GENETIC-LINKAGE STUDIES IN AUTOSOMAL-DOMINANT PARKINSONISM - EVALUATION OF 7 CANDIDATE GENES

Linkage studies were performed in three families (A, B, and C) with au tosomal dominantly inherited parkinsonism affecting multiple members i n three generations. Affected individuals exhibited the cardinal signs and symptoms of Parkinson's disease, with a mean age of onset of 51, 62, and 61 years in Families A, B, and C, respectively. Parkinsonian s ymptoms responded to L-dopa treatment, and an [F-18]6-fluoro-L-dopa po sitron emission tomography scan in 1 affected member of Family B showe d decreased striatal uptake typical of Parkinson's disease. Ancestors of all three families were traced to a small region in northern German y and southern Denmark, suggesting the possibility of a common mutatio n. Linkage studies were performed with polymorphic markers associated with the following candidate genes: the genes for glutathione peroxida se (GPX1, 3q11), tyrosine hydroxylase (TH, 11p15.5), brain-derived neu rotrophic factor (BDNF, 11p14), catalase (CAT, 11p13), amyloid precurs or protein (APP, 21q21), copper-zinc superoxide dismutase (SOD1, 21q21 ), and debrisoquin 4-hydroxylase (CYP2D6, 22q13.1). Summed lod scores for all families excluded linkage to the genes GPX1, TH, APP, SOD1, an d CYP2D6, as well as to the chromosomal region containing the genes CA T and BDNF. If families were analyzed individually, exclusion was poss ible for two (Family A), six (Family B), and five (Family C) of the se ven candidate genes. There was strong evidence against linkage for the remaining loci in all families analyzed individually, except for TH, which was uninformative in Families A and B, and CYP2D6, which gave sl ightly positive pairwise lod scores in Family A. Our results indicate that the candidate genes investigated are not involved in the etiology of parkinsonism in these families.