Patients with leukodystrophies (LDs) of unknown etiology are a heterogeneous group but constitute the second largest group of genetic white matter diseases. The purpose of this study is to: (a) define novel homogeneous groups of patients with LDs and (b) work toward finding the cause of these disorders. In order to achieve these goals, patients with LDs of unknown cause will be analyzed clinically, neurophysiologically, biochemically and genetically. Patients would have been diagnosed as having no known leukodystrophies at outside centers. At the Clinical Center, such patients will undergo a series of neuropsychological, blood, urine, spinal fluid, radiological, and peripheral tissue pathological tests. Some of these tests will be part of a standard battery while others will be tailored to individual patients. Patients will be followed for 3 years. Patients will be screened for mutations in genes coding for structural myelin proteins. In some patients in whom all tests yielded no information regarding the etiology of their disease, open brain biopsy will be considered. Brain biopsy tissue will be evaluated using a novel combination of approaches including detailed pathological, immunohistochemical, and biochemical analysis of myelin proteins and lipids. Oligodendroglial biology and expression of myelin genes in the brain will also be investigated in situ. 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.
- INCLUSION CRITERIA: 1. Candidates for participation in the protocol will be patients of all ages with clinical and radiographic signs of leukodystrophy who do not have a specific etiology despite a previous comprehensive workup. The preceding investigation would have excluded the following: adrenoleukodystrophy, adrenomyeloneuropathy, metachromatic leukodystrophy, Krabbe disease, Canavan disease, a well-defined amino acid organic acid disorder, or a systemic mitochondrial cytopathy. 2. First -degree relatives of patients with leukodystrophies of unknown etiology (father, mother, siblings, or sons and daughters of the patients) EXCLUSION CRITERIA: 1. Refusal to sign the protocol consent form. 2. Candidates who are unable to travel to the National Institutes of Health Clinical Center.