Importance of genetic testing and recognition of neonatal diabetes: A case report

Permanent neonatal diabetes (PND) is a rare form of diabetes characterised by a diagnosis within the first 6 months of life (Zung et al, 2004; Hattersley and Ashcroft, 2005). A molecular basis can be defined in approximately 60% of people with PND. Mutations in the KCNJ11 gene encoding the Kir6.2 subunit of the beta-cell adenosine triphosphate (ATP)-sensitive potassium (K_ATP) channel are the most common genetic cause of PND (Edghill et al, 2008).

People with neonatal diabetes caused by K_ATP-channel mutations are usually born with a low birth weight, with the majority weighing less than the 10th percentile for gestational age as a result of reduced insulin-mediated growth in utero. The majority of mutations in the KCNJ11 gene are spontaneous and, therefore, there is usually no family history (Slingerland et al, 2006). 

There is a spectrum of features associated with K_ATP-channel mutations. Isolated diabetes occurs in 80% of cases with these mutations, but neurological features described as DEND (developmental delay, early-onset generalised epilepsy and neonatal diabetes) syndrome are present in the remaining 20% (Slingerland et al, 2006). 

Mutations in the KCNJ11 gene inhibit K_ATP-channel closure in response to increased levels of ATP, thereby preventing membrane depolarisation and insulin secretion. Treatment with sulphonylureas, which bind to the SUR1 receptor of the K_ATP channel, allows insulin to be released from the pancreatic beta-cell (Zung et al, 2004). Therefore, many people with neonatal diabetes who have previously been dependent on insulin can now be successfully treated with sulphonylureas (Sagen et al, 2004; Pearson et al, 2006).

In September 2008, Agnieszka conducted an audit of the Broomfield Hospital Diabetes Centre database, which revealed 11 individuals to have been diagnosed with type 1 diabetes within the first 6 months of life. These people were contacted and invited to undergo further investigation to ascertain whether they had a monogenic form of diabetes. Of the 11 people contacted, only one was confirmed to have diabetes diagnosed at <6 months of age. A case report of this individual is presented here.

Case history
This 26-year-old, white male had previously been considered to have type 1 diabetes and “mild cerebral palsy”. In January 2000, at the age of 17, he had been referred to the adult diabetes clinic having formerly been under paediatric care. Unfortunately, his early medical notes could not be traced; however, he reported to have been diagnosed with diabetes at the age of 6 weeks and treated with insulin thereafter. The man was born at 40 weeks’ gestation by normal delivery, with a low birth weight. Neither his parents nor any other family members have diabetes.

His early treatment involved twice-daily insulin; however, at the age of 16 years he was switched to a four-times-daily insulin regimen as a result of poor glycaemic control (HbA_1c level range 9–14% [75–130 mmol/mol]). He continued with sporadic attendance at the diabetes clinic and his glycaemic control remained poor. 

In 2005, at the age of 23, he was referred back to his GP having repeatedly missed his follow-up appointments with the diabetes specialist team over a 4-year period. In addition, he was diagnosed with depression and overdosed on insulin twice. He also had several admissions to hospital presenting with diabetic ketoacidosis. In July 2006, he was diagnosed with retinopathy. 

Treatment transfer
Genetic testing revealed that this man had an activating KCNJ11 mutation. It was explained to him that other people with KCNJ11 PND had successfully undergone treatment transfer from insulin injections to sulphonylurea tablets. He agreed, with the support of the genetic diabetes nurse (GDN), to follow the Exeter Outpatient Protocol (see www.diabetesgenes.org) and attempt treatment transfer from insulin to glibenclamide. The GDN provided support and advice throughout the process of transfer. 

Prior to conversion, the man had been taking insulin lispro 6 units three times daily with meals and once-daily insulin glargine 28 units at night. At this time, his weight was 60 kg and HbA_1c level was 10.1% (87 mmol/mol). As his blood glucose levels were not well controlled, glibenclamide 10 mg/day (0.1 mg/kg/day) was initially added to his insulin doses. According to the protocol, the daily dose of glibenclamide should not exceed 1.0 mg/kg/day. 

Over the next 3 days, his insulin doses were reduced to once-daily insulin lispro 3 units with his evening meal only and once-daily insulin glargine 10 units at night. Two days later, the glibenclamide dose was increased to 15 mg/day (0.2 mg/kg/day), insulin lispro was discontinued and the insulin glargine dose was reduced to 6 units/day. 

At 3 weeks after the transfer, he stopped insulin completely and glibenclamide doses were gradually increased to 40 mg/day (0.6 mg/kg/day). At 8 weeks after transfer, glibenclamide doses were increased to 55 mg/day (0.9 mg/kg/day); at this time, his blood glucose levels ranged 4.1–7.6 mmol/L. 

At 3 months after the transfer, his HbA_1c level was 6.5% (48 mmol/mol); this decreased within 6 months to 5.8% (40 mmol/mol) (Table 1). His glibenclamide doses were subsequently reduced. At the time of writing (12 months following transfer) he was taking glibenclamide 45 mg/day (0.7 mg/kg/day) and had an HbA_1c level of 6.8% (51 mmol/mol) (Table 1). 

In addition to improvements in glycaemic control, the man also described improvements in his quality of life (QOL):

“I could not believe what was happening. At first I thought they had found a cure for diabetes, but then they explained the faulty gene to me. I feel like a new person now, like I have got my life back.” 

Conclusion
Recognition of PND is important as the majority of people with a K_ATP-channel mutation can successfully undergo treatment transfer from insulin to sulphonylureas. Such transfer may be attempted at any age, even after many years of receiving insulin injections (Jose et al, 2009). A correct diagnosis of PND, confirmed by molecular genetic testing, can predict the clinical course of diabetes and explain other associated clinical features. Most importantly, it guides the treatment, allows appropriate genetic counselling and improves QOL.

Acknowledgements
The authors would like to thank their patient for sharing his story. M Shepherd is supported by a National Institute for Health Research (NIHR) postdoctoral fellowship and by Peninsula NIHR Clinical Research Facility, University of Exeter.