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 the 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. This remaining group of patients (unclassified
leukodystrophy) offers the opportunity to describe novel disorders and provide improved
diagnostic tools. 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: many are systemic abnormalities that manifest only testing white matter. Finally,
little is known about the best symptomatic management of the many leukodystrophies without an
etiologic cure 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;
and (Aim 4) track current care and natural history of these patients to define the
longitudinal course and determinants of outcomes in these disorders.

It is hoped that the present study will help clarify the nosology of the leukodystrophies and
significantly advance our understanding of the pathogenesis of these diseases, the best
diagnostic testing tools, and the best symptomatic management of these conditions. Due to the
breadth of this approach, and the rarity of these conditions, these approaches will be
carried out at multiple clinical centers with specialized expertise in the leukodystrophies.

Inclusion Criteria:

- Suspected or confirmed diagnosis of leukodystrophy 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;

- Males or females of any age;

- Parental/guardian permission (informed consent) and if appropriate, child assent or
patient consent;

- Willingness to provide clinical data, participate in standardized assessment and
provide biologic samples.

Exclusion Criteria:

- Identification of a diagnosis not consistent with a genetic disorder of the white
matter such as an acquired demyelinating condition (e.g. Multiple Sclerosis) or an
infectious etiology prior to enrollment, with the exception of sequelae of congenital
infections such as cytomegalovirus (CMV);

- Inability to provide consent;

- Weight below safe range for biological sample collection (typically <3kg).