Neurological Measures of Progression in Children With Friedrich Ataxia
Conditions: Friedreich Ataxia
Sponsor: Children's Hospital of Philadelphia

 
 
Protocol No. 17-014390 
 
 
Title: 
Neurological Measures of Progression in Children with 
Friedreich Ataxia  
Protocol No: 
NCT Number: 
17-014390 
NCT03418740 
Protocol Date: 
November 2021 
Site Principal Investigator          David R. Lynch, MD, PhD 
 
 
 
 

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 Protocol No. 17-014390 
 
 
TABLE OF CONTENTS 
Table of Contents .............................................................................................................. ii 
Abbreviations and Definitions of Terms ..........................................................................iv 
Abstract ............................................................................................................................. v 
1 
BACKGROUND INFORMATION AND RATIONALE ................................................... 1 
1.1 
INTRODUCTION ....................................................................................................... 1 
1.2 
COMPLIANCE STATEMENT ....................................................................................... 2 
1.3 
RELEVANT LITERATURE AND DATA ........................................................................... 2 
2 
STUDY OBJECTIVES ................................................................................................. 2 
2.1 
PRIMARY OBJECTIVE (OR AIM) ................................................................................. 2 
2.2 
SECONDARY OBJECTIVES (OR AIM) .......................................................................... 2 
3 
INVESTIGATIONAL PLAN .......................................................................................... 2 
3.1 
GENERAL SCHEMA OF STUDY DESIGN ..................................................................... 2 
3.1.1 Screening Phase ............................................................................................... 3 
3.1.2 Assessment Phase ............................................................................................ 3 
3.1.3 Study Visit ......................................................................................................... 3 
3.1.4 Case Ascertainment .......................................................................................... 4 
3.1.5 Data sources ..................................................................................................... 4 
3.2 
CONTROLS AND BLINDING ....................................................................................... 4 
3.3 
STUDY DURATION, ENROLLMENT AND NUMBER OF SITES .......................................... 4 
3.3.1 Duration of Study ............................................................................................... 4 
3.3.2 Total Number of Study Sites/Total Number of Subjects Projected ..................... 4 
3.4 
STUDY POPULATION ............................................................................................... 4 
3.4.1 Inclusion Criteria ................................................................................................ 4 
3.4.2 Exclusion Criteria .............................................................................................. 5 
4 
STUDY PROCEDURES ............................................................................................... 5 
4.1 
NEUROLOGICAL OUTCOME MEASURES .................................................................... 5 
4.2 
BLOOD DRAW ......................................................................................................... 6 
4.3 
BUCCAL SWAB COLLECTION .................................................................................... 7 
4.4 
MAGNETIC RESONANCE IMAGING (MRI) MUSCLE PHENOTYPING ................................ 7 
4.5 
MEP MEASUREMENTS ............................................................................................ 8 
4.6 
ABSTRACTED DATA ELEMENTS ................................................................................ 9 
4.7 
PRIMARY AND SECONDARY ENDPOINTS ................................................................... 9 
4.8 
STATISTICAL METHODS ..........................................................................................10 
4.9 
SAMPLE SIZE AND POWER ......................................................................................11 
5 
STUDY ADMINISTRATION ........................................................................................11 
5.1 
DATA COLLECTION AND MANAGEMENT ....................................................................11 
5.2 
REGULATORY AND ETHICAL CONSIDERATIONS.........................................................12 
5.2.1 Risk Assessment ..............................................................................................12 
5.2.2 Potential Benefits of Study Participation ...........................................................13 
5.2.3 Risk-Benefit Assessment ..................................................................................13 
5.3 
RECRUITMENT STRATEGY ......................................................................................13 
5.4 
INFORMED CONSENT/ASSENT.................................................................................13 
5.5 
PAYMENT TO SUBJECTS/FAMILIES ..........................................................................13 
5.6 
CONFIDENTIALITY ..................................................................................................14 

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6 
PUBLICATION ...........................................................................................................14 
7 
REFERENCES ...........................................................................................................14 
Appendix ..........................................................................................................................16 

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ABBREVIATIONS AND DEFINITIONS OF TERMS 
9HPT 
ADL 
BBS 
CCFS 
CHOP 
CrCEST 
CRF 
DM 
FRDA 
FACT 
FARS 
HRQOL 
LCSLC 
LiSN-S 
MEP 
MLPA 
MRI 
MRS 
MSQLI 
NAF 
OXPHOS 
PedsQL 
T25W 
TMS 
TUG 
SDU 
UCLA 
 
 
 
Nine Hole Peg Test 
Activities of Daily Living  
Berg Balance Scale 
Composite Functional Cerebellar 
Children’s Hospital of Philadelphia 
Creatine Chemical Exchange Saturation Transfer 
Case Report Form 
Diabetes Mellitus 
Friedreich’s Ataxia 
Friedreich’s Ataxia Composite Test 
Friedreich’s Ataxia Rating Scale 
Health-related Quality of Life 
Low Contrast Sloan Letter Charts 
Listening in Spatialized Noise – Sentences test 
Motor Evoked Potentials 
Multiplex Ligation-dependent Probe Amplification 
Magnetic Resonance Imaging 
Magnetic Resonance Spectroscopy 
Multiple Sclerosis Quality of Life Inventory 
National Ataxia Foundation 
Oxidative Phosphorylation 
Pediatric Quality of Life 
Timed 25’ Walk 
Transcranial Magnetic Stimulation 
Timed Up and Go 
Standard Deviation Units 
University of California Los Angeles  
 
 
 
 
 
 
 

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 Protocol No. 17-014390 
 
 
 
