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International Journal of Diabetes in Developing Countries

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01-03-2016 | Original Article

Clinical, molecular, and therapeutic aspects of NDM in ten cases with diabetes in 1st 6 months of life

Authors: Noha Musa, Mona Hafez, Mona Hassan, Fatma El-Mougy, Sahar Sharaf, Michael Polak, Helene Cave, Sherif Mofeed

Published in: International Journal of Diabetes in Developing Countries | Issue 1/2016

Abstract

Neonatal diabetes mellitus (NDM) is defined as hyperglycemia occurring within the first 6 months of life; it may be permanent or transient. Diagnosis of NDM is vital for prognosis, genetic counseling, and treatment. The aim of this study was to study clinical, biochemical, molecular, and therapeutic aspects of diabetes presenting in the first 6 months of life. Ten cases with NDM were studied regarding perinatal and family history, clinical features and biochemical tests on admission and follow-up, HLA typing and molecular studies, and mode of therapy. Molecular studies for the common mutations associated with NDM (KCNJ11, INS, ABCC8 and methylation defects) were done using PCR amplification and gene sequencing. Ten cases developed diabetes in the first 6 months of life (three in the first 8 weeks, seven between 8 and 24 weeks). All presented with ketoacidosis, one had developmental delay with convulsions. Molecular studies revealed methylation defect in two cases, KCNJ11 in three cases, INS mutations in two cases, and no detectable defect in three cases. Insulin was stopped on follow-up in three cases (TND), successfully substituted with sulfonylurea (SU) in three cases, and continued in four cases (PND). Molecular genetic testing is essential in cases with NDM for guiding mode of therapy as SU receptor defects can be successfully treated with oral SU instead of insulin injections. SU was more effective in achieving diabetes control in cases with KCNJ11 mutations.

Shield JP. Neonatal diabetes: new insights into aetiology and implications. Horm Res. 2000;53(Suppl 1):7–11.CrossRefPubMed

Aguilar-Bryan L, Bryan J. Neonatal diabetes mellitus. Endocr Rev. 2008;29:265–91.CrossRefPubMedPubMedCentral

Polak M, Cavé H. Neonatal diabetes mellitus: a disease linked to multiple mechanisms. Orphanet J Rare Dis. 2007;9(2):12.CrossRef

Metz C, Cavé H, Bertrand AM, Deffert C, Gueguen-Giroux B, Czernichow P. Polak M; NDM French Study Group. Neonatal diabetes mellitus: chromosomal analysis in transient and permanent cases. J Pediatr. 2002;141(4):483–9.CrossRefPubMed

Mackay D, Bens S, Perez de Nanclares G, Siebert R, Temple IK. Clinical utility gene card for transient neonatal diabetes mellitus, 6q24-related. Eur J Hum Genet. 2014;22(9)

De León DD, Stanley CA. Permanent Neonatal Diabetes Mellitus. In: Pagon RA, Adam MP, Ardinger HH, Bird TD, Dolan CR, Fong CT, Smith RJH, Stephens K, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2014. 2008;08 [updated 2014 Jan 23]

Gloyn AL, Pearson ER, Antcliff JF, Proks P, Bruining GJ, Slingerland AS, Howard N, Srinivasan S, Silva JM, Molnes J, Edghill EL, Frayling TM, Temple IK, Mackay D, Shield JP, Sumnik Z, van Rhijn A, Wales JK, Clark P, Gorman S, Aisenberg J, Ellard S, Njølstad PR, Ashcroft FM, Hattersley AT. Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. N Engl J Med. 2004;350(18):1838–49.CrossRefPubMed

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(2):375–82.CrossRefPubMedPubMedCentral

Støy J, Edghill EL, Flanagan SE, Ye H, Paz VP, Pluzhnikov A, Below JE, Hayes MG, Cox NJ, Lipkind GM, Lipton RB, Greeley SA, Patch AM, Ellard S, Steiner DF, Hattersley AT, Philipson LH. Bell GI; Neonatal Diabetes International Collaborative Group. Insulin gene mutations as a cause of permanent neonatal diabetes. Proc Natl Acad Sci USA. 2007;104(38):15040–4.CrossRefPubMedPubMedCentral

10.

