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Indian Pediatr 2012;49: 486-488
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Permanent Neonatal Diabetes Caused by a Novel
Mutation
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Vandana Jain, Saroj Kumar, *Sarah E Flanagan and *Sian
Ellard
From the Department of Pediatrics, All India Institute
of Medical Sciences, New Delhi and *Institute of Biomedical and Clinical
Science, Peninsula Medical School, University of Exeter, Exeter, UK.
Correspondence to: Dr Vandana Jain, Associate
Professor, Division of Pediatric Endocrinology, Department of
Pediatrics, All India Institute of Medical Sciences, New Delhi.
Email: [email protected]
Received: July 22, 2011;
Initial review: August 16, 2011;
Accepted: September 26, 2011.
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Most cases of permanent form of neonatal diabetes mellitus (PNDM) are
due to dominant heterozygous gain of function (activating) mutations in
either KCNJ11 or ABCC8 genes, that code for Kir 6.2 and
SUR1 subunits, respectively of the pancreatic
b-cell
KATP channel. We describe the interesting case of an infant with PNDM,
in whom a compound heterozygous activating/ inactivating mutation was
found with clinically unaffected parents, each carrying a heterozygous
mutation in ABCC8, one predicting gain of function (neonatal
diabetes) and the other a loss of function (hyperinsulinemia).
Key words: ABCC8, Activating/ inactivating, Compound
heterozygous, Neonatal diabetes, Permanent, Sulphonylurea.
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Permanent neonatal diabetes (PNDM), which
refers to onset of diabetes before the age of 6 months with
persistence through life, is a rare disorder occurring in one in
0.2-0.5 million live births [1]. Almost all cases of neonatal
diabetes (NDM) are of monogenic etiology in contrast to the
autoimmune etiology of diabetes presenting in children beyond 6
months of age [2]. Activating mutations in KCNJ11 and
ABCC8 genes, that encode the Kir6.2 and SUR1 subunits,
respectively, of the pancreatic
b-cell KATP channel together account
for approximately 40% of all cases of PNDM [3].
Mutations in KCNJ11 and ABCC8 give
rise to two opposing phenotypes of congenital hyperinsulinemia (CHI)
and NDM. Loss of function (inactivating) mutations abrogate the
channel function, causing CHI while gain of function (activating)
mutations impair the ability of ATP to close the channel, causing
NDM [2]. While CHI is caused by recessively inherited homozygous
mutations, most cases of NDM are caused by heterozygous (dominant)
de novo mutations. Recessive inheritance of PNDM is rare and
has been described in only 8 patients till date, out of which 3 each
had homozygous and compound heterozygous activating mutations of
ABCC8, respectively [4]. Previously described in only 2 patients
[4], with our baby representing the third case, a novel mutational
mechanism has been observed in which there is compound heterozygous
activating/ inactivating mutation of the ABCC8 gene, i.e.,
one allele has a mutation with loss of function effect and the other
has a mutation that predicts gain of function.
Case report
A 4 week old baby boy was diagnosed as diabetes
mellitus (with ketoacidosis at onset) at a hospital in Punjab and
referred to us at the age of 8 weeks. He was the first born baby of
non-consanguineous parents, delivered at term with weight
appropriate for dates, with no significant perinatal problems. There
was history of diabetes in paternal grandfather and great
grandmother. The infant was managed with twice daily injections of
NPH insulin with regular insulin as needed, with frequent blood
sugar monitoring.
Blood samples of infant and both parents were
sent for molecular genetic analysis to Royal Devon and Exeter NHS
Foundation Trust, UK. The infant remained on frequent follow up,
with reasonable glycemic control, and no episode of ketoacidosis or
severe hypoglycemia. We received the genetic report when the infant
was 8 months old. At this time, he had appropriate growth but mild
motor delay, was on 0.3 U/kg/day of insulin and HbA1c was 8.1%.
