Combined Oxidative Phosphorylation Deficiency 17

A number sign (#) is used with this entry because combined oxidative phosphorylation deficiency-17 (COXPD17) is caused by homozygous or compound heterozygous mutation in the ELAC2 gene (605367) on chromosome 17p12.

Description

Combined oxidative phosphorylation deficiency-17 is an autosomal recessive disorder of mitochondrial dysfunction characterized by onset of severe hypertrophic cardiomyopathy in the first year of life. Other features include hypotonia, poor growth, lactic acidosis, and failure to thrive. The disorder may be fatal in early childhood (summary by Haack et al., 2013).

Clinical Features

Haack et al. (2013) reported 5 patients from 3 unrelated families with onset of severe hypertrophic cardiomyopathy between 2 and 5 months of age. Two of the families were consanguineous. The infants usually presented with poor growth, hypotonia, and lactic acidosis; most showed delayed psychomotor development after normal early development in the first few months of life. Two patients died before 12 months of age, and a third died at age 4 years, 9 months. One patient had additional abnormalities, including microcephaly, hearing impairment, and hyperintensities in the basal ganglia. Biochemical studies in patient skeletal muscle showed decreased mitochondrial complex I activity; some also had decreased activity of complex IV.

Inheritance

The transmission pattern of COXPD27 in the families reported by Haack et al. (2013) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 5 patients from 3 unrelated families with combined oxidative phosphorylation deficiency-17 manifest as severe infantile-onset hypertrophic cardiomyopathy, Haack et al. (2013) identified compound heterozygous or homozygous mutations in the ELAC2 gene (605367.0006-605367.0009). The initial mutations were found be exome sequencing. Patient tissue samples showed accumulation of unprocessed mt-tRNA intermediates that could be rescued by expression of wildtype ELAC2. The findings were consistent with impaired 3-prime end processing of mt-tRNAs. Although levels of mature mt-tRNA, mt-mRNA, and mt-rRNA were normal, patient cells showed increased levels of unprocessed mt-mRNA and mt-rRNA precursors and evidence of decreased translation of mitochondrial proteins. Haack et al. (2013) concluded that impaired RNase Z activity of ELAC2 causes a fatal failure in cellular energy metabolism by interfering with normal mitochondrial translation.

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