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Familial Leucine-Sensitive Hypoglycemia of Infancy Due to a Dominant Mutation of the ß-Cell Sulfonylurea Receptor

Division of Endocrinology, Children’s Hospital of Philadelphia (S.N.M., C.M., L.S., L.E.L.K., C.A.S.), Philadelphia, Pennsylvania 19104; Center for Research on Occupational and Environmental Toxicology, Oregon Health and Science University (S.-L.S.), Portland, Oregon 97239; and Department of Genetics, University of Pennsylvania School of Medicine (A.G.), Philadelphia, Pennsylvania 19104

Address all correspondence and requests for reprints to: Dr. Charles A. Stanley, Division of Endocrinology, Children’s Hospital of Philadelphia, Abramson Research Center, Room 802, 3615 Civic Center Boulevard, Philadelphia, Pennsylvania 19104-4318. E-mail: stanleyc{at}email.chop.edu.

Familial leucine-sensitive hypoglycemia of infancy was described in 1956 as a condition in which symptomatic hypoglycemia was provoked by protein meals or the amino acid, leucine. The purpose of this study was to determine the genetic basis for hypoglycemia in a family diagnosed with leucine-sensitive hypoglycemia in 1960. Recently diagnosed family members showed a dominantly transmitted pattern of diazoxide-responsive hyperinsulinism (HI). However, they did not fit the characteristics of HI caused by glutamate dehydrogenase gene mutations, previously felt to explain leucine-sensitive hypoglycemia. Islet function was examined using acute insulin response (AIR) tests to calcium, leucine, glucose, and tolbutamide as well as oral protein tolerance tests. Five of five affected family members showed an abnormal positive calcium AIR, and two of five showed a positive leucine AIR. Protein-induced hypoglycemia was demonstrated in five of six affected subjects. Mutation analysis of four known HI genes (sulfonylurea receptor 1, Kir6.2, glutamate dehydrogenase, and glucokinase) in family members identified an R1353H missense mutation in exon 33 of SUR1. ⁸⁶Rb⁺ efflux and electrophysiological studies of R1353H SUR1 coexpressed with wild-type Kir6.2 in COSm6 cells demonstrated partially impaired ATP-dependent potassium channel function. Leucine-sensitive hypoglycemia in this family was found to result from a dominantly expressed SUR1 mutation.

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