Clinical trial NCT03047369: The Myelin Disorders Biorepository Project
Official title: The Myelin Disorders Biorepository Project and Global Leukodystrophy Initiative Clinical Trials Network
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Leukodystrophy
White Matter Disease
Leukoencephalopathies
4H Syndrome
Adrenoleukodystrophy
AMN
ALD
ALD Gene Mutation
ALD (Adrenoleukodystrophy)
X-linked Adrenoleukodystrophy
X-ALD
Adrenomyeloneuropathy
Aicardi Goutieres Syndrome
AGS
Alexander Disease
Alexanders Leukodystrophy
AxD
ADLD
Canavan Disease
CTX
Cerebrotendinous Xanthomatoses
Krabbe Disease
GALC Deficiency
Globoid Leukodystrophy
TUBB4A-Related Leukodystrophy
H-ABC - Hypomyelination, Atrophy of Basal Ganglia and Cerebellum
HBSL
HBSL - Hypomyelination, Brain Stem, Spinal Cord, Leg Spasticity
LBSL
Leukoencephalopathy With Brain Stem and Spinal Cord Involvement and High Lactate Syndrome (Disorder)
Leukoencephalopathy With Brainstem and Spinal Cord Involvement and Lactate Elevation
ALSP
CSF1R Gene Mutation
HCC - Hypomyelination and Congenital Cataract
MLC1
Megalencephalic Leukoencephalopathy With Subcortical Cysts
MLD
Metachromatic Leukodystrophy
PMD
Pelizaeus-Merzbacher Disease
PLP1 Null Syndrome
PLP1 Gene Duplication &#X7C; Blood or Tissue &#X7C; Mutations
Pelizaeus Merzbacher Like Disease
Peroxisomal Biogenesis Disorder
Zellweger Syndrome
Refsum Disease
Salla Disease
Sialic Storage Disease
Sjögren
Sjogren-Larsson Syndrome
Van Der Knapp Disease
Vanishing White Matter Disease
Charcot-Marie-Tooth
CMT
Mct8 (Slc16A2)-Specific Thyroid Hormone Cell Transporter Deficiency
Allan-Herndon-Dudley Syndrome
Cadasil
Cockayne Syndrome
Multiple Sulfatase Deficiency
Gangliosidoses
GM2 Gangliosidosis
BPAN
Labrune Syndrome
LCC
Mucopolysaccharidoses
TBCK-Related Intellectual Disability Syndrome
Keywords: leukodystrophy
white matter disease
leukoencephalopathy
myelin
demyelinating
mdbp
Lead sponsor: Children's Hospital of Philadelphia
Sponsor class: OTHER
Collaborators: name: National Institutes of Health (NIH)
name: National Institute of Neurological Disorders and Stroke (NINDS)
name: National Center for Advancing Translational Sciences (NCATS)
name: Biogen
name: Eli Lilly and Company
name: Myrtelle Inc.
name: Orchard Therapeutics Ltd.
name: Passage Bio, Inc.
name: Synaptix Biotherapeutics Ltd.
name: Takeda
name: Boehringer Ingelheim
name: Ionis Pharmaceuticals, Inc.
name: Sanofi Winthrop Industrie
name: Sana Biotechnology
name: Yaya Foundation for 4H Leukodystrophy
name: University of Pennsylvania
name: United MSD Foundation
name: Foundation to Fight H-ABC
name: Calliope Joy Foundation
name: Don't Forget Me Foundation
First posted: 2017-02-09
Enrollment: 12000
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Affected subjects will have either a confirmed or suspected diagnosis of leukodystrophy, or a related heritable disorder affecting the white matter of the brain. Healthy controls must be individuals in whom no leukodystrophy or related disorder has been suspected or confirmed.

Brief summary: The Myelin Disorders Biorepository Project (MDBP) seeks to collect and analyze clinical data and biological samples from leukodystrophy patients worldwide to support ongoing and future research projects. The MDBP is one of the world's largest leukodystrophy biorepositories, having enrolled nearly 2,000 affected individuals since it was launched over a decade ago.

Researchers working in the biorepository hope to use these materials to uncover new genetic etiologies for various leukodystrophies, develop biomarkers for use in future clinical trials, and better understand the natural history of these disorders. The knowledge gained from these efforts may help improve the diagnostic tools and treatment options available to patients in the future.

Detailed description: Genetic white matter disorders (leukodystrophies) are estimated to have an incidence of approximately 1:7000 live births. In the past, patients with white matter disease of unknown cause evaluated by the investigator achieved a diagnosis in fewer than 46% of cases after extensive conventional clinical testing. Even when a diagnosis is achieved, the diagnosis takes an average of eight years and this "odyssey" results in testing charges to patients and insurers in excess of $8,000 on average per patient, including patients who never achieve a diagnosis at all. With next generation approaches such as whole exome sequencing, the diagnostic efficacy is closer to 70%, but approximately a third of individuals do not achieve a specific etiologic diagnosis. These diagnostic challenges represent an urgent and unresolved gap in knowledge and disease characterization, as obtaining a definitive diagnosis is of paramount importance for leukodystrophy patients.

