Autism Research and Treatment (STAART) Network, with co-funding from the 

NIMH, NINDS, NIDCD, and the National Institute of Environmental Health Sciences (NIEHS). 

These projects were highlighted in previous Branch reports to the NACHHD Council. 

AUTISM CENTERS OF EXCELLENCE (ACE) PROGRAM

To maximize coordination and cohesion of NIH-sponsored efforts in autism research, the NIH 

consolidated the CPEA and STAART Networks into the trans-NIH Autism Centers of 

Excellence (ACE) in 2007 to avoid duplication, allow pooling and most efficient use of 

resources, and involve a larger number of investigators in autism research. The NICHD is one of 

the five NIH Institutes (in addition to NIMH, NIDCD, NINDS, and NIEHS) sponsoring the ACE 

Program, which supports studies on a range of autism topics, including early identification and 

intervention in infants at risk for ASDs, early brain abnormalities and functioning, potential 

environmental risk factors and biomarkers, intensive early behavioral intervention, long-term 

effects of early intervention, multidisciplinary studies of insistence on sameness, and trials of

new medication treatments. The ACE Program includes ACE research centers that foster 

collaboration between teams of specialists who share the same facility to address a particular 

research problem in depth, and ACE research networks that consist of researchers at many 

facilities in locations throughout the country, all of whom work together on a single research 

question. To date, the NIH has funded six ACE research centers (via the P50 mechanism) and 

five ACE research networks (through the R01 mechanism). The NICHD has primary 
Research on Autism Spectrum Disorders (ASDs) 29

responsibility for four centers and one network (see Figure 14 for locations). The NICHDsupported ACE centers and their PIs include: 

• UCLA—Original PI: Marian Sigman; current PI: Susan Bookheimer. Researchers at the 

UCLA ACE center are seeking to determine the causes and treatments for social 

communication deficits in ASDs. 

• University of Washington—original PI: Geraldine Dawson; current PI: Bryan King. 

Researchers at this ACE center are trying to identify genetic and other factors that could 

predispose an individual to develop an ASD. These researchers are also examining factors 

that might be protective against ASDs. 

• University of Pittsburgh—PI: Nancy Minshew. Researchers at this ACE center are studying

how people with ASDs learn and understand information. 

• University of Illinois at Chicago—PI: Edwin Cook. Researchers at this ACE center focus 

their research on genetic factors, brain chemicals, and brain functions that might account for 

repetitive behaviors in people with ASDs. These investigators are also testing whether 

genetic differences influence how individuals respond to certain medications intended to 

reduce the occurrence of these behaviors. 

The NICHD-supported ACE network is at UNC, Chapel Hill—PI: Joe Piven. This network 

focuses on increasing understanding of the timing and pattern of brain development in very 

young children with autism. These investigators compare brain images of very young children 

who are at risk for developing ASDs to those who are not at risk. 

All ACE Program grantees must submit their data to the National Database for Autism Research

(NDAR), which is described in more detail below. The first annual meeting of ACE grantees 

will be held in 2010. Table 3 provides a more detailed listing of all the ACE Program projects, 

including those for which the NICHD has primary responsibility. 

INTERAGENCY AUTISM COORDINATING COMMITTEE (IACC) STRATEGIC PLAN FOR ASD

RESEARCH

The Children’s Health Act of 2000 (P.L. 106-310) included language to establish an IACC, to 

include representatives of federal and public agencies involved in ASD-related issues, members 

of the public, and an NIH Autism Coordinating Committee (NIHACC). In response to the 

heightened societal concern about ASDs, congress later passed the Combating Autism Act (P.L. 

109-416) in 2006. The 2006 Act requires the IACC to develop and annually update a strategic 

plan for ASD research, including proposed budgetary requirements. In addition to the directors 

of the NIH Institutes comprising the NIHACC, namely the NICHD, NIDCD, NIEHS, NIMH, 

and NINDS, members of the IACC include the following: Center for Medicare and Medicaid 

Services, U.S. Department of Education, Administration for Children and Families, HRSA, 

Substance Abuse and Mental Health Services Administration, CDC, Autism Society of America, 

Autism Speaks, Autism Spectrum Consulting, Coalition for Safe Minds, and the Autism Science 

Foundation, among others. 
30 Research on Autism Spectrum Disorders (ASDs)

The IACC Strategic Plan is organized around six critical questions asked by individuals and 

families living with ASDs:

• When should I be concerned? 

• How can I understand what is happening? 

• What caused an ASD to happen and can it be prevented?

• Which treatments and interventions will help with ASDs? 

• Where can I turn for ASD-related services?

• What does the future hold? 

The NICHD, through the IDD Branch, was an active participant in the development of the 

Strategic Plan. Branch staff were involved in scientific workshops to identify research 

opportunities, expert workgroup meetings to recommend research objectives and strategies, and 

programmatic expert meetings to develop and recommend budget estimates. The completed 

Strategic Plan was first released to the public in March 2009, and the current version is available 

at http://iacc.hhs.gov/strategic-plan/. 

NATIONAL DATABASE FOR AUTISM RESEARCH (NDAR)

As mentioned earlier in this report, the NICHD is one of several NIH Institutes that sponsors 

NDAR, a bioinformatics system created by the NIH to support ASD research and to accelerate 

scientific discovery. NDAR has facilitated the formation of a world-wide network of ASD 

researchers that seamlessly integrates data, research tools, and institutions by providing a 

common platform for data collection, retrieval, and archiving. This standardized data-sharing 

system was a key component of the IACC Strategic Plan, which called for wide adoption of this 

type of system to provide the infrastructure needed to propel ASD research forward during the 

next decade. 

ACE Program award recipients began contributing their common measures data to NDAR in 

July 2008. More recently, the NIH implemented procedures to allow NDAR to accept and share 

research data from non-ACE researchers. IDD Branch staff serve as active members of the 

NDAR Implementation Team and Subcommittee for Policies. Please visit http://ndar.nih.gov for 

more details on NDAR objectives and capabilities. 

OTHER ASD-RELATED RESEARCH ACTIVITIES

Congress tasked the Department of Defense Congressionally Directed Medical Research 

Program (CDMRP) to manage appropriations specifically targeting ASD research in 2007. An 

IDD Branch staff member has participated in setting CDMRP’s program priorities and making 

funding decisions since 2007. 

The Branch also participates in research funding activities related to vaccines and ASDs. For 

instance, a member of the IDD Branch staff serves as one of the NIH liaisons to the National 
Research on Autism Spectrum Disorders (ASDs) 31

Vaccine Advisory Committee. NICHD also participates in an NIH-wide PA, Research to 

Increase Vaccine Safety. 

Outreach to communities affected by ASDs, including advocacy groups and family support 

organizations, is another key focus of IDD Branch activities in ASDs. In February 2007, IDD 

Branch staff participated in meetings co-sponsored by the National Association of Broadcasters 

and the Special Olympics to discuss ways to decrease stereotypes of individuals with IDD. For 

these meetings, Branch staff provided scientific information about the behavioral heterogeneity 

and potential work-force productivity of individuals with IDD. The IDD Branch also partners 

with groups such as Autism Speaks to promote research and education activities with shared 

goals.

SCIENCE ADVANCES IN ASD RESEARCH

Identifying Early Risk Markers

Rapid progress is being made in the identification of the early behavioral phenotype of autism. 

Much of this progress has resulted from prospective studies of infant siblings of children with 

autism. The Baby Sibling Research Consortium, currently sponsored by Autism Speaks, 

originated at a 2003 meeting co-sponsored by the National Alliance for Autism Research (now 

Autism Speaks) and the NICHD. Through the IDD Branch, the NICHD funds many members of 

the Consortium. Research results have helped to identify and characterize the earliest behavioral 

characteristics and developmental trajectories of children at risk for ASDs. For example, 

because early intervention is known to improve developmental outcomes for children with 

ASDs, a crucial research area involves finding the earliest possible age for valid ASD screening. 

In a prospective longitudinal study co-funded by NICHD, researchers followed the development 

of social and communication skills in infant siblings, between six months and 36 months of age, 

of children with ASD and compared them with infants from unaffected families who were 

considered to be at low risk for ASDs. About one-half of the children with ASD could be 

diagnosed soon after their first birthdays. However, because others with the disorder may seem 

to develop normally until one year of age and then regress during their second year, screening 

would need to be repeated near the second birthday to detect children whose development 

becomes atypical during this interval (Landa et al, 2007). 

A more recent publication from the Baby Siblings Research Consortium summarized the current 

state of the science regarding the early signs of ASDs and various screening instruments. The 

researchers also described best practices for the diagnostic assessment of ASDs in children 

younger than two years of age, including use of the Modified Checklist for Autism in Toddlers 

(M-CHAT), the development of which was funded by NICHD (Pandey et al, 2008). 

(Researchers are also planning to use the M-CHAT to screen for ASDs in the National 

Children’s Study, a longitudinal assessment of 100,000 children from diverse backgrounds.) 

This research provides pediatricians and parents with desperately needed, empirically based 

guidelines for screening and managing young children suspected to have ASDs (Zwaigenbaum et 

al, 2009). 
32 Research on Autism Spectrum Disorders (ASDs)

Another NICHD-sponsored study sought to understand the stability of an ASD diagnosis at age 

two years. Although the diagnosis of an ASD is usually thought to be permanent, the study’s 

findings suggested otherwise. A portion of two-year-olds who had a diagnosis of ASD in the 

study no longer had the diagnosis by age four years. Children with Pervasive Developmental 

Disorder Not Otherwise Specified were significantly more likely than those with full autistic 

disorder to move off the spectrum. Motor skills at age two years were the clearest distinguishing 

factor (Sutera et al, 2007). 

Persons with autism have difficulty reading social cues and situations, which leads to 

inappropriate responses. Researchers measure eye-tracking movements, which emerge within 

the first few weeks of life, to ascertain the resources devoted to specific environmental cues, 

such as responses to social situations. Those with autism focus on less-essential or even 

irrelevant aspects of the social environment, such as mouths or objects, rather than on the eyes or 

face as a whole. By focusing on such aspects, they miss key information for assessing the 

situation. Interventions that teach persons with autism to focus on essential aspects of social 

environments may help alleviate some of the social difficulties related to the disorder (Jones et 

al, 2008; Klin et al, 2009).

Neuroimaging Studies

Using fMRI, scientists were able to show—for the first time—that instructing children and 

adolescents with ASDs to focus on a face or on a voice led to increased activity in the areas of 

the brain that people understand how others feel. These findings could enhance interventions to 

promote activity in the brain region that processes and integrates multiple sources of what might

be considered intangible information, such as the tone of voice and facial expression of another 

individual. 

In another fMRI study supported by the NICHD, in collaboration with the NIDCD, the National 

Alliance for Autism Research and Cure Autism Now (both now Autism Speaks), and the 

University of California, Davis, investigators compared how well boys with ASDs and typically 

developing (TD) boys understood the concept of irony. Compared to the TD group, the ASD 

group showed less activity in the medial prefrontal cortex and in the right superior temporal 

gyrus. After explicit instruction to focus on the face or the voice, however, the boys with ASDs 

showed a significant increase in brain activity in these regions. The TD group showed 

significant brain activity regardless of instructions. The findings also showed that individuals 

who were more socially impaired tended to show less brain activity when presented with an 

ironic scenario (Wang et al, 2007). 

Studies to Address Early Brain Overgrowth-Related Issues in ASDs

A consistent finding in individuals with ASD is the increased frequency of macrocephaly and 

enlargement of cerebral cortical gray and white matter starting at a young age. Studies funded 

through the NIH CPEA Program examined the developmental trajectory of brain overgrowth and 

its relation to ASD symptoms. In one unique prospective study of the trajectory of head growth 

in ASD, head circumference (HC) measures were taken during the first three years of life in 

infants who were later diagnosed with ASD. The study found a period of accelerated head 

growth during the first year of life, followed in the second year by slower head growth relative to 

the excessive early growth. Infants who had a larger HC at age 12 months and greater HC 
Research on Autism Spectrum Disorders (ASDs) 33

deceleration between 12 months and 24 months of age were more likely to exhibit ASD 

symptoms. The authors also described the timing of brain overgrowth relative to the emergence 

of ASD symptoms (often detected by age eight months to 12 months in rigorous studies of highrisk infants), as well as the phenomenon of regression or slowing of skills acquisition often 

reported in the second year of life. These findings may be useful in identifying very young 

children who may benefit from interventions to lessen the functional decline common in ASDs. 

These findings are also important clues to possible underlying genetic or other neurobiological 

mechanisms of abnormal brain growth in ASDs (Dawson et al, 2007; Elder et al, 2008). 

MRIs of individuals with ASDs show increased volumes of a number of brain structures 

compared to TD individuals. To learn more about this phenomenon, investigators on one 

longitudinal study, funded in part by NICHD, found that children with ASDs had an enlarged 

amygdala at age two years and again at age four years. The enlargement was stable during the 

two- to four-year-old time interval. The investigators also found that this enlargement was 

related to “joint attention”—the ability to share information and understand the thoughts and 

intentions of others—an outcome that extends previous findings from research on brain 

overgrowth in children with ASDs. Understanding the pattern of early brain changes in ASDs 

and the relationship of these changes to ASD-related behaviors could lead to improved early 

diagnosis and interventions for these brain and behavior changes (Mosconi et al, 2009).

