title: Novel Hypoglycemia Phenotype in Congenital Hyperinsulinism Due to Dominant Mutations of Uncoupling Protein 2.
abstract: The rarest genetic form of congenital hyperinsulinism (HI) has been associated with dominant inactivating mutations in uncoupling protein 2 (UCP2), a mitochondrial inner membrane carrier that modulates oxidation of glucose vs amino acids.
  
  
  
  To evaluate the frequency of UCP2 mutations in children with HI and phenotypic features of this form of HI.
  
  
  
  We examined 211 children with diazoxide-responsive HI seen at The Children's Hospital of Philadelphia (CHOP) between 1997 and October 2016.
  
  
  
  CHOP Clinical and Translational Research Center.
  
  
  
  Of 211 cases of diazoxide-responsive HI, we identified 5 unrelated children with UCP2 mutations (5 of 211; 2.4%). All 5 were diagnosed with HI before 6 months of age; diazoxide treatment was only partly effective in 3 of the 5. Among the 5 cases, 4 unique mutations (3 missense and 1 splicing) were identified. Three mutations were novel; 1 was previously reported. In vitro functional assays showed 30% to 75% decrease in UCP2 activity. Two of the children, when not taking diazoxide, developed hypoketotic-hypoglycemia after fasting 15 to 20 hours; a similar trend toward hypoglycemia after fasting 24 hours occurred in 4 adult carriers. In contrast, both children and 2 of the 4 carriers developed symptomatic hypoglycemia 4 hours following oral glucose. Unusual oscillating glucose and insulin responses to oral glucose were seen in both cases and carriers.
  
  
  
  These data indicate that dominant UCP2 mutations are a more important cause of HI than has been recognized and that affected individuals are markedly hypersensitive to glucose-induced hypoglycemia.
authors.affiliation: University of California, San Francisco, San Francisco, California 94122.
authors.forename: Christine T
authors.initials: CT
authors.lastname: Ferrara
authors.affiliation: Division of Endocrinology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104.
authors.forename: Kara E
authors.initials: KE
authors.lastname: Boodhansingh
authors.affiliation: Institute of Biomembranes and Bioenergetics, Consiglio Nazionale delle Ricerche, 70126 Bari, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Paradies
authors.affiliation: Department of Biosciences, Biotechnologies and Biopharmaceutics, Laboratory of Biochemistry and Molecular Biology, University of Bari, 70126 Bari, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Fiermonte
authors.affiliation: Alfred I. duPont Hospital for Children, Wilmington, Delaware 19803.
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Steinkrauss
authors.affiliation: Hasbro Children's Hospital and Alpert Medical School of Brown University, Providence, Rhode Island 02903; and.
authors.forename: Lisa Swartz
authors.initials: LS
authors.lastname: Topor
authors.affiliation: Hasbro Children's Hospital and Alpert Medical School of Brown University, Providence, Rhode Island 02903; and.
authors.forename: Jose Bernardo
authors.initials: JB
authors.lastname: Quintos
authors.affiliation: Departments of Genetics and.
authors.forename: Arupa
authors.initials: A
authors.lastname: Ganguly
authors.affiliation: Division of Endocrinology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104.|Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: Diva D
authors.initials: DD
authors.lastname: De Leon
authors.affiliation: Department of Biosciences, Biotechnologies and Biopharmaceutics, Laboratory of Biochemistry and Molecular Biology, University of Bari, 70126 Bari, Italy.|Institute of Biomembranes and Bioenergetics, Consiglio Nazionale delle Ricerche, 70126 Bari, Italy.
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Palmieri
authors.affiliation: Division of Endocrinology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104.|Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Stanley
mesh_terms: D001786:Blood Glucose / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D044903:Congenital Hyperinsulinism / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D003981:Diazoxide / Q000627:therapeutic use; D005215:Fasting / Q000378:metabolism*; D005260:Female; D005951:Glucose Tolerance Test; D006579:Heterozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007328:Insulin / Q000378:metabolism*; D008297:Male; D009154:Mutation; D020125:Mutation, Missense; D010641:Phenotype; D000071246:Uncoupling Protein 2 / Q000235:genetics*
chemical_list: D001786:Blood Glucose; D007328:Insulin; D000071246:Uncoupling Protein 2; D003981:Diazoxide