Combined Oxidative Phosphorylation Deficiency 36

A number sign (#) is used with this entry because of evidence that combined oxidative phosphorylation deficiency-36 (COXPD36) is caused by compound heterozygous mutation in the MRPS2 gene (611971) on chromosome 9q34.

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

Clinical Features

Gardeitchik et al. (2018) reported 2 unrelated patients, an 11-year-old girl of Austrian descent and an 11-year-old boy of Tunisian descent, with a relatively mild multisystem disease resulting from mitochondrial dysfunction. The patients presented in infancy with delayed psychomotor development and hypotonia, followed by speech delay associated with sensorineural hearing loss and episodic hypoglycemia. The girl had intellectual disability and mild dysmorphic features, including low-set ears, upslanting palpebral fissures, skin wrinkling, and strabismus. At age 11 years, the boy had a normal appearance, but moderate intellectual disability, frequent headaches, weakness of the lower limbs, and exercise intolerance. Both patients had normal brain MRI. Laboratory studies in both patients showed increased lactate, increased urinary Krebs cycle intermediates, such as 2-oxoglutaric aciduria, and decreased activities of multiple oxidative phosphorylation enzyme complexes (OXPHOS) in various tissues. The disorder was not progressive, and Gardeitchik et al. (2018) commented that these patients were at the less severe end of the clinical spectrum of mitochondrial disorders.

Inheritance

The transmission pattern of COXPD36 in the families reported by Gardeitchik et al. (2018) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 2 unrelated children with COXPD36, Gardeitchik et al. (2018) identified compound heterozygous or homozygous missense mutations in the MRPS2 gene (611971.0001-611971.0003). The mutations, which were found by exome sequencing, segregated with the disorder in the families. Patient fibroblasts showed decreased levels of the MRPS2 protein, as well as decreased levels of certain other MRPS proteins and the mt-DNA-encoded 12S rRNA, which are part of the smaller mitochondrial-specific ribosomal subunit 28S (mt-SSU). Complexome profiling of mitochondrial extracts from patient cells showed impaired assembly of the mt-SSU, resulting in a lack of functional mitoribosomes, inhibition of mitochondrial translation, and multiple deficiencies of the oxidative phosphorylation enzymes (OXPHOS). Patient cells showed a decrease in the abundance of fully assembled complexes I and IV and aberrant assembly of complex V. The defects could be rescued by complementation with wildtype MRPS2. Gardeitchik et al. (2018) noted that the phenotype in these patients was relatively mild compared to other COXPDs, and suggested that this may result from a combination of different effects of the mutations on the stability or activity of the affected protein, the presumed role of MRPS2 late in mitoribosomal biogenesis, and different thresholds at which individual tissues are affected by diminished energy supply.