Combined Oxidative Phosphorylation Deficiency 28

A number sign (#) is used with this entry because of evidence that combined oxidative phosphorylation deficiency-28 (COXPD28) is caused by homozygous or compound heterozygous mutation in the SLC25A26 gene (611037) on chromosome 3p14.

Description

Combined oxidative phosphorylation deficiency-28 (COXPD28) is a complex autosomal recessive multisystem disorder associated with mitochondrial dysfunction. The phenotype is variable, but includes episodic metabolic decompensation beginning in infancy that can result in mild muscle weakness, cardiorespiratory insufficiency, developmental delay, or even death. Biochemical studies of patient tissues show variable mitochondrial defects, including decreased activities of respiratory chain enzymes (summary by Kishita et al., 2015).

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

Clinical Features

Kishita et al. (2015) reported 3 unrelated children with a severe multisystem disorder apparent since infancy, although the manifestations differed somewhat among the patients. The children were of Iraqi, Japanese, and Moroccan descent, respectively; 2 of the families were consanguineous. The first child presented at age 4 weeks with acute circulatory collapse and pulmonary hypertension associated with severe lactic acidosis, which was successfully treated. At 3.5 years, he had a second episode of pulmonary hypertension, which normalized. At 6 years 3 months, he had slightly delayed development, weakness, fatigue, and recurrent abdominal pain. Muscle biopsy showed reduced activities of mitochondrial complexes I and IV, as well as decreased ATP production; there were also reduced levels of assembled complexes I and IV. Plasma glycine was increased. The second patient was a 3-year-old Japanese girl who developed respiratory failure associated with severe lactic acidosis soon after birth. The child improved, and gross development was normal until age 2 years, when she had an episode of lactic acidosis with cardiopulmonary arrest and hypoxic brain damage; afterwards she was severely handicapped. Mitochondrial respiratory chain enzymes were normal in fibroblasts, but complexes I, III, and IV were decreased in skeletal muscle. Muscle biopsy showed ragged-red fibers and COX-negative fibers. The third patient, a girl born of consanguineous Moroccan parents, was the most severely affected. She was delivered by Caesarian section at 30 weeks' gestation due to reduced fetal movements, polyhydramnios, and fetal hydrops. She had hypotonia, bradycardia, increased lactate and pyruvate, and cystic necrosis of the brain; she died at 5 days of age from respiratory and multiple organ failure. Fibroblasts showed decreased mitochondrial complex IV activity.

Inheritance

The transmission pattern of COXPD28 in the families reported by Kishita et al. (2015) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 3 unrelated children with COXPD28, Kishita et al. (2015) identified homozygous or compound heterozygous mutations in the SLC25A26 gene (611037.0001-611037.0004). The mutations, which were found by a combination of homozygosity mapping and exome sequencing, segregated with the disorder in the families. In vitro functional expression studies and studies in yeast indicated that the mutations resulted in a variable loss of mitochondrial SLC25A26 transport function. Studies of patient tissues showed variably decreased activities of mitochondrial complexes I, II, and IV, decreased ATP synthesis, decreased methylation of ribosomal transcripts and proteins, defective lipoic acid metabolism, and decreased synthesis of coenzyme Q10. There were some differences in these biochemical defects among patients and between tissues, namely skeletal muscle and fibroblasts. Overall, the findings were consistent with a primary defect in the mitochondrial methylome that resulted in compromised mitochondrial function.