1. RARS1 ‐related hypomyelinating leukodystrophy: Expanding the spectrum
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Chiara Aiello, Isabella Moroni, Mary Kay Koenig, Bryce A. Mendelsohn, Geneviève Bernard, Nicole I. Wolf, Enrico Bertini, Sarah von Spiczak, Gajja S. Salomons, Davide Tonduti, Adeline L. Vanderver, Desirée E.C. Smith, Ingo Helbig, Nicola Brunetti-Pierri, Shanice Beerepoot, Ettore Salsano, Jozef Hertecant, Marjo S van der Knaap, Jullie Rhee, Hiltrud Muhle, John H. Livingston, Gerarda Cappuccio, Laura Russell, Jamie L. Fraser, Lisa Emrick, Katherine L. Helbig, Franco Taroni, Marisa I. Mendes, Omar Ismayl, Lydia Green, Daniela Di Bella, Stefania Magri, Mendes, M. I., Green, L. M. C., Bertini, E., Tonduti, D., Aiello, C., Smith, D., Salsano, E., Beerepoot, S., Hertecant, J., von Spiczak, S., Livingston, J. H., Emrick, L., Fraser, J., Russell, L., Bernard, G., Magri, S., Di Bella, D., Taroni, F., Koenig, M. K., Moroni, I., Cappuccio, G., Brunetti-Pierri, N., Rhee, J., Mendelsohn, B. A., Helbig, I., Helbig, K., Muhle, H., Ismayl, O., Vanderver, A. L., Salomons, G. S., van der Knaap, M. S., Wolf, N. I., Laboratory Genetic Metabolic Diseases, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Laboratory Medicine, AGEM - Endocrinology, metabolism and nutrition, AGEM - Inborn errors of metabolism, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Pediatric surgery, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam Reproduction & Development (AR&D), and Functional Genomics
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Adult ,0301 basic medicine ,Pathology ,medicine.medical_specialty ,Adolescent ,Neurosciences. Biological psychiatry. Neuropsychiatry ,Nystagmus ,Severity of Illness Index ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Atrophy ,SDG 3 - Good Health and Well-being ,Demyelinating disease ,medicine ,Humans ,Missense mutation ,Spasticity ,Age of Onset ,RC346-429 ,Child ,Genetic Association Studies ,Research Articles ,business.industry ,General Neuroscience ,Leukodystrophy ,Genetic disorder ,Infant ,Arginine-tRNA Ligase ,medicine.disease ,Magnetic Resonance Imaging ,Hereditary Central Nervous System Demyelinating Diseases ,Cross-Sectional Studies ,030104 developmental biology ,Child, Preschool ,Neurology. Diseases of the nervous system ,Neurology (clinical) ,Age of onset ,medicine.symptom ,business ,030217 neurology & neurosurgery ,RC321-571 ,Research Article - Abstract
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.
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