Combined Oxidative Phosphorylation Deficiency 23

A number sign (#) is used with this entry because of evidence that combined oxidative phosphorylation deficiency-23 (COXPD23) is caused by homozygous or compound heterozygous mutation in the GTPBP3 gene (608536) on chromosome 19p13.

Description

Combined oxidative phosphorylation deficiency-23 is an autosomal recessive disorder characterized by early childhood onset of hypertrophic cardiomyopathy and/or neurologic symptoms, including hypotonia and delayed psychomotor development. Laboratory investigations are consistent with a defect in mitochondrial function resulting in lactic acidosis, impaired activities of respiratory complexes I and IV, and defective translation of mitochondrial proteins. Brain imaging shows abnormal lesions in the basal ganglia, thalamus, and brainstem. The severity of the disorder is variable, ranging from death in early infancy to survival into the second decade (summary by Kopajtich et al., 2014).

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

Clinical Features

Kopajtich et al. (2014) reported 11 children from 9 families with combined oxidative phosphorylation deficiency. Patients from 8 of the families presented between birth and age 2 years; 2 brothers from the ninth family presented later in childhood. All patients had lactic acidosis, 9 had cardiomyopathy, and 6 had variable neurologic symptoms, including feeding difficulties in infancy, hypotonia, developmental delay, and intellectual impairment. Less common features included seizures and visual impairment. Brain imaging, performed in 3 patients, showed T2-weighted hyperintensities variably apparent in the thalamus, basal ganglia, and/or brainstem, suggestive of Leigh syndrome (256000). The severity was variable, ranging from death from cardiac failure in early infancy to survival into the second decade with mild intellectual disability. One child had normal psychomotor development at age 5 years. Skeletal muscle biopsies from most patients showed severely decreased activities of mitochondrial complexes I and IV; however, 1 patient had normal activity of these enzymes in skeletal muscle biopsy.

Inheritance

The transmission pattern of COXPD23 in the families reported by Kopajtich et al. (2014) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 11 patients from 9 families with combined oxidative phosphorylation deficiency, Kopajtich et al. (2014) identified homozygous or compound heterozygous mutations in the GTPBP3 gene (see, e.g., 608536.0001-608536.0006). Mutations in 8 probands were found by whole-exome sequencing of a cohort of 790 individuals with a suspected mitochondrial disease. Studies of available patient fibroblasts showed decreased GTPBP3 protein levels, impaired oxidative phosphorylation, and severe decreases in the synthesis of mitochondrial-encoded proteins, consistent with a loss of function. Knockdown of GTPBP3 in HeLa cells resulted in a defect in mitochondrial translation similar to that observed in patient cells. The findings confirmed an important role for GTPBP3 in efficient mitochondrial protein synthesis, consistent with the postulated role of GTPBP3 in the posttranscriptional modification of mitochondrial tRNA.