Objectives: Long-term clinical follow-up and mutation analysis were performed in 27 Chinese congenital hyperinsulinism patients. Method: 27 hypoglycemia patients were diagnosed with CHI within 2 years of age. The long-term clinical outcome was analyzed and mutation analysis of 5 hyperinsulinism candidate genes was performed. Results: The median onset age of hypoglycemia in the patients was 60 days; 11 patients showed hypoglycemic symptoms in the neonatal stage, and hypoglycemia in most of the patients was first expressed as a seizure. Blood was collected during the hypoglycemic episode and insulin levels were significantly elevated. ABCC8, KCNJ11, GCK, HNF4a and GLUD1 genes were screened for mutation analysis. 14 mutations in ABCC8 or KCNJ11 genes in 12 cases were identified (44%). 57% (8/14) of the mutations have not been reported before. 83% (10/12) of the patients have a monoallelic mutation. 58% of these 12 patients were predicted to be focal. 73% of the patients without KATP channel mutations were sensitive to diazoxide. 26 patients were followed over a period of 1-13 years. 50% of all 27 patients showed brain impairment. Conclusions: Chinese CHI patients are similar to other ethnic groups in terms of prevalence of KATP-HI, onset age, severity of hypoglycemia and treatment. Mutations in ABCC8 and KCNJ11 are common causes of CHI in Chinese patients. Mutation analysis showed more novel and monoallele mutations in KATP genes.

Keywords:
Congenital hyperinsulinism, ATP-dependent potassium channel, Insulin secretion
1.
Kapoor RR, James C, Hussain K: Advances in the diagnosis and management of hyperinsulinemic hypoglycemia. Nat Clin Pract Endocrinol Metab 2009;5:101-112.
2.
James C, Kapoor RR, Ismail D, Hussain K: The genetic basis of congenital hyperinsulinism. J Med Genet 2009;46:289-299.
3.
Stanley CA, De León DD: Monogenic Hyperinsulinemic Hypoglycemia Disorders. Basel, Karger, 2012.
4.
Kumaran A, Kar S, Kapoor RR, Hussain K: The clinical problem of hyperinsulinemic hypoglycemia and resultant infantile spasms. Pediatrics 2010;126:e1231-e1236.
5.
Senniappan S, Shanti B, James C, Hussain K: Hyperinsulinaemic hypoglycaemia: genetic mechanisms, diagnosis and management. J Inherit Metab Dis 2012;35:589-601.
6.
Flanagan SE, Kapoor RR, Hussain K: Genetics of congenital hyperinsulinemic hypoglycemia. Semin Pediatr Surg 2011;20:13-17.
7.
Thomas PM, Cote GJ, Wohllk N, Haddad B, Mathew PM, Rabl W, Aguilar-Bryan L, Gagel RF, Bryan J: Mutations in the sulfonylurea receptor gene in familial persistent hyperinsulinemic hypoglycemia of infancy. Science 1995;268:426-429.
8.
Dunne MJ, Kane C, Shepherd RM, Sanchez JA, James RF, Johnson PR, Aynsley-Green A, Lu S, Clement JP, Lindley KJ, Seino S, Aguilar-Bryan L: Familial persistent hyperinsulinemic hypoglycemia of infancy and mutations in the sulfonylurea receptor. N Engl J Med 1997;336:703-706.
9.
Saint-Martin C, Arnoux JB, de Lonlay P, Bellanne-Chantelot C: KATP channel mutations in congenital hyperinsulinism. Semin Pediatr Surg 2011;20:18-22.
10.
Snider KE, Becker S, Boyajian L, Shyng SL, MacMullen C, Hughes N, Ganapathy K, Bhatti T, Stanley CA, Ganguly A: Genotype and phenotype correlations in 417 children with congenital hyperinsulinism. J Clin Endocrinol Metab 2013;98:E355-E363.
11.