ABSTRACT 
Context: Friedreich's ataxia (FRDA) is a rare autosomal recessive degenerative disorder 
characterized by ataxia, dysarthria, sensory loss, diabetes and cardiomyopathy. The 
discovery of the abnormal gene in FRDA and its product (frataxin) has provided insight into 
possible pathophysiological mechanisms and novel approaches to treatments in this 
disease. New therapies based on prevention of oxidant damage from abnormal 
mitochondrial function improve surrogate markers of disease such as muscle spectroscopy 
and echocardiography. While such methods for assessing disease progression may be 
useful, evaluation in clinical trials will require specific clinical outcome measures. Until 
recently, quantitative tools for clinical assessment of FRDA have been unavailable. For the 
past 10 years this group of investigators has collaborated on development of clinical 
measures that can quantitatively assess FRDA, particularly in children (1). While a large 
amount of measure refinement remains to be performed, the data from their collaboration 
provide a framework for further investigation and for creating a network for performing 
further clinical and translational research including clinical trials. 
Objectives: To advance clinical care, research and therapeutic approaches in FRDA 
through the development and validation of clinical outcome measures in FRDA, collection of 
quantitative serial clinical data on patients and expansion of our established research 
network. A secondary aim is to investigate frataxin dipsticks (buccal cells swabs and blood 
samples) designed to measure frataxin protein. A third objective is to define the progression 
of physiological dysfunction in affected tissues in FRDA. The study aims to quantify 
impaired skeletal muscle oxidative phosphorylation (OXPHOS) using a magnetic resonance 
imaging (MRI) protocol to assess post-exercise creatine chemical exchange saturation 
transfer (CrCEST) and to understand changes in motor evoked potentials (MEP) in subjects 
with FRDA.  
Study Design/Setting/Participants: This study will primarily take place at the Children’s 
Hospital of Philadelphia (CHOP), with a select number of subjects only participating in the 
clinical testing at the University of Florida and University of California Los Angeles (UCLA). 
We expect to recruit approximately 110 children across all three sites and study each of 
them over a 3 year period. Children with a genetically or clinically confirmed diagnosis of 
FRDA will be offered participation.  
Study Measures: For all 110 participants there will be biyearly assessments of a core set of 
clinical measures and quality of life assessment measures. These include: Friedreich’s 
Ataxia Rating Scale (FARS), timed 9-Hole Peg Test (9HPT), Timed 25 Foot Walk (T25FW), 
Pediatric Quality of Life questionnaire (PedsQL), Activities of Daily Living (ADL) scales, 
Ataxia disability score, and two extended walking tests for 1 minute and 6 minutes. Also 
included are the Timed up and go (TUG), Berg Balance scale (BBS), 2 tests of the 
Composite Functional Cerebellar (CCFS), electronic pegboard, and the click test. At each 
visit, whole blood and buccal swab samples will be obtained to monitor frataxin levels.   
12 of the study participants at CHOP will undergo annual MRI scan testing for the CrCEST 
protocol in addition to the core set of tests listed above.  
30 of the study participants at CHOP will have annual MEP measurements using 
transcranial magnetic stimulation (TMS) in addition to the core set of tests listed above. 

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Protocol No. 17-014390 
 
 
 
1 
BACKGROUND INFORMATION AND RATIONALE 
1.1 
Introduction 
Friedreich's ataxia (FRDA) is a rare autosomal recessive degenerative disorder 
characterized by ataxia, dysarthria, sensory loss, diabetes and cardiomyopathy. FRDA is a 
progressive neurodegenerative disorder with a prevalence of about 1 in 50,000 persons in 
the United States. The discovery of the abnormal gene in FRDA and its product (frataxin) 
has provided insight into possible pathophysiological mechanisms in this disease (1-3). An 
expanded GAA triplet repeat is found in both alleles of the FRDA gene in 97% of people 
with FRDA. This triplet repeat is located within an intron, leading to decreased RNA 
transcription and decreased levels of frataxin. While the basic-science-related 
understanding of FRDA has advanced rapidly, translational and clinical research has 
moved much more slowly. This reflects two aspects of FRDA. First it is uncommon—even 
large academic medical centers may only follow 10- 20 patients with this disorder. This 
requires that, in any clinical or translational study, multiple centers collaborate and assess 
patients in a coordinated manner. Secondly, until recently, quantitative tools for clinical 
assessment of FRDA have been unavailable. This has limited the ability of translational 
approaches to move forward and the initiation of therapeutic trials. Using recent support 
from the MDA and FARA, a group of investigators collaborated on development of clinical 
measures that can quantitatively assess FRDA (4). While a large amount of measure 
refinement remains to be performed, the data from their collaboration provides a framework 
for further investigation and for creating a network for performing further clinical and 
translational research including clinical trials. Still a major deficiency is the relative lack of 
sensitivity of measures in children, and their correlation with potential biomarkers. 
Therapeutic interventions are aimed primarily at either 1) up-regulating expression of the 
frataxin protein (patients all have residual levels of normal protein and experimental 
approaches have demonstrated proof of principle of this approach with various small 
drugable molecules), or 2) ameliorating the pathogenic effects of low frataxin levels, namely 
a) reduced activities of key mitochondrial enzymes involved in energy metabolism that are 
dependent on Frataxin-dependent mitochondrial iron metabolism (FeS cluster-containing 
enzymes such as aconitase and OXPHOS enzyme complexes I, II and III, and possibly 
heme-dependent enzymes such as OXPHOS enzyme complex IV), and b) generalized 
oxidative stress in mitochondria and its negative consequences on mtDNA, proteins and 
membrane lipids. 
Efficacy of these therapies can be monitored both by scoring clinically-defined neurologic 
parameters, and also by biochemical measurement of key mitochondrial enzymes, 
functions or metabolites or by genetic modifiers. Currently, genetic modifier studies have 
been limited to the lack of DNA samples linked to detailed clinical information that allows for 
stratification of the disease group based on disease severity and phenotypic variability.  
Frataxin levels will be a primary biochemical endpoint in therapeutic interventions designed 
to up regulate the steady-state levels of this protein.  Moreover, upregulated frataxin levels 
will of necessity precede any other markers of clinical efficacy, including neurological 
scores. Therefore, tests to monitor these levels should be able to use tissue samples that 
can be obtained repetitively and non-invasively. Examples of such samples are oral 
epithelial cells obtained by non-invasive gentle cheek swabs and whole blood obtained by 
standard blood draws or finger prick sampling. Additionally, physiological abnormalities 
from frataxin deficiency in affected tissues can be monitored using imaging techniques, 
including 31P magnetic resonance spectroscopy (MRS) and MEP.  
 

