Simon M.T.Eftekharian S.S.Stover A.E.Osborne A.F.Braffman B.H.Chang R.C.Wang R.Y.Steenari M.R.Tang S.WUH-LIANG HWUTaft R.J.Benke P.J.Abdenur J.E.2020-12-162020-12-1620191096-7192https://www.scopus.com/inward/record.uri?eid=2-s2.0-85057067454&doi=10.1016%2fj.ymgme.2018.11.001&partnerID=40&md5=ef9d72376c5876815f472ccf9eff4390https://scholars.lib.ntu.edu.tw/handle/123456789/525806Primary mitochondrial complex I deficiency is the most common defect of the mitochondrial respiratory chain. It is caused by defects in structural components and assembly factors of this large protein complex. Mutations in the assembly factor NDUFAF5 are rare, with only five families reported to date. This study provides clinical, biochemical, molecular and functional data for four unrelated additional families, and three novel pathogenic variants. Three cases presented in infancy with lactic acidosis and classic Leigh syndrome. One patient, however, has a milder phenotype, with symptoms starting at 27 months and a protracted clinical course with improvement and relapsing episodes. She is homozygous for a previously reported mutation, p.Met279Arg and alive at 19 years with mild neurological involvement, normal lactate but abnormal urine organic acids. We found the same mutation in one of our severely affected patients in compound heterozygosity with a novel p.Lys52Thr mutation. Both patients with p.Met279Arg are of Taiwanese descent and had severe hyponatremia. Our third and fourth patients, both Caucasian, shared a common, newly described, missense mutation p.Lys109Asn which we show induces skipping of exon 3. Both Caucasian patients were compound heterozygotes, one with a previously reported Ashkenazi founder mutation while the other was negative for additional exonic variants. Whole genome sequencing followed by RNA studies revealed a novel deep intronic variant at position c.223-907A>C inducing an exonic splice enhancer. Our report adds significant new information to the mutational spectrum of NDUFAF5, further delineating the phenotypic heterogeneity of this mitochondrial defect. ? 2018 The AuthorsComplex I; Hyponatremia; Leigh syndrome; Mitochondrial disease; NDUFAF5; Splicing[SDGs]SDG3carboxylic acid; citrate synthase; cytochrome c oxidase; lactic acid; mitochondrial DNA; reduced nicotinamide adenine dinucleotide dehydrogenase (ubiquinone); succinate dehydrogenase (ubiquinone); ubiquinol cytochrome c reductase; methyltransferase; mitochondrial protein; NDUFAF5 protein, human; reduced nicotinamide adenine dinucleotide dehydrogenase (ubiquinone); Article; case report; Caucasian; cell lysate; clinical article; disease course; enhancer region; family history; follow up; gene frequency; gene mutation; heterozygosity; heterozygote; human; human tissue; hyponatremia; immunoblotting; lactic acidosis; Leigh disease; missense mutation; muscle biopsy; neuroimaging; next generation sequencing; oxygen consumption; phenotype; point mutation; prediction; priority journal; punch biopsy; respiratory chain; reverse transcription polymerase chain reaction; Sanger sequencing; Taiwanese; whole exome sequencing; whole genome sequencing; adolescent; biopsy; child; deficiency; disorders of mitochondrial functions; female; genetics; infant; male; mutation; pathology; pedigree; preschool child; skin; young adult; Adolescent; Biopsy; Child; Child, Preschool; Electron Transport Complex I; Female; Humans; Infant; Leigh Disease; Male; Methyltransferases; Mitochondrial Diseases; Mitochondrial Proteins; Mutation; Pedigree; Phenotype; Skin; Whole Exome Sequencing; Whole Genome Sequencing; Young Adultjournal article10.1016/j.ymgme.2018.11.001304734812-s2.0-85057067454