Mitochondrial disorders can affect any organ system, but certain tissues, such as muscle, heart, and brain are more susceptible to oxidative phosphorylation (OXPHOS) defects because of their high energy requirements. Endocrinological manifestations, especially diabetes mellitus, are common in mitochondrial diseases but they rarely dominate the clinical picture. Primary adrenal insufficiency was reported only in an 18-month-old patient, with lipid storage myopathy and combined defect of respiratory chain enzymes. We detected a novel 6.9 Kb mtDNA deletion in muscle from a 5-year-old girl who died of a mitochondrial disease with lactic acidosis and primary adrenal insufficiency.
The patient presented at age 4 with short stature, hypotonia, ptosis, lactic acidosis, impaired glucose tolerance, hypoparathyroidism-related hypocalcemia, and primary adrenal insufficiency. Histochemistry of skeletal muscle showed ragged-red and cytochrome c oxidase negative fibers. Biochemical analysis of a muscle homogenate revealed decreased OXPHOS enzyme activities. Southern blot analysis revealed a novel heteroplasmic mtDNA deletion in muscle, the only tissue available for genetic studies. Direct sequencing showed that the deletion was 6,990 base pairs long, extending from nt 7,493 to nt 14,482, and the proportion of deleted mtDNA was 60%. No large-scale mtDNA rearrangement was detected in leukocyte DNA from the mother. Our observation broadens the already wide clinical spectrum associated with mtDNA deletions, and suggests that mtDNA mutations should be included in the differential diagnosis of primary adrenal insufficiency in childhood.
