Molecular epidemiology of hereditary ataxia in Finland

BMC Neurology

Hiroshi Doi¹  Fumiaki Tanaka¹  Seppo Helisalmi²  Joose Raivo²  Markku Laakso²  Mervi Ryytty³  Harri Rusanen³  Maria Lehtilahti³  Kari Majamaa³  Laura Kytövuori³  Ari Siitonen³  Joonas Lipponen³ 

[1] Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan;Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio, Finland;Research Unit of Clinical Neuroscience, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, P.O. Box 5000, 90014, Oulu, Finland;Department of Neurology, Oulu University Hospital, Oulu, Finland;

关键词: CANVAS;    Hereditary ataxia;    Molecular epidemiology;    Repeat expansion;   

DOI  :  10.1186/s12883-021-02409-z

来源: Springer

【 摘 要 】

BackgroundThe genetics of cerebellar ataxia is complex. Hundreds of causative genes have been identified, but only a few cause more than single cases. The spectrum of ataxia-causing genes differs considerably between populations. The aim of the study was to investigate the molecular epidemiology of ataxia in the Finnish population.Patients and methodsAll patients in hospital database were reviewed for the diagnosis of unspecified ataxia. Acquired ataxias and nongenetic ataxias such as those related to infection, trauma or stroke were excluded. Sixty patients with sporadic ataxia with unknown etiology and 36 patients with familial ataxia of unknown etiology were recruited in the study. Repeat expansions in the SCA genes (ATXN1, 2, 3, 7, 8/OS, CACNA1A, TBP), FXN, and RFC1 were determined. Point mutations in POLG, SPG7 and in mitochondrial DNA (mtDNA) were investigated. In addition, DNA from 8 patients was exome sequenced.ResultsA genetic cause of ataxia was found in 33 patients (34.4%). Seven patients had a dominantly inherited repeat expansion in ATXN8/OS. Ten patients had mitochondrial ataxia resulting from mutations in nuclear mitochondrial genes POLG or RARS2, or from a point mutation m.8561C > G or a single deletion in mtDNA. Interestingly, five patients were biallelic for the recently identified pathogenic repeat expansion in RFC1. All the five patients presented with the phenotype of cerebellar ataxia, neuropathy, and vestibular areflexia (CANVAS). Moreover, screening of 54 patients with Charcot-Marie-Tooth neuropathy revealed four additional patients with biallelic repeat expansion in RFC1, but none of them had cerebellar symptoms.ConclusionsExpansion in ATXN8/OS results in the majority of dominant ataxias in Finland, while mutations in RFC1 and POLG are the most common cause of recessive ataxias. Our results suggest that analysis of RFC1 should be included in the routine diagnostics of idiopathic ataxia and Charcot-Marie-Tooth polyneuropathy.

【 授权许可】

CC BY