Progress in Understanding Motor Impairments in ASDs

Two recent publications from NINDS- and NICHD-supported researchers shed light on the 

neurobiological basis of deficits in motor abilities often observed in children with ASDs. In one 

study, investigators sought to determine whether deficits in basic motor function in ASDs could 

account for dyspraxia, or impaired performance of skilled gestures, such as tool use or 

communicative signals. They found that children with ASD showed significantly poorer 

performance on skilled gestures beyond that expected from basic motor deficits. They also 

found that impaired skilled gesture performance strongly correlated with the social, 

communicative, and behavioral impairments characteristic of ASD, suggesting that dyspraxia 

may be a core feature of ASD or a marker of its underlying neurological abnormalities. 

In the second study, the same investigators used brain imaging to determine whether motor 

deficits in ASDs were related to variations in brain anatomy. Increased brain volume, 

particularly in white matter containing connecting nerve fibers, is the most consistent brainimaging finding in children with ASDs. This study showed an association between impaired 

motor performance and increased white matter volume in the primary motor cortex of children 

with ASDs. The mechanisms and types of anatomical variations that contribute to motor 

dysfunction may also contribute to other features of ASDs, such as deficits in socialization and 

communication. Because measures of motor function are more quantifiable and reproducible 

than measures of complex social behavior, studies of motor function provide an opportunity for 

increased understanding of ASDs and their causes (Dziuk et al, 2007; Mostofsky et al, 2007). 

Study of Psychosocial or Functional Analysis Approaches to ASD Treatment

Joint attention and engaging in symbolic play or “pretending” are key aspects of social 

interaction—and are often lacking in persons with ASDs. Evidence shows that early 

interventions can improve language outcomes and social skills in children with ASDs. Among 
34 Research on Autism Spectrum Disorders (ASDs)

individuals in one Branch-supported study, children who received intervention, regardless of 

whether it was a joint attention intervention or a symbolic play intervention, showed greater 

gains in expressive language than did those who received no intervention. High-functioning 

children also showed positive outcomes regardless of the type of intervention received. Lower 

functioning children made greater gains in language if they received the joint attention 

intervention than if they received the symbolic play intervention or no intervention. This study 

provides firm evidence that early interventions are an effective way to improve developmental 

outcomes for those with ASDs (Gulsrud et al, 2007; Kasari et al, 2008). 

Progress in Understanding Genetic Contributions to ASDs

Searching for the genetic causes for ASDs represents a major effort in both NICHD- and NIHfunded research. By comparing the DNA of people with ASDs to that of TD individuals, 

researchers have uncovered an increasing number of variations in specific genes and 

chromosomal regions (such as 15q and 16p) linked to ASDs and related disorders. Overall, 

discoveries in the past few years underscore the complexity of the genetics of ASDs. In 2007, 

researchers made significant advances in identifying specific genetic changes that contribute to a 

small portion of ASD cases. These findings suggest that changes in many different genes 

contribute to the development of ASDs. Researchers also proposed two types of genetic changes 

that may account for the genetic basis of ASDs. One involves rare and spontaneous deletions or 

duplications of genetic material that typically result in just one affected member in a family; the 

second involves the combination of multiple common variations in DNA sequence that are

transmitted from one or both parents, with the potential to result in more than one affected 

member in a family. 

In two recent studies, partially funded by NICHD, investigators identified both common and rare 

genetic factors that affect the risk for ASDs. These results pointed to the importance of genes 

involved in forming and maintaining the connections between brain cells, including neuronal 

cell-adhesion molecules, such as neurexin and cadherin, and those involved in the ubiquitin 

degradation pathway related to AS. These results, which validated previous findings 

demonstrating abnormal cortical connectivity in the brains of those with ASDs and specific gene 

mutations, represent a successful application of the genome-wide association study (GWAS) 

approach to identifying common genetic susceptibility alleles. This GWAS approach signifies a 

major step forward in the larger effort to understand the complex genetic architecture of ASDs 

(Wang et al, 2009; Glessner et al, 2009). 

PLANNED ASD RESEARCH ACTIVITIES: AMERICAN RECOVERY AND REINVESTMENT ACT OF 

2009 (ARRA)

On February 17, 2009, President Obama signed the ARRA legislation (also called the Recovery 

Act or the Stimulus Package) to preserve and create jobs, promote economic recovery, and 

provide investments to increase economic efficiency by spurring technological advances in 

science and health. The NIH received and distributed $10.4 billion from this legislation. 

The NICHD participated in the NIH-wide ARRA RFAs, Recovery Act 2009 Limited 

Competition: Research to Address the Heterogeneity in ASDs. The RFAs solicited R01, 
Newborn Screening 35

collaborative R01, R21, R34, and collaborative R34 applications addressing the IACC Strategic 

Plan in the following topic areas: measurement development, biomarkers/biological signatures, 

immune and central nervous system interactions, genetics/genomics, model development, 

treatments and intervention, and services research. The funding plans for these two-year awards 

have been finalized with a number of NICHD-funded investigators embarking on these 

additional projects to advance autism research progress.

NEWBORN SCREENING

Newborn screening research initiatives within the NICHD and specifically within the IDD 

Branch have experienced considerable growth and re-emphasis during the reporting period. 

Newborn screening enables identification of infants who are at risk for congenital disorders 

(often biochemical, endocrinologic, and/or genetic) for which early interventions and treatments 

have the potential to reduce morbidity and mortality. Although routine screening has occurred at 

the state level since the 1970s, screening tests available have historically varied significantly by 

state; similarly, few states have evaluated the rationale for or efficacy of the tests systematically. 

Because these programs screen more than 4 million infants per year, newborn screening 

represents the most common form of genetic testing performed in the United States. 

SECRETARY’S ADVISORY COMMITTEE ON HERITABLE DISORDERS IN NEWBORNS AND 

CHILDREN (ACHDNC)

The Children’s Health Act of 2000 (P.L. 106-310) established the Secretary’s ACHDNC, 

currently chaired by an NICHD staff member, to advise on grant programs associated with 

newborn screening legislation and to provide technical advice on heritable disorders as a means 

of enhancing and expanding newborn screening. Members of the ACHDNC include medical, 

scientific, and clinical professionals, members of the public with special expertise, and 

representatives from many federal agencies. Chartered in February 2003, the ACHDNC advises 

the Secretary of DHHS about the most appropriate application of universal newborn screening 

tests, technologies, policies, guidelines, and standards for effectively reducing morbidity and 

mortality in newborns and children having, or at risk for, heritable disorders. IDD Branch 

members participate in the meetings as observers to keep abreast of information and 

recommendations made by the scientific community and vetted by the ACHDNC. 

In 2005, the American College of Medical Genetics (ACMG), as commissioned by HRSA, 

developed a core panel of 29 primary conditions, called the Uniform Screening Panel, and 

published Newborn Screening: Toward a Uniform Screening Panel and System, available at

http://mchb.hrsa.gov/screening. After careful review, the ACHDNC approved the Universal 

Screening Panel and recommended it to the DHHS Secretary. States rapidly adopted the Panel, 

and now most states have a Panel similar to the recommended version. 
Newborn Screening 36

The following statistics attest to this remarkable adoption: 

• In 2000, 35 percent of states screened for fewer than five conditions, and none screened for 

more than 30 conditions. 

• By 2005, 23 states screened for at least 21 conditions. 

• By December 2008, 49 states screened for at least 21 conditions. 

The ACHDNC developed a structured, streamlined, and public process for nominating new 

disorders to the Panel that utilizes an independent, evidence-based review system; final approval 

is given by the Secretary of DHHS. As of April 2009, several new, potentially screenable 

conditions have undergone review, with the following outcomes: 

• Fabry Disease, SMA, and Niemann-Pick Disease were nominated for inclusion, but were 

deemed by the Committee as not ready for an evidence review.

• Pompe disease and Severe Combined Immune Deficiency went through formal evidence 

review, but were not recommended for addition to the Panel at this time. Both disorders 

were deemed very promising for newborn screening and their reconsideration would require 

specific additional information.

• Krabbe Disease is currently undergoing formal evidence review; the Committee will discuss 

the evidence at its meeting in September 2009. 

NEWBORN SCREENING SAVES LIVES ACT

In 2008, congress passed the Newborn Screening Saves Lives Act (P.L. 110-204) to establish 

grant programs providing for education and outreach on newborn screening and coordinated 

follow-up care once newborn screening is conducted. As part of the Act, the Secretary of DHHS

must ensure the quality of laboratories involved in newborn screening activities and develop a 

national contingency plan for newborn screening. The Act also authorized the NIH to carry out 

research in newborn screening, including identifying new screening technologies and researching 

disease-management strategies for the conditions that such screening can detect. The latter 

provision is known as the Hunter Kelly Newborn Screening Research Program, named for 

Hunter Kelly—son of Jim Kelly, former National Football League Hall of Fame quarterback. 

Hunter died at age eight from Krabbe leukodystrophy, a degenerative neurological disorder. 

This effort is being led by the IDD Branch and other members of the Center for Developmental 

Biology and Perinatal Medicine, and some of the advances from this effort are included in the 

next section. The legislation also expanded the role of the ACHDNC, mandated appropriations 

to help with the Committee’s activities and to fund newborn screening research, and authorized 

an interagency coordinating committee on newborn screening. 

ADVANCES IN NEWBORN SCREENING 

Because formal efforts related to newborn screening are still quite new and the infrastructure 

only being established, the Branch has few science advances to report. However, the Branch has 

made great progress in laying the foundation for future newborn screening research and in 
Newborn Screening 37

supporting ongoing research on various aspects of newborn screening. These types of advances 

are explained below.

Newborn Screening Translational Research Network Coordinating Center (NBSTRN-CC)

The Hunter Kelly Newborn Screening Research Program focuses on developing systematic 

methods to identify additional conditions appropriate for newborn screening; developing and 

testing innovative interventions and treatments to improve outcomes; educating the provider 

workforce; developing and implementing appropriate information and communication systems 

for parents and providers; and sponsoring ongoing programs of research and research training. 

One of the challenges to efficient and effective newborn screening is the variability of standards 

for screening across states and the lack of an infrastructure to connect existing resources. To 

address these critical needs, the IDD Branch awarded a five-year contract at the end of fiscal 

year 2008 to create the NBSTRN-CC, designed to establish the necessary infrastructure for 

research efforts in newborn screening. 

The NBSTRN-CC will facilitate development of new screening methods, enable the conduct of 

clinical trials for new therapeutic interventions, and support longitudinal research on the longterm health of children identified through newborn screening programs. The primary goals of 

the NBSTRN-CC are to:

• Establish an organized network of state newborn screening programs and clinical centers. 

• Develop, implement, and refine a national research informatics system for investigators and 

policy makers that dovetails with established national clinical networks.

• Establish and administer an efficient and reliable repository of residual dried bloodspots. 

• Provide expertise and support related to regulatory requirements associated with informed 

consent, Institutional Review Boards, and state and local research policies associated with 

newborn screening. 

• Facilitate research on the development of new methods and technologies by maintaining 

close contact with the scientific and biomedical research community.

• Facilitate research on screened and treated patients to define effectiveness of treatments and 

long-term outcomes.

• Provide statistical leadership and clinical trial design expertise for the individualized needs of 

researchers. 

• Facilitate the timely dissemination of research findings.

Biomedical Research: Novel Technologies in Newborn Screening

In fiscal year 2006, the Branch issued a Request for Proposals (RFP) titled Novel Technologies in 

Newborn Screening. As a result, the IDD Branch awarded two contracts to develop multiplexed 

screening assays that could be automated and utilized in a high throughput environment for 

newborn screening. The intended goal of these projects is to develop a screening technology 

platform of components based on a range of technologies. One contract, to the University of 

Washington, is evaluating the expansion of tandem mass spectrometry as an instrument for the 

enzymatic detection of lysosomal storage disorders, such as Fabry disease, Pompe disease, and 
38 Newborn Screening

Hurler syndrome, in newborn screening samples. The other contract, to the New York State 

Department of Health, is developing a Luminex® bead-based microarray assay for newborn 

screening. 

Innovative Therapies and Clinical Studies for Screenable Disorders 

Beginning in 2005, the NICHD, NIDCD, and NIDDK issued an ongoing FOA to stimulate 

translational research on potential therapeutic interventions for conditions currently screened by 

states, as well as other high-priority genetic conditions for which screening might be possible in 

the near future. The FOA placed special emphasis on research related to some of the highpriority conditions, defined as those for which the development of an efficacious therapy would 

make the condition amenable to newborn screening, identified in the 2005 ACMG report. The 

FOA also supported research designed to elucidate the natural history of these conditions to 

facilitate identification of potential therapeutic interventions, with the ultimate goal of 

developing more targeted and effective therapies. The IDD Branch currently funds nine projects

under this initiative, targeting the following disorders: Heritable gamma-hydroxybutyric 

aciduria, hyperammonemia, Gaucher disease, SMA, galactosemia, Krabbe disease, and 

phenylketonuria. 

