Combined Oxidative Phosphorylation Deficiency 31 (COXPD31) is a multi-visceral disorder characterized by developmental delay, microcephaly, seizures, uncontrollable movements, and facial dysmorphy, as well as cardiac, muscular, and ophthalmic abnormalities. Clinical features present at birth or during infancy; the disorder is considered fatal due to the onset of progressive hypertrophic cardiomyopathy (left ventricular non-compaction). Additional symptoms include hypotonia, dystonic hypertonia, cataracts, and vision loss. Biochemical symptoms include increased lactate and alanine, fat and glycogen deposits in skeletal muscle, as well as abnormal mitochondria with reduced activity.
COXPD31 is caused by dysfunction in MIPEP, a gene essential for mitochondrial biogenesis and ATP production.
COXPD31 is an autosomal recessive disorder caused by homozygous or compound heterozygous mutations in MIPEP. This gene is involved in processing precursor mitochondrial enzymes including proteins responsible for oxidative phosphorylation that are required for ATP production. Missense, nonsense, and deletion mutations have been reported in affected individuals. Functional studies of two identical missense mutations in the yeast homologue protein were found to be deleterious, causing either reduced protease activity or lack of protein localization to mitochondria.
Al-Shamsi et al., 2016 performed Whole Exome Sequencing (WES) in 85 Emirati patients who were admitted to the metabolic unit with un-diagnosable inborn errors of metabolism and other genetic disorders. Among the cohort in whom variants of uncertain significance were likely pathogenic, 1 patient with a mutation in MIPEP was diagnosed with Combined Oxidative Phosphorylation Deficiency 31 (COXPD31). The clinical presentation included developmental delay, dysmorphy, microcephaly, hypotonia, loss of visual acuity, and cardiac atrial septum defect.
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