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Recessive mutations in NDUFA2 cause mitochondrial leukoencephalopathy
Author(s) -
Perrier S.,
Gauquelin L.,
Tétreault M.,
Tran L.T.,
Webb N.,
Srour M.,
Mitchell J.J.,
BrunelGuitton C.,
Majewski J.,
Long V.,
Keller S.,
Gambello M.J.,
Simons C.,
Vanderver A.,
Bernard G.
Publication year - 2018
Publication title -
clinical genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.543
H-Index - 102
eISSN - 1399-0004
pISSN - 0009-9163
DOI - 10.1111/cge.13126
Subject(s) - leukoencephalopathy , exome sequencing , compound heterozygosity , genetics , mutation , exome , phenotype , biology , consanguinity , medicine , pathology , gene , disease
Deficiencies of mitochondrial respiratory chain complex I frequently result in leukoencephalopathy in young patients, and different mutations in the genes encoding its subunits are still being uncovered. We report 2 patients with cystic leukoencephalopathy and complex I deficiency with recessive mutations in NDUFA2 , an accessory subunit of complex I. The first patient was initially diagnosed with a primary systemic carnitine deficiency associated with a homozygous variant in SLC22A5 , but also exhibited developmental regression and cystic leukoencephalopathy, and an additional diagnosis of complex I deficiency was suspected. Biochemical analysis confirmed a complex I deficiency, and whole‐exome sequencing revealed a homozygous mutation in NDUFA2 (c. 134A >C, p. Lys45Thr ). Review of a biorepository of patients with unsolved genetic leukoencephalopathies who underwent whole‐exome or genome sequencing allowed us to identify a second patient with compound heterozygous mutations in NDUFA2 (c. 134A >C, p. Lys45Thr ; c.225del, p. Asn76Metfs *4). Only 1 other patient with mutations in NDUFA2 and a different phenotype (Leigh syndrome) has previously been reported. This is the first report of cystic leukoencephalopathy caused by mutations in NDUFA2 .