Neonatal diabetes mellitus (NDM) is a monogenic form of diabetes resulting from mutations in more than 20 different genes encoding proteins playing a key role in the normal function of the pancreatic beta-cell. Mutations in the genes encoding the ATP-sensitive potassium channel, ABCC8, and KCNJ11 and insulin (INS) gene are the most common causes of NDM; however, in consanguineous populations, EIF2AK3 mutations are more common. Identification of the causative mutations by genetic testing is critical for appropriate management and to guide genetic counseling. To determine the genetic etiology of NDM in diabetic neonates and infants diagnosed before the age of 1 year and to describe their phenotype/genotype characteristics, DNA sequencing of coding regions and intronic boundaries of ABCC8, KCNJ11, INS, and EIF2AK3 genes was undertaken in 20 patients. Further, targeted next-generation sequencing was performed for other genes known to cause NDM. ABCC8 mutations were found in two patients (10%), with compound heterozygous mutations (p.N131 K/p.R598*) in one patient and a homozygous mutation (p.R1554Q) in the another patient. Heterozygous p.A174G and p.V59M mutations of KCNJ11 were identified in two patients (10%), and homozygous EIF2AK3 mutations were identified in two further patients (p.T905fs and p.R653T) (10%). No INS mutations were identified. Further testing identified a SLC19A2 mutation (p.W387*) in one patient (5%) and the same homozygous GCK mutation in two siblings (p.A188T). ABCC8, KCNJ11, and EIF2AK3 mutations were the main genetic causes of permanent NDM among Egyptian neonates.
NDM in Egypt Genetic screening ABBC8 KCNJ11 INS mutations
This is a preview of subscription content, log in to check access.
This study was financially supported by the Egyptian Ministry of Higher Education-Culture Affairs and Missions Sector and by the Wellcome Trust. SEF has a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (Grant Number 105636/Z/14/Z).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from parents of all patients included in the study.
Carmody D, Støy J, Greeley SA, Bell GI, Philipson LH. A clinical guide to monogenic diabetes. In: Weiss RE, Refetoff S, editors. Genetic diagnosis of endocrine Disorders. 2nd ed. Philadelphia, PA: Elsevier; 2016. p. 19–30.Google Scholar
Ellard S, Lango Allen H, de Franco E, Flanagan SE, Hysenaj G, Colclough K, et al. Improved genetic testing for monogenic diabetes using targeted next-generation sequencing. Diabetologia. 2013;56:1958–63.CrossRefGoogle Scholar
De Franco E, et al. The effect of early, comprehensive genomic testing on clinical care in neonatal diabetes: an international cohort study. Lancet. 2015;386:957–63.CrossRefGoogle Scholar
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.CrossRefGoogle Scholar
Njolstad PR, et al. Permanent neonatal diabetes mellitus due to complete glucokinase deficiency. N Engl J Med. 2001;344:1588–92.CrossRefGoogle Scholar
Onal H, et al. Thiamine-responsive megaloblastic anemia: early diagnosis may be effective in preventing deafness. Turk J Pediatr. 2009;51(3):301–4.Google Scholar
Greeley SA, Tucker SE, Naylor RN, Bell GI, Philipson H. Neonatal diabetes mellitus: a model for personalized medicine. NIH Public Access. 2011;21(8):464–72.Google Scholar
Rubio-Cabezas O, Patch AM, Minton JA, Flanagan SE, Edghill EL, Hussain K, et al. Wolcott-Rallison syndrome is the most common genetic cause of permanent neonatal diabetes in consanguineous families. J Clin Endocrinol Metab. 2009;94(11):4162–70.CrossRefGoogle Scholar