Other examples of Branch-supported newborn screening projects include the following: 

• Digital Microfluidics—The IDD Branch currently funds the development of an automated, 

inexpensive, multi-analyte and multiplexed screening analyzer to help reduce blood analysis 

volumes and time-to-result. The project also aims to make the analyzer available at the 

point-of-delivery (for example, birthing centers). This disposable lab-on-a-chip will use

digital microfluidic manipulation of nanoliter-sized droplets of enzymatic reagents and 

sample for dispensing from on-chip reservoirs, high-speed transport, mixing, splitting and 

dilution, and absorbance, fluorescence, and luminescence detection of the assays. The 

project aims to demonstrate the feasibility of performing newborn screening for lysosomal 

storage disorders, including Fabry, Pompe, and Hurler diseases, from a single dried blood 

spot obtained from the heelstick of a newborn using this microfluidic technology. 

• Quality Control Tool for Newborn Screening Blood Samples—This project aims to develop a 

simple and economically advantageous imaging-based computer system to evaluate newborn 

screening blood cards for adequate quality and quantity for testing at the point of care (e.g., 

birthing center). Use of such a system would allow for the immediate correction of 

inadequate cards before the card is sent to the lab for testing and while the newborn is still in 

the birthing center, saving health care dollars and preventing any unnecessary delay in the 

diagnosis of important metabolic diseases. 

• Family Adaptation to Newborn Screening—The numerous ethical, behavioral, and social 

impacts of newborn screening have yet to be fully explored and understood. These include 

efforts to investigate the psychological and social impact of false-positive and false-negative 

results on children and their families—in particular, those newborns whose results are within 

the abnormal range, but who do not actually have a disease. This ongoing study, led by 

investigators at the Fragile X Research Center based at UNC, Chapel Hill, evaluates the 

following in relationship to newborn screening for FXS: 

o Extent to which families from diverse cultural and ethnic groups consent to newborn 

screening; 
Newborn Screening 39

o Reasons parents decline or accept screening, and family or sociocultural factors related to 

screening decisions; 

o Extent to which families of identified children believe they were adequately informed 

about the possible results from screening, are initially satisfied with their decision to 

participate, and whether and how their views about screening change over time; 

o Whether families experience adverse mental health outcomes following a diagnosis, and 

how adaptation varies as a function of child, family, and support variables; 

o Variation in the quality and evolution of parent-child relations following diagnosis; and

o Variation in the ways that parents and extended family members respond to, share, and 

use information gained from a newborn diagnosis. 

Newborn Screening in the Middle East and North Africa (MENA)

In 2006, Dr. Elias Zerhouni, then Director of the NIH, traveled to North Africa with an NIH 

delegation to discuss plans for collaboration and partnership. During this visit, newborn 

screening emerged as one of the top health priorities in the region, where such services are

limited. Following the initial delegation visit, the Ministry of Health of the Kingdom of 

Morocco partnered with the NICHD and other organizations to hold a regional conference, 

Strengthening Newborn Screening in the MENA Region, November 13-15, 2006, in Marrakech, 

Morocco. The meeting brought together representatives from 18 countries in the MENA region 

and 11 countries in Europe, North America, and Asia/Pacific Islands and received support from 

20 international public-private sponsors. 

A primary outcome of the meeting was the Marrakech Declaration, a document that affirmed 

newborn screening as a key public health priority for the region and recognized the need for a 

collaborative, cooperative network to facilitate the development of a newborn screening system 

for all nations (see Appendix F for the full declaration). In addition to the provision that all 

countries screen for at least one condition, key elements of the declaration stated that 

participating countries would: 

• Develop policies and establish a systematic national newborn screening program. 

• Assure that children identified as having screened positive for a genetic disorder have access 

to care. 

• Establish biannual regional meetings to assess progress and increase collaboration. 

• Develop training programs. 

• Establish national research priorities and stimulate regional research capacity. 

A Steering Committee was also established to plan for the region’s next meeting on newborn 

screening and to address recommendations of the Marrakech Declaration. The Committee 

included members from multilateral organizations, ministries of health, universities, and other 

health care provider groups, as well as international collaborators in the United States, Europe, 

and Asia/Pacific Islands. The Steering Committee also established a Congenital Hypothyroidism 

Training Working Group and a Survey Working Group. In response, several countries, including 

Morocco and Tunisia, have begun developing and expanding their newborn screening programs.
40 Research Resources

The 2nd Conference of the MENA Newborn Screening Initiative: Partnerships for Sustainable 

Newborn Screening Infrastructure and Research Opportunities, held in Cairo, Arab Republic of 

Egypt, April 12-14, 2008, included more than 30 policy makers, health care providers, health 

ministry representatives, scientific experts, and family and advocacy representatives from 17 

countries in the MENA region, Europe, Asia, and North America. The primary outcome of this 

effort was the development of National Plans of Action to implement or strengthen screening

programs in each of the participating countries. These National Plans detailed program 

leadership, blood-spot collection and storage, laboratory methods, and linkage to treatment and 

follow-up. An article summarizing these issues was published in Genetics in Medicine

(Krotoski, et al, 2009). 

Plans for a third conference, to be held in early 2010 in Doha, Qatar, are ongoing. The third 

meeting will seek to further expand upon these initiatives, build infrastructure, establish 

collaborations, and initiate newborn screening in MENA countries. 

Early Detection of Neuromuscular Diseases

In spring 2009, the NICHD, in conjunction with other NIH Institutes and Centers, including 

ORDR, NHGRI, and NIAMS, other federal sponsors, including HRSA and CDC, and the 

Muscular Dystrophy Association, held a 11⁄2 day workshop on March 16-17. Approximately 60 

participants, including scientists, health care providers, public health leaders, ethicists, and 

patient advocacy groups participated in this meeting to discuss early detection and screening for 

neuromuscular diseases and the steps necessary to consider newborn screening for these 

disorders. Possible outcomes of this meeting, with the overarching goal of determining the needs 

of the neuromuscular disease communities, might include funding opportunities, follow-up 

workshops, and development of networks to support efforts related to the process of newborn 

screening for these disorders. 

RESEARCH RESOURCES

REPOSITORY FOR MOUSE MODELS OF CYTOGENETIC DISORDERS

This project began in the 1970s to generate and distribute mouse models for cytogenetic 

disorders. With demonstration that a segment of mouse chromosome 16 contained genes closely 

related to the genes on a large segment of human chromosome 21, the trisomy 16 mouse became 

a model for studies relevant to Down syndrome. Subsequent genetic dissection of both mouse 

and human genomes located other genes present on human chromosome 21 that were closely 

related to genes on mouse chromosomes 10 and 17. In the 1980s, under contract with NICHD, 

investigators at Jackson Laboratories (JAX) in Bar Harbor, Maine, created mice with partial 

trisomies for a number of chromosomal segments. One of these partial trisomies, designated 

Ts65Dn, proved to include approximately 150 genes located in the “Down-syndrome critical 

region” of human chromosome 21. Subsequently and also under contract, JAX produced and 

distributed these mice to investigators approved for their receipt by the NICHD. 
Branch-supported Training Initiatives 41

The creation of a central repository for these mice has ensured maintenance of the appropriate 

genetic strains and their efficient distribution to investigators. Because Ts65Dn males are 

usually infertile and females produce fewer litters than normal females, generating large numbers 

of the trisomic mice is very difficult for any individual researcher. The repository serves the 

Down syndrome research community by providing mice for a wide variety of studies related to 

understanding the basic biology of Down syndrome, including neurocognitive dysfunction and 

Alzheimer-like disease findings that occur with increasing age. 

The contract was competitively awarded to JAX in May 1985, for four years and has undergone 

recompetition or extension since then. The current contract is under extension until mid-fiscal 

year 2010, by which date a renewal is planned. The Branch intends to revise the contract to 

ensure that adequate numbers of mice are available in a timely manner to investigators 

requesting them, so that this important resource can accommodate the increased demand for 

these valuable murine models.

BRAIN AND TISSUE BANK FOR DEVELOPMENTAL DISORDERS

The NICHD began funding a Brain and Tissue Bank for Developmental Disorders in 1991 to 

provide a research resource that would increase knowledge of the etiology and pathogenesis of 

neurodevelopmental disorders. The Bank has served the critical role of collecting, preserving, 

and distributing human tissues to qualified scientific investigators dedicated to the improved 

understanding, care, and treatment of individuals with neurodevelopmental disorders, including 

ASDs. 

The Branch released a Request for Information in December 2008 to notify the community that 

NICHD would publish an RFP for continuation of the Bank and to provide all interested parties 

with an opportunity to comment on the Bank. The Branch received more than 100 comments, 

mostly from prior recipients of tissue from the Bank. The comments unanimously affirmed the 

value and contributions of the Bank and were helpful in formulating the RFP. 

In August 2009, the NICHD awarded the contract to the University of Maryland to continue and 

expand the Brain and Tissue Bank with enhanced tissue processing capabilities and an increased 

emphasis on the collection and distribution of tissues related to ASDs. This expansion lays the 

groundwork for establishing an international network of biobanks to collect brain and other 

tissues. Creation of an international network of autism tissue collection sites is one of the goals 

of the IACC Strategic Plan on ASD Research. 

BRANCH-SUPPORTED TRAINING INITIATIVES

The IDD Branch supports a number of training activities, almost exclusively through 

investigator-initiated efforts; that is, none resulted from an IDD Branch-initiated RFA 
42 Future Directions for the Branch

(see Figure 15 and Appendix E). The RDCRC and the Senator Paul D. Wellstone Muscular 

Dystrophy Cooperative Research Centers have separate training components.

The Branch supports training and career development through a number of mechanisms, 

including F31, F32, K02, K08, K23, and K24. The Branch also supports one K99/R00 award via 

this relatively new mechanism that aids in career transition from mentored support to 

independent investigator status. 

The Branch also uses T32 grants to support predoctoral and/or postdoctoral trainees at academic 

institutions with a formal training program. Many of the T32s listed in Appendix E support 

training that has a direct clinical focus on IDD, while others comprise interdisciplinary training 

experiences in neurodevelopmental disorders with basic science components. In addition, the 

Branch supports a meeting that brings trainees together annually at the Gatlinburg Conference to 

make presentations and network through an R13, as previously described. 

One of the challenges associated with assessing the success of training programs is the difficulty 

in tracking the career development of trainees after they complete the program, a logistical 

dilemma, and one that Branch has not yet fully addressed. In addition, the number and quality of 

trainees supported in IDD research is relatively high in spite of the limited Branch funds 

committed to training experiences, but this is an area that the Branch would like to expand. 

Possible means for enhancing the Branch’s efforts in training are included in the Future 

Directions for the Branch section of this report. 

FUTURE DIRECTIONS FOR THE BRANCH

On April 30, 2009, in accordance with the NICHD process for improving the transparency of and 

enhancing public input toward strategic planning, the IDD Branch convened an expert panel to 

review its activities during the past four years and to suggest possible future directions for IDDrelated research. Members of the panel included professionals with expertise in the fields of 

pediatrics, genetics, neurology, neonatology, developmental pediatrics, psychology, 

neurobiology, metabolism, and newborn screening; members of the NACHHD Council; and 

public representatives and stakeholders (see Appendix C for a list of panel members). 

This group discussed key scientific opportunities, public health issues, and training efforts that 

the Branch will consider pursuing in the next four years, with a particular focus on prioritizing 

specific areas of the research agenda. Overall, there was broad consensus among the expert 

panel members that a major emphasis of the Branch should be efforts to reconceptualize IDD 

research into broader areas, such as shared pathways or systems approaches, in order to promote 

development of interventions for a wider population of individuals with IDD. A summary of the 

panel’s discussion is included below and is organized into six main areas of emphasis. 
Future Directions for the Branch 43

RESEARCH ON THERAPEUTIC INTERVENTIONS FOR IDD

Panel members noted that, in the past, the IDD Branch emphasized basic and clinical studies on 

the etiology and fundamental mechanisms underlying specific forms of cognitive impairment

with great success, but put only limited commitment toward research for developing new drugs 

and other treatments. The panel recommended a general emphasis on clinical and translational 

research to identify potential interventions for individuals with IDD. Although individual IDD 

conditions are somewhat rare, these conditions collectively impact a significant proportion of the 

population. Therefore, panel members felt that it was critical to fully exploit existing strategies 

and treatments in this population, particularly given the decrease in available health care 

resources. 

An underlying subtext of this discussion, and an element critical for the success of this approach, 

was the need to improve outcome measures and to develop biomarkers, both of which depend on 

accurate phenotyping in the IDD population. Precise definitions of clinical, genetic, epigenetic, 

and environmental features of various IDD conditions are necessary to understand which 

subpopulations might benefit from particular therapies. A corollary is the need to promote 

longitudinal natural history and population-based studies. Recognizing that natural history 

studies are expensive and not always as competitive in review as traditional, hypothesis-driven 

research, panel members and Branch staff acknowledged that a broad view and comprehensive 

approach may be necessary. 

