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Defects of the mitochondrial respiratory chain complexes in three pediatric cases with hypotonia and cardiac
D Figarella-Branger1, J F Pellissier, C Scheiner
1Laboratoire d'Anatomie Pathologique, Hôpital de la Timone, Marseille, France.
Insights
Mitochondrial myopathy can present without ragged-red fibers, showing cytochrome c oxidase deficiency. Diagnosis requires muscle biopsy and biochemical analysis of respiratory chain complexes, especially in cases with mtDNA depletion.
Area of Science:
- Biochemistry
- Genetics
- Pediatrics
Background:
- Mitochondrial myopathies are a group of inherited disorders affecting energy production.
- Cytochrome c oxidase (COX) deficiency is a known cause of mitochondrial myopathy, often associated with ragged-red fibers on muscle biopsy.
Observation:
- Three pediatric cases with hypotonia, cardiac issues, and COX deficiency are presented.
- Muscle biopsies revealed lipid storage myopathy and reduced COX activity, but lacked ragged-red fibers.
- Biochemical analysis confirmed COX deficiency, with additional complex deficiencies in two cases and mtDNA depletion in one.
Findings:
- Histochemical COX deficiency is a reliable indicator of mitochondrial myopathy, even without ragged-red fibers.
- Biochemical assessment of mitochondrial respiratory chain complexes is crucial for diagnosing multiple defects and mtDNA depletion.
- Case 3 showed an unusual clinical remission, highlighting the diverse presentations of these disorders.
Implications:
- This study emphasizes the diagnostic utility of COX histochemistry and biochemical analysis in pediatric mitochondrial myopathies.
- Understanding the spectrum of clinical and biochemical findings aids in accurate diagnosis and management.
- Further research into the genetic and molecular basis of these defects is warranted.
Abstract:
Three children displaying hypotonia, cardiac involvement and defects of the mitochondrial respiratory chain complexes are reported. The first case showed severe neonatal hypotonia, failure to thrive, hepatomegaly, dilation of the right cardiac cavities, profound lactic acidosis and amino aciduria. The boy died at the age of 7 weeks. In the second case hypotonia, severe cardiomyopathy, cyclic neutropenia, lactic acidosis and 3-methylglutaconic aciduria occurred. The boy died at the age of 27 months. The third case presented at the age of 16 months as an acute hypokinetic hypertrophic cardiomyopathy with transient hypotonia and mild lactic acidosis. Spontaneous clinical remission occurred. In all cases muscle biopsy was performed. Morphological studies failed to show ragged-red fibers but there was lipid storage myopathy and decreased cytochrome c oxidase activity. Biochemical studies confirmed the cytochrome c oxidase deficiency in muscle in all cases. It was associated with complex I III deficiency in case 1 and with severe deficits of all respiratory chain complexes in case 2. Post-mortem studies in case 1 indicated that complex IV was reduced in the liver but not in the heart and quantitative analysis of mtDNA revealed a depletion in muscle. Cases 1 and 2 shared some clinical features with fatal infantile myopathy associated with cytochrome c oxidase deficiency, while case 3 displayed a very unusual clinical presentation. The histochemical enzyme reaction of cytochrome c oxidase is useful for the diagnosis of mitochondrial myopathy because ragged-red fibers may be lacking. Finally, biochemical measurement of the different mitochondrial respiratory chain complexes is required because multiple defects are frequent and occasionally related to mtDNA depletion.