The Myelin Disorders Biorepository Project

Official title

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

Overview

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.

Primary outcome measures

• Define Novel Homogeneous Groups of Patients with Unclassified Leukodystrophy [Time frame: 10 years from enrollment]

Secondary outcome measures (6)

• Assess Validity of Next-Generation Sequencing in the Diagnosis of Leukodystrophies [Time frame: 10 years from enrollment]
• Assess Utility of Next-Generation Sequencing in the Diagnosis of Leukodystrophies [Time frame: 10 years from enrollment]
• Track Current Care of Leukodystrophy Patients [Time frame: 10 years from enrollment]
• Track Natural History of Leukodystrophy Patients [Time frame: 10 years from enrollment]
• Establish Disease Mechanisms in Leukodystrophies [Time frame: 10 years from enrollment]
• Contact for Future Research Studies and/or Clinical Programs [Time frame: 10 years from enrollment]

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, or in the presence of variant(s) of uncertain significance or genotype consistent with leukodytrophy;
• 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 (including affected patients' caregivers);
• 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Cohort

Study locations

United States · 23 centers

• Children's Hospital of Los Angeles — Los Angeles
• Children's Hospital of Orange County — Orange
• Stanford University (Lucile Packard Children's Hospital) — Palo Alto
• University of California, Davis (UC Davis Health) — Sacramento
• University of California, San Diego (Rady Children's Hospital) — San Diego
• UCSF Benioff Children's Hospital — San Francisco
• Children's National Medical Center — Washington D.C.
• Emory University (Children's Healthcare of Atlanta) — Atlanta
• … and 15 more centers

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 PMID 32749716

Identifiers

NCT: NCT03047369 · 14-011236 · U54NS115052 · U01NS106845

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