The Journal of clinical endocrinology and metabolism · 2017
Novel Hypoglycemia Phenotype in Congenital Hyperinsulinism Due to Dominant Mutations of Uncoupling Protein 2.
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Ferrara Christine T, Boodhansingh Kara E, Paradies Eleonora, Fiermonte Giuseppe, Steinkrauss Linda J, Topor Lisa Swartz, Quintos Jose Bernardo, Ganguly Arupa, De Leon Diva D, Palmieri Ferdinando, Stanley Charles A
Аннотация
CONTEXT: 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.
OBJECTIVE: To evaluate the frequency of UCP2 mutations in children with HI and phenotypic features of this form of HI.
DESIGN: We examined 211 children with diazoxide-responsive HI seen at The Children's Hospital of Philadelphia (CHOP) between 1997 and October 2016.
SETTING: CHOP Clinical and Translational Research Center.
RESULTS: 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.
CONCLUSIONS: 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.
OBJECTIVE: To evaluate the frequency of UCP2 mutations in children with HI and phenotypic features of this form of HI.
DESIGN: We examined 211 children with diazoxide-responsive HI seen at The Children's Hospital of Philadelphia (CHOP) between 1997 and October 2016.
SETTING: CHOP Clinical and Translational Research Center.
RESULTS: 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.
CONCLUSIONS: 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.