Rubio-Cabezas O, Hattersley AT, Njølstad PR, Mlynarski W, Ellard S, White N. ChiDV, CraigME. The diagnosis and management of monogenic diabetes in children and adolescents. Pediatr Diabet. 2014;15(Suppl. 20):47–64.CrossRef

11.

Murphy R, Ellard S, Hattersley AT. Clinical implications of a molecular genetic classification of monogenic beta-cell diabetes. Nat Clin Pract Endocrinol Metab. 2008;4:200–13.CrossRefPubMed

12.

Moritani M, Yokota I, Tsubouchi K, Takaya R, Takemoto K, Minamitani K, Urakami T, Kawamura T, Kikuchi N, Itakura M, Ogata T, Sugihara S, Amemiya S. Identification of INS and KCNJ11 gene mutations in type 1B diabetes in Japanese children with onset of diabetes before 5 year of age. Pediatr Diabetes. 2013;14(2):pp. 112–20.CrossRef

13.

Avraham A, Sandbank J, Yarom N, Shalom A, Karni T, Pappo I, Sella A, Fich A, Walfisch S, Gheber L, Evron E. A similar cell-specific pattern of HOXA methylation in normal and in cancer tissues. Epigenetics. 2010;5(1):41–6.CrossRefPubMed

14.

Slingerland AS, Shields BM, Flanagan SE, Bruining GJ, Noordam K, Gach A, Mlynarski W, Malecki MT, Hattersley AT, Ellard S. Referral rates for diagnostic testing support an incidence of permanent neonatal diabetes in three European countries of at least 1 in 260,000 live births. Diabetologia. 2009;52(8):1683–5.CrossRefPubMedPubMedCentral

15.

Tran F, Vu DC, Nguyen HT, Bui TP, Huynh LT, Nguyen KP, Nguyen VT, Tran HM, Tran D, Hoang TD, Harkin N, Armstrong K, Jameson K, Pham A, Cowell CT, Craig ME. Glycaemic control in children with neonatal diabetes and type 1 diabetes in Vietnam. Int Health. 2011;3(3):188–192

16.

Li YH, Yuan TM, Yu HM. Neonatal diabetes mellitus in China: a case report and review of the Chinese literature. Clin Pediatr (Phila). 2012;51(4):366–73.CrossRef

17.

Hattersley AT, Ashcroft FM. Activating mutations in Kir6.2 and neonatal diabetes: new clinical syndromes, new scientific insights, and new therapy. Diabetes. 2005;54(9):2503–13.CrossRefPubMed

18.

Massa O, Iafusco D, D'Amato E, Gloyn AL, Hattersley AT, Pasquino B, Tonini G, Dammacco F, Zanette G, Meschi F, Porzio O, Bottazzo G, Crinó A, Lorini R, Cerutti F, Vanelli M. Barbetti F; Early Onset Diabetes Study Group of the Italian Society of Pediatric Endocrinology and Diabetology. KCNJ11 activating mutations in Italian patients with permanent neonatal diabetes. Hum Mutat. 2005;25(1):22–7.CrossRefPubMed

19.

Vaxillaire M, Populaire C, Busiah K, Cavé H, Gloyn AL, Hattersley AT, Czernichow P, Froguel P, Polak M. Kir6.2 mutations are a common cause of permanent neonatal diabetes in a large cohort of French patients. Diabetes. 2004;53(10):2719–22.CrossRefPubMed

20.

