title: Recessive dystonia-ataxia syndrome in a Turkish family caused by a COX20 (FAM36A) mutation.
abstract: DYTCA is a syndrome that is characterized by predominant dystonia and mild cerebellar ataxia. We examined two affected siblings with healthy, consanguineous, Turkish parents. Both patients presented with a combination of childhood-onset cerebellar ataxia, dystonia, and sensory axonal neuropathy. In the brother, dystonic features were most pronounced in the legs, while his sister developed torticollis. Routine diagnostic investigations excluded known genetic causes. Biochemical analyses revealed a mitochondrial respiratory chain complex IV and a coenzyme Q10 deficiency in a muscle biopsy. By exome sequencing, we identified a homozygous missense mutation (c.154A >C; p.Thr52Pro) in both patients in exon 2 of the COX20 (FAM36A) gene, which encodes a complex IV assembly factor. This variant was confirmed by Sanger sequencing, was heterozygous in both parents, and was absent from 427 healthy controls. The exact same mutation was recently reported in a patient with ataxia and muscle hypotonia. Among 128 early-onset dystonia and/or ataxia patients, we did not detect any other patient with a COX20 mutation. cDNA sequencing and semi-quantitative analysis were performed in fibroblasts from one of our homozygous mutation carriers and six controls. In addition to the exchange of an amino acid, the mutation led to a shift in splicing. In conclusion, we extend the phenotypic spectrum of a recently identified mutation in COX20 to a recessively inherited, early-onset dystonia-ataxia syndrome that is characterized by reduced complex IV activity. Further, we confirm a pathogenic role of this mutation in cerebellar ataxia, but this mutation seems to be a rather rare cause.
authors.affiliation: Department of Neurology, Charité-University Medicine Berlin, Berlin, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Doss
authors.forename: Katja
authors.initials: K
authors.lastname: Lohmann
authors.forename: Philip
authors.initials: P
authors.lastname: Seibler
authors.forename: Björn
authors.initials: B
authors.lastname: Arns
authors.forename: Thomas
authors.initials: T
authors.lastname: Klopstock
authors.forename: Christine
authors.initials: C
authors.lastname: Zühlke
authors.forename: Karen
authors.initials: K
authors.lastname: Freimann
authors.forename: Susen
authors.initials: S
authors.lastname: Winkler
authors.forename: Thora
authors.initials: T
authors.lastname: Lohnau
authors.forename: Mario
authors.initials: M
authors.lastname: Drungowski
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.forename: Karin
authors.initials: K
authors.lastname: Wiegers
authors.forename: Ebba
authors.initials: E
authors.lastname: Lohmann
authors.forename: Sadaf
authors.initials: S
authors.lastname: Naz
authors.forename: Meike
authors.initials: M
authors.lastname: Kasten
authors.forename: Georg
authors.initials: G
authors.lastname: Bohner
authors.forename: Alfredo
authors.initials: A
authors.lastname: Ramirez
authors.forename: Matthias
authors.initials: M
authors.lastname: Endres
authors.forename: Christine
authors.initials: C
authors.lastname: Klein
mesh_terms: D000328:Adult; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D002524:Cerebellar Ataxia / Q000150:complications / Q000235:genetics* / Q000473:pathology; D004252:DNA Mutational Analysis; D020821:Dystonic Disorders / Q000150:complications / Q000235:genetics* / Q000473:pathology; D005192:Family Health; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D007473:Ion Channels / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D008297:Male; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D014162:Transfection; D014421:Turkey
chemical_list: D007473:Ion Channels; C515204:PIEZO1 protein, human; D012333:RNA, Messenger