1 Pouwels PJ, Vanderver A, Bernard G, et al. Hypomyelinating leukodystrophies: translational research progress and prospects. Ann Neurol 2014;76:5–9.24916848 [PubMed]
2 Pelizaeus F. Ueber eine eigenthümliche Form spastischer Lähmung mit Cerebralerscheinungen auf hereditärer Grundlage. Arch Psychiatr Nervenkr 1885;16:698–710.
3 Merzbacher L. Eine eigenartige familiär‐hereditäre Erkrankungsform (Aplasia axialis extracorticalis congenita). Zeitschr Ges Neurol Psychiatr 1910;3:1–134.
5 Kevelam S, Steenweg M, Srivastava S, et al. Update on leukodystrophies: a historical perspective and adapted definition. Neuropediatrics 2016;47:349–354.27564080 [PubMed]
9 Zheng Y‐G, Wei H, Ling C, et al. Two forms of human cytoplasmic arginyl‐tRNA synthetase produced from two translation initiations by a single mRNA. Biochemistry 2006;45:1338–1344.16430231 [PubMed]
- Amsterdam UMC - Vrije Universiteit Amsterdam Netherlands
- The University of Texas at Austin United States
- McGill University Health Centre Canada
- University of Leeds United Kingdom
- Children's Hospital of Philadelphia United States
- University Federico II of Naples Italy
- Baylor College of Medicine United States
- University of California, San Francisco United States
- Telethon Institute Of Genetics And Medicine Italy
- University of Pennsylvania United States
- Vrije Universiteit Amsterdam Netherlands
- Kiel University Germany
- Boston Children's Hospital United States
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.