A number sign (#) is used with this entry because combined oxidative phosphorylation deficiency-7 (COXPD7) is caused by homozygous mutation in the C12ORF65 gene (MTRFR; 613541) on chromosome 12q24.

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

Antonicka et al. (2010) reported 3 patients, including 2 sibs, with a complex phenotype associated with a combined mitochondrial oxidative phosphorylation deficiency. The first child was a girl, born of consanguineous Turkish parents, who showed failure to thrive and psychomotor regression beginning at age 1 year. At 18 months, she had psychomotor retardation, ataxia, and ptosis. She later developed nystagmus, severe optic atrophy, decreased vision, and ophthalmoplegia. Brain MRI showed bilateral lesions in the thalami, brainstem, and medulla spinalis, consistent with a diagnosis of Leigh syndrome (256000). By the time of her death at age 8 years, she was hypermobile with ataxia and used a wheelchair. The second family was Dutch and had 2 affected boys. Both had initial normal development but developed nystagmus in early childhood, followed by developmental regression at ages 3-4 and 7 years, respectively. One patient became wheelchair-dependent at age 8, and ventilator-dependent with a gastrostomy tube due to paralytic ileus at age 14. Examination at age 20 years showed significant ocular involvement with optic atrophy and diminished vision, divergent squint, and incomplete external ophthalmoplegia. Other features included bulbar paresis with facial diplegia, difficulty chewing and swallowing, and mild dysarthria. He also had evidence of an axonal polyneuropathy with global muscle atrophy, hypotonia, areflexia, and decreased distal sensory functions. The affected brother had a similar disease course and died at age 22 years. Brain MRI showed extensive signal abnormalities in the brainstem and signal abnormalities in the cerebellar white matter and thalamus. Magnetic resonance spectroscopy of the brainstem revealed highly elevated lactate. Antonicka et al. (2010) noted that the disease progression in these patients was slower than that seen in patients with classic Leigh syndrome.

By laboratory studies of fibroblasts isolated from patients with a complex neurologic disorder, Antonicka et al. (2010) found severe assembly defects of mitochondrial respiratory complexes I, IV, and V, with a milder defect in the assembly of complex III. There was also a 30% decrease in the synthesis of mtDNA-encoded polypeptides with normal transcript levels, indicating a deficiency of mitochondrial translation. Mitochondrial ribosomal proteins were normal on Western blot analysis.

COXPD7 is inherited in an autosomal recessive manner (Antonicka et al., 2010).

By genomewide linkage analysis followed by candidate gene sequencing in a patient with a combined oxidative phosphorylation defect born of consanguineous Turkish parents, Antonicka et al. (2010) identified a homozygous mutation in the C12ORF65 gene (613541.0001). Two affected brothers from a Dutch family with the same disorder carried a different homozygous mutation (613541.0002).