RARS1 ‐related hypomyelinating leukodystrophy: Expanding the spectrum

Autor: 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
Přispěvatelé: 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), Functional Genomics
Jazyk: angličtina
Předmět:
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
Zdroj: 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 2020, ' RARS1-related hypomyelinating leukodystrophy : Expanding the spectrum ', Annals of Clinical and Translational Neurology, vol. 7, no. 1, pp. 83-93 . https://doi.org/10.1002/acn3.50960
Annals of clinical and translational neurology, 7(1), 83-93. John Wiley and Sons Ltd
Annals of Clinical and Translational Neurology
Annals of Clinical and Translational Neurology, 7(1), 83-93. John Wiley and Sons Ltd
Annals of Clinical and Translational Neurology, Vol 7, Iss 1, Pp 83-93 (2020)
ISSN: 2328-9503
DOI: 10.1002/acn3.50960
Popis: 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.
Databáze: OpenAIRE
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