The panel also discussed support for empiric studies to assess existing, commonly used 

behavioral and educational interventions for IDD. In general, there are many interventions 

available for individuals with IDD, but little or no empiric data support their utility and validity; 

further, few analyses compare different treatment regimens, doses, or intensities for efficacy. In 

many cases, parents spend substantial time and energy on unproven interventions for their 

children, often at great expense to families, schools, care providers, and insurance companies, 

despite the lack of evidence suggesting that such interventions improve outcomes. 

The panel acknowledged that an emphasis on developing therapies for IDD would require a 

long-term commitment of resources and NICHD program staff, as well as creative collaborative 

approaches. The expert panel recommended increasing partnerships to build up research 

resources that might include registries, data-sharing plans, communication and outreach efforts, 

and public education. The panel reached broad consensus on the need for interventions in the 

IDD field, recognizing that this represents a far-reaching and ambitious goal. 

Within the context of the panel’s discussion, the IDD Branch will consider the following 

research activities during the next four years: 

• Explore ways to enhance clinical/translational research efforts in the field, including:

o Focusing on more common IDD conditions with established patient populations 

o Recognizing contributions from rare but well-defined disorders that may have broader 

applications to other IDD conditions 

o Supporting tests of drugs that have FDA approval for uses in the IDD population 

o Focusing on pathway disorders/systems biology approaches to develop tools for 

endpoints 
44 Future Directions for the Branch

• Support efforts to more precisely define clinical, genetic, epigenetic, and environmental 

features of various IDD conditions and to adopt these definitions throughout the research 

community. 

• Partner with other Branches, Centers, Institutes, and organizations to promote longitudinal, 

natural history and population-based studies that include individuals with IDD. Model 

successful examples of longitudinal efforts, such as the RDCRC, the Newborn Screening 

Translational Research Network, and the NIH-sponsored Clinical and Translational Science 

Awards (CTSAs).

• Support research to systematically evaluate commonly used behavioral and educational 

interventions for IDD to determine whether children who receive these interventions actually 

benefit from them. 

• Encourage and explore partnerships and collaborations to better utilize resources and 

expertise. Potential partners might include: Groups with multicenter translational research

and clinical trials; investigators who use the CTSA infrastructure; other NICHD Branches, 

Centers, and Programs (such as the National Children’s Study and the OPPB); other NIH 

Institutes and Centers; other federal agencies within DHHS, such as CDC, HRSA, and the 

Agency for Healthcare Research and Quality; the Institute of Education Sciences, U.S. 

Department of Education, and other education groups; advocacy groups and other private 

foundations; and international organizations and consortia. 

EARLY IDENTIFICATION AND DIAGNOSIS VIA NEWBORN SCREENING

The expert panel acknowledged the contributions of early identification and diagnosis of IDD to 

improved treatment and interventions for those with IDD and supported continued expansion of 

newborn screening programs and development of new technologies. Although newborn 

screening has significantly improved the ability to diagnose treatable inborn errors of metabolism 

in a newborn infant, the panel noted a need to develop screening tools for other forms of 

cognitive impairment not currently identifiable via available methodologies. In addition, the 

panel expressed interest in developing other modalities for early identification and screening, 

such as preconceptional testing (testing of parents for carrier status for conditions associated with 

IDD), prenatal testing (testing in utero for IDD), and early childhood screening (testing in the 

primary care physician’s office or educational setting). The panel observed that all of these 

approaches have associated ethical issues that need to be addressed, but added that they also have 

implications for public health policy, population surveillance measures, and health care resource 

allocation, given the need to continue to monitor and follow-up with children identified by 

screening and their families. 

A related topic of interest for the panel was the need to support research on preventable forms of 

IDD, such as those resulting from maternal drug or alcohol use, malnutrition, preterm birth, low 

birth weight, hypoxia/ischemia, and other perinatal insults that result in brain injury. Research to 

identify pregnancies at risk for these sequelae as well as to track infants after exposure to ensure 

appropriate follow-up could have a profound effect on reducing the incidence of these events 

leading to IDD and promoting the treatment of exposed infants to optimize outcomes. 
Future Directions for the Branch 45

Based on the panel’s discussion, the IDD Branch will consider pursuing the following research 

activities:

• Support efforts to develop screening tools for forms of cognitive impairment not detected 

through currently available means. 

• Encourage research to expand modalities for early identification and screening, such as 

preconceptional testing, prenatal testing, and early childhood screening. 

• Partner with allied health care providers to disseminate information related to newborn 

screening and follow-up. 

• Collaborate with health care providers and professional organizations to develop and 

disseminate counseling guidelines and information for at-risk individuals and families about 

IDD conditions discovered during routine newborn screening or other modalities.

• Expand research support for preventable forms of IDD to include identification of at-risk 

pregnancies and follow-up of infants and families; partner with appropriate groups, such as 

the NICHD PPB, to accomplish this goal. 

RESEARCH ON ADOLESCENT BRAIN DEVELOPMENT

The panel noted that adolescent brain development in IDD is an area of relative lack of emphasis 

in the Branch portfolio. Many experts in the field acknowledge that the adolescent brain is a 

unique entity with distinct neurobiological and neurochemical properties that may predispose to 

later development of neuropsychiatric disorders and addictions. The IDD population also has 

unique challenges in addition to those faced by TD adolescents. As the survival improves for 

many infants and children with IDD conditions, more members of the IDD community reach 

adolescence and adulthood. However, the dearth of research on adolescents in the IDD 

population leaves them vulnerable to poorer outcomes and reduced quality-of-life. Thus, the 

panel recommended additional research to address the medical, psychosocial, and psychiatric 

needs of a growing population of adolescents with IDD in the United States.

In light of the panel’s discussion, the IDD Branch will consider the following activities:

• Support research to create and expand the existing evidence base related to the adolescent 

brains of those with IDD and those without IDD to: 

o Better inform future research and treatment interventions

o Improve quality-of-life for adolescents with IDD and their families

o Address aspects of adolescent development that are specific to particular IDD conditions 

and those that are more generalizable

• Explore the characteristics of IDD comorbid conditions, such as obesity, disordered sleep, 

complications of pubertal or gynecological conditions (such as premenstrual syndrome or 

other menstrual disorders, fertility, and pregnancy) and support research on their 

management and intervention. 
Future Directions for the Branch 46

HEALTH DISPARITIES AND HEALTH PROMOTION RESEARCH RELATED TO IDD

The panel discussed several research topics related to reducing health disparities among IDD 

populations. Individuals from disadvantaged socioeconomic backgrounds are less likely to 

receive screening services, diagnostic evaluations, or treatment interventions. These individuals, 

who already represent a “vulnerable population,” have additional factors that increase the 

likelihood of poor outcomes related to IDD. Panel members noted that little or no research has 

focused on health disparities that impact life expectancy and quality-of-life for individuals with 

IDD throughout the lifespan. 

In the realm of health promotion, the panel suggested that nutrition, exercise, and obesity were 

particularly understudied within the IDD population. Obesity is a public health crisis in the 

United States, and the IDD population is at particularly high risk for a variety of reasons. 

Although many factors, such as overeating, lack of access to nutritious foods, and inactivity, 

contribute to this epidemic, the general public shares many of these factors. The panel expressed 

enthusiasm for development of a research agenda to identify the root causes of obesity and 

prevention strategies in the IDD population in partnership with other NICHD groups, such as the 

Obesity Research Strategic Core, that work in childhood obesity research. 

In addition, the panel noted a lack of evidence related to transition to adulthood within the IDD 

population. Adults with IDD often lack services or access to services once they reach age 21, in 

spite of a developmental IQ that may not match their chronological age. The panel also 

encouraged the Branch to explore partnerships and public education efforts within the IDD 

community around these issues. 

Within the context of this discussion, the IDD Branch will consider the following activities:

• Support research on the various factors that influence, contribute to, and/or ameliorate health 

disparities among IDD individuals. This work could include (but would not be limited to) 

studies on cultural factors, belief systems, educational background, community resources, 

neighborhood influences, and access to services and their roles in health disparities that 

impact individuals with IDD and their families. 

• Seek out ways to partner with or build upon the work of other entities, such as the NICHD 

Division of Special Populations, the Arc of the United States, and the American Association 

on IDD, to address health disparity issues in persons with IDD and their families.

• Support research on medical, emotional, and societal aspects of transition to adulthood in the 

IDD population and the factors related to positive outcomes and quality-of-life.

• Encourage health care providers who care for adult populations to expand their expertise in 

the unique medical, psychosocial, and behavioral issues for the IDD population as these 

individuals transition to adulthood. 

• Collaborate with support and advocacy groups to develop health promotion and public 

education efforts for use within the IDD community to address issues such as obesity, 

nutrition, diabetes, and other conditions. 
Future Directions for the Branch 47

TRAINING INITIATIVES IN THE IDD FIELD

All panel participants recognized the need to promote training-related initiatives and to 

encourage investigators to join the IDD research field. The panel emphasized outreach to 

advertise opportunities to young people and to promote public awareness about IDD at early ages

as critical to exposing young people to the field. Members recognized the need to support 

continued career development at all stages of training, but in particular, noted the need for earlystage investigators at the postdoctoral and junior faculty levels. Given the paucity of clinicianinvestigators entering the field and critical shortages of scientists in many pediatric subspecialty 

areas, the panel recommended that training initiatives be offered not only to medical doctors, but 

also to allied health professionals and other health care providers from related disciplines. In 

addition, they noted that the evolution of the IDD field and the complexity of the associated 

research issues dictate that training programs emphasize multidisciplinary approaches to training. 

In light of the panel’s comments, the Branch might consider the following strategies for 

enhanced training to promote recruitment and retention of investigators within the IDD field: 

• Promote IDD-related fellowships for high school and undergraduate students via summer 

research programs.

• Support residency programs in IDD-related critical areas, such as child neurology and 

genetics. 

• Partner with international training programs to produce well-rounded investigators and 

encourage foreign scientists to enter the field. 

• Develop well-structured, interdisciplinary programs that support novel career development 

paths for postdoctoral trainees. 

• Recognize that lifestyle considerations (i.e., marriage, family) might compete with the need 

for intensive training and that flexibility in training opportunities, including NIH career 

development awards, is essential to encourage promising junior investigators to join the field. 

• Explore incentives to induce M.D.s and Ph.D.s to enter the field. 

• Partner with advocacy groups and private foundations to promote training initiatives. 

• Encourage the IDDRCs to incorporate a mechanism for interdisciplinary training within their 

Centers. 

• Promote research to track the results and outcomes of training initiatives. 

TOWARD A NEW CONCEPTUALIZATION OF IDD RESEARCH 

Expert panel members and Branch staff also discussed the need for a shift in emphasis for IDD 

research to integrate the IDD field more broadly, rather than focus on individual, rare disorders. 

This reconceptualization could apply to basic research, genomic studies, clinical and 

translational approaches, and provision of services. Essentially, panel members felt that such a 

paradigm shift could encourage investigators to rethink the IDD field from the perspective of 

shared etiologic pathways, systems approaches, and interrelated networks, with the goal of 

developing interventions that may generalize across many conditions. Reconceptualizing many 

IDD conditions as pathway disorders could also generate new scientific questions and treatment 

approaches for the Branch to pursue. A systems approach could also stimulate cross-thinking 
48 Future Directions for the Branch

and would likely increase the impact of publications in the field and make findings more 

generally applicable and broadly disseminated. 

A “pathway” approach would also build power in numbers by bringing together advocacy and 

family groups impacted by ultra-orphan disorders to focus on similarities in the conditions. 

Many advocacy organizations are already collaborating in this manner and recognize the value of 

partnering with related groups and sharing and leveraging existing resources. For example, 

families affected by a variety of inborn errors of metabolism meet and exchange information at 

metabolic conferences. This new approach might also encourage advocacy groups to promote 

research on interrelated conditions and on the field as a whole.

The panel also indicated that workshops provide an excellent venue for shifting the focus to a 

systems approach and aligning partnerships based on novel criteria. Members suggested that 

program staff might discover such associations by examining research projects in their portfolios 

and looking for natural associations. Panel members cited a recent example of such a 

conference, the First International Conference on Hyperphagia. This meeting, sponsored by the 

Prader-Willi Association, brought together researchers with expertise in PWS, Bardet-Biedl 

syndrome, WAGR syndrome, Alström syndrome, and FXS, in addition to representatives from 

the pharmaceutical industry and relevant advocacy groups to discuss shared and unique 

characteristics of overeating in these disease populations. In another example, the Branch 

recently supported a conference on disorders involving the Ras/MAPK pathway, bringing 

together researchers who work on Costello syndrome, Noonan syndrome, cardiofaciocutaneous 

syndrome, and Neurofibromatosis 1, as well as advocacy groups for the different disorders. 

Such workshops could also include biotech and pharmaceutical companies developing treatments 

that target specific molecules involved in the relevant pathway to alleviate symptoms of one or 

more of these disorders. 

Overall, the panel expressed enthusiasm for continued commitment to basic, clinical, and 

translational research in the IDD field, with an additional emphasis on systems biology and a 

pathway disorders approach to expand the array of interventions and targeted therapies for 

individuals with IDD. 

In light of this discussion, the Branch might consider the following activities:

• Examine the benefits and limitations, specifically in terms of staffing expertise and cost 

effectiveness, of reconstructing the Branch portfolio horizontally into content areas, rather 

than vertically into disease areas. 