Jahnavi S, Poovazhagi V, Mohan V, Bodhini D, Raghupathy P, Amutha A, Suresh Kumar P, Adhikari P, Shriraam M, Kaur T, Das AK, Molnes J, Njolstad PR, Unnikrishnan R, Radha V. Clinical and molecular characterization of neonatal diabetes and monogenic syndromic diabetes in Asian Indian children. Clin Genet. 2013;83:439–45.CrossRefPubMed

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;49:1190–7.CrossRefPubMed

22.

Doneray H, Houghton J, Tekgunduz KS, Balkir F, Caner I. Permanent neonatal diabetes mellitus caused by a novel mutation in the KCNJ11 gene. J Pediatr Endocrinol Metab. 2014;27(3–4):367–71.PubMed

23.

Gloyn AL, Diatloff-Zito C, Edghill EL, Bellanné-Chantelot C, Nivot S, Coutant R, Ellard S, Hattersley AT, Robert JJ. KCNJ11 activating mutations are associated with developmental delay, epilepsy and neonatal diabetes syndrome and other neurological features. Eur J Hum Genet. 2006;14:824–30.CrossRefPubMed

24.

Shimomura K, Horster F, Wet H, Flanagan SE, Ellard S, Hattersley AT, Wolf NI, Ashcroft F, Ebinger F. A novel mutation causing DEND syndrome; a treatable channelopathy of pancreas and brain. Neurology. 2007;69:1342–9.CrossRefPubMed

25.

Greeley SA, Tucker SE, Naylor RN, Bell GI, Philipson LH. Neonatal diabetes mellitus: a model for personalized medicine. Trends Endocrinol Metab. 2010;21(8):464–72.CrossRefPubMedPubMedCentral

26.

Park SY, Ye H, Steiner DF, Bell GI. Mutant proinsulin proteins associated with neonatal diabetes are retained in the endoplasmic reticulum and not efficiently secreted. Biochem Biophys Res Commun. 2010;391(3):1449–54.CrossRefPubMedPubMedCentral

27.

Colombo C, Porzio O, Liu M, Massa O, Vasta M, Salardi S, Beccaria L, Monciotti C, Toni S, Pedersen O, Hansen T, Federici L, Pesavento R, Cadario F, Federici G, Ghirri P, Arvan P, Iafusco D, Barbetti F. Seven mutations in the human insulin gene linked to permanent neonatal/infancy-onset diabetes mellitus. J Clin Invest. 2008;118(6):2148–56.PubMedPubMedCentral

28.

Polak M, Dechaume A, Cavé H, Nimri R, Crosnier H, Sulmont V, de Kerdanet M, Scharfmann R, Lebenthal Y, Froguel P, Vaxillaire M. French ND (Neonatal Diabetes) Study Group. Heterozygous missense mutations in the insulin gene are linked to permanent diabetes appearing in the neonatal period or in early infancy: a report from the French ND (Neonatal Diabetes) Study Group. Diabetes. 2008;57(4):1115–9.CrossRefPubMed

29.

Temple IK, Shield JP. 6q24 transient neonatal diabetes. Rev Endocr Metab Disord. 2010;11(3):199–204.CrossRefPubMed

30.

Temple IK, Gardner RJ, Mackay DJ, Barber JC, Robinson DO, Shield JP. Transient neonatal diabetes: widening the understanding of the etiopathogenesis of diabetes. Diabetes. 2000;49(8):1359–66.CrossRefPubMed

31.

Stanik J, Gasperikova D, Paskova M, Barak L, Javorkova J, Jancova E, Ciljakova M, Hlava P, Michalek J, Flanagan SE, Pearson E, Hattersley AT, Ellard S, Klimes I. Prevalence of permanent neonatal diabetes in Slovakia and successful replacement of insulin with sulfonylurea therapy in KCNJ11 and ABCC8 mutation carriers. J Clin Endocrinol Metab. 2007;92(4):1276–82.CrossRefPubMed

32.

