Clinical manifestations of mitochondrial DNA depletion
1H. Houston Merritt Clinical Research Center for Muscular Dystrophy and Related Diseases, Columbia University, New York, NY 10032, USA.
Objective:
We studied five new patients with mitochondrial DNA (mtDNA) depletion to better define the clinical spectrum of this disorder.
Background:
mtDNA depletion has been associated with myopathy or hepatopathy, or both, in infants and young children. Involvement of the CNS and peripheral nervous system has not been clearly established.
Methods:
We reviewed the clinical course and performed morphologic, biochemical, and genetic analyses of muscle samples from five patients.
Results:
Age at onset ranged from 3 months to 5 years, and one patient survived until age 10 1/2 years. Two patients had laboratory and clinical features reminiscent of dystrophinopathy, two had evidence of brain involvement, and two had peripheral neuropathy. Muscle biopsy specimens in all patients showed abundant ragged-red fibers. Biochemistry showed cytochrome c oxidase deficiency in all patients tested and decreased activities of other respiratory chain complexes in some.
Conclusions:
Inheritance appeared to be autosomal recessive, suggesting that mutations in nuclear DNA are responsible for mtDNA depletion. mtDNA depletion should be considered in children with mitochondrial disorders of uncertain etiology, and criteria for diagnosis are proposed.
Insights
Mitochondrial DNA (mtDNA) depletion, a disorder affecting infants and children, presents with varied symptoms including muscle, brain, and nerve involvement. Autosomal recessive inheritance suggests nuclear DNA mutations are the cause.
Area of Science:
- Mitochondrial genetics and pathophysiology.
- Pediatric neurology and myology.
Background:
- Mitochondrial DNA (mtDNA) depletion typically presents in infants and children with myopathy or hepatopathy.
- Central nervous system (CNS) and peripheral nervous system involvement in mtDNA depletion remain incompletely understood.
Observation:
- Five pediatric patients with mitochondrial DNA depletion were analyzed for clinical, morphological, biochemical, and genetic features.
- Clinical presentations varied, with some exhibiting features of dystrophinopathy, CNS involvement, or peripheral neuropathy.
- Muscle biopsies consistently showed ragged-red fibers, and biochemical assays revealed cytochrome c oxidase deficiency in all tested patients.
Findings:
- Onset ranged from 3 months to 5 years, with survival up to 10.5 years in one case.
- Two patients showed dystrophinopathy-like features, two had brain involvement, and two had peripheral neuropathy.
- All patients displayed ragged-red fibers on muscle biopsy and cytochrome c oxidase deficiency.
Implications:
- Autosomal recessive inheritance suggests nuclear gene mutations underlie mtDNA depletion.
- mtDNA depletion should be considered in pediatric mitochondrial disorders of unknown origin.
- Diagnostic criteria for mtDNA depletion are proposed based on these findings.
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