The expanding LARS2 phenotypic spectrum: HLASA, Perrault syndrome with leukodystrophy, and mitochondrial myopathy.

Autor: Riley LG; Rare Diseases Functional Genomics, Kids Research, The Children's Hospital at Westmead and The Children's Medical Research Institute, Sydney, Australia.; Discipline of Child & Adolescent Health, Sydney Medical School, Sydney, Australia., Rudinger-Thirion J; Université de Strasbourg, Architecture et Réactivité de l'ARN, CNRS, IBMC, Strasbourg, France., Frugier M; Université de Strasbourg, Architecture et Réactivité de l'ARN, CNRS, IBMC, Strasbourg, France., Wilson M; Department of Clinical Genetics, The Children's Hospital at Westmead, Sydney, Australia.; Discipline of Genomic Medicine, University of Sydney, Sydney, Australia., Luig M; Department of Neonatology, Westmead Hospital, Sydney, Australia., Alahakoon TI; Westmead Institute for Maternal & Fetal Medicine, Westmead Hospital & University of Sydney, Sydney, Australia., Nixon CY; Neuroscience Research Australia (NeuRA), University of New South Wales, Sydney, Australia.; Genetics Laboratory, NSW Health Pathology, Sydney, Australia., Kirk EP; Genetics Laboratory, NSW Health Pathology, Sydney, Australia.; Centre for Clinical Genetics, Sydney Children's Hospital, Sydney, Australia., Roscioli T; Centre for Clinical Genetics, Sydney Children's Hospital, Sydney, Australia., Lunke S; Victorian Clinical Genetics Services, The Royal Children's Hospital, Melbourne, Australia.; Department of Pathology, University of Melbourne, Melbourne, Australia.; Australian Genomics Health Alliance, Melbourne, Australia., Stark Z; Victorian Clinical Genetics Services, The Royal Children's Hospital, Melbourne, Australia.; Australian Genomics Health Alliance, Melbourne, Australia.; Department of Paediatrics, University of Melbourne, Melbourne, Australia., Wierenga KJ; Department of Pediatrics, University of Oklahoma Health Sciences Center (OUHSC), Oklahoma City, OK.; Department of Clinical Genomics, Mayo Clinic, Jacksonville, Florida., Palle S; Department of Pediatrics, University of Oklahoma Health Sciences Center (OUHSC), Oklahoma City, OK., Walsh M; Genetic Medicine & Familial Cancer Centre, Royal Melbourne Hospital, Melbourne, Australia., Higgs E; Genetic Medicine & Familial Cancer Centre, Royal Melbourne Hospital, Melbourne, Australia., Arbuckle S; Department of Pathology, The Children's Hospital at Westmead, Sydney, Australia., Thirukeswaran S; Department of Paediatrics, University of Melbourne, Melbourne, Australia.; Murdoch Children's Research Institute, The Royal Children's Hospital, Melbourne, Australia., Compton AG; Department of Paediatrics, University of Melbourne, Melbourne, Australia.; Murdoch Children's Research Institute, The Royal Children's Hospital, Melbourne, Australia., Thorburn DR; Victorian Clinical Genetics Services, The Royal Children's Hospital, Melbourne, Australia.; Department of Paediatrics, University of Melbourne, Melbourne, Australia.; Murdoch Children's Research Institute, The Royal Children's Hospital, Melbourne, Australia., Christodoulou J; Discipline of Child & Adolescent Health, Sydney Medical School, Sydney, Australia.; Victorian Clinical Genetics Services, The Royal Children's Hospital, Melbourne, Australia.; Australian Genomics Health Alliance, Melbourne, Australia.; Department of Paediatrics, University of Melbourne, Melbourne, Australia.; Murdoch Children's Research Institute, The Royal Children's Hospital, Melbourne, Australia.
Jazyk: angličtina
Zdroj: Human mutation [Hum Mutat] 2020 Aug; Vol. 41 (8), pp. 1425-1434.
DOI: 10.1002/humu.24050
Abstrakt: LARS2 variants are associated with Perrault syndrome, characterized by premature ovarian failure and hearing loss, and with an infantile lethal multisystem disorder: Hydrops, lactic acidosis, sideroblastic anemia (HLASA) in one individual. Recently we reported LARS2 deafness with (ovario) leukodystrophy. Here we describe five patients with a range of phenotypes, in whom we identified biallelic LARS2 variants: three patients with a HLASA-like phenotype, an individual with Perrault syndrome whose affected siblings also had leukodystrophy, and an individual with a reversible mitochondrial myopathy, lactic acidosis, and developmental delay. Three HLASA cases from two unrelated families were identified. All were males with genital anomalies. Two survived multisystem disease in the neonatal period; both have developmental delay and hearing loss. A 55-year old male with deafness has not displayed neurological symptoms while his female siblings with Perrault syndrome developed leukodystrophy and died in their 30s. Analysis of muscle from a child with a reversible myopathy showed reduced LARS2 and mitochondrial complex I levels, and an unusual form of degeneration. Analysis of recombinant LARS2 variant proteins showed they had reduced aminoacylation efficiency, with HLASA-associated variants having the most severe effect. A broad phenotypic spectrum should be considered in association with LARS2 variants.
(© 2020 Wiley Periodicals LLC.)
Databáze: MEDLINE
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