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Protocol No. 17-014390 
 
 
1.2 
Compliance Statement 
This study will be conducted in full accordance with all applicable Children’s Hospital of 
Philadelphia, and participating sites (University of Florida and University of California Los 
Angeles) Research Policies and Procedures and all applicable Federal and state laws and 
regulations including 45 CFR 46, and the HIPAA Privacy Rule. Any episode of 
noncompliance will be documented. 
The investigators will perform the study in accordance with this protocol, will obtain consent 
and assent (unless a waiver is granted), and will report unexpected problems in accordance 
with all participating sites’ IRB Policies and Procedures and all federal requirements. 
Collection, recording, and reporting of data will be accurate and will ensure the privacy, 
health, and welfare of research subjects during and after the study.  
1.3 
Relevant Literature and Data 
See references/ Appendix 1 of the attached grant. 
2 
STUDY OBJECTIVES  
Overall Aim: To advance clinical care, research and therapeutic approaches in FRDA 
through the development of valid yet sensitive clinical and biochemical measures crucial to 
outcome assessment of children with Friedreich’s Ataxia  
2.1 
Primary Objective (or Aim) 
Aim 1: Identify markers of disease progression in children with FRDA and assess potential 
clinical measures of disease progression in the youngest subjects (n=110). 
2.2 
Secondary Objectives (or Aim) 
Aim 2: Assess the biochemistry of frataxin deficiency in children with FRDA. Measure 
frataxin deficiency and downstream metabolic function. Understand how these biochemical 
markers change over time. Support genetic modifier studies and biomarker studies. 
Evaluate the clinical utility of measuring frataxin levels in easily-accessible tissue samples, 
cheek swabs, suitable for the repetitive testing needed to monitor efficacy of therapies 
designed to up-regulate levels of frataxin protein. 
Aim 3: Define the progression of physiological dysfunction in affected tissues in children 
with FRDA. Use noninvasive testing to assess the physiological correlates of progression of 
FRDA.  
3 
INVESTIGATIONAL PLAN 
3.1 
General Schema of Study Design 
Pediatric Subjects will be recruited from each site’s ongoing practice and the Friedriech 
Ataxia natural history study and invited to participate in this study. Dr. Lynch will recruit up 
to 90 children from his practice to participate at CHOP, and the remaining two sites, UCLA 
and University of Florida, will recruit up to 20 children in a similar manner to participate. 
Such subjects will return every 6 months for neurological measures, and biochemical 
measures (frataxin levels, platelet metabolic biomarkers). At each annual visit a select 
number of participants at CHOP will also complete tests assessing anatomical biomarkers. 
Data will be analyzed based on the change in measures over time to identify those that 
change serially in FA and the ability of disease features to predict such change. 

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Protocol No. 17-014390 
 
 
3.1.1 Screening Phase 
Subjects will be identified from natural history studies and clinical practices. Informed 
consent will be obtained by trained personnel at each site.  
3.1.2 Assessment Phase 
Visit 1 (0 months) Subjects will be assessed by medical history, neurological tests (FARS, 
Timed 25 foot walk (T25W), Timed 1 and 6 minute walks, Timed up and go (TUG), Berg 
Balance scale (BBS), 9 hole peg test (9HPT), PedsQL, ADL score and ataxia disability 
scale), biochemical tests (frataxin level, platelet metabolic biomarkers), and physiological 
testing (CrCEST, MEP). Data will be collected over a one day visit. 
Visit 2. (6 months) Subjects will be assessed by medical history, neurological tests (FARS, 
Timed 25 foot walk (T25W), Timed 1 and 6 minute walks, TUG, BBS, 9HPT, PedsQL, ADL 
score, ataxia disability scale), and biochemical tests (frataxin level, platelet metabolic 
biomarkers). Data will be collected over a one day visit. 
Visit 3 (12 months) Subjects will be assessed by medical history, neurological tests (FARS, 
Timed 25 foot walk (T25W), Timed 1 and 6 minute walks, Timed up and go (TUG), Berg 
Balance scale (BBS), 9 hole peg test (9HPT), PedsQL, ADL score and ataxia disability 
scale), biochemical tests (frataxin level, platelet metabolic biomarkers), and physiological 
testing (CrCEST, MEP). Data will be collected over a one day visit. 
Visit 4. (18 months) Subjects will be assessed by medical history, neurological tests (FARS, 
Timed 25 foot walk (T25W), Timed 1 and 6 minute walks, TUG, BBS, 9HPT, PedsQL, ADL 
score, ataxia disability scale), and biochemical tests (frataxin level, platelet metabolic 
biomarkers). Data will be collected over a one day visit. 
Visit 5 (24 months) Subjects will be assessed by medical history, neurological tests (FARS, 
Timed 25 foot walk (T25W), Timed 1 and 6 minute walks, Timed up and go (TUG), Berg 
Balance scale (BBS), 9 hole peg test (9HPT), PedsQL, ADL score and ataxia disability 
scale), biochemical tests (frataxin level, platelet metabolic biomarkers), and physiological 
testing (CrCEST, MEP). Data will be collected over a one day visit. 
Visit 6 (36 months) Subjects will be assessed by medical history, neurological tests (FARS, 
Timed 25 foot walk (T25W), Timed 1 and 6 minute walks, Timed up and go (TUG), Berg 
Balance scale (BBS), 9 hole peg test (9HPT), PedsQL, ADL score and ataxia disability 
scale), biochemical tests (frataxin level, platelet metabolic biomarkers), and physiological 
testing (CrCEST, MEP). Data will be collected over a one day visit. 
Visit 7 (subject dependent) Subjects will be assessed by medical history, neurological tests 
(FARS, Timed 25 foot walk (T25W), Timed 1 and 6 minute walks, Timed up and go (TUG), 
Berg Balance scale (BBS), 9 hole peg test (9HPT), PedsQL, ADL score and ataxia disability 
scale), biochemical tests (frataxin level, platelet metabolic biomarkers), and physiological 
testing (CrCEST, MEP). Data will be collected over a one day visit. 
Data will be analyzed by Lynch and collaborators. No subject visits occur during this time. 
3.1.3 Study Visit  
All procedures will be conducted over a one day visit. For the 12 participants for the 
physiological tests (CrCEST evaluation) at CHOP, participants will be taken for the MRI 
scan in the morning and complete the neurological and biochemical assessments in the 
afternoon. For the 30 participants enrolled in the MEP protocol at CHOP, this procedure 
can be arranged either before or after the clinical assessment.   

