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Distal hereditary motor neuropathies: Mutation spectrum and genotype–phenotype correlation
Author(s) -
Frasquet Marina,
RojasGarcía Ricard,
ArgenteEscrig Herminia,
VázquezCosta Juan Francisco,
Muelas Nuria,
Vílchez Juan Jesús,
Sivera Rafael,
Millet Elvira,
Barreiro Marisa,
DíazManera Jordi,
TuronSans Janina,
CortésVicente Elena,
Querol Luis,
RamírezJiménez Laura,
MartínezRubio Dolores,
SánchezMonteagudo Ana,
Espinós Carmen,
Sevilla Teresa,
Lupo Vincenzo
Publication year - 2021
Publication title -
european journal of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.881
H-Index - 124
eISSN - 1468-1331
pISSN - 1351-5101
DOI - 10.1111/ene.14700
Subject(s) - proband , sanger sequencing , medicine , genetic heterogeneity , genetic testing , genotype , genetics , mutation , phenotype , gene , biology
Background 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.