A 2.3 kilogram full-term male infant was born to a 26 year primigravida
mother by uncomplicated vaginal delivery. Despite adequate breast feeding,
there was slow growth and poor weight gain. At 4 months of age, the child
presented to a local hospital with fever, drowsiness and breathing
difficulty for 2 days. There was no history of rash, diarrhea, bleeding,
vomiting, recurrent infections, developmental delay or seizures. The
weight was 3.9 kg. Apart from drowsiness and mild tachypnea, the systemic
examination was normal. Investigations revealed a blood sugar of 1245 mg/dL
with severe metabolic acidosis (pH:7.108, bicarbonate:5.2mEq/L with
base-deficit:-22.3mEq/L). He was managed as diabetic-ketoacidosis (with
hydration, insulin therapy, antibiotics and strict electrolyte and
cardiorepiratory monitoring) and subsequently started on intermittent
subcutaneous regular insulin (at 0.1 Units/kg/dose) 3 times a day. The
child continued to have episodes of hyperglycemia documented by blood
sugar measurements. While on insulin therapy, the child also had
intermittent episodes of jitteriness with documented hypoglycemia
requiring intravenous glucose boluses and/or feeding. The child was
referred to our institute for further management.
On enquiry, the mother revealed that he had grown
increasingly hungry and persistently demanded feeds, especially at night.
Furthermore, the diaper used to be relatively heavy since a month, needing
frequent changing.
His blood counts, renal and liver function tests were
normal. Serum potassium was raised (6.1mEq/L), as was the glycosylated-hemoglobin
(14.2%) while insulin levels [2.5 mIU/mL (0.104 microgram/L); normal:
2.6-24.9 mIU/mL] were low. The C-peptide levels were also low (0.26ng/dL,
normal range:0.48-5.05ng/dL). Anti-insulin antibodies were negative.
Ultrasound abdomen was normal.
In view of age, non-response to insulin, low C-peptide
and elevated glycosylated-hemoglobin levels; neonatal diabetes was
suspected and genetic analysis for KCNJ11, ABCC8 and INS gene mutations
was performed. The patient was heterozygous for the E227K missense-mutation
in the KCNJ11 gene. This G>A mutation at nucleotide 679 (c.679G>A),
resulting in the substitution of lysine for glutamic acid at codon 227
(p.Glu227Lys), confirmed the diagnosis of transient neonatal diabetes (TND)
(OMIM 601410) due to a mutation in the Kir6.2 subunit of the KATP
channel(1,2). Parental testing was negative, hence, it was a de novo
mutation.
He was managed with insulin (intermittent doses of
insulin up to 0.2 U/kg/dose) and regular blood sugar monitoring.
Thereafter, he was switched over to glibenclamide according to standard
protocols(1). Glibenclamide was administered orally as powder dissolved in
water. C-peptide started rising on day 2 (1.3-1.42 ng/dL). At 3 months
follow-up, the child had normal insulin, C-peptide and blood sugar levels
and was on 0.2 mg/kg glibenclamide that was titrated and tapered
gradually. Currently, at 6 months of follow-up, the child is off
glibenclamide.
Neonatal diabetes is a insulin-requiring hyperglycemia
diagnosed within first 3 months of life. It may be transient, resolving
within 18 months, or permanent. A proportion of the cases with TND may
subsequently relapse and are diagnosed with diabetes in adolescence or
early adulthood(1). Recently, TND has been shown to be genetically
heretogenous and mutations in KCNJ11 have been shown to be associated with
it. To the best of our knowledge, this is the first report from India
describing TND due to E227K missense mutation in KCNJ11 gene(3,4).
Patients with TND are at an increased risk of permanent
diabetes mellitus and several molecular forms of TND are associated with
increased risk to siblings, adverse neurodevelopmental outcome and
chanellopathies(1-5).
Glibenclamide can effectively attain euglycemia and
obviate the need for insulin in many molecular forms of TND, as observed
by us(4,5). The response to sulfonylureas may result from the closing of
mutant KATP channels independent of adenosine-triphosphate, thereby
augmenting insulin secretion in response to incretins and glucose
metabolites(4,6).
Titration of insulin dose in these patients requires
serial insulin levels and or blood glucose levels. Obtaining serial
insulin levels may often be difficult in a resource limited setting. As
used in our patient, C-peptide levels could be used as a surrogate marker
of insulin levels and could ease dose adjustment and titration during
acute phases as well as during follow up. This could obviate the need for
stringent blood glucose/insulin level moitoring during switch over to
sulphonylureas from insulin therapy. We emphasize the utility of C-peptide
levels in titration of glibenclamide/sulfonylureas and maintenance of
euglycemia, which has not been reported earlier in TND(6).
Acknowledgement
Dr Sean Ellard and Dr Jayne Milton, Peninsula Medical
School, University of Exeter and Plymouth, UK, for their help in molecular
genetic analysis.
References
1. Gloyn AL, Reimann F, Girald C, Edghill El, Proks P,
Pearson ER, et al. Relapsing diabetes can result form moderately
activating mutations in KCNJ11. Hum Mol Genet 2005; 14: 925-934.
2. Flanagan SE, Patch A, Mackay DJG, Edghill EL, Gloyn
AL, Robinson D, et al. Mutations in ATP-sensitive K+ channel genes
cause transient neonatal diabetes and permanent diabetes in childhood and
adulthood. Diabetes 2007; 56: 1930-1937.
3. Letha S, Mammen D, Valamparampil JJ. Permanent
neonatal diabetes mellitus due to KCNJ11 gene mutation. Indian J Pediatr
2007; 74: 947-949.
4. Pearson ER, Flechtner I, Njolstad 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: 467-477.
5. Landau Z, Wainstein J, Hanukoglu A, Tuval M, Lavie
J, Glaser B. Sulphonylurea-responsive diabetes in childhood. J Pediatr
2007; 150: 553-555.
6. Sperling MA. ATP-sensitive potassium
channels-neonatal diabetes mellitus and beyond. N Engl J Med 2006; 355:
507-510.