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

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 thes...

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Published in:European journal of neurology 2021-04, Vol.28 (4), p.1334-1343
Main Authors: Frasquet, Marina, Rojas‐García, Ricard, Argente‐Escrig, Herminia, Vázquez‐Costa, Juan Francisco, Muelas, Nuria, Vílchez, Juan Jesús, Sivera, Rafael, Millet, Elvira, Barreiro, Marisa, Díaz‐Manera, Jordi, Turon‐Sans, Janina, Cortés‐Vicente, Elena, Querol, Luis, Ramírez‐Jiménez, Laura, Martínez‐Rubio, Dolores, Sánchez‐Monteagudo, Ana, Espinós, Carmen, Sevilla, Teresa, Lupo, Vincenzo
Format: Article
Language:English
Subjects:
Charcot-Marie-Tooth Disease - genetics
Charcot‐Marie‐Tooth
Child
Child, Preschool
Degeneration
Diagnosis
Disorders
distal hereditary motor neuropathy
distal spinal muscular atrophy
Genes
Genetic Association Studies
Genetic disorders
Genetic screening
Genetic Testing
Genotypes
Hereditary Sensory and Motor Neuropathy
Heterogeneity
Heterozygote
HSP40 Heat-Shock Proteins
Humans
Molecular Chaperones
Mutation
Neuromuscular diseases
Peripheral nerves
Peripheral neuropathy
Phenotypes
Signs and symptoms
Sorbitol
SORD
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Summary: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. Distal hereditary motor neuropathies (dHMNs) are rare and genetically heterogeneous diseases. In this study, the diagnosis rate is 47.8%, and the calculated minimum prevalence is at least 2.3 per 100,000 individuals. The most frequent genetic causes of dHMN in our population are mutations in the HSPB1, GARS1, BICD2, and DNAJB2 genes, whereas 3.1% of patients carry biallelic mutations in SORD.
ISSN:1351-5101
1468-1331
DOI:10.1111/ene.14700