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3.1.4 Case Ascertainment 
Subjects recruited at the CHOP site are expected to be patients with Friedreich Ataxia 
followed by Dr. Lynch through the Neurogenetics clinics at the Children’s Hospital of 
Philadelphia and the Hospital of the University of Pennsylvania. This study will also be 
posted on clinicaltrials.gov. Additional recruitment may take place by posting notices on the 
internet through FRDA support and advocacy groups such as Friedreich’s Ataxia Research 
Alliance. Such advertisements would be forwarded to the IRB for approval. 
3.1.5 Data sources 
The Friedreich Ataxia Clinical Outcomes Study (FACOMS) (CHOP IRB study #01-002609) 
will serve as a supplemental data source for the study. For participants enrolled in both 
studies, and who have consented to the optional future use of their data as part of #01-
002609, data will be shared from that study for those participants only. 
3.2 
Controls and Blinding 
Not applicable 
3.3 
Study Duration, Enrollment and Number of Sites 
3.3.1 Duration of Study 
The total duration for each subject is three years, and initial recruitment will occur over a 
two year period.  
3.3.2 Total Number of Study Sites/Total Number of Subjects Projected 
The study will be conducted at 3 investigative sites in the United States. Clinical 
neurological (Aim 1) assessments and frataxin sample collections (Aim 2) will be carried out 
at all three sites. Physiological assessments (Aim 3) will only be conducted at CHOP.  
The following is a list of sites included in the study: 
Children’s Hospital of Philadelphia 
University of California Los Angeles 
University of Florida 
The University of Rochester will provide database support 
Recruitment will stop when 110 children are enrolled (up to 90 at CHOP, up to 20 at other 
sites). The majority of subjects will be enrolled at the CHOP site and some will be included 
to participate in the MEP (n=30) and CrCEST (n=12) measures. A substantial number of 
participants will be recruited from the ongoing natural history study of all ages, FACOMS, in 
which some children are already enrolled. Dr. Lynch sees 30 new FRDA patients per year, 
with the majority being children. Study advertisements will be sent through the Friedreich 
Ataxia Research Alliance (FARA) registry, which is a database that includes 141 children 
living in the United States and over 2000 patients worldwide.  
3.4 
Study Population 
3.4.1 Inclusion Criteria  
1) 
Males or females age 2 to 18 years.   

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Protocol No. 17-014390 
 
 
2) 
Genetically confirmed diagnosis of FRDA or clinically confirmed diagnosis of 
FRDA, pending confirmatory genetic testing through a commercial or 
research laboratory  
3) 
Parental/guardian permission (informed consent) and if appropriate, child 
assent. 
4) 
Weight ≥ 10 kg (for the MEP measures only) 
3.4.2 Exclusion Criteria  
1) 
Inability to complete study evaluations 
2) 
Severe cardiomyopathy/congestive heart failure (for MEP) 
3) 
A pacemaker, any metal-based medical or non-medical implants/devices, 
any non-removable metal-based object (e.g. body piercings, jewelry, etc.) 
(for the CrCEST measures only) 
4) 
Any history of intraocular injury or fragment in or around the orbit that cannot 
be cleared through radiologic evaluation (for the CrCEST measures only) 
5) 
Any history of bullet, shrapnel, or stabbing wounds that cannot be cleared 
through radiologic evaluation (for the CrCEST measures only)  
6) 
Claustrophobia or any known medical conditions which can be exacerbated 
by stress, anxiety, or panic attacks triggered by enclosed spaces (for the 
CrCEST measures and MEP only)  
7) 
Inability to lie flat on a patient bed in an MRI machine for up to 90 minutes 
(for the CrCEST measures only)  
8) 
Pregnancy (for the CrCEST measures and MEP only)  
4 
STUDY PROCEDURES 
4.1 
Neurological Outcome Measures  
a) Medical history: In the following description of study procedures, the term “patient” 
refers to individuals with Friedreich Ataxia. In order to obtain data and validate clinical 
outcome measures the following studies will be done. Quantitative and descriptive 
clinical data collection on all subjects, including medical history and medications. We 
will also try to obtain copies of subject’s most recent Echocardiograms and EKG 
reports, as found in their medical records. 
b) Friedreich ataxia rating scale: The FARS is a rating scale based upon the clinical 
neurologic examination and will be administered by a neurologist who is masked to 
scores from the other measures. FARS ratings range from 0 to 125, based on 
summation of 25 different neurologic exam features.  
c) The timed 25-foot walk (T25W): A timed measure of how fast a subject walks 25 feet. 
d) The 9-hole peg test (9HPT): A timed test of how long it takes for a subject to place pegs 
in a standard pegboard. It also has an electronically measured version (the CCFS) and 
a “click test” in which patients click a button as fast as they can. 
e) Extended timed walking tests: A 1-minute timed walk and a 6-minute timed walk (but 
not to exceed 6 minutes in length) will be conducted. The timed 1-minute and 6-minute 
walks are quantitative mobility and leg function performance tests based on distance 

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Protocol No. 17-014390 
 
 
traveled in one and six minutes, respectively. The subject is directed to one end of a 
clearly marked large rectangular course and is instructed to walk around as quickly as 
possible for one or six minutes. The distance is calculated by measuring how far the 
subject travels along the marked course. Subjects may use assistive devices during this 
task. The 1 minute walk will be performed twice, separated by 5 minutes of rest.  
f) Specific gait and balance tools utilized in other gait disorders of childhood, including the 
Timed Up and Go (TUG) and Berg balance scales (BBS). The TUG is a test of the time 
to rise from a chair, walk three meters (10 feet), turn around, walk balk to the chair, and 
sit down. It has previously been tested in older subjects with FRDA and has been used 
in both elderly populations and very young cerebral palsy cohorts. The BBS is a semi-
quantitative rating scale based on ability to stand sit and balance in various positions 
(5). 
g) The Pediatric Quality of Life (PedsQL) and the FARS ADL scores. Subjects aged 2-7 
inclusive will not need to complete a PedsQL scale. The PedsQL scale is the Pediatric 
Quality of Life Inventory. This scale has two separate questionnaires: one is designed 
for subjects between the ages of 8-12, the other for subjects between 13-18. The 
subject will answer the questionnaire with the help of the study coordinator. The 
subject’s parent or guardian will also answer a separate questionnaire on the same 
topic. The FARS ADL score is a similar questionnaire asking the participant how they 
view their performance on tasks such as dressing, bathing, etc. Subjects and their 
guardians will be asked to complete questionnaires annually. 
In some situations, such as a global pandemic, travel restrictions, as well as poor health or 
an overall concern for safety, it may not be possible for subjects to have an in-person visit 
every year. Under these circumstances, for subjects who have previously consented for this 
study it is possible to conduct a visit remotely via phone or video/telehealth. A remote visit 
will not include the 9HPT or any sample collection. Remote visits can include the following: 
review of consent forms, medical history and medications, completion of questionnaires that 
can be mailed or emailed to subjects, certain assessments of gait and motor functioning 
including answers to the surveys which ask questions about gait and motor abilities, parts 
of the FARS exam (for example, the Bulbar facial nerve function exam which can be 
performed and viewed over video), and timed standing and/or walking tests that can be 
viewed over video (provided that it has been determined ahead of time to be a low fall risk 
to the subject - fall risk will be determined by taking a recent detailed fall history of each 
subject prior to any standing or walking test). 
 
