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Fatal infantile cytochrome c oxidase deficiency: decrease of immunologically detectable enzyme in muscle
Insights
This study investigated a fatal mitochondrial disease in an infant, revealing a severe deficiency in cytochrome c oxidase activity due to potential subunit synthesis issues. The findings highlight a novel cause of complex IV deficiency in skeletal muscle.
Area of Science:
- Biochemistry
- Cell Biology
- Pediatric Neurology
Background:
- Mitochondrial disorders can cause severe, multi-systemic illness in infants.
- Cytochrome c oxidase (Complex IV) is crucial for cellular respiration.
- Defects in Complex IV assembly or function lead to energy deficits and disease.
Observation:
- An infant presented with progressive weakness, hypotonia, respiratory failure, seizures, and recurrent infections.
- Muscle biopsies revealed excessive mitochondria, lipid, and glycogen, with later fibrosis and fat infiltration.
- Chronically elevated serum lactate and undetectable cytochrome c oxidase activity were observed.
Findings:
- Muscle mitochondria showed a complete absence of cytochrome aa3 and severely reduced cytochrome c oxidase activity.
- Immunological assays indicated decreased amounts of reactive enzyme protein.
- SDS-PAGE confirmed the presence of all cytochrome c oxidase subunits, suggesting a synthesis or assembly defect.
Implications:
- This case suggests that decreased synthesis of one or more cytochrome c oxidase subunits can lead to a severe deficiency of functional Complex IV in skeletal muscle.
- Understanding these defects is vital for diagnosing and potentially treating mitochondrial myopathies.
- Further research into subunit assembly pathways is warranted for complex mitochondrial diseases.
Abstract:
A 2-month-old boy had progressive generalized weakness, hypotonia, and respiratory insufficiency requiring assisted ventilation. At age 3 1/2 months, he started having seizures and recurrent pulmonary infections; he died at age 7 months. Serum lactate was chronically elevated, but there was no aminoaciduria. Histochemical and ultrastructural studies of muscle biopsies at ages 2 and 3 months showed excessive mitochondria, lipid, and glycogen; a third biopsy at 6 months showed marked increase in perimysial fibrous and fat tissue. Cytochrome c oxidase activity was 7% of normal in the first biopsy and undetectable in the others. Cytochrome spectra of mitochondria isolated from postmortem muscle showed complete lack of cytochrome aa3. Antibodies were obtained against cytochrome c oxidase purified from normal human heart. Immunotitration and enzyme-linked immunosorbent assay (ELISA) showed decreased immunologically reactive enzyme protein in the patient's muscle, but SDS-PAGE electrophoresis of immunoprecipitates of muscle mitochondrial extracts showed the presence of all cytochrome c oxidase subunits. These data suggest that decreased synthesis of one or more subunits may result in markedly decreased concentration of electrophoretically normal complex IV in skeletal muscle.