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BMC Neurology
Published in: BMC Neurology 1/2021

Open Access 01-12-2021 | Polyneuropathy | Research

Molecular epidemiology of hereditary ataxia in Finland

Authors: Joonas Lipponen, Seppo Helisalmi, Joose Raivo, Ari Siitonen, Hiroshi Doi, Harri Rusanen, Maria Lehtilahti, Mervi Ryytty, Markku Laakso, Fumiaki Tanaka, Kari Majamaa, Laura Kytövuori

Published in: BMC Neurology | Issue 1/2021

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Abstract

Background

The 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 methods

All 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.

Results

A 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.

Conclusions

Expansion 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.
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Metadata
Title
Molecular epidemiology of hereditary ataxia in Finland
Authors
Joonas Lipponen
Seppo Helisalmi
Joose Raivo
Ari Siitonen
Hiroshi Doi
Harri Rusanen
Maria Lehtilahti
Mervi Ryytty
Markku Laakso
Fumiaki Tanaka
Kari Majamaa
Laura Kytövuori
Publication date
01-12-2021
Publisher
BioMed Central
Published in
BMC Neurology / Issue 1/2021
Electronic ISSN: 1471-2377
DOI
https://doi.org/10.1186/s12883-021-02409-z

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