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Distal hereditary motor neuropathies: Mutation spectrum and genotype–phenotype correlation

Lookup NU author(s): Professor Jordi Diaz ManeraORCiD


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© 2020 European Academy of NeurologyBackground and purpose: Distal hereditary motor neuropathies (dHMNs) are a heterogeneous group of disorders characterized by degeneration of the motor component of peripheral nerves. Currently, only 15% to 32.5% of patients with dHMN are characterized genetically. Additionally, the prevalence of these genetic disorders is not well known. Recently, biallelic mutations in the sorbitol dehydrogenase gene (SORD) have been identified as a cause of dHMN, with an estimated frequency in undiagnosed cases of up to 10%. Methods: In the present study, we included 163 patients belonging to 108 different families who were diagnosed with a dHMN and who underwent a thorough genetic screening that included next-generation sequencing and subsequent Sanger sequencing of SORD. Results: Most probands were sporadic cases (62.3%), and the most frequent age of onset of symptoms was 2 to 10 years (28.8%). A genetic diagnosis was achieved in 37/108 (34.2%) families and 78/163 (47.8%) of all patients. The most frequent cause of distal hereditary motor neuropathies were mutations in HSPB1 (10.4%), GARS1 (9.8%), BICD2 (8.0%), and DNAJB2 (6.7%) genes. In addition, 3.1% of patients were found to be carriers of biallelic mutations in SORD. Mutations in another seven genes were also identified, although they were much less frequent. Eight new pathogenic mutations were detected, and 17 patients without a definite genetic diagnosis carried variants of uncertain significance. The calculated minimum prevalence of dHMN was 2.3 per 100,000 individuals. Conclusions: This study confirms the genetic heterogeneity of dHMN and that biallelic SORD mutations are a cause of dHMN in different populations.

Publication metadata

Author(s): Frasquet M, Rojas-Garcia R, Argente-Escrig H, Vazquez-Costa JF, Muelas N, Vilchez JJ, Sivera R, Millet E, Barreiro M, Diaz-Manera J, Turon-Sans J, Cortes-Vicente E, Querol L, Ramirez-Jimenez L, Martinez-Rubio D, Sanchez-Monteagudo A, Espinos C, Sevilla T, Lupo V

Publication type: Article

Publication status: Published

Journal: European Journal of Neurology

Year: 2021

Volume: 28

Issue: 4

Pages: 1334-1343

Print publication date: 08/03/2021

Online publication date: 28/12/2020

Acceptance date: 17/12/2020

ISSN (print): 1351-5101

ISSN (electronic): 1468-1331

Publisher: John Wiley and Sons Inc


DOI: 10.1111/ene.14700

PubMed id: 33369814


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