Combined Oxidative Phosphorylation Deficiency 31

A number sign (#) is used with this entry because of evidence that combined oxidative phosphorylation deficiency-31 (COXPD31) is caused by homozygous or compound heterozygous mutation in the MIPEP gene (602241) on chromosome 13q12.

Description

Combined oxidative phosphorylation deficiency-31 is an autosomal recessive multisystem disorder characterized by left ventricular noncompaction (LVNC), global developmental delay, and severe hypotonia. More variable features include seizures, cataract, and abnormal movements. The disorder becomes apparent soon after birth or in early infancy, and patients may die in early childhood. Biochemical studies are consistent with a defect in mitochondrial function (summary by Eldomery et al., 2016).

For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).

Clinical Features

Eldomery et al. (2016) reported 4 unrelated children with a severe multisystem disorder apparent from infancy. The patients had failure to thrive, hypotonia, LVNC, hypertrophic cardiomyopathy, and global developmental delay. Three patients died in the first weeks or years of life; the fourth was alive at age 4.5 years. Three patients had infantile seizures. The 4.5-year-old boy developed hypertonia with abnormal movements, dystonic posturing, and gastrointestinal difficulties, but he did not have overt seizures and EEG was normal. More variable features included microcephaly and cataract. Patient 1 was initially suspected of having a mitochondrial disorder. Laboratory studies in all patients showed variably increased serum lactate, lactic acidosis, and increased alanine. Skeletal muscle biopsies, performed in 3 patients, showed glycogen deposits and accumulation of lipid droplets; 2 patients had evidence of mitochondrial proliferation and aggregation and abnormal mitochondria. Mitochondrial electron transport chain analysis in skeletal muscle, performed in 3 patients, showed mildly decreased activities of complexes I+III and complex IV. Postmortem examination of 2 patients showed LVNC with dilated cardiomyopathy; the brain of 1 patient showed diffuse neuronal loss with parenchymal rarefaction and gliosis. Variable dysmorphic features were noted in 2 unrelated children: 1 had a wide mouth and bulbous nasal tip, whereas the other had deep-set eyes, anteverted nares, depressed nasal bridge, midface hypoplasia, severe micrognathia, facial asymmetry, and an accessory palmar crease on the right hand. Two probands had a similarly affected deceased sib.

Inheritance

The transmission pattern of COXPD31 in the families reported by Eldomery et al. (2016) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 4 unrelated children with COXPD31, Eldomery et al. (2016) identified homozygous or compound heterozygous mutations in the MIPEP gene (602241.0001-602241.0006). The mutations were found by whole-exome sequencing and segregated with the disorder in the families for whom parental DNA was available. There were 5 missense mutations, 1 nonsense mutation, and 1 large deletion encompassing the MIPEP gene. In vitro functional expression assays using the yeast homolog Oct1 demonstrated that the missense mutations had deleterious effects. The yeast mutations L339F (human L306F; 602241.0003) and K376E (human K343E; 602241.0005) resulted in a severe decrease of Oct1 protease activity with accumulation of nonprocessed Oct1 substrates, resulting in impaired viability under respiratory growth conditions. The L83Q (human L71Q; 602241.0002) mutant failed to localize to the mitochondria and fully abolished Oct1 processing. The findings were consistent with a loss of function.