Kapoor RR, Flanagan SE, Arya VB, Shield JP, Ellard S, Hussain K: Clinical and molecular characterisation of 300 patients with congenital hyperinsulinism. Eur J Endocrinol 2013;168:557-564.
12.
Fernandez-Marmiesse A, Salas A, Vega A, Fernandez-Lorenzo JR, Barreiro J, Carracedo A: Mutation spectra of ABCC8 gene in Spanish patients with hyperinsulinism of infancy (HI). Hum Mutat 2006;27:214.
13.
Sandal T, Laborie LB, Brusgaard K, Eide SA, Christesen HB, Sovik O, Njolstad PR, Molven A: The spectrum of ABCC8 mutations in Norwegian patients with congenital hyperinsulinism of infancy. Clin Genet 2009;75:440-448.
14.
Yorifuji T, Kawakita R, Nagai S, Sugimine A, Doi H, Nomura A, Masue M, Nishibori H, Yoshizawa A, Okamoto S, Doi R, Uemoto S, Nagasaka H: Molecular and clinical analysis of Japanese patients with persistent congenital hyperinsulinism: predominance of paternally inherited monoallelic mutations in the KATP channel genes. J Clin Endocrinol Metab 2011;96:E141-E145.
15.
Ohkubo K, Nagashima M, Naito Y, Taguchi T, Suita S, Okamoto N, Fujinaga H, Tsumura K, Kikuchi K, Ono J: Genotypes of the pancreatic β-cell K-ATP channel and clinical phenotypes of Japanese patients with persistent hyperinsulinaemic hypoglycaemia of infancy. Clin Endocrinol (Oxf) 2005;62:458-465.
16.
Park SE, Flanagan SE, Hussain K, Ellard S, Shin CH, Yang SW: Characterization of ABCC8 and KCNJ11 gene mutations and phenotypes in Korean patients with congenital hyperinsulinism. Eur J Endocrinol 2011;164:919-926.
17.
Bellanne-Chantelot C, Saint-Martin C, Ribeiro MJ, Vaury C, Verkarre V, Arnoux JB, Valayannopoulos V, Gobrecht S, Sempoux C, Rahier J, Fournet JC, Jaubert F, Aigrain Y, Nihoul-Fekete C, de Lonlay P: ABCC8 and KCNJ11 molecular spectrum of 109 patients with diazoxide-unresponsive congenital hyperinsulinism. J Med Genet 2010;47:752-759.
18.
Diao C, Chen S, Xiao X, Wang T, Sun X, Wang O, Song H, Zhang Y, Yu M, Zhang Q, Wang H: Two unrelated Chinese patients with hyperinsulinism/hyperammonemia (HI/HA) syndrome due to mutations in glutamate dehydrogenase gene. J Pediatr Endocrinol Metab 2010;23:733-738.
19.
Xu ZD, Yu HF, Sang YM, Zhang YN, Yan J, Wu YJ, Zhu C, Ni GC: ABCC8, KCNJ11 and GLUD1 gene mutation analysis in congenital hyperinsulinism pedigree (in Chinese). Zhonghua Yi Xue Za Zhi 2013;93:1089-1092.
20.
Arnoux JB, Verkarre V, Saint-Martin C, Montravers F, Brassier A, Valayannopoulos V, Brunelle F, Fournet JC, Robert JJ, Aigrain Y, Bellanne-Chantelot C, de Lonlay P: Congenital hyperinsulinism: current trends in diagnosis and therapy. Orphanet J Rare Dis 2011;6:63.
21.
Flanagan SE, Edghill EL, Gloyn AL, Ellard S, Hattersley AT: Mutations in KCNJ11, which encodes Kir6.2, are a common cause of diabetes diagnosed in the first 6 months of life, with the phenotype determined by genotype. Diabetologia 2006;49:1190-1197.
22.
