title: The frequency of spinocerebellar ataxia type 23 in a UK population.
abstract: Spinocerebellar ataxias (SCA) are a genetically heterogeneous group of neurodegenerative diseases characterised by progressive cerebellar ataxia, dysarthria and oculomotor abnormalities. Recently the prodynorphin (PDYN) gene was identified as the cause of SCA23 in four Dutch families displaying progressive gait and limb ataxia. In this study we aimed to assess the frequency of PDYN gene defects and extend the phenotype of SCA23 patients in a UK ataxia series and also in patients from Greece, Egypt and India. We sequenced the coding and flanking intronic regions of the PDYN gene in a total of 852 ataxia patients, of which 356 were sporadic with no family history, 320 had a positive family history, and 176 probands had a positive family history and at least one family member had also been investigated. We also analysed 190 patients with multiple-system atrophy with cerebellar features (MSA-C), a phenocopy of SCA23. We identified a novel putative pathogenic heterozygous missense variant in the PDYN gene in an early onset SCA patient with an unknown family history. This variant was not present in 570 matched British controls. This is the first study to screen for SCA23 in UK patients and confirms that PDYN mutations are a very rare cause of spinocerebellar ataxia, accounting for ~ 0.1 % of ataxia cases but perhaps with a higher frequency in pure cerebellar ataxia. Given the rarity of PDYN mutations, front-line diagnostic evaluation of UK familial and early onset pure spinocerebellar ataxia patients should focus on other known ataxia genes.
authors.affiliation: Department of Molecular Neuroscience, Institute of Neurology and The National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, UK. kath.a.fawcett@googlemail.com
authors.forename: Katherine
authors.initials: K
authors.lastname: Fawcett
authors.forename: Mohadeseh
authors.initials: M
authors.lastname: Mehrabian
authors.forename: Yo-Tsen
authors.initials: YT
authors.lastname: Liu
authors.forename: Sherifa
authors.initials: S
authors.lastname: Hamed
authors.forename: Elahe
authors.initials: E
authors.lastname: Elahi
authors.forename: Tamas
authors.initials: T
authors.lastname: Revesz
authors.forename: Georgios
authors.initials: G
authors.lastname: Koutsis
authors.forename: Joshua
authors.initials: J
authors.lastname: Herscheson
authors.forename: Lucia
authors.initials: L
authors.lastname: Schottlaender
authors.forename: Mark
authors.initials: M
authors.lastname: Wardle
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Morrison
authors.forename: Huw R
authors.initials: HR
authors.lastname: Morris
authors.forename: Paola
authors.initials: P
authors.lastname: Giunti
authors.forename: Nicholas
authors.initials: N
authors.lastname: Wood
authors.forename: Henry
authors.initials: H
authors.lastname: Houlden
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D004745:Enkephalins / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011159:Population Surveillance / Q000379:methods; D015995:Prevalence; D011498:Protein Precursors / Q000235:genetics*; D013132:Spinocerebellar Degenerations / Q000175:diagnosis / Q000453:epidemiology* / Q000235:genetics*; D006113:United Kingdom / Q000453:epidemiology
chemical_list: D004745:Enkephalins; D011498:Protein Precursors; C033660:preproenkephalin