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COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 30; COXPD30

COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 30; COXPD30

Metodiev et al. (2016) reported 2 unrelated infants with a fatal systemic mitochondrial disease. One patient was of Caucasian descent and the other was of Kurdis...

Metodiev et al. (2016) reported 2 unrelated infants with a fatal systemic mitochondrial disease. One patient was of Caucasian descent and the other was of Kurdish descent. The patients presented at birth with hypotonia, feeding difficulties, and deafness. One also had cardiac left ventricular hypertrophy and brain imaging suggestive of frontal polymicrogyria. Laboratory studies in both patients showed lactic acidosis, increased cerebrospinal fluid lactate levels, increased serum alanine, and abnormal liver function tests. Both infants died of respiratory failure at age 5 months. Patient skeletal muscle cells showed decreased activities of mitochondrial complexes I and IV in both patients, and decreased complex III activity in only 1 patient. Muscle biopsy, performed in 1 patient, showed COX-deficient ragged-red fibers.

▼ Inheritance

The transmission pattern of COXPD30 in the families reported by Metodiev et al. (2016) was consistent with autosomal recessive inheritance.

▼ Molecular Genetics

In 2 unrelated infants with fatal COXPD30, Metodiev et al. (2016) identified homozygous or compound heterozygous missense mutations in the TRMT10C gene (R181L, 615423.0001 and T272A, 615423.0002). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Patient fibroblasts showed decreased assembly of complexes I and IV, with mildly decreased complex III. This was associated with impaired mitochondrial protein synthesis as well as impaired mt-RNA processing efficiency with a mild accumulation of mitochondrial precursor RNA, but without severe effects on mature mt-mRNA or mt-tRNA steady-state levels. There was no effect on m(1)R9 methyltransferase activity. Transfection of patient cells with wildtype TRMT10C rescued the respiratory chain complex deficiencies and the defects in mitochondrial translation.

Tags: 3q12.3