6 8 8 North et al. The Journal of Pediatrics May 1996 Oxidative phosphorylation defect associated with primary adrenal insufficiency Kathryn North, MD, Mark S. Korson, MD, Nicolas Krawiecki, MD, John M. Shoffner, MD, and Ingrid A. Holm, MD From the Department of Medicine, Children's Hospital, Boston, Massachusetts, and the De- partment of Genetics and Molecular Medicine, Emory University School of Medicine, Atlanta, Georgia An 18-month-old girl with an oxidative phosphorylation defect had neonatal on- set of chronic lactic acidosis, lipid storage myopathy, bilateral cataracts, and primary adrenal insufficiency. Chronic lactic acidosis responded to treatment with dichloroacetate. Sequential muscle biopsies demonstrated resolution of the lipid storage myopathy associated with the return to normal muscle free carnitine lev- els. This case demonstrates a new clinical phenotype associated with a defect in oxidative phosphorylation and the need to consider mitochondrial disorders in the differential diagnosis of primary adrenal insufficiency in childhood. (J Pediatr 1996; 128:688-92) Oxidative phosphorylation is responsible for the production of the majority of adenosine triphosphate required for nor- mal cellular function and is mediated by complexes I to V of the respiratory chain within the mitochondrial matrix.1 Disorders of oxidative phosphorylation can affect function or morphogenesis in a variety of tissues; any organ in which cellular adenosine triphosphate production does not meet threshold requirements may be affected. However, adreno- cortical insufficiency has not been reported as a manifesta- tion of mitochondrial disease. We describe an 18-month-old patient with an oxidative phosphorylation defect who has a new phenotype characterized by neonatal onset of chronic lactic acidosis, lipid storage myopathy, bilateral cataracts, and primary adrenal insufficiency. CASE REPORT The patient was a 2.8 kg term female infant who, soon after de- livery, had tachypnea and metabolic acidosis (pH 7.26, partial pressure of carbon dioxide 19 mm Hg, and serum bicarbonate 7 mmol/L). Results of an evaluation for sepsis were negative. The se- rum lactate concentration was repeatedly elevated, despite normal peripheral perfusion, with a maximal level of 20.8 mmol/L (normal Supported in part by the Emory Clinical Research Center (National Institutes of Health grant No. M01RR-00039) and National Insti- tutes of Health grant No. R01-NS33999. Submitted for publication June 20, 1995; accepted Jan. 6, 1996. Reprint requests: Mark S. Korson, MD, Genetics Division, Enders 5, Children's Hospital, 300 Longwood Ave, Boston, MA 02115. Copyright © 1996 by Mosby-Year Book, Inc. 0022-3476/96/$5.00 + 0 9/22/71927 <2.2 mmol/L), and a lactate/pyruvate ratio of 100:1 (normal <25:1). Serum ammonia and amino acid levels, urinalysis results, and urine amino acid values were normal; urine and cerebrospinal fluid organic acid analysis showed only increased lactate concentration. The infant was treated with intravenously administered dichloroac- etate, and the serum lactate level decreased to normal levels within 16 hours. Dichloroacetate therapy was discontinued after 2 weeks. During the first month of life the infant had poor feeding, irrita- bility, and progressive hepatomegaly with normal liver function. Protein malabsorption led to poor weight gain and hypoproteinemia, necessitating insertion of a gastrostomy tube and feeding with an elemental formula. Echocardiographic findings and renal function were normal. Neurologic examination showed truncal hypotonia and appendicular hypertonia. Results of a magnetic resonance im- aging examination of the brain were normal. The patient was the first child of unrelated white parents. The family history was nota- ble for migraine and manic-depressive illness in the mother, mater- nal grandmother, maternal uncle, and two maternal great-aunts. The mother's serum lactate value was normal. A muscle biopsy at 3 weeks of age showed lipid storage myop- athy, increased glycogen storage, and normal mitochondrial mor- phologic findings (Figure). Biochemical assay of the components of the electron transport chain in frozen muscle 2 revealed complete absence of activity in complex I and significantly reduced activity of complex IV (Table I). Plasma acylcarnitine and urine acylglycine profiles were normal. The patient was given coenzyme Q, carnitine, riboflavin, and vitamin C. During the next few months the patient gained weight, the mal- absorption, hepatomegaly, and hypoproteinemia resolved, and her neurologic status improved. Chronic lactic acidosis (range 4 to 8 mmol/L) was treated with bicarbonate~ supplementation. At 5 months of age bilateral dense cataracts developed and resulted in loss of visual fixation. She underwent sequential bilateral cataract