All procedures detailed above (except the BBS and TUG) have been included on other IRB 
approved studies at CHOP, including a currently open study (IRB 01-002609). 
4.2 
Blood Draw for Frataxin Protein Assay, and Platelet Metabolic Biomarkers  
A standard venous blood draw is performed by a trained phlebotomist or equivalently 
trained study coordinator or nurse. No more than 40 ml whole blood will be collected from 
study subjects, which is a smaller amount than the NIH-recommended limit for all but the 
smallest children and below the NIH-recommended maximum limit for children. The 
maximum amount of blood collected from a participant will be determined based on either 
the above maximum volumes or based on the maximum amount of sample allowed based 
on weight (2cc/kg), whichever volume is lower, for safety purposes samples collected from 
subjects will not be sent to each laboratory involved in the study.   

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The sample will be used for the blood frataxin protein assay, and platelet metabolomics 
biomarkers. The samples are fractionated in Dr. Lynch’s lab and are either frozen for 
frataxin analysis, or incubated with C13 metabolic precursors, then frozen for platelet 
metabolic assay. Both are performed in Dr. Blair’s lab at the University of Pennsylvania.  
5 ml of blood will be used for frataxin dipstick analysis. Immediately after the blood draw, 
the blood will be transported and stored at -80 degrees Celsius in the lab of Dr. Lynch. The 
sample remains in the freezer until it is ready to be analyzed. Specimen collections will 
function as exploratory measures and will be determined by lateral flow assay in samples 
from whole blood. These samples will be analyzed by a trained laboratory technician in the 
lab of Dr. David Lynch.  
When samples are to be analyzed by outside laboratories, they will be shipped on dry ice 
according to proper guidelines. Samples will be sent with elements of dates labeled on 
tubes (date of collection). Each sample will be given a unique number. 
4.3 
Buccal Swab Collection 
Sterile, disposable Epicentre MasterAmp Buccal Swab Brushes will be used to isolate 
buccal cells (cells lining the mouth) from the inner cheek as suggested by the 
manufacturer. The procedure is very gentle and causes no discomfort. The inner cheeks 
are first gently cleansed by light brushing with a new moist, soft toothbrush and then rinsed 
with a sip of water. An Epicentre MasterAmp Buccal Swab Brush is then gently but firmly 
used to brush both cheeks, collecting a light layer of easily sloughed-off epithelial cells on 
the surface of the brush. Exfoliated cells are then transferred to ice-cold extraction buffer 
preloaded in a small sample collection tube. The sample is then immediately coded and 
processed for frozen storage in Dr. Lynch’s laboratory. The specimen is analyzed by lateral 
flow assay and performed by a trained laboratory technician.  
As with the frataxin blood sample, the cheek swab will be processed in Dr. Lynch’s lab. 
Samples from other sites will again be shipped on dry ice according to proper guidelines. 
Samples will not be sent with any PHI. Again, the purpose of sending the samples to Dr. 
Lynch’s lab at CHOP is to ensure that similar results are obtained on this assay across 
multiple locations. This is required to validate the assay.  
4.4 
Magnetic Resonance Imaging (MRI) muscle phenotyping  
At CHOP, 12 of the approximately 90 participants will be included for muscle phenotyping 
assessment as part of the study’s aim to define the progression of physiological dysfunction 
in affected tissues. All participants will be offered the opportunity to participate, but 12 
children will be selected on a first-come basis and must meet inclusion criteria. 12 children 
will participate in the protocol and be studied annually at 0, 12, 24, and 36 months, unless 
the subject wishes to complete their annual visit remotely. Creatine chemical exchange 
saturation transfer (CrCEST) is a technique that will be carried in the same session as 31P 
Magnetic Resonance Spectroscopy (MRS) at CHOP using a 3-Tesla Magnet. 31P MRS is 
an established method to measured oxidative phosphorylation (OXPHOS) in muscles. 
Briefly, the rate of creatine recovery (CrCEST) or phosphocreatine (PCr) resynthesis (PCrτ, 
31P MRS) was estimated, each after a 3-minute bout of plantar extension/flexion exercises. 
These studies showed that CrCEST produced similar results with respect to recovery 
kinetics, but offered superior anatomical resolution (6).  
The participant will safely lie on an MRI bed and a coil will be placed around part of the 
body under investigation. The study participant may also wear ear-plugs to reduce the 
volume of MRI signal noise. They will then be moved directly into the magnet so that the 
body part under investigation is observable through the MRI program. The procedure will 