Molecular genetic analysis: Sequencing
analysis showed that the infant was heterozygous for two missense
mutations, R168C and G1256S, in exons 4 and 31 of the ABCC8
gene. The C>T mutation at nucleotide 502 (c.502C>T) results in
substitution of cysteine for arginine at codon 168 (p.Arg168Cys) and
has been reported previously in a patient with CHI [5]. The G>A
mutation at nucleotide 3766 (c.3766G>A) results in the substitution
of serine for glycine at codon 1256 (p.Gly1256Ser), and has been
identified in another patient with PNDM (Flanagan and Ellard,
unpublished data). Testing of parents showed that the father was
heterozygous for the missense mutation G1256S while the mother was
heterozygous for the missense mutation R168C, implying that father
was a carrier of NDM while mother was a carrier of CHI. In the
proband, the mutations were in trans and this was consistent with a
diagnosis of recessively inherited NDM due to compound heterozygous
activating/ inactivating mutations in ABCC8 gene.
The infant was admitted for transfer from insulin
to oral sulphonylurea. NPH insulin was stopped and glibenclamide was
started in gradually increasing dose along with short acting insulin
when required. Glycemic control was achieved at 0.4 mg/kg/day of
glibenclamide which was decreased further to 0.3 mg/kg/day on
follow-up. Subsequently, blood sugar was maintained in the range of
80- 140 mg/dL with no hypoglycemic episodes and no requirement of
short acting insulin. HbA1c was 6.8% when checked 4 months after
switchover with further decline to 5.2% at 8 months.
Discussion
Significant advances in elucidating the genetic
basis of NDM have been made since the initial description in 1995
[6]. In 1997, the first mutation leading to PNDM with pancreatic
agenesis (IPF/PDX1) was identified [7], followed between 2004 and
2008, by identification of mutations in KCNJ11, ABCC8 and INS genes
as responsible for majority of PNDM [3,4,8]. Sulphonylureas, which
bind to SUR1 and close the KATP channel, triggering insulin
secretion, have been found to be effective in most patients with
mutations in KCNJ11 or ABCC8 genes [9]. Among patients with KCNJ11
related PNDM, efficacy and safety of sulfonylurea has been
documented over follow-up of 34 months [9].
Although, there are many examples of genes in
which mutations with opposite effects can result in opposing
clinical phenotypes, e.g., activating GCK mutations, cause
hypoglycemia while inactivating mutations result in hyperglycemia
[10]; to the best of our knowledge, PNDM is the first disease
phenotype reported to be a result of compound heterozygosity for
both gain of function and loss of function mutations.
Attempting to make a genetic diagnosis in
patients with PNDM is important, not only because it can lead to
transfer of patients with KCNJ11 or ABCC8 mutations to
sulphonylureas, but also for genetic counselling. While all KCNJ11
mutations in patients with NDM reported to date are heterozygous
dominant; the ABCC8 mutations may be heterozygous dominant
(commonest), homozygous recessive, or compound heterozygous for
another activating mutation or rarely an inactivating mutation of
the other allele. The risk that unaffected parents will have a
second affected child is considerably higher for recessive mutations
than de novo dominant mutations (25% vs. the risk of germline
mosaicism), but, in the next generation, the offspring of the
proband are very unlikely to be affected for a recessive acting
mutation, compared with the 50% risk for a dominant heterozygous
mutation.
An interesting observation in our family was that
although the 28 year old father, who carried the heterozygous
activating mutation, was unaffected; his own father and grandmother
had diabetes from the age of 51 and 62 years, respectively. We were
not able to test the grandparents for the mutation, an interesting
theoretical possibility remains that heterozygous missense mutation
G1256S in ABCC8 gene may manifest as type 2 diabetes in late
adulthood.
Contributors: VJ and SK were involved in the
clinical evaluation and management of the child; SF performed the
molecular genetic testing which was interpreted by SE. All authors
contributed to the review of literature and preparation of the
manuscript. VJ will act as guarantor.
Funding: None; Competing interests:
None stated.
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