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.

Fig. 1

a Pedigrees of UK and Irish families. Arrows the index patients of each family. b Image of patient II/4 in UK family 1 showing predominantly lower limb symptoms manifesting with bilateral pes cavus and severe feet drop. Index patient of the same UK1 family (III/1) representing moderate intrinsic hand muscles wasting accompanied by lower limb distal wasting and weakness. Image of patient (II.1) from UK family 3 showing severe bilateral foot drop and distal muscle wasting

Fig. 2

Sequenced c.986G>A missense mutation in AARS in affected UK and Irish index patients. Illustrated positions of AARS mutations and conservation of affected residues across species