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Protocol No. 17-014390 
 
 
proceed with the study team conducting communication with the participant via a two-way 
radio communication system.  We will employ resting and post-exercise chemical exchange 
saturation transfer (CrCEST) to assess muscle OXPHOS capacity.  During the session, we 
will ask subjects to perform several brief sub-maximal leg exercises (about 5 minutes in 
total). Subjects will be asked to press down on a pedal, similar to a car accelerator or piano 
foot pedal, approximately 90 times, or as many as they are able, over a 2 minute period.  A 
member of the study team will remain in contact with the subject through a two-way 
intercom and will count aloud each repetition. A certified medical professional will continue 
to closely monitor the patient for safety and any sign of discomfort during the MRI 
procedures. Time in the MRI machine will not exceed 90 minutes. After completion of the 
imaging, they will be carefully and slowly removed from the MRI machine to prevent any 
lightheadedness caused by orthostatic hypotension.  
Creatine CEST imaging sequence will be used to assess creatine distribution and 
concentrations in muscle (lower extremity), both at rest and after recovery from a brief foot 
pedal depression exercise (7,8). The CrCEST sequence is based on a standard single-slice 
FLASH pulse sequence with prep saturation pulses in front.  The acquisition time for the 
CEST sequence is only about 30 seconds, but we need to acquire the images at varying 
saturation amplitude and pulse duration.  Typical parameters used are: slice thickness = 8 
mm, flip angle = 10, TR = 5.6 ms, TE = 2.7 ms, field of view = 140 x 140 mm2, matrix size 
= 128 x 128. 
If time permits, we will also perform mechanical and structural properties of bone (lower 
extremity) using MRI and finite element analysis. This test takes less than 10 minutes and 
will be added on at the end of the standard sequence in patients who have time  
The CrCEST MRI sequences performed for this protocol are non-FDA approved and are 
therefore considered experimental. The bone strength MRI sequence is part of an FDA-
approved sequence but its use is being re-purposed for the study, which requires special 
post-processing techniques. Results from the FDA-approved bone strength sequence will 
be entered into the medical record, but results from the non-FDA approved CrCEST 
research sequence will not. If we identify any incidental findings from non-investigational 
MRI sequences, we will evaluate them to determine if medical attention is needed. In 
addition, subjects have the option to have any findings forwarded to their primary care 
provider for review. 
The procedure detailed above has been included on other IRB approved studies at CHOP, 
including an open study in mitochondrial disease by co-investigator Dr. Shana McCormack 
(IRB 15-012445). 
4.5 
MEP Measurements 
At CHOP, 30 of approximately 90 participants will be included for muscle phenotyping 
assessment as part of the study’s aim to define the progression of physiological dysfunction 
in affected tissues. All participants will be offered the opportunity to participate, but 30 
children will be selected on a first-come basis and must meet inclusion criteria. MEPs are 
measured using transcranial magnetic stimulation (TMS), a device which produces a 
momentary electromagnetic pulse which stimulates the motor cortex of the brain. We will 
use a Magstim 2002 machine with a 70 mm figure-of-eight coil (Magstim Co, Wales, UK). 
Motor evoked potentials will be obtained from adhesive surface electrodes placed on the 
first dorsal interosseous (FDI) of the dominant hand, and recorded using an amplifier (CED 
1902 isolated amplifier, CED, Cambridge UK), an analog-to-digital converter (CED 1401), 
and Signal 3.13 for Windows software (CED, Cambridge, UK). In the unlikely event that a 

9  
 
Protocol No. 17-014390 
 
 
participant is ambidextrous, the right side will be measured. The TMS machine emits a low 
volume click with each stimulus; for safety considerations (see below) each subject will 
wear foam earplugs during the session.  
Resting motor threshold (RMT) will be measured as the minimum stimulus intensity needed 
to elicit MEPs of at least 50uV in 5 of 10 trials. The optimal site of stimulation for the FDI 
muscle will be determined as the site with the lowest RMT for eliciting MEPs. Finding the 
RMT and optimal site will take approximately 20-30 single stimuli. Stimulation will consist of 
20 stimuli, each separated by at least 4 seconds, at a pulse intensity of 110% MT, with the 
option to deliver up to 30 additional stimuli if more than half of the trials are affected by 
movement. No sessions will exceed 1800 pulses of TMS, a safety standard we have 
specified in prior studies at CHOP (IRB 12-009124) and by the stimulation lab at the 
University of Pennsylvania (Penn IRB #806532). The expected time for MEP recording, 
including set up time is 60 minutes.  
The procedure detailed above has been included on other IRB approved studies at CHOP, 
including an open study by principle-investigator Dr. Sudha Kessler (IRB 14-011627). 
Useful References for Observational and Descriptive Research: 
A copy of a recent publication describing the validation of these measures has been 
included.  
4.6 
Abstracted Data Elements  
Friedreich Ataxia Clinical Outcome Measures Study (CHOP IRB# 01-002609): Below are 
the listed data elements that will be abstracted from this study. This includes data collected 
before and during the participant’s enrollment. 
• 
Functional Staging for Ataxia Score 
• 
Friedreich Ataxia Rating Scale (FARS)  
• 
Medical History Update- FA Symptoms Review 
• 
Medical History Update - Medical Conditions Log 
• 
Medical History Update – Medications 
• 
Vital Signs- height, weight, BMI, blood pressure 
• 
9 Hole Peg Test 
• 
Timed 25 Foot Walk 
• 
Extended Timed Walks  
• 
Activities of Daily Living 
• 
Pediatric Quality of Life Questionnaires  
4.7 
Primary and Secondary Endpoints  
The primary goal of this study is to gather long-term serial quantitative clinical data using 
the measures validated during the three years of the study. 
Aims 1: The primary endpoint (s) are the change in each of the clinical measures over time. 
The rate of change of each of these will be compared for responsiveness to change (SD of 
change/mean change). 

10  
 
Protocol No. 17-014390 
 
 
Aim 2: Biochemical measures: The rate of change of frataxin and each platelet biomarker 
will be determined as primary endpoints. The rate of change over time will be determined to 
define which measures are most sensitive to disease progression.  
Aim 3: Anatomical measures: The primary endpoints are the post exercise recovery time, 
Tau, for CrCest and the MEP size for MEP testing. The rate of change over time will be 
determined to define which measures are most sensitive to disease progression. 
The secondary analyses are:  
The rate of change of each measure the (neurological measures, biochemical measures 
and anatomic measures) as a function of age, GAA repeat length and sex, as determined 
by linear regression models  
4.8 
Statistical Methods  
Aim 1: Results will be summarized with standard descriptive statistics using parametric or 
non-parametric methods, as appropriate given the variable distributions. Each of the 
parameters tested here have been abnormal in FRDA patients previously, including 
children. However, the specific features of how they behave in large pediatric cohorts is 
unclear. Thus, the most important analyses will be how the tests behave over time and how 
they reflect disease severity. Data for test-retest for the first 5 subjects at the primary site 
will be evaluated by determining the coefficient of variation over the tests. This will be 
performed immediately after study initiation as a separate analysis to confirm that the initial 
protocols have sufficient reproducibility to be useful. Full data collection will then proceed. 
Data from measures that were repeated (timed walks, TUG, CCFS tests) will be analyzed 
as means of the repeated tests and test retest features between trials. CCFS values will be 
analyzed as each hand separately (dominant vs non dominant) and hands together. Each 
test will be assessed in regression or mixed linear models accounting for age, sex and GAA 
repeat length. In addition the change over time will be established as well as the 
reproducibility of that change.  
Aim 2: Results will be summarized with standard descriptive statistics using parametric or 
non-parametric methods, as appropriate given the variable distributions. In this biochemical 
aim, the major analysis will examine the relationship of frataxin levels and downstream 
biomarkers with disease progression. This will be perfomed in 2 ways. First using cross 
sectional data, we will construct mixed linear models that allow the assessment of their 
relationship of marker values (frataxin, 13C metabolite levels, Apo A1) to age, GAA repeat 
length and sex. Secondly, we will assess the change in values over time both in absolute 
value and percent change to understand the overall meaning of results. In addition, the 
change over time will be examined in relation to age, sex, and GAA repeat length in linear 
models. We will also examine the levels of each marker at baseline with the change in 
clinical measures from aim 1. This will allow us to understand the degree to which clinical 
change reflects individual biochemical events and whether clinical and biochemical events 
correlate temporally. This analysis will be supplemented by analysis assessing whether the 
change in levels of the biomarkers predicts clinical change. 
Aim 3. Each of the measures here (MEP, CrCEST) has differentiated FRDA subjects from 
controls in previous studies. For this proposal though, the crucial analyses should ascertain 
the relationship between physiological values from CrCEST and MEP and disease status 
from clinical measures. Results will be summarized with standard descriptive statistics 
using parametric or non-parametric methods, as appropriate given the variable 
distributions. In cross sectional analyses, results from each of the outcome measures 
(frataxin levels, platelet metabolic markers, ApoA-1, and recovery time from CrCEST) will 

