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Outcome of pyruvate dehydrogenase deficiency treated with ketogenic diets

Studies in patients with identical mutations

From the Departments of Pediatrics and Biochemistry (Drs. Wexler, Hemalatha, Patel, and Kerr, and J. McConnell), Rainbow Babies and Children Hospital, Case Western Reserve University School of Medicine, Cleveland, OH; the Oregon Health Sciences University (Dr. Buist), Portland, OR; the Murdoch Institute (Dr. Dahl), Royal Children's Hospital, Melbourne, Australia; the Department of Pediatrics (Dr. Berry), University of Minnesota, Minneapolis, MN; the Neuropsychiatric Institute (Dr. Cederbaum), University of California, Los Angeles, CA; and the Department of Biochemistry (Dr. Patel), State University of New York at Buffalo, Buffalo, NY.

Address correspondence and reprint requests to Dr. Douglas Kerr, Department of Pediatrics, School of Medicine, Case Western Reserve University, 11100 Euclid Avenue, Cleveland, OH 44106-6004.

Inborn errors of the pyruvate dehydrogenase complex (PDC) are associated with lactic acidosis, neuroanatomic defects, developmental delay, and early death. PDC deficiency is a clinically heterogeneous disorder, with most mutations located in the coding region of the X-linked subunit of the first catalytic component, pyruvate dehydrogenase (E₁). Treatment of E₁ deficiency has included cofactor replacement, activation of PDC with dichloroacetate, and ketogenic diets. In this report, we describe the outcome of ketogenic diet treatment in seven boys with E₁ deficiency. These patients were divided into two groups based on their mutations (R349H, three patients; and R234G, four patients, two sibling pairs). All seven patients received ketogenic diets with varying degrees of carbohydrate restriction. Clinical outcome was compared within each group and between siblings as related to the intensity and duration of dietary intervention. Subjects who either had the diet initiated earlier in life or who were placed on greater carbohydrate restriction had increased longevity and improved mental development. Based on the improved outcomes of patients with identical mutations, it appears that a nearly carbohydrate-free diet initiated shortly after birth may be useful in the treatment of E₁ deficiency.

Supported in part by grants from the National Institute of Child Health and Human Development (I.D.W., HD 00878); the National Institute of Diabetes, Digestive, and Kidney Diseases (M.S.P. and D.S.K., R01-DK-20478); the Children Research Foundation of Cleveland (D.S.K.); and the Mental Retardation Research Center of UCLA (S.D.C.).

Received February 7, 1997. Accepted in final form June 18, 1997.

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