Natural History of the Leukodystrophies

Study Overview
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Brief Summary
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The purpose of this study is to: define novel homogeneous groups of patients with LDs and work toward finding the cause of these disorders.

Detailed Description
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Patients with leukodystrophies (LDs) of unknown etiology are a heterogeneous group but constitute the second largest group of genetic white matter diseases. In order to find the cause of leukodystrophies, 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 Baylor University Medical 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 yearly or as necessary. 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, and in whom there is evidence to suggest involvement of the peripheral nervous system, a sural nerve biopsy will be considered. Sural nerve biopsy tissue will be evaluated using a novel combination of approaches including detailed pathological, immunohistochemical, and biochemical analysis of myelin proteins and lipids. Schwann cell 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.

Official Title
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The Etiology, Pathogenesis, and Natural History of the Leukodystrophies

Conditions
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Leukodystrophies

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must: have clinical and radiographic signs of leukodystrophy without a specific etiology no diagnosis of adrenoleukodystrophy, adrenomyeloneuropathy, metachromatic leukodystrophy, Krabbe disease, Canavan disease, a well-defined amino acid organic acid disorder, or a systemic mitochondrial cytopathy. First-degree relatives of patients with leukodystrophies of unknown etiology (father, mother, siblings, or sons and daughters of the patients) Be able to travel to Baylor University Medical Center in Dallas Texas for evaluation and spend 5-8 working days on site Be able to tolerate a general exam and neurological exam Be able to tolerate a modest amount of blood drawing, provide a urine specimen, and have a skin biopsy(if not previously done) Be able to tolerate the performance of necessary neuroimaging studies to include EEG and Head MRI Be able to tolerate a neuropsychological testing and rehabilitation evaluation Be able to tolerate spinal tap or nerve biopsy if needed Exclusion Criteria: Unable to travel to Baylor University Medical Center in Dallas Texas for evaluation Refusal to sign a study consent form Unable to tolerate the performance of the required testing
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Leukodystrophy of unknown etiology<br>Subjects who may have an undiagnosed form of leukodystrophy | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neuropsychological evaluation to measure baseline cognitive function and detect signs of dementia over time | Neuropsychological status is evaluated at Baseline and no less than once every year for the duration of the study to assess for any deterioration in function | Every 52 weeks up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evoked potentials to assess involvement of different areas of brain over time | Evoked potentials are evaluated at Baseline and no less than once every year for the duration of the study to assess for changes in function | Every 52 weeks up to 5 years | 
| MRI of the brain to assess involvement of different areas of the brain over time | Changes in the brain are assessed at Baseline and no less than once every year for the duration of the study to assess for changes | Every 52 weeks | 
| Electroencephalogram to assess involvement of different areas of the brain over time | EEG is assessed at Baseline and no less than once a year for the duration of the study to assess for changes in function | Every 52 weeks up to 5 years | 
| Electromyelogram to assess for changes in muscle function over time | EMG is assessed at Baseline and no less than once a year for the duration of the study to assess for changes in function | Every 52 weeks up to 5 years | 
| Nerve Conduction study to assess abnormalities in affected nerves | Nerve conduction is assessed at Baseline and no less than once a year for the duration of the study to assess for changes in function | Every 52 weeks up to 5 years | 
| Skin biopsy for to look for evidence of storage disease |  | Baseline | 
| DNA Studies to search for mutations in genes of structural myelin proteins or genes that control myelin production |  | Baseline | 
| Spinal Tap to look for diagnostic markers of leukodystrophy |  | Baseline | 
| Nerve Biopsy to look for pathological abnormalities in affected nerves |  | Baseline | 
| Neuro-ophthalmological exam to assess for abnormalities in the eye | Eyes are assessed at Baseline and no less than once a year for the duration of the study to assess for changes in function | Every 52 weeks up to 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Leukodystrophy, Myelin Gene, Myelin Protein, Sural Nerve Biopsy, Undiagnosed Disease, Schwann Cell, White Matter Pathology, Motor Delay, Cognitive Regression, Motor Deterioration, Unknown Disease