The Myelin Disorders Biorepository Project (MDBP)

The Myelin Disorders Biorepository Project and Global Leukodystrophy Initiative Clinical Trials Network

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.

Study Overview

• Status: Recruiting
• Conditions: Mucopolysaccharidoses; Leukoencephalopathies; Leukodystrophy; Adrenoleukodystrophy; Adrenomyeloneuropathy; X-linked Adrenoleukodystrophy; Gangliosidoses; Metachromatic Leukodystrophy; Krabbe Disease; Refsum Disease; Cadasil; Sjogren-Larsson Syndrome; Allan-Herndon-Dudley Syndrome; White Matter Disease; GM2 Gangliosidosis; Zellweger Syndrome; ALSP; Pelizaeus-Merzbacher Disease; ALD (Adrenoleukodystrophy); Cockayne Syndrome; Cerebrotendinous Xanthomatoses; Canavan Disease; CTX; Aicardi Goutieres Syndrome; AMN; X-ALD; Mct8 (Slc16A2)-Specific Thyroid Hormone Cell Transporter Deficiency; LBSL; Leukoencephalopathy With Brainstem and Spinal Cord Involvement and Lactate Elevation; PMD; Charcot-Marie-Tooth; Alexander Disease; TUBB4A-Related Leukodystrophy; 4H Syndrome; Multiple Sulfatase Deficiency; Megalencephalic Leukoencephalopathy With Subcortical Cysts; Vanishing White Matter Disease; Labrune Syndrome; ADLD; Peroxisomal Biogenesis Disorder; CMT; Sjögren; MLD; ALD; AGS; Alexanders Leukodystrophy; AxD; GALC Deficiency; Globoid Leukodystrophy; H-ABC - Hypomyelination, Atrophy of Basal Ganglia and Cerebellum; HBSL; HBSL - Hypomyelination, Brain Stem, Spinal Cord, Leg Spasticity; Leukoencephalopathy With Brain Stem and Spinal Cord Involvement and High Lactate Syndrome (Disorder); CSF1R Gene Mutation; HCC - Hypomyelination and Congenital Cataract; MLC1; PLP1 Null Syndrome; PLP1 Gene Duplication | Blood or Tissue | Mutations; Salla Disease; Sialic Storage Disease; Van Der Knapp Disease; BPAN; LCC; TBCK-Related Intellectual Disability Syndrome; ALD Gene Mutation; Pelizaeus Merzbacher Like Disease

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.

• Study Type: Observational
• Enrollment (Estimated): 12000

Contacts and Locations

• Study Contact: Name: Omar S. Sherbini, MPH; Phone Number: 215-590-3068; Email: sherbinio@chop.edu

Study Locations

• United States
  • California
    • Palo Alto, California, United States, 94304
      • Recruiting
      • Stanford University (Lucile Packard Children's Hospital)
      • Contact: Keith Van Haren, MD
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Recruiting
      • Children's National Medical Center
      • Contact: Jamie Fraser, MD, PhD
  • Georgia
    • Atlanta, Georgia, United States, 30342
      • Recruiting
      • Emory University (Children's Healthcare of Atlanta)
      • Contact: Stephanie Keller, MD
  • Maryland
    • Baltimore, Maryland, United States, 21205
      • Recruiting
      • Kennedy Krieger Institute
      • Contact: Ali Fatemi, MD, MBA
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Recruiting
      • Massachusetts General Hospital (MGH)
      • Contact: Florian Eichler, MD
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Recruiting
      • University of Pennsylvania
      • Contact: Jennifer Orthmann-Murphy, MD, PhD
    • Philadelphia, Pennsylvania, United States, 19104
      • Recruiting
      • The Children's Hospital of Philadelphia
      • Sub-Investigator: Laura Adang, MD, PhD, MSTR
      • Sub-Investigator: Amy Waldman, MD, MSCE
      • Contact: Omar Sherbini, MPH; Phone Number: 215-590-3068; Email: sherbinio@chop.edu
      • Principal Investigator: Adeline Vanderver, MD
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • Baylor College of Medicine (Texas Children's Hospital)
      • Contact: Lisa Emrick, MD
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Recruiting
      • University of Utah (Primary Children's Hospital)
      • Contact: Joshua Bonkowsky, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

• 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.

Description

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.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Define Novel Homogeneous Groups of Patients with Unclassified Leukodystrophy	In patients with an unclassified leukodystrophy, the study team will collect as much information as available from existing medical records including existing clinical evaluations, neuropsychological/rehabilitation evaluations, and results from blood, urine, spinal fluid, radiological, and peripheral tissue pathological tests. This data will be evaluated to create nosologic groups amongst patients with unclassified leukodystrophy. Additionally, this aim includes the collection and long-term banking of biological samples in subjects with classified and unclassified leukodystrophies to develop a biorepository. These samples will be compared to samples collected from control subjects, either collected directly from enrolled subjects or through existing banked biological samples.	01/08/2016 - 01/08/2026

