Distal hereditary motor neuropathies: Mutation spectrum and genotype-phenotype correlation
Por:
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
Publicada:
1 abr 2021
Ahead of Print:
1 ene 2021
Resumen:
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.
Filiaciones:
Frasquet, M:
Hosp Univ & Politecn La Fe, Dept Neurol, Neuromuscular Dis Unit, Valencia, Spain
Inst Invest Sanitaria La Fe, Neuromuscular & Ataxias Res Grp, Valencia, Spain
Ctr Invest Biomed Red Enfermedades Raras CIBERER, Valencia, Spain
Rojas-Garcia, R:
Ctr Invest Biomed Red Enfermedades Raras CIBERER, Valencia, Spain
Hosp Santa Creu & Sant Pau, Dept Neurol, Neuromuscular Dis Unit, Barcelona, Spain
Univ Autonoma Barcelona, Barcelona, Spain
Argente-Escrig, H:
Inst Invest Sanitaria La Fe, Neuromuscular & Ataxias Res Grp, Valencia, Spain
Ctr Invest Biomed Red Enfermedades Raras CIBERER, Valencia, Spain
Vazquez-Costa, JF:
Hosp Univ & Politecn La Fe, Dept Neurol, Neuromuscular Dis Unit, Valencia, Spain
Inst Invest Sanitaria La Fe, Neuromuscular & Ataxias Res Grp, Valencia, Spain
Ctr Invest Biomed Red Enfermedades Raras CIBERER, Valencia, Spain
Univ Valencia, Dept Med, Valencia, Spain
Muelas, N:
Hosp Univ & Politecn La Fe, Dept Neurol, Neuromuscular Dis Unit, Valencia, Spain
Inst Invest Sanitaria La Fe, Neuromuscular & Ataxias Res Grp, Valencia, Spain
Ctr Invest Biomed Red Enfermedades Raras CIBERER, Valencia, Spain
Vilchez, JJ:
Inst Invest Sanitaria La Fe, Neuromuscular & Ataxias Res Grp, Valencia, Spain
Ctr Invest Biomed Red Enfermedades Raras CIBERER, Valencia, Spain
Sivera, R:
Hosp Francesc Borja, Dept Neurol, Gandia, Spain
Millet, E:
Hosp Univ & Politecn La Fe, Dept Clin Neurophysiol, Valencia, Spain
Barreiro, M:
Inst Invest Sanitaria La Fe, Neuromuscular & Ataxias Res Grp, Valencia, Spain
Diaz-Manera, J:
Ctr Invest Biomed Red Enfermedades Raras CIBERER, Valencia, Spain
Hosp Santa Creu & Sant Pau, Dept Neurol, Neuromuscular Dis Unit, Barcelona, Spain
Univ Autonoma Barcelona, Barcelona, Spain
Turon-Sans, J:
Ctr Invest Biomed Red Enfermedades Raras CIBERER, Valencia, Spain
Hosp Santa Creu & Sant Pau, Dept Neurol, Neuromuscular Dis Unit, Barcelona, Spain
Univ Autonoma Barcelona, Barcelona, Spain
Cortes-Vicente, E:
Ctr Invest Biomed Red Enfermedades Raras CIBERER, Valencia, Spain
Hosp Santa Creu & Sant Pau, Dept Neurol, Neuromuscular Dis Unit, Barcelona, Spain
Univ Autonoma Barcelona, Barcelona, Spain
Querol, L:
Ctr Invest Biomed Red Enfermedades Raras CIBERER, Valencia, Spain
Hosp Santa Creu & Sant Pau, Dept Neurol, Neuromuscular Dis Unit, Barcelona, Spain
Univ Autonoma Barcelona, Barcelona, Spain
Ramirez-Jimenez, L:
Ctr Invest Principe Felipe CIPF, Dept Genom & Translat Genet, Valencia, Spain
Martinez-Rubio, D:
Ctr Invest Principe Felipe CIPF, Unit Genet & Genom Neuromuscular & Neurodegenerat, Valencia, Spain
INCLIVA & IIS La Fe CIPF, Rare Dis Joint Units, Valencia, Spain
Sanchez-Monteagudo, A:
Ctr Invest Principe Felipe CIPF, Unit Genet & Genom Neuromuscular & Neurodegenerat, Valencia, Spain
INCLIVA & IIS La Fe CIPF, Rare Dis Joint Units, Valencia, Spain
Espinos, C:
Ctr Invest Principe Felipe CIPF, Unit Genet & Genom Neuromuscular & Neurodegenerat, Valencia, Spain
INCLIVA & IIS La Fe CIPF, Rare Dis Joint Units, Valencia, Spain
Sevilla, T:
Hosp Univ & Politecn La Fe, Dept Neurol, Neuromuscular Dis Unit, Valencia, Spain
Inst Invest Sanitaria La Fe, Neuromuscular & Ataxias Res Grp, Valencia, Spain
Ctr Invest Biomed Red Enfermedades Raras CIBERER, Valencia, Spain
Univ Valencia, Dept Med, Valencia, Spain
Lupo, V:
Ctr Invest Principe Felipe CIPF, Unit Genet & Genom Neuromuscular & Neurodegenerat, Valencia, Spain
INCLIVA & IIS La Fe CIPF, Rare Dis Joint Units, Valencia, Spain
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