Combined Oxidative Phosphorylation Deficiency 5

A number sign (#) is used with this entry because combined oxidative phosphorylation deficiency-5 (COXPD5) can be caused by homozygous mutation in the MRPS22 gene (605810) on chromosome 3q23.

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

Clinical Features

Saada et al. (2007) reported 3 sibs, born of consanguineous parents, with antenatal onset of a severe mitochondrial disorder. Late in gestation, ultrasound showed generalized edema, especially of the neck, labia, and palms, with prominent subcutaneous edema and ascites at birth. Laboratory investigations showed severe lactic acidemia and increased serum ammonia. Hypertrophic cardiomyopathy and tubulopathy developed within the first week, and the infants died within the first month of life. Skeletal muscle biopsy of 1 affected infant showed that enzymatic activities of mitochondrial complexes I, II, IV, and V were reduced to between 8 and 30% of normal controls, but complex II activity was normal. Southern blot analysis showed decreased mtDNA content.

Smits et al. (2011) reported a boy, born of consanguineous Pakistani parents, with combined oxidative phosphorylation deficiency-5. At birth, the patient had microcephaly, dilated cardiomyopathy, dysmorphic features, and hypotonia. He developed severe chronic metabolic acidosis and had transient seizures at age 2. At age 5.5 years, he had very poor growth, lack of development, truncal hypotonia, and spastic tetraplegia. He did not develop tubulopathy. Brain MRI showed hypoplasia of the corpus callosum, leukoencephalopathy, and delayed myelination. Studies in patient fibroblasts showed that activities of mitochondrial respiratory chain complexes I, III, and IV were reduced to between 36 and 59% of controls. Pulse labeling of mitochondrial protein synthesis products showed a marked and generalized defect in mitochondrial translation, which was about 26% that of controls.

Molecular Genetics

By homozygosity mapping, followed by sequence analysis, Saada et al. (2007) identified a homozygous mutation in the MRPS22 gene (605810.0001) in 3 sibs with combined mitochondrial oxidative phosphorylation deficiency. In vitro studies showed that recombinant MRPS22 restored COX enzyme activities in patient cells.

In a Pakistani boy with COXPD5, Smits et al. (2011) identified a homozygous mutation in the MRPS22 gene (L215P; 605810.0002).