A CLINICAL AND MOLECULAR-GENETIC STUDY OF DENTATORUBROPALLIDOLUYSIAN ATROPHY IN 4 EUROPEAN FAMILIES

Dentatorubropallidoluysian atrophy is a neurodegenerative disorder wit h characteristic pathology, chiefly described in reports from Japan, a nd is associated with an unstable CAG trinucleotide repeat in a gene o n chromosome 12. We describe four European families, three British and one Maltese, with this mutation. All exhibited autosomal dominant inh eritance, and there was evidence for anticipation associated with an i ncrease of the expansion with paternal transmission in two families. A ffected chromosomes from patients with dentatorubropallidoluysian atro phy had CAG expansions of 58 to 74 repeats, compared to 7 to 26 in con trol chromosomes, and the size of repeat was significantly inversely c orrelated with age of onset. The clinical features were diverse, even within individual families, and comprised a combination of a movement disorder (chorea, myoclonus, dystonia, or parkinsonism), cerebellar at axia, epilepsy, psychosis, and dementia. A clinical diagnosis of Hunti ngton's disease had been made in affected individuals from all familie s. Neuropathological examination of 2 patients showed no specific abno rmality in one and degenerative changes predominantly affecting the sp inal cord in the other. Investigation of 55 patients who might represe nt sporadic examples of dentatorubropallidoluysian atrophy did not det ect any expanded alleles. Dentatorubropallidoluysian atrophy is likely to be more common than previously recognized in non-Japanese populati ons, and should be considered in any patient with a dominantly inherit ed neurodegenerative disorder with the above-mentioned clinical featur es.