Mitochondrial disease with hypertrophic cardiomyopathy
-Rare cardiac disease
-Rare genetic disease
Mitochondrial disorder due to a defect in mitochondrial protein synthesis
-Rare developmental defect during embryogenesis
-Rare genetic disease
-Rare neurologic disease
Comment:
Transcription of the mitochondrial genome generates large polycistronic transcripts punctuated by the 22 mitochondrial (mt) tRNAs that are conventionally cleaved by the RNase P-complex and the RNase Z activity of ELAC2 (= COXPD17) at 5' and 3' ends, respectively. ELAC2 mutations cause therefore a mitochondrial RNA processing defect associated with hypertrophic cardiomyopathy. Accumulated mtRNA precursors in affected individuals muscle and fibroblasts were observed. Although mature mt-tRNA, mt-mRNA, and mt-rRNA levels were not decreased in fibroblasts, the processing defect was associated with impaired mitochondrial translation (PMID:23849775).
Involved genes:
ELAC2 (COXPD17) (PMID:23849775),
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 ... 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).
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, ... 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.
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 ... 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.