title: Dentatorubral-pallidoluysian atrophy in three generations, with clinical courses from nearly asymptomatic elderly to severe juvenile, in an Australian family of Macedonian descent.
abstract: We report a three-generation Caucasian family of Macedonian origin with dentatorubral-pallidoluysian atrophy (DRPLA), manifesting as very mild elderly onset, severe young adult onset, and severe childhood onset presentations in the three generations. The grandparental trinucleotide expansion size (52 repeats) is the smallest overtly pathogenic mutation yet reported. This 67-year-old man displayed only subtle neurological and cognitive deficits on formal examination and very slight signs on MRI. His son had developed a choreiform disorder at age 32 years, and by his 40s suffered severe dementia and motor decline. The grandson, the proband, presented as a teenager with progressive myoclonic epilepsy, dysarthria, ataxia, and cognitive decline, having manifesting learning difficulties from the age 5 years. Atrophin-1 expansion sizes of 52, 57, and 66 repeats were demonstrated in the three patients, respectively. Given an absence of any other indicative history in the family, we speculate that the mutation may have expanded from a 'high-end' normal allele to a pathogenic size at the grandfather's conception, or that one of his parents may have had a pathogenic mutation at the lowest end of the expanded range.
authors.affiliation: Department of Neurology, the Royal Melbourne Hospital, The University of Melbourne, Australia.
authors.forename: Anita
authors.initials: A
authors.lastname: Vinton
authors.forename: Michael C
authors.initials: MC
authors.lastname: Fahey
authors.forename: Terence J
authors.initials: TJ
authors.lastname: O'Brien
authors.forename: Janet
authors.initials: J
authors.lastname: Shaw
authors.forename: Elsdon
authors.initials: E
authors.lastname: Storey
authors.forename: R J McKinlay
authors.initials: RJ
authors.lastname: Gardner
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Mitchell
authors.forename: Desirée
authors.initials: D
authors.lastname: Du Sart
authors.forename: John O
authors.initials: JO
authors.lastname: King
mesh_terms: D000328:Adult; D000368:Aged; D001315:Australia; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D006801:Humans; D008297:Male; D020191:Myoclonic Epilepsies, Progressive / Q000235:genetics* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010375:Pedigree; D018843:Republic of North Macedonia / Q000208:ethnology; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*
chemical_list: D009419:Nerve Tissue Proteins; C095278:atrophin-1; D004247:DNA