Moreover, the mechanisms of disease in many leukodystrophies of known cause are very poorly understood, with little known about the best symptomatic management and, thus, limited standards of care are available for the management of these patients.

The purpose of this study is to: (Aim 1) Define novel homogeneous groups of patients with unclassified leukodystrophy and work toward finding the cause of these disorders; (Aim 2) assess the validity and utility of next-generation sequencing in the diagnosis of leukodystrophies; (Aim 3) establish disease mechanisms in selected known leukodystrophies; (Aim 4) track current care and natural history of these patients to define the longitudinal course and determinants of outcomes in these disorders; (Aim 5) contact subjects for future research studies and/or clinical programs.

This biorepository will use available basic science and clinical research approaches to establish novel diagnoses, biomarkers, and outcome measures for future clinical diagnostic and therapeutic approaches.

Eligibility criteria: Inclusion Criteria (Affected Subjects):

* Male or female of any age;
* Suspected or confirmed diagnosis of leukodystrophy or other disorder affecting the white matter of the brain based primarily on the finding of central nervous system neuroimaging consistent with this diagnosis or on an existing diagnosis of a leukodystrophy or genetic leukoencephalopathy as defined in existing classification systems;
* Documentation of informed consent by the subject, parent, or legal guardian, and, if appropriate, documentation of assent;
* Willingness to provide clinical data, participate in standardized assessments, and/or provide biologic samples.

Exclusion Criteria (Affected Subjects)

* Established diagnosis at the time of referral that is not consistent with a genetic disorder of the white matter, such as an acquired demyelinating condition (e.g. multiple sclerosis), or an infectious etiology, with the exception of sequelae of congenital infections such as CMV;
* Inability to provide consent.

Inclusion Criteria (Healthy Controls)

* Male or female of any age;
* Individuals with no confirmed or suspected diagnosis of leukodystrophy or other disorder affecting the white matter of the brain;
* Documentation of informed consent by the subject, parent, or legal guardian, and, if appropriate, documentation of assent.

Exclusion Criteria (Healthy Controls)

- Inability to provide consent.

Primary outcomes:
measure: Define Novel Homogeneous Groups of Patients with Unclassified Leukodystrophy
timeFrame: 01/08/2016 - 01/08/2026
Secondary outcomes:
measure: Assess Validity of Next-Generation Sequencing in the Diagnosis of Leukodystrophies
timeFrame: 01/08/2016 - 01/08/2026
measure: Assess Utility of Next-Generation Sequencing in the Diagnosis of Leukodystrophies
timeFrame: 01/08/2016 - 01/08/2026
measure: Track Current Care of Leukodystrophy Patients
timeFrame: 01/08/2016 - 01/08/2026
measure: Track Natural History of Leukodystrophy Patients
timeFrame: 01/08/2016 - 01/08/2026
measure: Establish Disease Mechanisms in Leukodystrophies
timeFrame: 01/08/2016 - 01/08/2026
measure: Contact for Future Research Studies and/or Clinical Programs
timeFrame: 01/08/2016 - 01/08/2026
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Children's Hospital of Los Angeles
state: California
city: Orange
country: United States
facility: Children's Hospital of Orange County
state: California
city: Palo Alto
country: United States
facility: Stanford University (Lucile Packard Children's Hospital)
state: California
city: Sacramento
country: United States
facility: University of California, Davis (UC Davis Health)
state: California
city: San Diego
country: United States
facility: University of California, San Diego (Rady Children's Hospital)
state: California
city: San Francisco
country: United States
facility: UCSF Benioff Children's Hospital
state: California
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Atlanta
country: United States
facility: Emory University (Children's Healthcare of Atlanta)
state: Georgia
city: Chicago
country: United States
facility: Ann & Robert H. Lurie Children's Hospital of Chicago
state: Illinois
city: Baltimore
country: United States
facility: Kennedy Krieger Institute
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital (MGH)
state: Massachusetts
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Winston-Salem
country: United States
facility: Atrium Health Wake Forest Baptist
state: North Carolina
city: Akron
country: United States
facility: Akron Children's Hospital
state: Ohio
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Philadelphia
country: United States
facility: The Children's Hospital of Philadelphia
state: Pennsylvania
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
city: Houston
country: United States
facility: Baylor College of Medicine (Texas Children's Hospital)
state: Texas
city: Houston
country: United States
facility: UT Health Houston
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah (Primary Children's Hospital)
state: Utah
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
Study officials:
affiliation: Children's Hospital of Philadelphia
name: Adeline Vanderver, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Adang LA, Schlotawa L, Groeschel S, Kehrer C, Harzer K, Staretz-Chacham O, Silva TO, Schwartz IVD, Gartner J, De Castro M, Costin C, Montgomery EF, Dierks T, Radhakrishnan K, Ahrens-Nicklas RC. Natural history of multiple sulfatase deficiency: Retrospective phenotyping and functional variant analysis to characterize an ultra-rare disease. J Inherit Metab Dis. 2020 Nov;43(6):1298-1309. doi: 10.1002/jimd.12298. Epub 2020 Aug 20.