title: Genotype/phenotype correlations in AARS-related neuropathy in a cohort of patients from the United Kingdom and Ireland.
abstract: Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy with heterogeneous clinical presentation and genetic background. The axonal form (CMT2) is characterised by decreased action potentials indicating primary axonal damage. The underlying pathology involves axonal degeneration which is supposed to be related to axonal protein dysfunction caused by various gene mutations. The overlapping clinical manifestation of CMT2 with distal hereditary motor neuropathy (dHMN) and intermediate CMT causes further diagnostic difficulties. Aminoacyl-tRNA synthetases have been implicated in the pathomechanism of CMT2. They have an essential role in protein translation by attaching amino acids to their cognate tRNAs. To date six families have been reported worldwide with dominant missense alanyl-tRNA synthetase (AARS) mutations leading to clinically heterogeneous axonal neuropathies. The pathomechanism of some variants could be explained by impaired amino acylation activity while other variants implicating an editing defect need to be further investigated. Here, we report a cohort of six additional families originating from the United Kingdom and Ireland with dominant AARS-related neuropathies. The phenotypic manifestation was distal lower limb predominant sensorimotor neuropathy but upper limb impairment with split hand deformity occasionally associated. Nerve conduction studies revealed significant demyelination accompanying the axonal lesion in motor and sensory nerves. Five families have the c.986G>A, p.(Arg329His) variant, further supporting that this is a recurrent loss of function variant. The sixth family, of Irish origin, had a novel missense variant, c.2063A>G, p.(Glu688Gly). We discuss our findings and the associated phenotypic heterogeneity in these families, which expands the clinical spectrum of AARS-related neuropathies.
authors.affiliation: John Walton Muscular Dystrophy Research Centre, MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Boglarka
authors.initials: B
authors.lastname: Bansagi
authors.forename: Thalia
authors.initials: T
authors.lastname: Antoniadi
authors.forename: Sarah
authors.initials: S
authors.lastname: Burton-Jones
authors.forename: Sinead M
authors.initials: SM
authors.lastname: Murphy
authors.forename: John
authors.initials: J
authors.lastname: McHugh
authors.forename: Michael
authors.initials: M
authors.lastname: Alexander
authors.forename: Richard
authors.initials: R
authors.lastname: Wells
authors.forename: Joanna
authors.initials: J
authors.lastname: Davies
authors.forename: David
authors.initials: D
authors.lastname: Hilton-Jones
authors.forename: Hanns
authors.initials: H
authors.lastname: Lochmüller
authors.forename: Patrick
authors.initials: P
authors.lastname: Chinnery
authors.forename: Rita
authors.initials: R
authors.lastname: Horvath
mesh_terms: D000328:Adult; D000368:Aged; D000604:Amino Acyl-tRNA Synthetases / Q000235:genetics*; D001369:Axons / Q000473:pathology; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics / Q000503:physiopathology; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D005838:Genotype; D015417:Hereditary Sensory and Motor Neuropathy / Q000235:genetics* / Q000503:physiopathology*; D006801:Humans; D007494:Ireland; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D006113:United Kingdom; D055815:Young Adult
chemical_list: D000604:Amino Acyl-tRNA Synthetases