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Mitochondrial DNA rearrangements with onset as chronic diarrhea with villous atrophy
V Cormier-Daire1, J P Bonnefont, P Rustin
1Hôpital des Enfants-Malades, Paris, France.
Insights
Genetic defects in mitochondrial energy supply can cause chronic diarrhea and villous atrophy in children. This study identifies complex III deficiency and mitochondrial DNA rearrangements as a cause of these symptoms.
Area of Science:
- Biochemistry
- Genetics
- Pediatrics
Background:
- Mitochondrial disorders can present with diverse clinical manifestations.
- Chronic diarrhea and villous atrophy in early childhood warrant investigation into underlying metabolic causes.
Observation:
- Two unrelated children presented with chronic diarrhea and villous atrophy in infancy.
- Elevated plasma lactate and altered lactate/pyruvate ratios indicated a defect in oxidative phosphorylation.
Findings:
- Muscle analysis revealed mitochondrial respiratory chain complex III deficiency in both patients.
- Mitochondrial DNA rearrangements, including deletion and deletion-duplication, were identified.
- These rearrangements occurred at directly repeated sequences in the mitochondrial genome.
Implications:
- Mitochondrial disorders should be considered in the differential diagnosis of unexplained chronic diarrhea and villous atrophy.
- Genetic defects in mitochondrial energy metabolism can manifest initially with gastrointestinal symptoms.
- Early diagnosis of mitochondrial disorders is crucial for appropriate management and genetic counseling.
Abstract:
We report two unrelated children with onset of chronic diarrhea and villous atrophy in the first years of life. Elevated plasma lactate concentrations and lactate/pyruvate and ketone body molar ratios suggested a genetic defect of oxidative phosphorylation. Analysis of the mitochondrial respiratory chain showed a complex III deficiency in muscle of both patients. Southern blot analysis provided evidence of heteroplasmic mitochondrial DNA rearrangements that involve deletion and deletion-duplication. Directly repeated sequences (10 and 11 base pairs, respectively) were present in the wild type of mitochondrial genome at the boundaries of the deletion. Neither parent of either patient had rearranged molecules in their circulating lymphocytes. It appears that a mitochondrial disorder can have chronic diarrhea and villous atrophy as the initial clinical feature. On the basis of these observations, we suggest that genetic defects of mitochondrial energy supply be considered in elucidating the origin of unexplained chronic diarrheas, especially when other, unrelated symptoms occur in the course of the disease.