The Myelin Disorders Biorepository Project

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 outcomes

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

Secondary outcomes

• Assess Validity of Next-Generation Sequencing in the Diagnosis of Leukodystrophies [10 years from enrollment]: 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.
• Assess Utility of Next-Generation Sequencing in the Diagnosis of Leukodystrophies [10 years from enrollment]: 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.
• Track Current Care of Leukodystrophy Patients [10 years from enrollment]: Includes a longitudinal collection of clinical data on diagnostic and therapeutic interventions in leukodystrophy patients and related controls.
• Track Natural History of Leukodystrophy Patients [10 years from enrollment]: Includes longitudinal collection of clinical data on disease presentation, progression and morbidities.
• Establish Disease Mechanisms in Leukodystrophies [10 years from enrollment]: 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.
• Contact for Future Research Studies and/or Clinical Programs [10 years from enrollment]: 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.

Sex: All

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.

• Results publication: 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. PMID 32749716

• Adeline Vanderver, MD, Principal investigator, Children's Hospital of Philadelphia

NIH grants: U54NS115052, U01NS106845