Ellard S, Flanagan SE, Girard CA, Patch AM, Harries LW, Parrish A, Edghill EL, Mackay DJ, Proks P, Shimomura K, Haberland H, Carson DJ, Shield JP, Hattersley AT, Ashcroft FM: Permanent neonatal diabetes caused by dominant, recessive, or compound heterozygous SUR1 mutations with opposite functional effects. Am J Hum Genet 2007;81:375-382.
23.
Schwarz JM, Rodelsperger C, Schuelke M, Seelow D: MutationTaster evaluates the disease-causing potential of sequence alterations. Nat Methods 2010;7:575-576.
24.
Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR: A method and server for predicting damaging missense mutations. Nat Methods 2010;7:248-249.
25.
Ilamaran V, Venkatesh C, Manish K, Adhisivam B: Persistent hyperinsulinemic hypoglycemia of infancy due to homozygous KCNJ11 (T294M) mutation. Indian J Pediatr 2010;77:803-804.
26.
Shimomura K, Flanagan SE, Zadek B, Lethby M, Zubcevic L, Girard CA, Petz O, Mannikko R, Kapoor RR, Hussain K, Skae M, Clayton P, Hattersley A, Ellard S, Ashcroft FM: Adjacent mutations in the gating loop of Kir6.2 produce neonatal diabetes and hyperinsulinism. EMBO Mol Med 2009;1:166-177.
27.
Yan FF, Lin YW, MacMullen C, Ganguly A, Stanley CA, Shyng SL: Congenital hyperinsulinism associated ABCC8 mutations that cause defective trafficking of ATP-sensitive K+ channels: identification and rescue. Diabetes 2007;56:2339-2348.
28.
Hussain K, Bryan J, Christesen HT, Brusgaard K, Aguilar-Bryan L: Serum glucagon counterregulatory hormonal response to hypoglycemia is blunted in congenital hyperinsulinism. Diabetes 2005;54:2946-2951.
29.
Someya T, Miki T, Sugihara S, Minagawa M, Yasuda T, Kohno Y, Seino S: Characterization of genes encoding the pancreatic β-cell ATP-sensitive K+ channel in persistent hyperinsulinemic hypoglycemia of infancy in Japanese patients. Endocr J 2000;47:715-722.
30.
Tanizawa Y, Matsuda K, Matsuo M, Ohta Y, Ochi N, Adachi M, Koga M, Mizuno S, Kajita M, Tanaka Y, Tachibana K, Inoue H, Furukawa S, Amachi T, Ueda K, Oka Y: Genetic analysis of Japanese patients with persistent hyperinsulinemic hypoglycemia of infancy: nucleotide-binding fold-2 mutation impairs cooperative binding of adenine nucleotides to sulfonylurea receptor 1. Diabetes 2000;49:114-120.
31.
Fournet JC, Junien C: The genetics of neonatal hyperinsulinism. Horm Res 2003;59(suppl 1): 30-34.
32.
De Leon DD, Stanley CA: Mechanisms of disease: advances in diagnosis and treatment of hyperinsulinism in neonates. Nat Clin Pract Endocrinol Metab 2007;3:57-68.
33.
Tornovsky S, Crane A, Cosgrove KE, Hussain K, Lavie J, Heyman M, Nesher Y, Kuchinski N, Ben-Shushan E, Shatz O, Nahari E, Potikha T, Zangen D, Tenenbaum-Rakover Y, de Vries L, Argente J, Gracia R, Landau H, Eliakim A, Lindley K, Dunne MJ, Aguilar-Bryan L, Glaser B: Hyperinsulinism of infancy: novel ABCC8 and KCNJ11 mutations and evidence for additional locus heterogeneity. J Clin Endocrinol Metab 2004;89:6224-6234.
34.
Flanagan SE, Kapoor RR, Banerjee I, Hall C, Smith VV, Hussain K, Ellard S: Dominantly acting ABCC8 mutations in patients with medically unresponsive hyperinsulinaemic hypoglycaemia. Clin Genet 2011;79:582-587.
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