An infant with diabetes mellitus: Is it always T1DM?

An infant with diabetes mellitus: Is it always T1DM?

Accepted Manuscript An infant with diabetes mellitus: Is it always T1DM? Mukherjee Soham, Rastogi Ashu, Venkatesan Radha, Sundaramoorthi Gopi, Mohan V...

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Accepted Manuscript An infant with diabetes mellitus: Is it always T1DM? Mukherjee Soham, Rastogi Ashu, Venkatesan Radha, Sundaramoorthi Gopi, Mohan Viswanathan, Bhansali Anil PII: DOI: Reference:

S0168-8227(16)30269-8 http://dx.doi.org/10.1016/j.diabres.2016.07.014 DIAB 6697

To appear in:

Diabetes Research and Clinical Practice

Received Date: Accepted Date:

28 January 2016 23 July 2016

Please cite this article as: M. Soham, R. Ashu, V. Radha, S. Gopi, M. Viswanathan, B. Anil, An infant with diabetes mellitus: Is it always T1DM?, Diabetes Research and Clinical Practice (2016), doi: http://dx.doi.org/10.1016/ j.diabres.2016.07.014

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An infant with diabetes mellitus: Is it always T1DM?

Mukherjee Soham1, Rastogi Ashu1, Venkatesan Radha2, Sundaramoorthi Gopi2, Mohan Viswanathan 2, Bhansali Anil1 1. Dept. of Endocrinology, PGIMER, Chandigarh 2. Dept. of Molecular Genetics, Madras Diabetes Research Foundation

Abbreviated title: Novel mutation in ABCC 8 gene in neonatal diabetes

Key terms: Neonatal diabetes novel ABCC 8 gene mutation

Ward count: 878

Numbers of figure: 1

Acknowledgement: We would like acknowledge the support of ICMR extended for the genetic study. Corresponding author: Anil Bhansali Prof. and HOD Dept. of Endocrinology PGIMER, Chandigarh Email:

[email protected]

Disclosure statement: The authors have nothing to disclose.

Title: An infant with diabetes mellitus: Is it always T1DM?

Abstract: Here we describe a 2 1/2 month old infant with neonatal diabetes mellitus (NDM) who was initially misdiagnosed to have T1DM and initiated on insulin. He was found to have a novel heterozygous mutation Arg992Cys in ABCC 8 gene and successfully switched to oral antidiabetic drug. Introduction: Neonatal diabetes mellitus (NDM) is a monogenic disorder which usually presents within the first 6 months of life and usually misdiagnosed as T1DM1. It is a genetically heterogeneous group of disorders, which may results from developmental defect of pancreas and islets or β - cell dysfunction (KATP channel dysfunction).2 NDM can be transient or permanent.2 We here report a case of permanent neonatal diabetes with novel mutation in ABCC8 gene. Case Report: A 21/2 month old male infant, born to non consanguineous parents presented with polyuria and polyphagia for the last 1 month. At presentation his RBG was 460 mg/dl, serum β (OH) butyrate 0.1mmol/ L, arterial blood gas showing no evidence of acidosis (pH-7.36) and HbA1C 10.7 %. Anti GAD-65 antibody was negative. Ultrasonography ruled out structural disease of pancreas. There was no history of similar illness in the family. Patient was born off normal vaginal delivery and had birth weight of 2.5 Kg. The antenatal period was unremarkable with normal motor and developmental milestones. On examination he was conscious and had no dysmorphic feature. His weight was 4.3 kg, length 62 cm and head

circumference 38 cm. He was initiated on insulin infusion, but his insulin requirement was very high (4.9 unit/kg/day). As T1DM is uncommon before 6 months of age, therefore the possibility of NDM was considered and glibenclamide was added. Insulin requirement markedly reduced to 1.4units/kg/day on the first day and later insulin was discontinued. Patient was discharged with glibenclamide 2.5 mg per day with blood glucose values between 100 – 200 mg/dl. During follow-up at 3 months he had FPG 118 mg/ dl, fasting plasma Insulin 12.46µIu/ ml, fasting C peptide 2.22 ng/ ml and HbA1C was 5.7 %. Genetic analysis revealed a novel heterozygous mutation Arg992Cys in ABCC8 gene in both patient and his mother. Father did not carry the same mutation. Chromatogram of this mutation is depicted in Figure 1. Gradually his requirement for glibenclamide reduced to 0.6125 mg/day and at 1 year of follow-up his HbA1c was 5.2% and glibenclamide was stopped. At 2 years of followup his HbA1c was 6% which suggests persistent dysglycemia. Discussion: We describe a case of NDM who had a novel mutation in ABCC8 gene and responded to sulfonylurea and had a normal HbA1C. After discontinuation of sulfonylurea the HbA1C of the child again had a rising trend suggesting permanent form of the disease. NDM usually presents before 6 months of age.3 DM with onset before 6 month of age is unlikely to be autoimmune in origin as immune system is immature till this age.4 NDM is an uncommon disorder with prevalence of one case per 300,000 to 500,000 live births. It can be subdivided into (i) transient NDM (TNDM, 50%); (ii) permanent NDM (PNDM, 50%).5 TNDM usually presents within first several days or weeks of life, remits by 12 weeks.4 In 50 % of cases they relapse in adolescence or early adulthood.4

