A number sign (#) is used with this entry because combined oxidative phosphorylation deficiency-8 (COXPD8) is caused by homozygous or compound heterozygous mutation in the AARS2 gene (612035) on chromosome 6p21.

Combined oxidative phosphorylation deficiency-8 (COXPD8) is an autosomal recessive disorder caused by dysfunction of the mitochondrial respiratory chain. The main clinical manifestation is a lethal infantile hypertrophic cardiomyopathy, but there may also be subtle skeletal muscle and brain involvement. Biochemical studies show combined respiratory chain complex deficiencies in complexes I, III, and IV in cardiac muscle, skeletal muscle, and brain. The liver is not affected (summary by Gotz et al., 2011).

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

Gotz et al. (2011) reported a Finnish girl who presented at age 3.5 months with failure to thrive, delayed motor development, and severe generalized muscle weakness. She was found to have severe hypertrophic cardiomyopathy with decreased contractility and an ejection fraction of 40%. There was no clear neurologic involvement, and brain imaging was normal, although EEG showed mild background abnormalities. Muscle biopsy showed scattered complex IV (COX)-deficient fibers, which suggested generalized muscle dysfunction and was considered a contraindication for heart transplant. There was no liver involvement. She died at age 10 months of cardiac insufficiency. Light microscopy showed histiocytoid cardiomyopathy. Postmortem, 80% of cardiomyocytes and 60% of skeletal muscle fibers were COX-deficient. There was a near-total deficiency of respiratory complex I and IV in the heart, severe complex I and IV deficiency in the brain, and partial complex III deficiency in both tissues; all complexes were unaffected in the liver. These findings indicated a tissue-specific defect in several components of the mitochondrial respiratory chain. Gotz et al. (2011) also reported a second unrelated Finnish female infant who was severely affected at birth. She had a large hypertrophic heart with poor myocardial contractility and severe metabolic acidosis. There was some neurologic involvement, with staring gaze, periodic stiffness, and abnormal EEG. She died at postnatal day 3, and autopsy showed an enlarged, hypertrophic heart and pulmonary hypoplasia, but no pathologic changes in the brain or liver. There was severe deficiency of complex I and complex IV in the heart, brain, and skeletal muscle, but not in the liver. Family history revealed an affected brother who had died in utero of hypertrophic cardiomyopathy.

Taylor et al. (2014) reported 5 unrelated children of British or German descent with COXPD8 manifest as fatal infantile cardiomyopathy. The patients developed symptoms between birth and 6 months of age, and all died between 1 and 11 months of age. Three patients had additional muscular involvement and 2 had central nervous system involvement; further clinical details were not provided. Biochemical analysis of patient tissue showed decreased activities of mitochondrial complexes I, III, and IV in all patients.

The transmission pattern of COXPD8 in the patients reported by Gotz et al. (2011) was consistent with autosomal recessive inheritance.

By exome sequencing, Gotz et al. (2011) identified a homozygous mutation in the AARS2 gene (R592W; 612035.0001) in a Finnish girl with fatal infantile hypertrophic mitochondrial cardiomyopathy. A second Finnish female infant with a more severe mitochondrial cardiomyopathy resulting in death at age 3 days was found to be compound heterozygous for the R592W mutation and a second missense mutation (L155R; 612035.0002). The mutations affected the editing and catalytic aminoacylation domains, respectively.

In 5 unrelated patients of European descent with COXPD8 manifest as fatal infantile cardiomyopathy, Taylor et al. (2014) identified homozygous or compound heterozygous mutations in the AARS2 gene (see, e.g., 612035.0001 and 612035.0003). All of the patients carried the R592W mutation on at least 1 allele, and haplotype analysis indicated a founder effect for this mutation. Functional studies of the variants were not performed. The patients were part of a study of 53 patients with mitochondrial respiratory chain complex deficiencies who underwent whole-exome sequencing.