• Explore ways to integrate the Branch’s research portfolio to increase the emphasis on a 

pathway or systems approach, rather than on specific diseases/conditions. 

• Use thematic workshops, rather than disease-specific workshops, as venues for new and 

exciting research findings and as a way to align people into partnerships and collaborations. 
References 49

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Figures and Tables-1 

FIGURES AND TABLES

Please Note: The numbers and amounts presented in these figures and tables represent unofficial 

figures prepared by the NICHD Referral and Program Analysis Branch. Some of the amounts 

may differ from those reported by the NIH Research, Condition, Disease, and Categorization 

Process, which provides the only official amounts for the NIH. Please visit 

http://report.nih.gov/rcdc to view official numbers and amounts for specific disease categories. 

All figures shown are in U.S. dollars unless otherwise indicated.

FIGURE 1: BRANCH FUNDS IN CURRENT AND CONSTANT DOLLARS, FISCAL YEAR 2005

THROUGH FISCAL YEAR 2008 

$106.8 $103.3

$106.3 $106.4 $106.8

$98.8

$97.7

$94.6

$90

$100

$110

2005 2006 2007 2008

Amount (In Millions)

Fiscal Year

Current Dollars Constant Dollars
Figures and Tables-2 

FIGURE 2: BRANCH FUNDS BY SUPPORT MECHANISM, FISCAL YEAR 2008 

Research 

Projects

44.5%

$47.3 Million

Fellowships

0.2%

$0.2 Million

P01s

13.5%

$14.4 Million

Research Career 

Program

0.9%

$1.0 Million

Research Centers

26.6%

$28.3 Million

Small Business 

Innovative 

Research

5.5%

$5.8 Million

Research 

Contracts

4.0%

$4.3 Million

Training

1.9%

$2.0 Million

Cooperative 

Agreements

2.9%

$3.1 Million

Total: $106.4 Million 
Figures and Tables-3 

FIGURE 3: BRANCH FUNDING BY RESEARCH AREA, FISCAL YEAR 2005 THROUGH 

FISCAL YEAR 2008 

$52.9 $51.0 $49.7

$19.9 $20.1 $22.4 $22.4

$29.8 $30.3 $32.9 $34.3

$57.0

$0

$20

$40

$60

$80

$100

$120

2005 2006 2007 2008

Fiscal Year

Amount (In Millions)

Biomedical Behavioral Biobehavioral

$106.8 $103.3 $106.3 $106.4
Figures and Tables-4 

FIGURE 4: BRANCH FUNDING FOR PROJECTS INVOLVING HUMANS BY RESEARCH AREA,

FISCAL YEAR 2005 THROUGH FISCAL YEAR 2008 

$19.8 $19.9 $22.3 $22.2

$25.7 $26.0 $27.3 $27.2

$29.9 $29.0 $29.8 $33.1

$0

$10

$20

$30

$40

$50

$60

$70

$80

$90

2005 2006 2007 2008

Fiscal Year

Funds (In Millions)

Biomedical Behavioral Biobehavioral

$78.6 $75.8 $78.6 $79.2
Figures and Tables-5 

FIGURE 5: BRANCH FUNDING FOR PROJECTS INVOLVING ANIMALS BY RESEARCH AREA,

FISCAL YEAR 2005 THROUGH FISCAL YEAR 2008 

$4.1 $4.3 $5.6

$7.1

$23.9 $23.0 $22.0 $19.9

$0.2 $0.2 $0.1

$0.2

$0

$5

$10

$15

$20

$25

$30

2005 2006 2007 2008 Fiscal Year

Funds (In Millions)

Biomedical Behavioral Biobehavioral

$28.2 $27.5 $27.7 $27.2
Figures and Tables-6 

FIGURE 6: BRANCH FUNDING FOR SELECTED DISORDERS, FISCAL YEAR 2005 THROUGH 

F Y 2008 ISCAL EAR 

$19.6 $20.6

$22.3

$25.7

$8.4 $7.9 $8.2 $8.9

$12.5 $10.2 $10.4 $11.1

$14.0

$16.9

$14.4 $14.6

$4

$8

$12

$16

$20

$24

$28

2005 2006 2007 2008

Funds (In Millions)

Fiscal Year

Autism Spectrum Disorders Down Syndrome

Fragile X Syndrome Metabolic/Mitochondrial Disorders

FIGURE 7: BRANCH FUNDING FOR SELECTED DISORDERS OR TOPICS, FISCAL YEAR 2005

THROUGH FISCAL YEAR 2008 

$3.3

$2.4

$1.5

$2.7 $2.6

$2.2

$2.1

$0.9 $0.9 $0.9 $0.7

$5.0

$3.8

$4.9

$4.5

$1.1

$3.0

$3.8

$6.0

$0

$1

$2

$3

$4

$5

$6

$7

2005 2006 2007 2008

Funds (In Millions)

Fiscal Year

Rett Syndrome Williams Syndrome Prader-Willi Syndrome

Muscular Dystrophy Newborn Screening
Figures and Tables-7 

FIGURE 8: EUNICE KENNEDY SHRIVER INTELLECTUAL AND DEVELOPMENTAL DISABILITY 

RESEARCH CENTERS (IDDRCS), FISCAL YEAR 2008 
Figures and Tables-8 

FIGURE 9: NUMBER OF PROJECTS SUPPORTED BY IDDRC CORES, CATEGORIZED BY PRIMARY 

SOURCE OF FUNDING, FISCAL YEAR 2005 AND FISCAL YEAR 2008 

0

200

400

600

800

1000

1200

1400

2005 2008

Number of Projects

Fiscal Year

Non Government

Government, non NIH

NICHD

NIH (Excludes NICHD)
Figures and Tables-9 

FIGURE 10: FRAGILE X SYNDROME RESEARCH CENTERS (FXSRCS), FISCAL YEAR 2008 
Figures and Tables-10

FIGURE 11: RARE DISEASES COOPERATIVE RESEARCH CONSORTIA (RDCRC): UREA CYCLE 

RARE DISEASE CONSORTIUM, FISCAL YEAR 2008 

Affiliated International Sites (not shown): The Hospital for Sick Children (Toronto, Canada), and 

University Children’s Hospital (Zurich, Switzerland) 
Figures and Tables-11

FIGURE 12: RARE DISEASES COOPERATIVE RESEARCH CONSORTIA (RDCRC): CONSORTIUM 

FOR RARE EPIGENETIC DISORDERS, FISCAL YEAR 2008 
Figures and Tables-12

FIGURE 13: SENATOR PAUL D. WELLSTONE MUSCULAR DYSTROPHY COOPERATIVE 

RESEARCH CENTERS, FISCAL YEAR 2008

Note: Johns Hopkins University is a joint primary site with University of Pennsylvania and is a 

collaborating site with both the Children’s National Medical Center and the Boston Biomedical 

Research Institute. 
Figures and Tables-13

FIGURE 14: AUTISM CENTERS OF EXCELLENCE (ACE) NETWORKS AND CENTERS,

FISCAL YEAR 2008 

For a description of Center and Network projects, please see Table 3 in this document. 
Figures and Tables-14

FIGURE 15: IDD BRANCH TRAINING AND CAREER DEVELOPMENT PORTFOLIO BY 

MECHANISM, FISCAL YEAR 2008

F31

1 Grant

F32

3 Grants

K02

1 Grant

K08

3 Grants

K23

K24 3 Grants

1 Grant

K99/R00

1 Grant

T15

1 Grant

T32

8 Grants

Total = $3.2 Million, 22 Grants 
Figures and Tables-15

TABLE 1: BRANCH PORTFOLIO BY SUPPORT MECHANISM, FISCAL YEAR 2008 

Support Mechanism Number of Projects Funds (U.S. $)

Research Projects (R01, R03, R13, R15, R21, R37) 154 47,304,785

Research Program Projects (P01) 13 14,372,226

Research Centers (P30, P50) 21 28,253,411

Small Business Innovative Research (R42, R43, R44) 16 5,832,415

Research Career Program (K02, K08, K23, K24, K99) 9 1,043,359

National Research Service Awards (F31, F32) 4 157,308

Research Contracts (N01) 6 4,323,233

Training Programs (T15, T32) 9 1,968,589

Cooperative Agreements (U01, U13, U54) 4 3,125,275

Totals 236 106,380,601

TABLE 2: SELECTED RESEARCH OBJECTIVES FROM THE NIH RESEARCH PLAN ON DOWN 

SYNDROME

Research Area 

Short-term Objective 

(0 to 3 Years) 

Medium-term 

Objective 

(4 to 6 Years) 

Long-term Objective 

(7 to 10 Years) 

Pathophysiology of 

Down Syndrome and 

Disease Progression 

Continue testing 

cognitive and synaptic 

function In Down 

syndrome model mice. 

Study whether the 

impact of aging on 

certain processes is 

greater than on others. 

Explore genetic and 

environmental 

determinants of 

cognitive function in 

Down syndrome 

throughout the lifespan.

Diagnosis, Screening, 

and Functional 

Measures 

Identify the cognitive 

phenotype of Down 

syndrome in a cohort 

throughout the lifespan. 

Link human and mouse 

cognitive studies 

relating to Down 

syndrome. 

Develop better 

measures of 

hippocampal and 

cognitive function. 

Treatment and 

Management 

Increase research on 

comorbid psychiatric 

and medical conditions 

throughout the lifespan. 

Continue learning from 

the Alzheimer disease 

research community 

regarding the best 

therapeutics. 

Investigate the impact of 

early intervention on 

psychomotor and 

cognitive development. 

Living with Down 

Syndrome 

Develop a more 

complete demographic 

knowledge base. 

Study real-world 

outcomes for Down 

syndrome families. 

Explore new 

intervention research, 

especially during 

transitional stages. 

Research Infrastructure Improve and expand 

availability of animal 

models. 

Discuss the best 

mechanisms to use in 

fostering crossdisciplinary research. 

Include cohorts of 

people with Down 

syndrome in longitudinal 

studies. 

Please visit http://www.nichd.nih.gov/publications/pubs_details.cfm?from=&pubs_id=5695 for 

the full Research Plan.
Figures and Tables-16

TABLE 3: NIH ACE PROGRAM RESEARCH PROJECTS

(* Indicates primary support from NICHD) 

ACE Center Projects

Site Project(s) Description

University of 

California, 

San Diego

Principal Investigator (PI): Eric Courchesne—Researchers at this ACE Center use brain 

imaging to track brain development in children believed to be at risk for ASDs. Unlike other 

ACE projects, which attempt to identify forerunners of ASD in the siblings of children with 

ASDs, these researchers study infants who were referred by their physicians on the basis 

of behaviors similar to those of older children with ASDs. The primary goal of this research 

is to identify brain or other physical differences that might predispose a child to ASDs. The 

Center is collecting some of the first information ever obtained on how the brains of very 

young children with ASDs process and respond to information.

University of 

California, 

Los 

Angeles* 

PI: Susan Bookheimer—Researchers at this ACE Center seek to understand how ASDs 

affect the ability to communicate. The researchers are looking for clues to languagerelated communication problems by examining genes, behavior, and brain structure and 

function. The researchers are also interested in disorders that affect and ways to stimulate 

mirror neurons, brain cells that become active either when a person performs an action or 

watches the action performed by someone else. When many ASD patients are asked to 

imitate behaviors, neuroimages of their brains show less-active mirror neurons compared 

to those who don’t have ASDs. 

University of 

Illinois* 

PI: Edwin H. Cook—This ACE Center focuses on understanding repetitive behavior or 

“insistence on sameness," a hallmark of ASDs. Examples of this behavior include: wanting 

to wear the same clothes every day, taking the same route to work or school, or becoming 

fixated on a certain subject matter, such as buildings or cars. Center researchers focus on 

genetic factors, brain chemicals, and brain functions that could account for repetitive 

behaviors, and test whether genetic differences influence how individuals respond to 

certain medications intended to reduce the occurrence of these behaviors.

University of 

Pittsburgh* 

PI: Nancy Minshew—This ACE Center studies how people with ASDs learn and 

understand information. Research shows that the ability to organize information into 

categories is critical to language development. These researchers use brain-imaging 

techniques to study how infants at risk for ASDs and toddlers diagnosed with ASDs

categorize information. Researchers also use brain-imaging techniques to study which 

parts of the brain are activated in people with and without ASDs when processing 

information and emotions.

University of 

Washington* 

PI: Bryan King—Researchers at this ACE Center seek to identify genes and other potential 

factors that may predispose an individual toward an ASD, as well as factors that might 

protect against ASDs. In addition to genes, the researchers study the risk of developing an 

ASD by examining communication difficulties, early behaviors, patterns in the sounds 

babies make, and brain structure and activity patterns. Researchers also aim to determine 

whether certain types of interactions between the parent and baby can decrease the 

chances for ASDs. 