11  
 
Protocol No. 17-014390 
 
 
be used as dependent variables in multiple linear regression models or mixed models 
examining the independent effects of age, GAA repeat length and sex as dependent 
variables. This will allow us to define the degree to which each outcome marker is predicted 
by genetic severity (GAA repeat length), disease progression (age) or both. We will also 
directly correlate results between MEP and CrCEST to ascertain the degree to which they 
reflect the same construct (FRDA disease progression). Finally, we will examine 
correlations and regression modelling between physiological results and clinical measures 
(Aim 1) and frataxin levels (Aim 2) 
4.9 
Sample Size and Power  
The sample size of main parts of the study is dictated by previous studies and by 
practicality. Previous power calculations suggest that even using even well-defined clinical 
measures, the sample size for therapeutic trials will be more than 100 subjects, even using 
selected cohorts (9-13). However, the tests performed in the present study generally show 
robust differences between FRDA subjects and controls, and should provide more sensitive 
measures of disease if they retain sufficient fidelity in children. A sample size of 110 
subjects should allow us to assess the independent effects of age, sex and genetic severity 
(GAA length) on measure results, facilitating a true understanding of the degree they can 
be used in children. One hundred subjects is also practically the upper limit of intervention 
studies in rare disease, and thus is appropriate for this study. In the present, study subjects 
will return every year for MEP and CrCEST, and every six months for clinical testing and 
blood tests through 36 months. MEP and CrCEST will have smaller samples size (30 and 
12 respectively) as they are more precise but more labor intensive tests. Total duration for 
each subject is approximately 3-4 years, and initial recruitment will occur over a 2 year 
period. In the present study the goal is to define how each of the tests change over time in 
children with FRDA, and the factors (age, GAA length) that predict such changes. Each 
marker has been differentiated from control values previously; however, here control 
subjects will be used only if needed to confirm the differences, to provide a context and to 
be sure that tests perform similarly in all sites as a quality control measure. 
5 
STUDY ADMINISTRATION 
5.1 
Data Collection and Management 
The study will use a database constructed through the University of Rochester for the 
FACOMS study. The University of Rochester database is compatible with the federal 
regulations for clinical trials. The University of Rochester also acts as the data center for 
many other neurological diseases, such as Parkinson’s and Huntington’s.  
We will use CRFs compatible with this database.  The CRFs do not ask for subject name, 
social security number, address or telephone number. The CHOP PI and coordinator will 
maintain a password protected list of this information which does not leave CHOP. The 
University of Rochester or others will not have any access to subject’s name, address or 
contact information.    
In addition to the data collected at each study visit, study data will be supplemented by the 
FACOMS study (IRB #01-002609). This will include data created on, before, and after the 
date of initial IRB submission (8/31/2017).  For participants enrolled in FACOMS and who 
have consented for that study’s data sharing component, data collected from #01-002609 
prior to enrollment in the current (#14390) study may be shared with the current study. Data 
from overlapping study procedures will be shared from study #01-002609 to the current 
study #14390. This specifically includes data from the following performance measures: 

12  
 
Protocol No. 17-014390 
 
 
medical history review, FARS, T25FW, 9HPT, extended timed walks, PedsQL and FARS 
ADL questionnaires. Other sites (UCLA, University of Florida) will handle data in the same 
manner. 
The CHOP site will continue to maintain paper copies of all CRFs for three years following 
completion of the study.  
5.2 
Regulatory and Ethical Considerations 
5.2.1 Risk Assessment 
Clinical outcome measures (ataxia scales, speech testing, auditory testing, vision testing, 
timed walks, and peg test), questionnaires are non-invasive and are very similar to standard 
clinical evaluation. The risks to all aspects of the study are minimal and include fatigue and 
boredom. There is a small risk a participant may fall and be injured when trying to complete 
the walking tests; however this risk is minimal.  Assistive devices may be used to complete 
these tasks, and study staff will be present to supervise and assist. 
A standard venous blood draw of up to 40 mls is of minimal risk for a person 40 lbs or more.  
There is a risk of pain at the insertion of the needle, this is only for a short time. There are 
low risks of fainting and infection. All venipunctures will be performed by a trained 
phlebotomist or equivalently trained study coordinator or nurse. All precautions will be taken 
to reduce the risks. No adverse events are expected. 
The risks associated with the blood tests are directly related to confidentiality. All samples 
will be labeled with a unique identifier. Laboratory personnel handling the patient samples 
and performing the genetic studies will not have access to subject personal identifiers.  
When any data is published all identifiers will be removed. When data or resources are 
shared with other study PIs or collaborators no personal identifiers will be shared. 
For participants undergoing CrCEST and bone strength sequences, the main risk to study 
participation is related to MRI scanning. Risk is minimized with telephone screening for 
contraindications to MRI, screening in-person at the study visit via detailed medical record 
review, as well as testing for metal-based objects before any MRI procedures. In addition, 
all participants are screened for any condition that may affect their safety and wellbeing 
during the study via careful medical record review. The study team will also closely monitor 
patients before, during, and after study procedures (e.g., follow-up). 
MRI is the least invasive of all imaging modalities, and there are no known risks from MRI 
examinations provided subjects are carefully screened for contraindications. Two potential 
sources of concern lie in the strength and duration of the radio frequency pulse and of 
gradient pulses. These effects are the subject of very close study by the FDA, and the 
Siemens Verio Avanto, Sonata & Trio, Siemens is carefully manufactured (with both 
software and hardware interlocks) so that it is not possible (even by accident) to exceed the 
FDA guidelines. MRI is listed by the FDA as approvable as a non-significant risk device, 
and the studies themselves are of minimal risk. The effects of MRI on an unborn baby are 
unknown.  We will therefore exclude pregnant women. An MRI has the potential to identify 
incidental findings. During the study visit, if a participant is found to have any previously 
unknown medical conditions, they will be referred to their primary care physician or 
metabolic physician for care. The Children’s Hospital of Philadelphia MRI protocols and 
safety measures will be observed. 
In the MEP procedure the main risk is associated with the safety and tolerability of TMS 
application. There are more than 100 published studies with reports of TMS applied to more 
than 800 normal and more than 300 neurologically abnormal children (most receiving single 

