Neonatal diabetes is diagnosed within the first 6 months of life and affects approximately 1 in 100,000 live births. The diabetes can occur in isolation or feature as part of a multi-organ disease (syndromic neonatal diabetes). Two main subgroups are recognised in about equal proportions: permanent neonatal diabetes (PNDM) and transient neonatal diabetes (TNDM). The latter remits in infancy or early childhood but may recur later in life. A genetic diagnosis is possible for approximately 80% of patients with neonatal diabetes with mutations in 22 different genes reported. Sporadic, dominant, recessive and X-linked inheritance have all been described. An early genetic diagnosis is clinically important since some forms involve the ATP-sensitive potassium (KATP) channel within the pancreatic beta cell and respond to treatment with high dose sulfonylureas which results in improved glycemic control for these patient.
Permanent Neonatal Diabetes (PNDM)
Mutations in 19 different genes have been reported to cause PNDM. These mutations cause diabetes through abnormal pancreatic development, beta cell dysfunction or accelerated beta cell destruction. Patients typically have reduced birth weight, a reflection of reduced insulin production in utero, and whilst most are diagnosed with diabetes before 6 months a few rare cases have been reported with diabetes diagnosed between 6 and 12 months of life. In contrast to Type 1 diabetes PNDM is not associated with high risk HLA haplotypes or the presence of pancreatic autoantibodies.
The most common cause of PNDM results from Mutations in the insulin gene (INS) or Mutations in the K-ATP channel genes (KCNJ11 and ABCC8). Whilst the majority of patients with K-ATP channel mutations have isolated diabetes, severe developmental delay and epilepsy (termed DEND syndrome) has been reported in some cases. These features are consistent with the expression of K-ATP channels in the pancreas and central nervous system.
Mutations in a number of pancreatic transcription factor genes crucial for beta-cell development and/or function have been identified in patients with PNDM. In some cases these mutations cause complete agenesis of the pancreas (GATA4, GATA6, PDX1, PTF1A) (see Monogenic causes of pancreatic agenesis). Extra-pancreatic features are often observed in individuals with transcription factor gene mutations and reflect the expression profile of the gene in various tissues. Whilst mutations in some of the PNDM genes are extremely rare, having been identified in just 1 or 2 unrelated probands (e.g. NEUROD1, IER3IP1, NEUROG3, NKX2-2), recessively inherited mutations in the EIF2AK3 gene, which cause Wolcott Rallison Syndrome, are the most common cause of PNDM in consanguineous populations.
Transient Neonatal Diabetes (TNDM)
In the year 2000 the incidence of TNDM was estimated at 1 in 400,000 live births; however recent advances in our understanding of the genetic mechanisms underlying this condition has resulted in an increase in the number of referrals for genetic testing suggesting that TNDM is likely to be more common than previously considered. TNDM is differentiated from Permanent Neonatal Diabetes Mellitus (PNDM) in that the diabetes remits in infancy or early childhood. A relapse of diabetes in late childhood or adolescence is thought to occur in up to 50% of cases, although this is likely to be an underestimate as many patients with TNDM are lost to follow up during the remission phase.
A genetic diagnosis is possible for >90% of patients with the majority (~70%) having a methylation defect at chromosome 6q24 which results in the overexpression of paternally-expressed genes (ZAC and/or HYMAI).
Results of genetic testing for 97 patients with Transient Neonatal Diabetes Reported genetic mechanisms include paternal uniparental disomy, a paternal 6q24 duplication and maternal hypomethylation. The common phenotype is one of severe intrauterine growth failure (mean birth weight about 2000g), diabetes usually in the first week of life, remission at about 3 months and relapse (in ~55%) in adolescence or early adulthood. Macroglossia (30%), umbilical hernia (9%) and developmental delay may also be present. Initial treatment is with insulin, but for some patients the diabetes can be treated with diet or oral agents following relapse.
For approximately 20-25% of patients TNDM results from an activating mutation in one of the K-ATP channel genes (ABCC8 or KCNJ11).
Comparison of clinical characteristics of patients with 6q24 and K-ATP channel TNDMThese mutations can exhibit a variable penetrance within families with some individuals, who are heterozygous for the same mutation, often not being diagnosed with diabetes until adulthood. In contrast to those patients with chromosome 6q24 methylation defects, the infants with K-ATP channel mutations are heavier at birth (about 2500g) and present slightly later (average age 4 weeks). The diabetes also enters remission later (35 vs 13 weeks) and relapses earlier (5 vs 14 years). Neurological features may also be present. For these patients a genetic diagnosis is clinically important as the patients are likely to respond to sulphonylurea therapy either during the initial presentation or at relapse of the diabetes.
In a few cases mutations in the HNF1B, INS and SLC2A2 genes have been reported in patients with transient neonatal diabetes.
Further details on subgroups of neonatal diabetes are provided in the sections that follow this.
^ Aguilar-Bryan L, Bryan J. Neonatal diabetes mellitus. Endocr Rev 2008;29:265–91
^ Gloyn AL et al. Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. New Engl J Med 2004;350:1838-49
^ Temple IK, Shield JP. Transient neonatal diabetes, a disorder of imprinting. J Med Genet 2002;3:872–5
^ Flanagan SE et al. Mutations in ATP-sensitive channel genes cause transient neonatal diabetes and permanent diabetes in childhood or adulthood. Diabetes 2007;56:1930–7