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The expanding LARS2 phenotypic spectrum: HLASA, Perrault syndrome with leukodystrophy, and mitochondrial myopathy
Author(s) -
Riley Lisa G.,
RudingerThirion Joëlle,
Frugier Magali,
Wilson Meredith,
Luig Melissa,
Alahakoon Thushari Indika,
Nixon Cheng Yee,
Kirk Edwin P.,
Roscioli Tony,
Lunke Sebastian,
Stark Zornitza,
Wierenga Klaas J.,
Palle Sirish,
Walsh Maie,
Higgs Emily,
Arbuckle Susan,
Thirukeswaran Shalini,
Compton Alison G.,
Thorburn David R.,
Christodoulou John
Publication year - 2020
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.24050
Subject(s) - leukodystrophy , lactic acidosis , hearing loss , agenesis of the corpus callosum , myopathy , mitochondrial disease , phenotype , leukoencephalopathy , biology , medicine , genetics , pathology , corpus callosum , disease , mitochondrial dna , audiology , gene
Abstract 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.