Mitochondrial complex IV deficiency, caused by mutated COX6B1, is associated with encephalomyopathy, hydrocephalus and cardiomyopathy.
Isolated cytochrome c oxidase (COX) deficiency is a prevalent cause of mitochondrial disease and is mostly caused by nuclear-encoded mutations in assembly factors while rarely by mutations in structural subunits. We hereby report a case of isolated COX deficiency manifesting with encephalomyopathy, hydrocephalus and hypertropic cardiomyopathy due to a missense p.R20C mutation in the COX6B1 gene, which encodes an integral, nuclear-encoded COX subunit. This novel mutation was predicted to be severe in silico. In accord, enzymatic activity was undetectable in muscle and fibroblasts, was severely decreased in lymphocytes and the COX6B1 protein was barely detectable in patient's muscle mitochondria. Complementation with the wild-type cDNA by a lentiviral construct restored COX activity, and mitochondrial function was improved by 5-aminoimidazole-4-carboxamide ribonucleotide, resveratrol and ascorbate in the patient's fibroblasts. We suggest that genetic analysis of COX6B1should be included in the investigation of isolated COX deficiency, including patients with cardiac defects. Initial measurement of COX activity in lymphocytes may be useful as it might circumvent the need for invasive muscle biopsy. The evaluation of ascorbate supplementation to patients with mutated COX6B1 is warranted.
1] Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel [2] Department of Pediatrics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Ulla Najwa
UN
Abdulhag
Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Devorah
D
Soiferman
Department of Microbiology and Molecular Genetics, Institute for Medical Research Israel-Canada, Hadassah Medical School, Hebrew University, Jerusalem, Israel.
Ora
O
Schueler-Furman
Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Chaya
C
Miller
Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Avraham
A
Shaag
Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Orly
O
Elpeleg
1] Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel [2] Pediatric Neurology Unit, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Simon
S
Edvardson
Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Ann
A
Saada
D009202:Cardiomyopathies / Q000175:diagnosis / Q000235:genetics*; D003576:Electron Transport Complex IV / Q000235:genetics* / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D006849:Hydrocephalus / Q000175:diagnosis / Q000235:genetics*; D007231:Infant, Newborn; D008297:Male; D008931:Mitochondria, Muscle / Q000378:metabolism; D017237:Mitochondrial Encephalomyopathies / Q000175:diagnosis / Q000235:genetics*; D018482:Muscle, Skeletal / Q000378:metabolism; D009154:Mutation; D013577:Syndrome
C513775:COX6B1 protein, human; D003576:Electron Transport Complex IV