PNDM is

characterised by hyperglycaemia early in life without the intervening period of remission. 10 genes have been identified as a cause of PNDM.1 PNDM is most commonly caused by

heterozygous mutation in ATP sensitive K+ channel (K ATP).6 K ATP channel is formed by four SUR1 subunits and four Kir6.2 subunits. KCNJ11 encodes for Kir6.2 and ABCC8 for SUR1. When glucose enters β cell it generates ATP through glycolysis. Increased ATP / ADP ratio cause closure of this channel (preventing K+ efflux ) resulting in β cell membrane depolarisation which results in opening of voltage gated Ca ++ channel . This leads to calcium intrusion into β-cell which in turn results in insulin secretion.6 With activating mutations in KCNJ11 or ABCC8 KATP channel become relatively less sensitive to ATP and more channels remains in an open state even in hyperglycaemic state. This results in impaired insulin secretion and NDM.6

1/

3

to

1/

2

of cases of permanent neonatal diabetes result from activating

mutations in Kir 6.2 and SUR1 subunits of the KATP channels and ABCC8 gene mutation is responsible for 10% of all cases of neonatal diabetes7. About 40 different ABCC8 mutations have been described that lead to neonatal diabetes.8,

9

Most of the ABCC8 mutations are

sporadic. But autosomal dominant and recessive inheritance also occurs. In our case we have found a novel mutation in ABCC 8 gene. Although both mother and son have the same mutation, only the son is manifesting the disease which can be explained by variable expressibility of allele. It is likely that the mutation is incompletely penetrant causing different expression in the members of the same family. Though initial metabolic control in NDM should be achieved with insulin only, majority of patients having KCNJ11 (approximately 90%) and ABCC8 mutations (85% in one series) can be switched to oral sulfonylurea with better glycaemic control.10, 11 After binding to the SUR1 subunits sulfonylurea close the KATP Channel. It is an ATP-independent mechanism. Sulfonylurea related insulin secretion in these cases is meal-dependent. The mechanism might be related, to improved β-cells response to incretins.12

References:

1. Aguilar-Bryan L, Bryan J. Neonatal Diabetes Mellitus. Endocrine Reviews 2008; 29:265– 291 2. Polak M, Cave H. Neonatal diabetes mellitus: a disease linked to multiple mechanisms. Orphanet J Rare Dis 2007; 2:1-11 3. Stoy J, Greeley SAW, Paz VP,et al.Diagnosis and treatment of neonatal diabetes: an United States experience.Pediatr Diabetes 2008; 9: 450–459

4. Naylor RN, Greeley SA, Bell GI, Philipson LH. Genetics and pathophysiology of neonatal diabetes mellitus. Journal of diabetes investigation 2011;2:158-169

5. Edghill EL, Hattersley AT. Genetic disorders of the pancreatic beta cell and diabetes (permanent neonatal diabetes and maturity-onset diabetes of the young). In: Seino S, Bell GI (eds). Pancreatic Beta Cell in Health and Disease. Springer, Japan, 2008; 389–420

6. Ashcroft FM, Rorsman P. KATP channels and islet hormone secretion: new insights and controversies. Nature Reviews Endocrinology 2013;9:660-669

7. Babenko AP, Polak M, Cave H, Busiah K, Czernichow P, Scharfmann R, Bryan J, Aguilar-Bryan L, Vaxillaire M, Froguel P. Activating mutations in the ABCC8 gene in neonatal diabetes mellitus. N Engl J Med 2006; 355:456–466 8. Ellard S, Flanagan SE, Girard CA,et al. Permanent neonatal diabetes caused by dominant, recessive, or compound heterozygous SUR1 mutations with opposite functional effects. Am J Hum Genet 2007; 81: 375–382

9. Patch A M, Flanagan S E, Boustred C, Hattersley A T, Ellard S. Mutations in ABCC8 gene encoding the SUR1 subunit of the K ATP channel cause transient neonatal diabetes or permanent diabetes diagnosed outside the neonatal period. Diabetes Obes Metab 2007; 9( S2);28 –39

10. Stanik J, Gasperikova D, Paskova M,et al.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; 92:1276–1282

11. Jahnavi S, Poovazhagi V, Mohan V, et al. Clinical and molecular characterization of neonatal diabetes and monogenic syndromic diabetes in Asian Indian children. Clin Genet 2013;83:439-445

12. Pearson ER, Flechtner I, Njolstad PR,et al. Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations. N Engl J Med 2006; 355: 467–477

Heilights:

-Novel heterozygous mutation Arg992Cys in ABCC 8 gene, causing neonatal diabetes in an infant -He was initiated on insulin therapy, but later successfully switched to oral antidiabetic drug -On follow-up he was found to have permanent form of neonatal diabetes