Peripheral neuropathy and cognitive impairment associated with a novel monoallelic HARS variant

• Published in: Annals of clinical and translational neurology Vol. 6; no. 6; pp. 1072 - 1080
• Main Authors: Royer‐Bertrand, Béryl, Tsouni, Pinelopi, Mullen, Patrick, Campos Xavier, Belinda, Mittaz Crettol, Lauréane, Lobrinus, Alexander J., Ghika, Joseph, Baumgartner, Matthias R., Rivolta, Carlo, Superti‐Furga, Andrea, Kuntzer, Thierry, Francklyn, Christopher, Tran, Christel
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01-06-2019; John Wiley and Sons Inc; Wiley
• Subjects: Adult; Alleles; Aminoacylation; Ataxia; Brain - diagnostic imaging; Cognitive Dysfunction - genetics; Cognitive Dysfunction - pathology; Disease; Enzymes; Fibroblasts - ultrastructure; Genes; Genotype & phenotype; Glucans; Histidine-tRNA Ligase - genetics; Humans; Male; Middle Aged; Mutation; Nervous system; Peripheral Nervous System Diseases - genetics; Peripheral Nervous System Diseases - pathology; Peripheral neuropathy; Protein synthesis; Proteins; Whole Exome Sequencing
• ISSN: 2328-9503; 2328-9503
• DOI: 10.1002/acn3.791

Background
A 49‐year‐old male presented with late‐onset demyelinating peripheral neuropathy, cerebellar atrophy, and cognitive deficit. Nerve biopsy revealed intra‐axonal inclusions suggestive of polyglucosan bodies, raising the suspicion of adult polyglucosan bodies disease (OMIM 263570).
Methods and Results
While known genes associated with polyglucosan bodies storage were negative, whole‐exome sequencing identified an unreported monoallelic variant, c.397G>T (p.Val133Phe), in the histidyl‐tRNA synthetase (HARS) gene. While we did not identify mutations in genes known to be associated with polygucosan body disease, whole‐exome sequencing revealed an unreported monoallelic variant, c.397G>T in the histidyl‐tRNA synthetase (HARS) gene, encoding a substitution (Val133Phe) in the catalytic domain. Expression of this variant in patient cells resulted in reduced aminoacylation activity in extracts obtained from dermal fibroblasts, without compromising overall protein synthesis.
Interpretation
Genetic variants in the genes coding for the different aminoacyl‐tRNA synthases are associated with various clinical conditions. To date, a number of HARS variant have been associated with peripheral neuropathy, but not cognitive deficits. Further studies are needed to explore why HARS mutations confer a neuronal‐specific phenotype.