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

Marjo S. van der Knaap, Marianna Bugiani, Marisa I. Mendes, Lisa G. Riley, Desiree E. C. Smith, Joëlle Rudinger-Thirion, Magali Frugier, Marjolein Breur, Joanna Crawford, Judith van Gaalen, Meyke Schouten, Marjolaine Willems, Quinten Waisfisz, Frederic Tran Mau-Them, Richard J. Rodenburg, Ryan J. Taft, Boris Keren, John Christodoulou, Christel Depienne, Cas Simons & 2 others Gajja S. Salomons, Fanny Mochel

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

To 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 patients' 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 patients' 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.
Original languageEnglish
Pages (from-to)E1225-E1237
JournalNeurology
Volume92
Issue number11
DOIs
Publication statusPublished - 2019

Cite this

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. / Biallelic variants in LARS2 and KARS cause deafness and (ovario)leukodystrophy. In: Neurology. 2019 ; Vol. 92, No. 11. pp. E1225-E1237.
@article{1ce25cec8728499ebda701b23a447801,
title = "Biallelic variants in LARS2 and KARS cause deafness and (ovario)leukodystrophy",
abstract = "To 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 patients' 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 patients' 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.",
author = "{van der Knaap}, {Marjo S.} and Marianna Bugiani and Mendes, {Marisa I.} and Riley, {Lisa G.} and Smith, {Desiree E. C.} and Jo{\"e}lle Rudinger-Thirion and Magali Frugier and Marjolein Breur and Joanna Crawford and {van Gaalen}, Judith and Meyke Schouten and Marjolaine Willems and Quinten Waisfisz and Mau-Them, {Frederic Tran} and Rodenburg, {Richard J.} and Taft, {Ryan J.} and Boris Keren and John Christodoulou and Christel Depienne and Cas Simons and Salomons, {Gajja S.} and Fanny Mochel",
year = "2019",
doi = "10.1212/WNL.0000000000007098",
language = "English",
volume = "92",
pages = "E1225--E1237",
journal = "Neurology",
issn = "0028-3878",
publisher = "Lippincott Williams and Wilkins",
number = "11",

}

van der Knaap, MS, Bugiani, M, Mendes, MI, Riley, LG, Smith, DEC, Rudinger-Thirion, J, Frugier, M, Breur, M, Crawford, J, van Gaalen, J, Schouten, M, Willems, M, Waisfisz, Q, Mau-Them, FT, Rodenburg, RJ, Taft, RJ, Keren, B, Christodoulou, J, Depienne, C, Simons, C, Salomons, GS & Mochel, F 2019, 'Biallelic variants in LARS2 and KARS cause deafness and (ovario)leukodystrophy' Neurology, vol. 92, no. 11, pp. E1225-E1237. https://doi.org/10.1212/WNL.0000000000007098

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.

In: Neurology, Vol. 92, No. 11, 2019, p. E1225-E1237.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Biallelic variants in LARS2 and KARS cause deafness and (ovario)leukodystrophy

AU - van der Knaap, Marjo S.

AU - Bugiani, Marianna

AU - Mendes, Marisa I.

AU - Riley, Lisa G.

AU - Smith, Desiree E. C.

AU - Rudinger-Thirion, Joëlle

AU - Frugier, Magali

AU - Breur, Marjolein

AU - Crawford, Joanna

AU - van Gaalen, Judith

AU - Schouten, Meyke

AU - Willems, Marjolaine

AU - Waisfisz, Quinten

AU - Mau-Them, Frederic Tran

AU - Rodenburg, Richard J.

AU - Taft, Ryan J.

AU - Keren, Boris

AU - Christodoulou, John

AU - Depienne, Christel

AU - Simons, Cas

AU - Salomons, Gajja S.

AU - Mochel, Fanny

PY - 2019

Y1 - 2019

N2 - To 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 patients' 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 patients' 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.

AB - To 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 patients' 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 patients' 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.

UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85062888821&origin=inward

UR - https://www.ncbi.nlm.nih.gov/pubmed/30737337

U2 - 10.1212/WNL.0000000000007098

DO - 10.1212/WNL.0000000000007098

M3 - Article

VL - 92

SP - E1225-E1237

JO - Neurology

JF - Neurology

SN - 0028-3878

IS - 11

ER -