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assess Validity of Next-Generation Sequencing in the Diagnosis of Leukodystrophies	Unclassified leukodystrophy patients enrolled in this study may undergo next generation sequencing approaches, including research whole exome sequencing (WES), whole genome sequencing (WGS), RNA sequencing and high throughput genomics analysis in parallel to standard clinical testing to achieve novel molecular classifications.	01/08/2016 - 01/08/2026
Assess Utility of Next-Generation Sequencing in the Diagnosis of Leukodystrophies	Clinical utility defined as changes in care and clinical state, included changes in medical morbidities, surgeries, pharmacologic management of complications and implementation of disease specific therapies.	01/08/2016 - 01/08/2026
Track Current Care of Leukodystrophy Patients	Includes a longitudinal collection of clinical data on diagnostic and therapeutic interventions in leukodystrophy patients and related controls.	01/08/2016 - 01/08/2026
Track Natural History of Leukodystrophy Patients	Includes longitudinal collection of clinical data on disease presentation, progression and morbidities.	01/08/2016 - 01/08/2026
Establish Disease Mechanisms in Leukodystrophies	Specific leukodystrophies will be selected for further mechanistic study, using clinical and laboratory tools to establish increased understanding of the underlying pathophysiology. The over-riding hypothesis of this aim is that integrated biochemical, genomic, metabolic, histologic and immunologic profiles of patients with leukodystrophy will define downstream pathway changes consistent with primary defects causing white matter disease. Appropriate controls will be used for comparison to disease related samples.	01/08/2016 - 01/08/2026
Contact for Future Research Studies and/or Clinical Programs	Individuals enrolled in the study may be informed of other research studies, either at the Children's Hospital of Philadelphia or another site affiliated or not affiliated with this study, that may be of interest to them and/or their their families based on a specific diagnosis or lack thereof.	01/08/2016 - 01/08/2026

Collaborators and Investigators

• Sponsor: Children's Hospital of Philadelphia
• Collaborators: Eli Lilly and Company; University of Pennsylvania; Takeda; National Institute of Neurological Disorders and Stroke (NINDS); Boehringer Ingelheim; National Institutes of Health (NIH); Biogen; National Center for Advancing Translational Sciences (NCATS); Homology Medicines, Inc; Passage Bio, Inc.; Myrtelle Inc.; Affinia Therapeutics; Orchard Therapeutics Ltd.; Synaptix Biotherapeutics Ltd.; Ionis Pharmaceuticals; Sanofi Winthrop Industrie; Sana Biotechnology, Inc.; Yaya Foundation for 4H Leukodystrophy
• Investigators: Principal Investigator: Adeline Vanderver, MD, Children's Hospital of Philadelphia

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): December 8, 2016
• Primary Completion (Estimated): December 8, 2030
• Study Completion (Estimated): December 8, 2030

Study Registration Dates

• First Submitted: February 1, 2017
• First Submitted That Met QC Criteria: February 8, 2017
• First Posted (Estimated): February 9, 2017

Study Record Updates

• Last Update Posted (Actual): December 18, 2023
• Last Update Submitted That Met QC Criteria: December 11, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: white matter disease; leukoencephalopathy; demyelinating; leukodystrophy; myelin; mdbp
• Additional Relevant MeSH Terms: Mental Disorders; Digestive System Diseases; Ischemia; Pathologic Processes; Necrosis; Cardiovascular Diseases; Vascular Diseases; Metabolic Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Skin Diseases; Immune System Diseases; Demyelinating Diseases; Autoimmune Diseases; Kidney Diseases; Urologic Diseases; Eye Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Endocrine System Diseases; Disease; Congenital Abnormalities; Infant, Newborn, Diseases; Liver Diseases; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Neuromuscular Diseases; Stomatognathic Diseases; Mouth Diseases; Neurodegenerative Diseases; Peripheral Nervous System Diseases; Skin Diseases, Genetic; Brain Ischemia; Bone Diseases; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Lysosomal Storage Diseases; Mucinoses; Mental Retardation, X-Linked; Heredodegenerative Disorders, Nervous System; DNA Repair-Deficiency Disorders; Lipid Metabolism Disorders; Dementia; Lacrimal Apparatus Diseases; Neurodevelopmental Disorders; Brain Diseases, Metabolic; Infarction; Stroke; Brain Infarction; Brain Diseases, Metabolic, Inborn; Skin Abnormalities; Nervous System Malformations; Abnormalities, Multiple; Cerebral Arterial Diseases; Intracranial Arterial Diseases; Sphingolipidoses; Lysosomal Storage Diseases, Nervous System; Cerebral Small Vessel Diseases; Lipidoses; Lipid Metabolism, Inborn Errors; Dwarfism; Bone Diseases, Developmental; Arthritis, Rheumatoid; Xerostomia; Salivary Gland Diseases; Dry Eye Syndromes; Adrenal Gland Diseases; Polyneuropathies; Hereditary Central Nervous System Demyelinating Diseases; Adrenal Insufficiency; Sulfatidosis; Keratosis; Ichthyosis; Cerebral Infarction; Dementia, Vascular; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Syndrome; Mucopolysaccharidoses; Sjogren's Syndrome; Intellectual Disability; Peroxisomal Disorders; Leukoencephalopathies; Adrenoleukodystrophy; Gangliosidoses; Leukodystrophy, Metachromatic; Leukodystrophy, Globoid Cell; Nerve Compression Syndromes; Charcot-Marie-Tooth Disease; Hereditary Sensory and Motor Neuropathy; CADASIL; Refsum Disease; Sjogren-Larsson Syndrome; Xanthomatosis, Cerebrotendinous; Xanthomatosis; Gangliosidoses, GM2; Tay-Sachs Disease; Zellweger Syndrome; Pelizaeus-Merzbacher Disease; Cockayne Syndrome; Canavan Disease; Sialic Acid Storage Disease; Alexander Disease; Multiple Sulfatase Deficiency Disease
• Other Study ID Numbers: 14-011236; U54NS115052 (U.S. NIH Grant/Contract); U01NS106845 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: IPD will be made available to researchers, sponsors, and other stakeholders. Data Use Agreement (DUA) must be put in place with any recipient of IPD. Only aggregate data will be shared publicly.
• IPD Sharing Time Frame: IPD may be shared at any time.
• IPD Sharing Access Criteria: Only aggregate data will be shared publicly. Please contact a member of the central study team for information regarding the release of IPD.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No