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Biallelic variants in LARS2 and KARS cause deafness and (ovario)leukodystrophy

van der Knaap, Marjo S ; Bugiani, Marianna ; Mendes, Marisa I ; Riley, Lisa G ; Smith, Desiree E.C ; Rudinger-Thirion, Joëlle ; Frugier, Magali ; Breur, Marjolein ; Crawford, Joanna ; van Gaalen, Judith ; Schouten, Meyke ; Willems, Marjolaine ; Waisfisz, Quinten ; Mau-Them, Frederic Tran ; Rodenburg, Richard J ; Taft, Ryan J ; Keren, Boris ; Christodoulou, John ; Depienne, Christel ; Simons, Cas ; Salomons, Gajja S ; Mochel, Fanny

Neurology, 2019-03, Vol.92 (11), p.e1225-e1237 [Periódico revisado por pares]

United States: American Academy of Neurology

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Biallelic variants in LARS2 and KARS cause deafness and (ovario)leukodystrophy
Autor: van der Knaap, Marjo S ; Bugiani, Marianna ; Mendes, Marisa I ; Riley, Lisa G ; Smith, Desiree E.C ; Rudinger-Thirion, Joëlle ; Frugier, Magali ; Breur, Marjolein ; Crawford, Joanna ; van Gaalen, Judith ; Schouten, Meyke ; Willems, Marjolaine ; Waisfisz, Quinten ; Mau-Them, Frederic Tran ; Rodenburg, Richard J ; Taft, Ryan J ; Keren, Boris ; Christodoulou, John ; Depienne, Christel ; Simons, Cas ; Salomons, Gajja S ; Mochel, Fanny
Assuntos: Adult ; Amino Acyl-tRNA Synthetases - genetics ; Biological Assay ; Brain - diagnostic imaging ; Brain - pathology ; Child ; Deafness - genetics ; Female ; Genetics ; Human genetics ; Humans ; Leukoencephalopathies - diagnostic imaging ; Leukoencephalopathies - genetics ; Leukoencephalopathies - pathology ; Leukoencephalopathies - physiopathology ; Life Sciences ; Lysine-tRNA Ligase - genetics ; Magnetic Resonance Imaging ; Magnetic Resonance Spectroscopy ; Male ; Middle Aged ; Mitochondria ; Neurons and Cognition ; Ovarian Diseases - diagnostic imaging ; Ovarian Diseases - genetics ; Ovarian Diseases - pathology ; Ovarian Diseases - physiopathology ; Transfer RNA Aminoacylation
É parte de: Neurology, 2019-03, Vol.92 (11), p.e1225-e1237
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SourceType-Scholarly Journals-1
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Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
Descrição: OBJECTIVETo describe the leukodystrophy caused by pathogenic variants in LARS2 and KARS, encoding mitochondrial leucyl transfer RNA (tRNA) synthase and mitochondrial and cytoplasmic lysyl tRNA synthase, respectively. METHODSWe composed a group of 5 patients with leukodystrophy, in whom whole-genome or whole-exome sequencing revealed pathogenic variants in LARS2 or KARS. Clinical information, brain MRIs, and postmortem brain autopsy data were collected. We assessed aminoacylation activities of purified mutant recombinant mitochondrial leucyl tRNA synthase and performed aminoacylation assays on patientsʼ lymphoblasts and fibroblasts. RESULTSPatients had a combination of early-onset deafness and later-onset neurologic deterioration caused by progressive brain white matter abnormalities on MRI. Female patients with LARS2 pathogenic variants had premature ovarian failure. In 2 patients, MRI showed additional signs of early-onset vascular abnormalities. In 2 other patients with LARS2 and KARS pathogenic variants, magnetic resonance spectroscopy revealed elevated white matter lactate, suggesting mitochondrial disease. Pathology in one patient with LARS2 pathogenic variants displayed evidence of primary disease of oligodendrocytes and astrocytes with lack of myelin and deficient astrogliosis. Aminoacylation activities of purified recombinant mutant leucyl tRNA synthase showed a 3-fold loss of catalytic efficiency. Aminoacylation assays on patientsʼ lymphoblasts and fibroblasts showed about 50% reduction of enzyme activity. CONCLUSIONThis study adds LARS2 and KARS pathogenic variants as gene defects that may underlie deafness, ovarian failure, and leukodystrophy with mitochondrial signature. We discuss the specific MRI characteristics shared by leukodystrophies caused by mitochondrial tRNA synthase defects. We propose to add aminoacylation assays as biochemical diagnostic tools for leukodystrophies.
Editor: United States: American Academy of Neurology
Idioma: Inglês

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Biallelic variants in LARS2 and KARS cause deafness and (ovario)leukodystrophy

United States: American Academy of Neurology

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