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Neurogenetics

We have previously reported the exclusion of seven candidate genes in three families (families A, B, and C) with autosomal dominant parkinsonism by linkage analysis (Gasser et al., Ann Neurol 1994; 36: 387-396)). These studies have been extended to include a fourth family with autopsy proven Lewy body parkinsonism with multiple affected family members over four generations. Affecteds of all four families exhibited the cardinal signs and symptoms of Parkinson's disease without additional neurologic deficit except dementia in two patients of family B and amyotrophy in a patient of family A. Mean age of onset was between 51 and 62 years. 18F-6-fluoro-L-Dopa-PET in two affected individuals showed decreased striatal uptake consistent with Parkinson's disease. Autopsy in affecteds from three families showed depigmentation of the substantia nigra and Lewy bodies.
Linkage studies were performed with more than 100 polymorphic markers covering a total distance of 700 to 800 cM of genomic DNA. The chromosomal regions investigated included several genes, which can be considered as candidate genes in autosomal dominant parkinsonism, such as the genes for glutathione peroxidase (GPXl, 3q11), the human dopamine transporter (HUMDPTR, 5p15), Mn-superoxide dismutase (SOD2, 6q25), tyrosine hydroxylase (TH, 11p15.5), brain derived neurotrophic factor (BDNF, 11p14), catalase (CAT, 11p13), the gene for Dopa-responsive Dystonia (DRD, 14q23), amyloid precursor protein (APP, 21q21), Cu/Zn superoxide dismutase (SOD1, 2lq2l), and debrisoquine hydroxilase (CYP2D6, 22q11). Most of the regions bearing these candidate genes could be excluded as carrying the disease gene in these families. These results argue against the involvement of these candidate genes in the etiology of familial parkinsonism.


Headings
autosomal dominant parkinsonism

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