Mitochondrial DNA depletion: prevalence in a pediatric population referred for neurologic evaluation.

Mitochondrial DNA depletion is a quantitative disorder of mtDNA, characterized by tissue-specific reductions in mtDNA copy number, that presents in infancy or early childhood. It is most likely transmitted as an autosomal recessive trait, although about half of the described cases are sporadic. To estimate its prevalence we measured relative mtDNA copy number (mtDNA: 18S rDNA ratio) by Southern blot analysis in muscle biopsy samples from all children with compatible histories referred between 1983 and 1994. Of the 304 biopsies evaluated, 54 met the study criteria. We found 6 patients (2 male, 4 female) with mtDNA depletion (relative mtDNA copy number 7.9-33.2% of control). Their clinical course and findings were heterogeneous, however all but one manifested weakness, hypotonia, and developmental delay. Clinical severity was not obviously related to the degree of mtDNA depletion. No patient had ragged-red fibers, although 2 had a lipid storage myopathy. Immunofluorescence with antibodies to double-stranded DNA, COX IV, and COX II demonstrated homogeneously reduced reactivity to all three antibodies compared with control. mtDNA depletion may be a relatively common neurogenetic disorder of infancy and early childhood and should be considered in children with unexplained weakness, hypotonia, or developmental delay.