Clinical characteristics and muscle pathology in myopathic mitochondrial DNA depletion

Four nonrelated children with myopathic mitochondrial DNA depletion are described. Two of them initially had normal motor development and two had mild motor delay. Motor arrest and regression started at age 6 to 21 months. All four had mitochondrial DNA:nuclear DNA ratios reduced to 16 to 22% of the control mean and mutations in their mitochondrial thymidine kinase 2. Muscle pathology was genotype related: homozygosity for a missense mutation at position 181 was associated with severe myopathic changes, including marked variation in muscle fiber size, myofiber necrosis, regeneration, and interstitial fibrosis, whereas homozygosity for a missense mutation at position 90 was associated with essentially normal muscle histology. No ragged red fibers were detected in any study child. Mitochondrial DNA depletion should be considered in children with myopathy, worsening hypotonia, motor regression, and death during infancy or early childhood. The severity of pathologic findings on muscle biopsy is variable and may correlate with specific mutations and thymidine kinase 2 protein residual activity.