RELATIONS BETWEEN GENOTYPE AND PHENOTYPE IN GERMAN PATIENTS WITH THE MACHADO-JOSEPH-DISEASE MUTATION

Objective-Machado-Joseph disease (MJD) is an autosomal dominant cerebe llar ataxia with extensive phenotypic variability originally described in families of Portuguese ancestry. Recently, the mutation causing th e disease has been identified as an expanded CAG trinucleotide repeat. In this study relations between genotype and phenotype were investiga ted. Methods-A series of 180 German patients with degenerative forms o f ataxia were clinically and genetically examined. Patients bearing th e MJD mutation were assigned to three phenotypes: phenotype 1 characte rised by early onset and dystonia or pronounced rigidity associated wi th ataxia and spasticity. Main symptoms in phenotype 2 were ataxia and spasticity. In phenotype 3 onset was relatively late and peripheral n europathy accompanied ataxia. Clinical and molecular data were correla ted. Results-An expanded CAG array was found in 42 patients from 22 fa milies. Repeat length of CAG varied between 67 and 80 CAG motifs and s howed an inverse correlation with the age of onset. For the developmen t of phenotype 1 early onset (< 20 years) seemed more decisive than ex tensive repeat length. Phenotype 2 was present in all patients with mo re than 73 CAG motifs and onset between 20 and 40. Phenotype 3 develop ed in most patients with less than 73 CAG motifs and onset was regular ly beyond the age of 40. Intrafamilial variability of both repeat leng th and phenotype was large reflecting meiotic instability of the expan ded CAG repeat. Conclusion-The MJD mutation is the most frequent cause of dominantly inherited ataxia in Germany. Variations in repeat lengt hs substantially influence age of onset as well as phenotype but canno t explain why MJD characteristics of Portuguese families such as ('bul ging eyes'', dystonia, and rigidity are essentially missing in German families. Despite the genotypic and phenotypic relations found in this study a reliable individual prognosis of the course of the disease is not possible at a presymptomatic stage.