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Biallelic mutations in mitochondrial tryptophanyl-tRNA synthetase cause Levodopa-responsive infantile-onset Parkinsonism

Lookup NU author(s): Dr Kyle Thompson, Professor Robert Taylor



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2018 John Wiley & Sons A/S. Mitochondrial aminoacyl-tRNA synthetases (mtARSs) are essential, ubiquitously expressed enzymes that covalently attach amino acids to their corresponding tRNA molecules during translation of mitochondrial genes. Deleterious variants in the mtARS genes cause a diverse array of phenotypes, many of which involve the nervous system. Moreover, distinct mutations in mtARSs often cause different clinical manifestations. Recently, the gene encoding mitochondrial tryptophanyl tRNA synthetase (WARS2) was reported to cause 2 different neurological phenotypes, a form of autosomal recessive intellectual disability and a syndrome of severe infantile-onset leukoencephalopathy. Here, we report the case of a 17-year-old boy with compound heterozygous mutations in WARS2 (p.Trp13Gly, p.Ser228Trp) who presented with infantile-onset, Levodopa-responsive Parkinsonism at the age of 2years. Analysis of patient-derived dermal fibroblasts revealed decreased steady-state WARS2 protein and normal OXPHOS content. Muscle mitochondrial studies suggested mitochondrial proliferation without obvious respiratory chain deficiencies at the age of 9years. This case expands the phenotypic spectrum of WARS2 deficiency and emphasizes the importance of mitochondrial protein synthesis in the pathogenesis of Parkinsonism.

Publication metadata

Author(s): Burke EA, Frucht SJ, Thompson K, Wolfe LA, Yokoyama T, Bertoni M, Huang Y, Sincan M, Adams DR, Taylor RW, Gahl WA, Toro C, Malicdan MCV

Publication type: Article

Publication status: Published

Journal: Clinical Genetics

Year: 2018

Volume: 93

Issue: 3

Pages: 712–718

Print publication date: 01/03/2018

Online publication date: 05/02/2018

Acceptance date: 05/11/2017

Date deposited: 20/02/2018

ISSN (print): 0009-9163

ISSN (electronic): 1399-0004

Publisher: Blackwell Publishing Ltd


DOI: 10.1111/cge.13172

PubMed id: 29120065


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Funder referenceFunder name
203105/Z/16/ZWellcome Trust