Yale 

University

PI: Ami Klin—These researchers study early social interactions and development and 

disruptions in these processes in children ages 12 months to 24 months with ASDs. The 

researchers also aim to identify rare genetic variants that may be involved in ASD in this 

same group of young children. The researchers are using brain-imaging tools to study the 

structure and functioning of connections in the brains of an additional group of 10-year-old 

children with ASDs who have been followed since age 24 months in previous research 

studies. These projects build upon existing research on the behavioral, brain, and 

molecular aspects of ASDs and may lead to new discoveries on causes and treatments. 
Figures and Tables-17

ACE Network Projects

Site Project(s) Description

Drexel 

University

PI: Craig Newschaffer—This Network, which includes Children’s Hospital of Philadelphia, 

Johns Hopkins University, University of California, Davis, and Kaiser Permanente Division 

of Research, studies possible risk factors and biological indicators for ASDs that occur 

during the prenatal, neonatal, and early postnatal periods. Researchers are following

1,200 mothers of children with ASDs at the start of a new pregnancy and will document 

development of the newborn siblings through age 3 years. This study, Early Autism Risk 

Longitudinal Investigation (EARLI), will provide a unique opportunity to study possible ASD

environmental risk factors and biomarkers during different developmental windows, and to 

investigate the interplay of genetic susceptibility and environmental exposure. EARLI 

could investigate environmental exposures ranging from suspected neurotoxins, such as

persistent organic pollutants, to medications taken during pregnancy using data and 

samples collected. The study will also track the natural history and progression of ASDs. 

University of 

California, 

Davis

PI: Sally Rogers—This Network, under the direction of the University of California, Davis, 

will compare intensive behavioral intervention to standard community-based treatment in 

18-to 24-month-old children with ASDs to address the need for controlled studies of 

treatments for autism in very young children. This work builds on previous research 

suggesting that intensive early treatment provided better outcomes than standard 

community-based treatment. This research is examining factors that can inform efforts to 

provide the best treatment outcomes for very young children with ASDs. 

University of 

California, 

Los Angeles

PI: Daniel Geschwind—Researchers in this Network will add to their earlier collaborative 

effort, which produced the Autism Genetic Resource Exchange (AGRE). The group will

recruit 400 additional families with one child affected by an ASD to expand the existing 

data on the relationship between ASD-related genes and physical traits (phenotype). Of 

the additional families, 200 will be of African American descent to determine whether 

African Americans share the same genetic risk factors as those identified in the primarily 

white, European AGRE sample. The researchers also seek to identify rare genetic 

variants, mutations, and abnormalities that affect the risk for ASDs. Studying a large 

population lends greater reliability to the genetic findings, so that the results might be 

applicable to a wider range of children who have ASDs. 

University of 

North 

Carolina, 

Chapel Hill* 

PI: Joseph Piven—Researchers in this Network, operating under the direction of the 

University of North Carolina, will use brain-imaging techniques to compile images of the 

brains of very young infants to identify brain differences among those who have ASDs. 

Brain images of children who later develop ASDs will be compared to those from infants

who did not develop ASDs. Although previous studies documented enlarged brains in 

many individuals with ASDs, little is known about the abnormal processes during early 

brain development in these children. Research findings could offer new insights for earlier 

diagnosis of ASDs.

Wayne State 

University

PI: Diane Chugani—Researchers in this Network are studying the effects of using 

buspirone (Buspar®) to promote more normal growth and development in the brains of

children with ASDs. These children tend to have abnormal levels of the neurotransmitter 

serotonin during important periods of development. Buspirone stimulates serotonin 

production and, in a pilot study by these researchers, improved social interaction and 

reduced repetitive behaviors, sensory dysfunction, and anxiety in children with ASDs. 

Findings from these studies could provide an evidence base for new medication treatments 

for the symptoms of ASDs. 
Figures and Tables-18
Appendices-1 

APPENDIX A: IDD BRANCH PERSONNEL

Gilian Engelson, M.P.H., joined the IDD Branch as a health scientist administrator in December 

2004 to assist Dr. Rodney Howell⊗ with development of the NICHD’s Newborn Screening 

Initiative and to provide programmatic support for IDD Branch grants and contracts related to 

newborn screening. Ms. Engelson received her bachelor’s degree in biology from the University 

of Michigan, Ann Arbor, and her master’s degree in public health, with a focus on public health 

genetics, from Columbia University. At the Maternal and Child Health Bureau of the Health 

Resources and Services Administration (HRSA), she served as a program officer within the 

Genetic Services Branch, where she managed grants for the Sickle Cell Disease and Newborn 

Screening Programs, and for the Regional Genetics and Newborn Screening Collaboratives, 

while also providing administrative assistance to the Secretary’s Advisory Committee on 

Heritable Disorders in Newborns and Children. Prior to her position at HRSA, Ms. Engelson 

worked at the American Cancer Society, Planned Parenthood, and the March of Dimes. Since 

October 2007, Ms. Engelson has worked part-time with the Branch to coordinate the Early 

Detection of Neuromuscular Diseases Conference and other newborn screening activities. 

Alice Kau, Ph.D., joined the IDD Branch as a health scientist administrator in June 2003. Dr. 

Kau is responsible for activities in the Branch’s Biobehavioral Research Program. She also 

serves as a key member of the autism spectrum disorders (ASDs) and behavioral science 

research communities on behalf of the Branch and assists in formulating and planning activities 

of these programs. Dr. Kau received her doctorate degree in developmental psychology from 

Ohio State University and completed a postdoctoral fellowship in clinical psychology in the 

Department of Pediatrics at the Johns Hopkins University School of Medicine. Prior to coming 

to the NICHD, Dr. Kau was an assistant professor/psychologist at the Kennedy Krieger Institute, 

Johns Hopkins University. Dr. Kau serves as the NICHD representative for the NIH Autism 

Coordinating Committee and serves as the NICHD liaison to the Interagency Autism 

Coordinating Committee. She is also the NIH representative on the Department of Defense 

Autism Funding Committee.

Mary Lou Oster-Granite, Ph.D., joined the IDD Branch as a health scientist administrator in 

July 1999. A long-time grantee of the NICHD, Dr. Oster-Granite served as a tenured professor 

of biomedical sciences at the University of California before joining the Branch. As a 

developmental neuroembryologist, neurovirologist, and neurogeneticist, her research interests 

include genetic models of IDD and animal models of Down syndrome and urea cycle disorders 

such as ornithine transcarbamylase deficiency. Her programmatic interests include brain 

function at the cellular/molecular level, developmental neurobiology, neurochemistry, 

neurovirology, molecular genetics, and gene therapy. Dr. Oster-Granite serves as the chair of the 

NIH Down Syndrome Working Group, which drafted the NIH Research Plan on Down 

Syndrome in 2007. 

 

⊗ Dr. Howell, a former member of the National Advisory Child Health and Human Development Council, now 

provides expert guidance for the Institute’s Newborn Screening Initiative and chairs the Secretary’s Advisory 

Committee on Heritable Disorders in Newborns and Children.
Appendices-2

Melissa Parisi, M.D., Ph.D., joined the IDD Branch in October 2008 as chief, after serving as 

assistant professor in the Department of Pediatrics at the University of Washington and Seattle 

Children’s Hospital, where she was active as a clinical geneticist and as a researcher in the field 

of congenital malformations of the human hindbrain. She earned her M.D. degree and her Ph.D. 

in developmental biology from Stanford University, where her research focused on 

mitochondrial transcription. Dr. Parisi completed a pediatric residency at the University of 

Washington, followed by fellowship training in medical genetics. In her clinical practice in the 

states of Washington and Alaska, Dr. Parisi was involved in the evaluation, diagnosis, and 

management of children and adults with genetic syndromes, the majority of whom had major 

congenital defects and/or developmental disabilities, including behavioral disorders such as 

ASDs. In Seattle, she served as the physician leader for the Gender Assessment Team, a 

multidisciplinary team that provides diagnosis and management for infants, children, and 

adolescents with disorders of sex development. She is the former chair of the Scientific 

Advisory Board of the Joubert Syndrome and Related Disorders Foundation.

Tiina Urv, Ph.D., joined the IDD Branch as a health scientist administrator in October 2006. 

Dr. Urv is a developmental disabilities specialist with a Ph.D. from Columbia University and 

25 years of experience working with individuals with IDD in both clinical and research settings. 

Prior to joining the Branch, she was assistant professor at the University of Massachusetts 

Medical School’s Eunice Kennedy Shriver Center and a research scientist at the New York State 

Institute for Basic Research in Developmental Disabilities. The focus of her work has been the 

behavioral aspects of aging and Alzheimer disease in adults with Down syndrome and IDD. Dr. 

Urv’s work in the IDD Branch focuses on behavioral, biobehavioral, and social sciences research 

with a primary focus on Fragile X syndrome (FXS). Dr. Urv serves as the chair for the NIH FXS 

Research Coordinating Group, which developed the Research Plan on FXS and Associated 

Disorders. She also serves as coordinator for the research program in newborn screening and 

manages a diverse portfolio of grants for the IDD Branch related to these efforts.

Ljubisa Vitkovic, Ph.D., joined the Branch as a health scientist administrator in January 2003. 

Dr. Vitkovic manages the Eunice Kennedy Shriver IDD Research Centers Program and the 

NICHD-funded Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Centers. 

He is responsible for neuroscience research related to neurodevelopmental disorders such as 

pediatric seizures, hydrocephalus, neurofibromatosis, spinal muscular atrophy, and tuberous 

sclerosis. Dr. Vitkovic has an M.S. degree in nuclear physics and a doctorate degree in 

biophysics from Michigan State University. Prior to joining the NICHD, he worked for the 

National Institute of Mental Health, National Institute of Allergy and Infectious Diseases, and 

the National Institute of Neurological Disorders and Stroke. He has received numerous awards,

including an NIH Director’s Individual Award, and was nominated for the U.S. Department of 

Health and Human Services Secretary’s Award for Distinguished Service. He was also a 

professor for the French Academy of Sciences in Montpellier, France, and has served as a private 

consultant. Dr. Vitkovic has published more than 50 peer-reviewed scientific articles and edited 

several books. He serves on the editorial boards of Molecular Psychiatry and IDD Research 

Reviews.
Appendices-3 

APPENDIX B: BRANCH FUNDING INITIATIVES,

FISCAL YEAR 2005 THROUGH FISCAL YEAR 2008 

REQUESTS FOR APPLICATIONS (RFAS) 

Title Activity Code Announcement No.

Autism Centers of Excellence R01

P50

RFA-HD-06-004

RFA-HD-06-016

Biomarkers for Neurodegeneration R21 RFA-NS-07-004

Eunice Kennedy Shriver Intellectual and 

Developmental Disabilities Research Centers 

(Formerly Mental Retardation and Developmental 

Disabilities Research Centers)

P30 RFA-HD-09-012

RFA-HD-08-016

RFA-HD-07-012 

RFA-HD-05-030

Facilitating Interdisciplinary Research via 

Methodological and Technological Innovation in 

the Behavioral and Social Sciences 

R21 RFA-RM-07-004

Factors Affecting Cognitive Function in Adults with 

Down Syndrome 

R01 RFA-HD-09-028

Limited Competition for Fragile X Research Center 

Revision Applications 

P30 Supplements RFA-HD-07-013

Identifying Autism Susceptibility Genes R01/ Collaborative R01 RFA MH-05-007

National Research Service Award for 

Interdisciplinary Individual Postdoctoral Fellows for 

Training in Neurodegeneration Research 

F32 RFA-AG-07-004

Senator Paul D. Wellstone Muscular Dystrophy 

Cooperative Research Centers 

U54 RFA-HD-09-027

RFA-NS-08-002

Rare Diseases Clinical Research Consortia for the 

Rare Diseases Clinical Research Network; 

Data Management and Coordinating Center for the 

Rare Diseases Clinical Research Network

U54 RFA-OD-08-001 

RFA-OD-08-002

Recovery Act Limited Competition: Research to 

Address the Heterogeneity in Autism Spectrum 

Disorders 

R01 

Collaborative R01

R21

R34/Collaborative R34

RFA-MH-09-170 

RFA-MH-09-171 

RFA-MH-09-172

RFA-MH-09-173

Short-Term Interdisciplinary Career Enhancement 

Awards for Neurodegeneration Research 

K18 RFA-DC-07-005

Therapeutics Delivery for Neurodegenerative 

Diseases 

R21 RFA-EY-07-001
Appendices-4 

PROGRAM ANNOUNCEMENTS (PAS/PARS/PASS) 

Title Activity Code Announcement No.

