Combined oxidative phosphorylation deficiency-18 is an autosomal recessive disorder of mitochondrial function characterized by intrauterine growth retardation, hypotonia, visual impairment, speech delay, and lactic acidosis associated with decreased mitochondrial respiratory chain activity. Affected patients may also show hematologic ... Combined oxidative phosphorylation deficiency-18 is an autosomal recessive disorder of mitochondrial function characterized by intrauterine growth retardation, hypotonia, visual impairment, speech delay, and lactic acidosis associated with decreased mitochondrial respiratory chain activity. Affected patients may also show hematologic abnormalities, mainly macrocytic anemia (summary by Hildick-Smith et al., 2013). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).
Hildick-Smith et al. (2013) reported a 14-year-old Italian girl with mitochondrial disease and macrocytic erythroid abnormalities. She showed intrauterine growth retardation and poor postnatal growth. Mitochondrial abnormalities became apparent soon after birth, with increased serum lactate, ammonia, and ... Hildick-Smith et al. (2013) reported a 14-year-old Italian girl with mitochondrial disease and macrocytic erythroid abnormalities. She showed intrauterine growth retardation and poor postnatal growth. Mitochondrial abnormalities became apparent soon after birth, with increased serum lactate, ammonia, and uric acid. Muscle biopsy showed mildly increased numbers of mitochondria and lipid droplets, as well as a severe deficiency of complex I activity. Global defects in mitochondrial respiratory chain activity were later found in patient fibroblasts. At age 3 months, she developed macrocytic anemia; later blood studies showed hypersegmented neutrophils. At the time of the report, she had atrophic muscles, difficulty running, tremor, dysmetria, language delay, mild intellectual disability, and a severe visual defect. An unrelated 6-year-old German girl had a similar but less severe phenotype. She also had intrauterine growth retardation, but later had normal growth. From birth, she had elevated lactate concentrations in blood and cerebrospinal fluid. Muscle biopsy showed significantly reduced complex I activity. She had severe visual deficit with delayed bilateral visual-evoked potential, but EEG, nerve conduction studies, and auditory-evoked potential were normal. She also had deficits in fine motor skills and coordination. Erythrocyte mean corpuscular volume was in the upper range of normal. Patient fibroblasts showed decreased activities of multiple respiratory chain enzymes. Generalized defects in the expression of the mitochondrial respiratory complexes and mitochondrial mass were excluded by immunoblot analysis in both patients.
In 2 unrelated patients with combined oxidative phosphorylation deficiency, Hildick-Smith et al. (2013) identified homozygous or compound heterozygous mutations in the SFXN4 gene (615564.0001-615564.0003). Expression of wildtype SFXN4 restored the mitochondrial respiratory defect in patient cells.