title: Novel mutation in ATP13A2 widens the spectrum of Kufor-Rakeb syndrome (PARK9).
abstract: Kufor-Rakeb syndrome (KRS) is a rare autosomal recessive inherited juvenile parkinsonian syndrome caused by mutations in ATP13A2. We describe six patients from a consanguineous Greenlandic Inuit family, homozygous for a novel frame-shift mutation in exon 22 of ATP13A2 (c.2473C>AA, p.Leu825AsnfsX32). Disease onset varied from 10 to 29 years of age, the latest reported, and the clinical features were highly variable within a wide spectrum of an extrapyramidal-pyramidal syndrome with cognitive/psychiatric features. Ataxia was seen in two patients and axonal neuropathy in one, features not previously related to KRS. Dopamine transporter scans showed symmetrical, severely reduced uptake in striatum in two patients. Magnetic resonance imaging was without atrophy in one patient despite disease duration of 17 years, and cerebral and cerebellar atrophy was seen in another patient after 4 years of disease duration. The molecular pathogenic mechanisms of ATP13A2 mutations are discussed. The observation that the mutant transcript is not degraded by nonsense-mediated RNA decay and the fact that none of the eight heterozygous carriers from the family have KRS symptoms suggest that the mutant protein does not interfere and destroy the function of the wild-type ATP13A2 protein.
authors.affiliation: Department of Cellular and Molecular Medicine, Faculty of Health, University of Copenhagen, Copenhagen, Denmark. he@sund.ku.dk
authors.forename: H
authors.initials: H
authors.lastname: Eiberg
authors.forename: L
authors.initials: L
authors.lastname: Hansen
authors.forename: L
authors.initials: L
authors.lastname: Korbo
authors.forename: I M
authors.initials: IM
authors.lastname: Nielsen
authors.forename: K
authors.initials: K
authors.lastname: Svenstrup
authors.forename: S
authors.initials: S
authors.lastname: Bech
authors.forename: L H
authors.initials: LH
authors.lastname: Pinborg
authors.forename: L
authors.initials: L
authors.lastname: Friberg
authors.forename: L E
authors.initials: LE
authors.lastname: Hjermind
authors.forename: O R
authors.initials: OR
authors.lastname: Olsen
authors.forename: J E
authors.initials: JE
authors.lastname: Nielsen
mesh_terms: D000328:Adult; D001921:Brain / Q000473:pathology; D005838:Genotype; D006116:Greenland; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009154:Mutation; D059365:Nonsense Mediated mRNA Decay; D020734:Parkinsonian Disorders / Q000201:enzymology / Q000235:genetics*; D010641:Phenotype; D006180:Proton-Translocating ATPases / Q000235:genetics* / Q000378:metabolism
chemical_list: C514983:ATP13A2 protein, human; D006180:Proton-Translocating ATPases