Basic and Clinical Research on Rett Syndrome R03 

R21

PA-06-273 

PA-06-274 

Basic and Clinical Research on Rett Syndrome and 

MeCP2 

R01 PAS-07-192

Brain Disorders in the Developing World: Research 

Across the Lifespan 

R01, R21

R21

R01 

R01

R21

PAR-05-100

PAR-06-420

PAR-07-268

PAR-08-112 

PAR-08-113

Data Ontologies for Biomedical Research R01 PAR-07-425

Innovative Therapies and Clinical Studies for

Screenable Disorders

R21 

R01

R03

R03

R21

PAR-06-059 

PAR-06-060

PAR-06-061

PAR-06-341

PAR-06-342

Muscular Dystrophy: Pathogenesis and Therapies R01, R21

R21 

R01

PA-05-038

PA-06-508 

PA-07-125

Psychosocial/Behavioral Interventions and 

Services Research in Autism Spectrum Disorders 

R34 PA-07-343

Research on Autism and Autism Spectrum 

Disorders 

R01 

R03

R21

R01

PA-06-390 

PA-06-391

PA-06-392

PA-07-085

Research to Advance Vaccine Safety R01

R21

PA-08-256

PA-08-257

Shared Neurobiology of Fragile X Syndrome and 

Autism 

R01, R03, R21 

R03

R21

R01

PA-05-108

PA-06-429

PA-06-430

PA-07-284

Sharing Data and Tools: Federation using the BIRN 

and caBIG Infrastructures 

R01 PAR-07-426

Exploratory/Developmental Program for 

Translational Research in Muscular Dystrophy

R21 PAR-06-203

Understanding and Treating Ataxia Telangiectasia R01

R21

R03

PA-07-272

PA-07-273

PA-07-274
Appendices-5 

NOTICES (NOT)

Title Type Number

Acquisition, Processing, Preservation, and 

Distribution of Human Tissues to Advance 

Understanding and Treatment of Developmental 

Disabilities

Request for Information 

(RFI)

NOT-HD-09-005

Research Priorities in Fragile X Syndrome, Fragile 

X Tremor Ataxia Syndrome, Premature Ovarian 

Failure and Other Relevant Conditions Associated 

with FMR1 Gene Function

RFI NOT-HD-08-003
Appendices-6 

APPENDIX C: EXPERT PANEL MEMBERS

Don Bailey, Ph.D. 

Distinguished Fellow 

RTI International, Inc. 

Research Triangle Park, North Carolina 

Mark L. Batshaw, M.D. 

Chief Academic Officer

Children’s Research Institute (CRI) 

George Washington University 

Professor and Chairman, Pediatrics

Associate Dean, Academic Affairs

Children’s National Medical Center

Washington, D.C. 

Susan A. Berry, M.D. 

Professor and Director 

Division of Genetics and Metabolism 

Department of Pediatrics 

University of Minnesota 

Minneapolis, Minnesota 

Frances E. Jensen, M.D. 

Professor of Neurology 

Children’s Hospital, Boston 

Boston, Massachusetts

*Priya Kishnani, M.D.

Professor, Department of Pediatrics-Medical 

Genetics

Duke University Medical Center

Durham, North Carolina 

Ian D. Krantz, M.D. 

Associate Professor of Pediatrics 

Division of Human Genetics 

Children’s Hospital of Philadelphia 

Philadelphia, Pennsylvania 

*COL David S. Louder, III, M.D. 

U.S. Air Force 

Materiel Command Director, Medical 

Operations 

Air Force Medical Operations Agency 

Bolling Air Force Base

Washington, D.C. 

Jana Monaco 

Parent

Woodbridge, VA 

Richard T. Moxley, III, M.D. 

Associate Chair for Academic Affairs 

Professor of Neurology and Pediatrics 

Helen Aresty Fine and Irving Fine Professor 

of Neurology 

Director, Neuromuscular Disease Center 

University of Rochester School of Medicine 

and Dentistry 

Rochester, New York 

Andy Shih, Ph.D. 

Vice President

Scientific Affairs 

Autism Speaks 

New York, New York

Steven F. Warren, Ph.D. 

Vice Provost for Research and Graduate 

Studies 

Professor of Applied Behavioral Science 

Office of Research and Graduate Studies 

University of Kansas 

Lawrence, Kansas

* Denotes NACHHD Council Member 
Appendices-7 

APPENDIX D: BRANCH-SPONSORED CONFERENCES AND WORKSHOPS

2005 

Clinical Trials in Rett Syndrome, June 24-28, 2005 

The goal of this conference was to form an international alliance that would conduct clinical 

trials and early interventions in Rett syndrome with sufficient numbers of participating 

individuals to make the clinical studies valid. The workshop objectives included: an assessment 

of the current state-of-the-art research in diagnosis, treatment, clinical trials, and early 

interventions in Rett syndrome; identification of areas of limited knowledge in Rett syndrome; 

development of recommendations for future clinical research in Rett syndrome; and recruitment 

of researchers from different disciplines at all levels of training to the field of Rett syndrome 

research, diagnosis, and treatment. 

Expert Panel Work Group on New Tests and Technologies in Newborn Screening, 

July 28-29, 2005 

In 2005, the American College of Medical Genetics issued a report recommending conditions 

considered scientifically and medically appropriate for inclusion in state newborn screening 

programs (available at http://mchb.hrsa.gov/screening). This report further highlighted issues 

surrounding the need to inform the newborn screening community about new technologies 

emerging from industry and academia that might have applicability to newborn screening, 

especially with many states lacking significant research capabilities and operating their programs 

somewhat independently of one another. This work group was formed as a mechanism to 

respond to this particular issue. 

Muscular Dystrophy Coordinating Committee (MDCC) Scientific Working Group, 

August 16-17, 2005 

The Muscular Dystrophy Community Assistance, Research, and Education Amendments of 

2001, also called the MD-CARE Act (P.L. 107-84), authorized establishment of the MDCC to 

develop a plan for research and education on muscular dystrophy. Comprising representatives 

from Institutes and Centers with research involvement in the muscular dystrophies, other federal 

agencies and centers, advocacy groups, and public members, the MDCC held a two-stage 

planning process. The first stage resulted in the MDCC Research and Education Plan for NIH 

(available at http://www.ninds.nih.gov/find_people/groups/mdcc/MD_Plan_submitted.pdf), 

which provided broad guidelines for the NIH on research priorities for the muscular dystrophies 

and was submitted to congress in August 2004. Convening the MDCC Working Group, which 

developed the Action Plan for Muscular Dystrophies (available at 

http://www.ninds.nih.gov/find_people/groups/mdcc/MDCC_Action_Plan.pdf) with specific 

objectives for coordination of research in muscular dystrophies, was the second stage of this 

process. 

Annual Baby Siblings Research Consortium Meeting, August 24-26, 2005

This collaboration, formed in 2003 between the NICHD and the National Alliance for Autism 

Research, now part of Autism Speaks, is a consortium comprised of researchers investigating

autism spectrum disorders (ASDs) among the infant siblings of those diagnosed with ASDs, a 
Appendices-8 

group considered to be at high risk for developing these conditions. The goal of the consortium 

is to identify behavioral and biological markers for ASDs that enable clinicians to make more 

definitive diagnoses in children at younger ages. The initial meeting occurred in August 2004 

with the purpose to finalize plans for the initial project focused on head circumference and brain 

volume in children with ASDs, and this second meeting extended that original purpose to 

develop additional collaborative projects. 

Access to Quality Testing for Rare Diseases, September 26-27, 2005 

Although individually rare, rare diseases and conditions collectively affect a significant portion 

of the population. The majority of the 6,000 to 7,000 rare diseases known today are viewed as

genetic conditions, making genetic testing an essential element for the diagnosis and 

management of the patients and their families. However, the development of tests for rare 

genetic diseases has not keep pace with the progress of knowledge about the genetic bases of rare 

diseases. This conference sought to raise national awareness of the growing public need to 

improve the availability, quality, and accessibility of genetic testing for rare diseases, and to 

promote development of multiple processes and models to enhance the translation of genetic 

tests from research to clinical practice. 

Workshop on Diet, Nutrition, and Dietary Supplement Use in ASDs: Evaluation of the 

Evidence, October 6, 2005 

Research to document the occurrence of dietary deficiencies or to support the efficacy of dietary 

intervention in individuals with ASDs has been limited. The purpose of this workshop was to 

discuss ways of encouraging evaluation of various dietary and non-traditional biomedical 

supplements to provide the necessary evidence in support of meaningful policies addressing their 

use. Participants at the workshop included diverse experts in dietary supplement research, 

evidence-based research, and ASDs. 

2006 

Mental Retardation and Developmental Disabilities Research Centers (MRDDRC) 

Program: Planning for the Fiscal Year 2007 Hiatus & Beyond, June 9, 2006 

In 2006, the MRDDRC Program (now the Eunice Kennedy Shriver IDD Research Centers 

Program) funded P30 grants at 14 universities across the country to provide infrastructure for 

independently funded research to ameliorate IDD. For each of four years of the five year cycle, 

three to four existing and several new centers compete for P30 grants. In fiscal year 2007, a 

hiatus in competition allowed the Branch to convene this workshop to discuss potential changes 

in the Program. Leaders in research on IDD and developmental biology, several of the existing

MRDDRC directors, and members of the advocacy community met with NICHD staff to discuss 

the evolution of the Program and ideas for the future. 

Strengthening Newborn Screening in the Middle East and North Africa (MENA), 

November 15-17, 2006 

Health care providers in the MENA region expressed interest in developing newborn screening 

programs in their areas, particularly because birth defects and genetic diseases have become an 

increasingly larger public health issue as the infant mortality rate due to infections has declined. 
Appendices-9 

Given the high proportion of consanguineous marriages in many of these countries, there is 

growing recognition of the value of newborn screening and the role it plays in preventing or 

ameliorating disabilities resulting from genetic conditions amenable to screening, particularly 

those with simple and relatively inexpensive treatments available. This conference brought 

together an international group of experts in the field of newborn screening from countries in the 

MENA region, Europe, and the United States. The conference summarized the current state of 

newborn screening in the region and outlined areas for future collaboration and knowledgesharing in the Marrakech Declaration (see Appendix F). For additional information about this 

meeting, visit http://www.nichd.nih.gov/about/meetings/2006/mena.cfm. 

2007 

Gatlinburg Conference: Down Syndrome: Genes, Brain, and Behavior, March 7-9, 2007 

The Gatlinburg Conference represents one of the premier conferences in the United States for 

behavioral scientists conducting research in IDD. The theme for the 2007 conference was Down 

syndrome, the leading genetic cause of IDD in the United States. Because research on Down 

syndrome has achieved a level of “maturity” with regard to the multidisciplinary approaches 

investigators have developed to study the causal pathways from genes to behavior, it has become

a model for planning investigations into less well-understood genetic conditions associated with 

IDD. The Gatlinburg conference reflected this multidisciplinary approach to understanding 

Down syndrome with invited speakers from all disciplines relevant to understanding the causes, 

consequences, life-course trajectories, and environmental circumstances in this condition. 

Smith-Lemli-Opitz Syndrome and Inborn Errors of Cholesterol Synthesis, June 27-29, 

2007 

The goal of this meeting was to promote interactions between scientists with expertise in 

cholesterol homeostasis, brain cholesterol metabolism, embryonic development, and oxysterol 

and neurosteroid biology with clinician-scientists studying and treating patients with inborn 

errors of cholesterol synthesis. It was anticipated that these interactions would lead to 

collaborative projects that will ultimately improve understanding and treatment of these genetic 

disorders. 

Down Syndrome Expert Meeting: Factors that Affect Cognitive Function in Down 

Syndrome throughout the Lifespan, July 12-13, 2007 

The NIH Working Group on Down Syndrome convened experts in Down syndrome research and 

related fields, advocacy community members, and members from other federal organizations 

with relevant research or funding programs (i.e., Centers for Disease Control and Prevention) to 

focus on the state of the science relative to Down syndrome research. This meeting provided a 

forum for discussion of future research directions and priorities for Down syndrome research in 

preparation for the creation of the NIH Research Plan on Down Syndrome (available at 

http://www.nichd.nih.gov/publications/pubs_details.cfm?from=&pubs_id=5695). Broadly 

identified areas of research focus included: medical issues, behavioral and family issues, clinical 

trials, and research infrastructure. 
Appendices-10

Expert Workshop on the Biology of Chromosome 21 Genes, September 28-October 2, 2007 

This meeting, an international assembly of experts on Down syndrome convened every two or 

three years with partial NICHD support, brought together experts to discuss recent progress in 

understanding the impact of specific genes and metabolic and molecular pathways on the 

etiology and pathogenesis of Down syndrome. Investigators reflected a collaborative spirit in 

sharing resources, data, and biological specimens to further understand relevant genes on 

chromosome 21. Topics of discussion included the integration of pathway approaches to 

understanding specific developmental defects, the influence of specific genes located on other 

chromosomes whose expression is impacted by triplication of genes on chromosome 21, the 

development of new partial trisomic mouse models for Down syndrome, and observations from 

studies of humans with either complete or partial trisomy 21.

2008 

Second Conference of the MENA Newborn Screening Initiative: Partnerships for 

Sustainable Newborn Screening Infrastructure and Research Opportunities, 

April 12-14, 2008 

More than 30 policy makers, health care providers, health ministry representatives, experts, and 

family and advocacy representatives from 17 countries in the MENA region, Europe, Asia, and 

North America attended this second meeting of the MENA Newborn Screening Working Group. 

The primary outcome of the meeting was the development of National Plans of Action for 

implementation of newborn screening programs in each of the participating countries. These 

National Plans detailed newborn screening program leadership, blood spot collection and 

storage, laboratory methods, and linkage to treatment and follow-up. An article summarizing 

these issues was published (Krotoski et al, 2009, Genet Med, Sep;11(9):663-668). Visit 

http://www.nichd.nih.gov/about/meetings/2008/mena2.cfm for additional information. 

