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Publication . Article . 2020

RARS1-related hypomyelinating leukodystrophy: Expanding the spectrum.

Expanding the spectrum
Marisa I. Mendes; Lydia Green; Enrico Bertini; Davide Tonduti; Chiara Aiello; Desirée E.C. Smith; Ettore Salsano; +25 Authors
Open Access
Published: 01 Jan 2020 Journal: Annals of clinical and translational neurology, volume 7, issue 1 (issn: 2328-9503, Copyright policy )
Country: Netherlands

OBJECTIVE: Biallelic variants in RARS1, encoding the cytoplasmic tRNA synthetase for arginine (ArgRS), cause a hypomyelinating leukodystrophy. This study aimed to investigate clinical, neuroradiological and genetic features of patients with RARS1-related disease, and to identify possible genotype-phenotype relationships.METHODS: We performed a multinational cross-sectional survey among 20 patients with biallelic RARS1 variants identified by next-generation sequencing techniques. Clinical data, brain MRI findings and genetic results were analyzed. Additionally, ArgRS activity was measured in fibroblasts of four patients, and translation of long and short ArgRS isoforms was quantified by western blot.RESULTS: Clinical presentation ranged from severe (onset in the first 3 months, usually with refractory epilepsy and early brain atrophy), to intermediate (onset in the first year with nystagmus and spasticity), and mild (onset around or after 12 months with minimal cognitive impairment and preserved independent walking). The most frequent RARS1 variant, c.5A>G, led to mild or intermediate phenotypes, whereas truncating variants and variants affecting amino acids close to the ArgRS active centre led to severe phenotypes. ArgRS activity was significantly reduced in three patients with intermediate and severe phenotypes; in a fourth patient with intermediate to severe presentation, we measured normal ArgRS activity, but found translation mainly of the short instead of the long ArgRS isoform.INTERPRETATION: Variants in RARS1 impair ArgRS activity and do not only lead to a classic hypomyelination presentation with nystagmus and spasticity, but to a wide spectrum, ranging from severe, early-onset epileptic encephalopathy with brain atrophy to mild disease with relatively preserved myelination.

Subjects by Vocabulary

Microsoft Academic Graph classification: Leukodystrophy medicine.disease medicine Atrophy Nystagmus medicine.symptom Age of onset Genetic disorder Missense mutation Spasticity business.industry business Pathology medicine.medical_specialty Demyelinating disease


Adolescent, Adult, Age of Onset, Arginine-tRNA Ligase, Child, Child, Preschool, Cross-Sectional Studies, Genetic Association Studies, Hereditary Central Nervous System Demyelinating Diseases, Humans, Infant, Magnetic Resonance Imaging, Severity of Illness Index, Young Adult, Research Article, Research Articles, SDG 3 - Good Health and Well-being, /dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being, SDG 3 - Good Health and Well-being, Neurology (clinical), General Neuroscience, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429

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  • Funder: Canadian Institutes of Health Research (CIHR)
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