The purpose of this project is to determine the genetic causes of the autosomal dominant cerebellar ataxias (ADCA) by linkage analysis and to define intra- and interfamilial phenotypic variation and disease progression by serial measurements of biochemical, electrophysiologic, clinical and radiographic parameters. The following issues will be addressed in this study: (1) Is there true genetic heterogeneity or are there other influences that cause the clinical variation in ADCA? (2) Since monoaminergic metabolism is altered in ADCA, how do these abnormalities correlate with disease severity? (3) Can quantitative MRI abnormalities be correlated with the ACRS? (4) Can the addition of psychometric and neuro-physiologic test results with ACRS scores and functional stages yield a comprehensive and clinically useful genetically-based staging classification? (5) Can a longitudinal prospective study monitoring these parameters yield a staging classification with enough statistical power to detect changes in the natural progression of the disease during therapeutic drug trials? Results of studies demonstrate a relationship between subscores on the Ataxia Clinical Rating Scale (ACRS) and the midsagittal areas of the cerebellum, pons and cervical spinal cord on quantitative MRI. Low levels of CSF HVA, a dopamine metabolite, are found in ADCA patients and is related to the degree of pontine atrophy on MRI. In contrast to other studies, 5-HIAA levels were found to be normal when compared to age- matched controls. Although the low levels of CSF HVA probably reflect neuronal loss, the possibility of a metabolic block in dopamine metabolism is being investigated. Genetic screening of 77 patients from 24 families in the Middle Atlantic States Region with ADCA for a trinucleotide repeat expansion on chromosome 6p identified 3 individuals from 2 families with this abnormality. A locus for ADCA was mapped to chromosome 14q24.3-qter in one family and other large kindreds are being tested for candidate loci.