Pearson ER, Flechtner I, Njølstad PR, Malecki MT, Flanagan SE, Larkin B, et al. Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations. N Engl J Med. 2006;355:467–77.CrossRefGoogle Scholar
American Diabetes Association(ADA). Standards of medical care in diabetes. Diabetes Care. 2013;36(1):S11–66.CrossRefGoogle Scholar
Ellard S, Flanagan SE, Girard CA, Patch AM, Harries LW, Parrish A, et al. 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.CrossRefGoogle Scholar
Klupa T, Edghill EL, Nazim J, Sieradzki J, Ellard S, Hattersley AT, et al. The identification of a R201H mutation in KCNJ11 which encodes Kir 6.2, and successful transfer to sustained release sulfonylurea therapy in a subject with neonatal diabetes: evidence for heterogeneity of beta cell function among carriers of the R201H mutation. Diabetologia. 2005;48(5):1029–31.CrossRefGoogle Scholar
Moritani M, Yokota I, Tsubouchi K, Takaya R, Takemoto K, Minamitani K, et al. Identification of INS and KCNJ11 gene mutations in type 1B diabetes in Japanese children with onset of diabetes before 5 years of age. Pediatr Diabetes. 2013;14(2):112–20.CrossRefGoogle Scholar
Rubio-Cabezas O, Hattersley AT, Njølstad PR, Mlynarski W, Ellard S, White N, et al. The diagnosis and management of monogenic diabetes in children and adolescents. Pediatr Diabetes. 2014;15(20):47–64.CrossRefGoogle Scholar
Rubio-Cabezas O, Flanagan SE, Damhuis A, Hattersley AT, Ellard S. KATP channel mutations in infants with permanent diabetes diagnosed after 6 months of life. Pediatr Diabetes. 2012;13:322–5.CrossRefGoogle Scholar
Mohnike K, Wieland I, Barthlen W, Vogelgesang S, Empting S, Mohnike W, et al. Clinical and genetic evaluation of patients with KATP channel mutations from the German registry for congenital hyperinsulinism. Horm Res Pediatr. 2014;81(3):156–68.CrossRefGoogle Scholar
Suzuki S, Makita Y, Mukai T, Matsuo K, Ueda O, Fujieda K. Molecular basis of neonatal diabetes in Japanese patients. J Clin Endocrinol Metab. 2007;92:3979–85.CrossRefGoogle Scholar
Gloyn AL, Pearson ER, Antcliff JF, Proks P, Bruining GJ, Slingerland AS, et al. 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.CrossRefGoogle Scholar
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.CrossRefGoogle Scholar
Madani HA, Fawzy N, Afif S, Abdelghaffar S, Gohar N. Study of KCNJ11 gene mutations in association with monogenic diabetes of infancy and response to sulfonylurea treatment in a cohort study in Egypt. Acta Endocrinologica (Buc). 2016;XII(2):157–60.CrossRefGoogle Scholar
Banka S, de Goede C, Yue WW, Morris AAM, von Bremen B, Chandler KE, et al. Expanding the clinical and molecular spectrum of thiamine pyrophosphokinase deficiency: a treatable neurological disorder caused by TPK1 mutations. Mol Genet Metab. 2014;113(4):301–6.CrossRefGoogle Scholar
Mikstiene V, Songailiene J, Byckova J, Rutkauskiene G, Jasinskiene E, Verkauskiene R, et al. Thiamine responsive megaloblastic anaemia syndrome: a novel homozygous SLC19A2gene mutation identified. Am J Med Genet A. 2015;167(7):1605–9.CrossRefGoogle Scholar
Aycan Z, Baş VN, Çetinkaya S, Ağladioğlu SY, Kendirci HNP, Şenocak F. Thiamine-responsive megaloblastic anemia syndrome with atrial standstill: a case report. J Pediatr Hematol Oncol. 2011;33(2):144–7.CrossRefGoogle Scholar
Rubio-Cabezas O, Klupa T, Malecki MT, CEED3 Consortium. Permanent neonatal diabetes mellitus-the importance of diabetes differential diagnosis in neonates and infants. Eur J Clin Investig. 2011;41(3):323–33.CrossRefGoogle Scholar
Thomson, et al. Identification of 21 novel glucokinase (GCK) mutations in UK and European Caucasians with maturity-onset diabetes of the young (MODY). Hum Mutat. 2003;22:417–22.CrossRefGoogle Scholar