Pearson ER, Flechtner I, Njølstad PR, Malecki MT, Flanagan SE, Larkin B, Ashcroft FM, Klimes I, Codner E, Iotova V, Slingerland AS, Shield J, Robert JJ, Holst JJ, Clark PM, Ellard S, Søvik O, Polak M. Hattersley AT; Neonatal Diabetes International Collaborative Group. Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations. N Engl J Med. 2006;355(5):467–77.CrossRefPubMed

33.

Tonini G, Bizzarri C, Bonfanti R, Vanelli M, Cerutti F, Faleschini E, Meschi F, Prisco F, Ciacco E, Cappa M, Torelli C, Cauvin V, Tumini S, Iafusco D, Barbetti F. Early-Onset Diabetes Study Group of the Italian Society of Paediatric Endocrinology and Diabetology. Sulfonylurea treatment outweighs insulin therapy in short-term metabolic control of patients with permanent neonatal diabetes mellitus due to activating mutations of the KCNJ11 (KIR6.2) gene. Diabetologia. 2006;49(9):2210–3.CrossRefPubMed

34.

Gurgel LC, Crispim F, Noffs MH, Belzunces E, Rahal MA, Moisés RS. Sulfonylurea treatment in permanent neonatal diabetes due to G53D mutation in the KCNJ11 gene: improvement in glycemic control and neurological function. Diabetes Care. 2007;30(11):e108.CrossRefPubMed

35.

Bremer AA, Ranadive S, Lustig RH. Outpatient transition of an infant with permanent neonatal diabetes due to a KCNJ11 activating mutation from subcutaneous insulin to oral glyburide. Pediatr Diabetes. 2008;9(3 Pt 1):236–9.CrossRefPubMed

36.

Koster JC, Cadario F, Peruzzi C, Colombo C, Nichols CG, Barbetti F. The G53D mutation in Kir6.2 (KCNJ11) is associated with neonatal diabetes and motor dysfunction in adulthood that is improved with sulfonylurea therapy. J Clin Endocrinol Metab. 2008;93(3):1054–61.CrossRefPubMedPubMedCentral

37.

Mohamadi A, Clark LM, Lipkin PH, Mahone EM, Wodka EL, Plotnick LP. Medical and developmental impact of transition from subcutaneous insulin to oral glyburide in a 15-yr-old boy with neonatal diabetes mellitus and intermediate DEND syndrome: extending the age of KCNJ11 mutation testing in neonatal DM. Pediatr Diabetes. 2010;11(3):203–207

38.

Zwaveling-Soonawala N, Hagebeuk EE, Slingerland AS, Ris-Stalpers C, Vulsma T, van Trotsenburg AS. Successful transfer to sulfonylurea therapy in an infant with developmental delay, epilepsy and neonatal diabetes DEND syndrome and a novel ABCC8 gene mutation. Diabetologia. 2011;54(2):469–71.CrossRefPubMedPubMedCentral

39.

Barone JV, Tillman EM, Ferry RJ. Treatment of transient neonatal diabetes mellitus with subcutaneous insulin glargine in an extremely low birth weight neonate. J Pediatr Pharmacol Ther. 2011;16(4):291–7.PubMedPubMedCentral

40.

Yafi M. A case of neonatal diabetes presentation, Diagnosis and Management Austin J Pediatr 2014;1(1): 1004.

Title: Clinical, molecular, and therapeutic aspects of NDM in ten cases with diabetes in 1st 6 months of life
Authors: Noha Musa
Mona Hafez
Mona Hassan
Fatma El-Mougy
Sahar Sharaf
Michael Polak
Helene Cave
Sherif Mofeed
Publication date: 01-03-2016
Publisher: Springer India
Published in: International Journal of Diabetes in Developing Countries / Issue 1/2016
Print ISSN: 0973-3930
Electronic ISSN: 1998-3832
DOI: https://doi.org/10.1007/s13410-015-0431-z

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