Outcome Measures for Clinical Trials with Children with Fragile X Syndrome (FXS), May 

8-9, 2008

This meeting was a collaborative effort between the IDD Branch and the Obstetric and Pediatric 

Pharmacology Branch within NICHD, in support of Best Pharmaceuticals for Children Act 

activities to describe outcome measures for safety and efficacy when treating children with FXS; 

assess validation of those measures for clinical studies; and describe approaches for preclinical 

toxicology studies to define efficacy and safety. The goal of the meeting was to develop 

recommendations related to outcome measures for clinical trials in children with FXS. A followup meeting to develop a white paper is planned for late 2009. 

2009 

Early Detection and Screening of Neuromuscular Diseases Conference, March 16-17, 2009 

The NICHD, in conjunction with other NIH Institutes and Centers, federal agencies, and 

advocacy groups, organized this 11⁄2-day workshop with a diverse group of invitees, including 

experts in the fields of neuromuscular disease research, bioethics, and newborn screening. The 

goals of the conference were to assess the status of neuromuscular diseases in terms of their 
Appendices-11

readiness for early detection and screening; share the qualifying parameters for consideration for 

early detection and screening; and determine the needs of the neuromuscular disease 

communities and the required opportunities (fiscal and intellectual) needed to support the quest 

to screen for these conditions. Visit http://www.nichd.nih.gov/about/meetings/2009/031609.cfm

for more information.

The First International Conference on Hyperphagia, June 5, 2009

This unique conference crossed boundaries between clinical and research disciplines and 

syndromes to help participants, including researchers, clinicians, and family and advocacy 

members, better understand hunger, the drive to overeat, and obesity associated with certain IDD 

conditions. Speakers included recognized experts in five distinct conditions associated with 

hyperphagia: Prader-Willi syndrome, Bardet-Biedl syndrome, Alström syndrome, WAGR 

syndrome (characterized by Wilms’ tumor, aniridia, genitourinary anomalies, mental 

retardation), and a subset of individuals with FXS. Objectives included discussion of the similar 

and unique clinical features of the hyperphagia disorders, criteria to facilitate more accurate and 

earlier diagnosis, management issues, and family and quality-o- life issues. The meeting 

promoted collaboration among participants with diverse professional and personal experiences 

but with a shared challenging clinical issue. 

Third International Conference on Urea Cycle Disorders, August 27-28, 2009, and the 

Society for Inherited Metabolic Disorders (SIMD) 32nd Annual Meeting, August 29-

September 2, 2009

NICHD, in cooperation with the NIH Office of Rare Disorders Research, provided primary 

support for the 2009 SIMD meeting, which was held in conjunction with the 11th International 

Congress of Inborn Errors of Metabolism. The Third International Conference on Urea Cycle 

Disorders, a jointly sponsored satellite meeting that preceded the SIMD meeting, focused on the 

theme of understanding urea cycle disorders and catalyzing research collaborations. In part 

because of new technologies for and expanded programs in newborn screening, a broader clinical 

and molecular spectrum of inherited metabolic disorders is being elucidated with more affected 

individuals than previously appreciated. The SIMD’s mission is to promote the advancement of 

research, training, and medical treatment of inherited metabolic disorders. At the annual SIMD 

meeting, researchers review the current state of metabolic disorders with regard to underlying 

etiology, diagnostic evaluation, management, and development of new therapies. 
Appendices-12

APPENDIX E: BRANCH-SUPPORTED TRAINING AND CAREER DEVELOPMENT 

GRANTS, FISCAL YEAR 2005 THROUGH FISCAL YEAR 2008 

PREDOCTORAL INDIVIDUAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS) (F31S) 

• Predoctoral Fellowships for Students with Disabilities, University of California, Los Angeles 

(UCLA), California (2005, 2006) 

• Predoctoral Fellowships for Students with Disabilities, Virginia Commonwealth University, 

Virginia (2005) 

• A Longitudinal Study: Adaptations of Families with Children with Developmental 

Disabilities, Arizona State University, Arizona (2007, 2008) 

POSTDOCTORAL INDIVIDUAL NRSAS (F32S) 

• Visual Object Representation in Williams Syndrome, Johns Hopkins University, Maryland 

(2005) 

• Mouse Models of Down Syndrome, Johns Hopkins University, Maryland (2005) 

• Identifying Down Syndrome Heart Defect Candidate Genes, Emory University, Georgia 

(2005, 2006) 

• Fragile X Repression of Localized mRNA Translation, University of Pennsylvania, 

Pennsylvania (2005, 2006) 

• Analysis of Regional Cortical Development Genes, Beth Israel Deaconess Medical Center, 

Massachusetts (2005, 2006) 

• ERK Regulation of Hippocampal Potassium Channels, Baylor College of Medicine, Texas

(2005) 

• Analysis of Genomic Imprinting at the Ube3a Locus, Baylor College of Medicine, Texas 

(2005, 2007) 

• fMRI of Serotonergic Genetic Variation in Autism, University of Florida, Florida (2005, 

2006) 

• Migration of Cajal-Retzius Cells, University of California, San Francisco, California (2005, 

2006, 2007) 

• CK2 Regulation of Fragile X in Circadian Clocks, Northwestern University, Illinois (2006) 

• Laminopathy Treatment with Farnesyltransferase Inhibitors, UCLA, California (2006, 2007) 

• Hindbrain Dysgenesis in Rett Syndrome and Other Autism Spectrum Disorders, University 

of California, Davis, California (2007, 2008) 

• Retrograde Transport at the Crossroads of Cognitive Decline and Neurodegeneration, 

Stanford University, California (2007, 2008) 

• Neural Substrate for Language and Social Cognition: Autism and Typical Development, 

Massachusetts Institute of Technology, Massachusetts (2008) 
Appendices-13

RESEARCH SCIENTIST DEVELOPMENT AWARD (K02) 

• Neural Substrates of Socioemotional Development, Georgetown University, Washington, 

D.C. (2005, 2006, 2007) 

• Self-Injury: Pain and Stress Mechanisms, University of Minnesota, Twin Cities, Minnesota 

(2006, 2007, 2008) 

CLINICAL INVESTIGATOR AWARDS (K08S) 

• Attention in Children with the 22q11 Deletion Syndrome, Rockefeller University, New York 

(2005) 

• COX-2 and Injury in the Immature Brain, Children’s Hospital of Pittsburgh/University of 

Pittsburgh Medical Center, Pennsylvania (2005) 

• Chromosome Analysis in Single Cells, Mount Sinai School of Medicine of New York 

University, New York (2005) 

• Chromosome Analysis in Single Cells, Columbia University Medical Center, New York 

(2005, 2006, 2007) 

• Effects of Inflammation on Developing Glia, Children’s National Medical Center, 

Washington, D.C. (2005, 2006, 2007) 

• In Vivo Substrate Utilization in Newborn Rat Brain, University of Minnesota, Twin Cities, 

Minnesota (2005, 2006) 

• Cohesin Complex and Cornelia de Lange Syndrome, Children’s Hospital of Philadelphia, 

Pennsylvania (2007, 2008) 

• The Immune Response to Viral Vectors and Transgenes in Fetus, UCLA, California (2007, 

2008) 

• Mitochondria, Superoxide, and MnSOD in Fetal Cerebral Palsy Model, Evanston 

Northwestern Healthcare Center, Illinois (2008) 

MENTORED PATIENT-ORIENTED RESEARCH CAREER DEVELOPMENT AWARDS (K23S) 

• Clinical Phenotype of Imprinted Genes on Chromosome 15, Baylor College of Medicine, 

Texas (2005) 

• Predicting Severe Neonatal Hyperbilirubinemia, Children’s Hospital of Philadelphia, 

Pennsylvania (2005, 2006, 2007) 

• Identification of Genes Responsible for X-Linked Mental Retardation, Johns Hopkins 

University, Maryland (2005, 2006, 2007) 
Appendices-14

• Attentional Dysfunction in Children with Phenylketonuria, University of Rochester, New 

York (2005, 2006, 2007, 2008) 

• Identification and Management of Developmental Delays, Case Western Reserve University, 

Ohio (2005, 2006, 2007) 

• Elucidation of the Genetic Etiology of Costello Syndrome, University of California, San 

Francisco, California (2005, 2006, 2007, 2008) 

• Identification and Management of Developmental Delays, Boston Medical Center, 

Massachusetts (2007, 2008) 

MIDCAREER INVESTIGATOR AWARD IN PATIENT-ORIENTED RESEARCH (K24) 

Genetic Analyses of Cerebellar Malformations, University of Washington, Seattle, Washington 

(2005, 2006, 2007, 2008) 

CAREER TRANSITION AWARD (K99/R00) 

Epigenetic Mechanisms of X-Chromosome Inactivation, University of North Carolina, Chapel 

Hill, North Carolina (2007, 2008) 

CONTINUING EDUCATION TRAINING GRANT (T15) 

Course in Medical and Experimental Mammalian Genetics, Jackson Laboratories, Maine (2005, 

2006, 2007, 2008) 

INSTITUTIONAL NRSAS (T32S)

• Mental Retardation and Developmental Disabilities, UCLA, California (2005, 2006, 2007, 

2008) 

• Mental Retardation and Developmental Disabilities, Mt. Sinai School of Medicine, New 

York (2005, 2006, 2007) 

• Genetics and Genomics of Human Disease, Yale University, Connecticut (2005, 2006, 2007, 

2008) 

• Behavioral Research Training in Intellectual/Developmental Disabilities, Vanderbilt 

University, Tennessee (2005, 2006, 2007, 2008) 

• Training in Mental Retardation/Developmental Disabilities, University of Miami, Florida 

(2005, 2006, 2007, 2008) 

• Postdoctoral Training in Mental Retardation Research, University of Wisconsin, Madison, 

Wisconsin (2005, 2006, 2007, 2008) 
Appendices-15

• Postdoctoral Research in Neurodevelopmental Disorders, University of North Carolina, 

Chapel Hill, North Carolina (2005, 2006, 2007, 2008) 

• Research Training in Mental Retardation, University of Notre Dame, Indiana (2006, 2007, 

2008) 

• Postdoctoral Training in Developmental Disabilities Research, Children’s National Medical 

Center, Washington, D.C. (2006, 2007, 2008) 
Appendices-16

APPENDIX F: MARRAKECH DECLARATION 

STRENGTHENING NEWBORN SCREENING IN THE MIDDLE EAST AND NORTH AFRICA 

CONFERENCE

November 15, 2006 

The international community has achieved important advances in infant survival and the 

reduction of neonatal mortality. As a consequence, in view of the United Nation’s Convention 

on the Rights of the Child (1989), governments must now focus increased attention on assuring 

our children’s optimal development and to put in place policies to ensure that tomorrow’s adults 

are as free as possible from disability that will limit achieving their potential. This is facilitated 

by early screening for congenital genetic disorders that are responsible for major disability; if not 

treated early, the costs of treatment of preventable disability will be prohibitive for society and 

the lives of children and their families will be tragically and unnecessarily limited. Systematic 

newborn screening for these genetic disorders is, thus, a necessity for public health programs 

based on the resources available. 

Participants of the first meeting of Strengthening Newborn Screening in the Middle East and 

North Africa recognize that our children’s health is a high priority for our countries. Newborn 

screening is an important tool in the prevention of disease and disability in our children and thus 

should be a key part of a comprehensive public health system in all of our countries. Each 

country should prioritize the panel of genetic disorders and system of care that is appropriate to 

their situation. 

Based on the meeting’s deliberations, the following recommendations have received high 

priority:

• Encourage all countries to develop policies and provide necessary support to establish a 

systematic national newborn screening program within the context of a global national policy 

for children's health that will provide access to all newborn infants in these countries and 

provide follow-up services. Such services should integrate both public and private health 

care delivery systems. 

• All countries in the region should screen for at least one condition and develop a national 

model program that takes into account all aspects for post-testing care. 

• Establish national research priorities around newborn screening, through culturally relevant 

and ethical strategies. 

• Reduce disability and death by assuring that the children identified as having screened 

positive for a genetic disorder have the opportunity to a good quality of life through access to 

medical treatment including behavioral, physical therapeutic interventions as well as assistive 

technology in order to preserve healthy development and improve autonomy and 

independence. 

• Develop population studies to determine the incidence of genetic disorders in the region and 

consider linking to national databases with standardized measurements. Clearly population 
Appendices-17

genetic data needs to be accumulated country by country as it is anticipated that each country 

will have unique disorders related to their own population. 

• Begin regionalization and cooperation among countries by sharing of expertise, information, 

and other resources. 

• Develop training programs that focus on role-specific activities that build the 

interdisciplinary teams needed for newborn screening systems of care. 

• Stimulate regional research capacity that addresses the specific conditions of priority to the 

Middle East and North Africa. 

In view of all of the above recommendations, the attendees recognize the need for establishment 

of collaborative, cooperative networking to facilitate the development of a newborn screening 

system for all nations. 

To develop such a collaborative network it would be of value to: 

• Hold annual meetings to assess country advances 

• Develop smaller focused meetings on issues of particular importance (e.g., training) 

• Establish structures for increased communication across the region including a regional Web 

site and biennial regional meetings. 

• Establish an advisory committee to set up an agenda for addressing the recommendations 

identified above. 

• Establish working groups that can implement identified priorities. 
Appendices-18