13  
 
Protocol No. 17-014390 
 
 
or paired-pulse TMS). No serious adverse events have ever been reported in this 
population, suggesting that single pulse TMS in children is a minimal risk procedure. A 
2009 report from the Safety of TMS Consensus Group specifies single pulse studies as 
minimal risk and offers further discussion of the safety of TMS in pediatric populations (14). 
Single pulse TMS is used as a clinical procedure in children with epilepsy, brain tumors, or 
other neurologic disorders for mapping of the primary motor cortex. The main safety 
concerns regarding TMS are the potential for provoking seizures, the potential to effect 
hearing, and pain or discomfort. 
5.2.2 Potential Benefits of Study Participation 
This study will provide long-term data on quantitative measurements of disease progression 
in children that will provide natural history data for FRDA. This study will also test and 
validate a non-invasive approach to measuring frataxin protein which will be necessary for 
future clinical trials. It will also seek to identify metabolic and anatomical biomarkers 
required for clinical trials. Lastly, this proposal will further develop the infrastructure and 
support for evaluating new clinical outcome measures and biomarkers. Subjects will not 
benefit directly but their participation will contribute to the necessary clinical research 
required to support the advancement of therapeutics in FRDA. 
5.2.3 Risk-Benefit Assessment 
The risks are minimal and given the potential benefits, the risk/benefit ratio is therefore 
extremely small. 
5.3 
Recruitment Strategy 
Subjects will be recruited from multiple sources. A substantial number will be recruited from 
the ongoing natural history study of all ages, FACOMS, in which some children are already 
enrolled, and from the new diagnoses presenting to the sites. The FACOMS study collects 
detailed data on phenotype, neurological testing, medical history, and genetic severity; this 
data is available for the present work, and the present study will extend it by adding new 
tests and addressing new age groups. Dr. Lynch alone sees 30 new FRDA patients per 
year, most of them children. The other two sites (University of Florida and UCLA) will also 
recruit through their practices’ new patients and their FACOMS participants. In addition, 
study advertisements will be sent through the FARA registry. This database includes names 
of > 2000 FRDA pts worldwide, including 141 children living in the USA.  
5.4 
Informed Consent/Assent 
The principal investigator and clinical coordinator will obtain informed consent or assent and 
parental consent from potential participants.  
5.5 
Payment to Subjects/Families 
Participants will not receive financial rewards or inducements. There is also no cost to 
participation in the study. Participants who receive clinical care from any investigator or 
participating research sites, including the Children’s Hospital of Philadelphia, will be 
responsible for those charges, as they are separate from the study. 
Funds are available to reimburse some travel and hotel costs for all individuals traveling to 
the study sites. Our grant does provide funds to reimburse travel expenses up to $500 per 
visit for participants. This must be arranged with the study coordinator prior to your arrival, 
and will require an IRS Form W-9. Only full name and social security number will be 

14  
 
Protocol No. 17-014390 
 
 
collected on the W-9 form. Participants will receive reimbursement checks within 8 weeks 
after each visit.  
5.6 
Confidentiality 
Enrollment or non-enrollment in the study will not affect the patient’s clinical care in any 
way. All participation is voluntary. Subjects who are non-ambulatory, more severely 
affected, or who have cardiomyopathy will not be asked to complete the timed walks. All 
study team will use a CHOP approved video platform to conduct these visits remotely to 
maintain subject confidentiality All data will be kept confidential except as required by law 
and kept in a secure data at the Children’s Hospital of Philadelphia. All source documents 
will be stored in locked cabinets with access only for the principal investigator and co-
investigators. Patients will be identified by identification numbers not by personal identifiers. 
Patient names will be anonymized in publications and only the personnel involved in the 
studies will be able to link results with patient names.  
6 
PUBLICATION 
The identity of all subjects will be withheld from any publication, abstract, lecture or other 
oral presentation that derives from this investigation.  Publications will state that the study 
had the approval of the Institutional Review Board at The Children's Hospital of 
Philadelphia. 
7 
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Koenig M. Clinical and genetic abnormalities in patients with Friedreich's ataxia. N Engl 
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8) Mostoufi-Moab S, Magland J, Isaacoff EJ, et al. Adverse Fat Depots and Marrow 
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Neurology.2013;80(16):1509-17. PMID: 23535489; Goodman AD, Brown TR, Edwards 
KR, Krupp LB, Schapiro RT, Cohen R, Blight AR; MSF204 Investigators. A phase 3 trial 
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13) Patel M, Isaacs CJ, Seyer L, Brigatti K, Gelbard S, Strawser C, Foerster D,Shinnick J, 
Schadt K, Yiu EM, Delatycki MB, Perlman S, Wilmot GR, Zesiewicz T,Mathews K, 
Gomez CM, Yoon G, Subramony SH, Brocht A, Farmer J, Lynch DR. Progression of 
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APPENDIX 
1) Blum L, Korner-Bitensky N. Usefulness of the Berg Balance Scale in stroke 
rehabilitation: 
a 
systematic 
review. 
Phys 
Ther. 
2008 
May;88(5):559-66. 
doi:10.2522/ptj.20070205. 
Epub 
2008 
Feb 
21. 
Review. 
PubMed 
PMID: 
18292215.Yelnik A, Bonan I. Clinical tools for assessing balance disorders. 
Neurophysiol Clin. 2008 Dec;38(6):439-45. doi: 10.1016/j.neucli.2008.09.008. Epub 
2008 Oct 18. Review. PubMed PMID: 19026963.