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8501: Myelin Disorders Biorepository Project (MDBP)


The biorepository supports several GLIA-CTN projects by defining novel homogeneous groups of patients with unclassified leukodystrophies and work toward finding the cause of these disorders (Aim 1), assess the validity and utility of next-generation sequencing in the diagnosis of leukodystrophies (Aim 2), characterize the molecular mechanisms in known leukodystrophies (Aim 3), conduct retrospective and prospective natural history studies to develop a more robust understanding of the disease-specific trajectories and outcomes (Aim 4), and to inform subjects of other research and/or clinical programs that may be applicable and/or beneficial based on their diagnosis or lack thereof (Aim 5).

Study Designs

This is an observational study, involving retrospective review of health records and other data, as well as prospective collection of biological samples, clinical outcome assessments, and patient reported outcomes for individuals with known or suspected leukodystrophies, as well as healthy controls.

There is no strict schedule of visits for any subjects. Collection of updated clinical records, biological samples, and/or standardized COA/PRO data will occur at a frequency of every six (6) months or greater, as this is consistent with the interval at which affected individuals are typically evaluated clinically. Individuals who are unable to visit a participating study site may be invited to participate in remote sample collection and/or assessments.

Additional data will be collected when the subject has an event complicating the leukodystrophy, such as an unexpected hospitalization or a scheduled clinical procedure not related to this study. Data and samples may continue to be collected on control subjects for the purpose of ongoing comparisons between cases and controls. Samples will be retained indefinitely to assist in the identification of rare molecular etiologies, which may present only in an exceptionally small number of individuals, and to assist in the development of biomarkers for established disorders.


This study will take place primarily in inpatient/outpatient settings at the Children’s Hospital of Philadelphia (CHOP), as well as several other domestic pediatric hospitals participating by way of IRB Reliance Agreements. The study also includes remote research activities, such as outcome assessments and questionnaires, that may be administered in a subject’s home.

The number of participants may change over time, however currently a recruitment ceiling of 12,000 total affected subjects and healthy controls is estimated. Affected subjects must have a confirmed or suspected diagnosis of leukodystrophy or other disorder affecting the white matter of the brain. Healthy controls will be recruited for comparison purposes in the context of various assays approved as part of this study.

Inclusion Criteria


  1. Male or female of any age;
  2. 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 (Vanderver et al., 1993, Parikh et al., 2015, Vanderver et al., 2015);
  3. Documentation of informed consent by the subject, parent, or legal guardian, and, if appropriate, documentation of assent;
  4. Willingness to provide clinical data, participate in standardized assessments, and/or provide biologic samples.

Healthy Controls

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

Exclusion Criteria


  1. 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;
  2. Inability to provide consent.

Healthy Controls

Inability to provide consent.

Study procedures may include review of data (e.g., medical records, radiology studies, genetic sequencing files, etc.), as well as biological samples (e.g., blood, tissue samples, CSF, urine, etc.) collected either for research or in the context of clinically-indicated procedures. Subjects may also participate in standardized assessments, interviews, and questionnaires.

Detailed clinical information will be collected for enrolled subjects and analyzed in a standardized, descriptive fashion to identify novel disorders and/or subtypes of existing leukodystrophies. For subjects evaluated clinically at the Children’s Hospital of Philadelphia, the Study Team will review clinical records to obtain information about the subject’s diagnosis, treatment, follow-up, clinic visits, and medical procedures. For subjects evaluated at hospitals, clinics, etc. other than the Children’s Hospital of Philadelphia, the subject will be asked to sign one or more release of information (ROI) forms to allow researchers to collect information from their local physicians and/or hospitals, as needed. Medical records with relevance to understanding the subject’s genetic and medical background, including prenatal records (if the subject’s biological mother has been consented as a healthy control), will be reviewed and abstracted.

Research-based genetic testing, including exome, genome, and RNA sequencing in conjunction with high-throughput genomics analysis may be performed using samples obtained from subjects and healthy controls. These may be obtained specifically for research purposes, or as leftover samples from procedures performed as part of a subject’s routine clinical care. Genetic findings achieved on a research basis must be validated by confirmatory testing in a CLIA/CAP-certified clinical sequencing laboratory prior to being disclosed to subjects.

Affected subjects with specific leukodystrophies may be selected for further mechanistic study, using clinical and laboratory tools to establish increased understanding of the underlying pathophysiology. In this select group, biological samples will be submitted to analyses including histologic, immunologic, genomic, metabolomic, proteomic, and biochemical approaches for the purpose of identifying changes that may help determine the molecular etiology or downstream changes related to the mechanism of disease.

For most leukodystrophies, the natural history of disease, including age at presentation, clinical features, long-term complications, and standard symptomatic management, as well as their impact, are not known. This aim seeks to review clinical records to create a longitudinal dataset of these features. Established clinical outcome assessments (COA) may be used in selected leukodystrophies. Finally, patient reported outcomes (PRO) may be collected from subjects and controls at standardized intervals to help characterize the impact a diagnosis of leukodystrophy has on a patient and family.

Projects Involved with This Study

Project 1

Project 3

Project 4