KCNJ11 and ABCC8 Neonatal Diabetes: Effects on the brain
Around 20% of patients with KCNJ11 or ABCC8 Neonatal Diabetes will have delayed development as well as diabetes. In these people the KCNJ11 and ABCC8 genetic change affects the potassium channels in the brain in addition to the channels in the pancreas which control insulin release. This is known as DEND syndrome as the key features are : Developmental delay, Epilepsy and Neonatal Diabetes. When it is less marked epilepsy is rare and it is called intermediate DEND syndrome (iDEND)
Who is likely to have developmental delay?
The specific genetic change determines whether the brain is likely to be affected and if it is how severe the affect is. The more severe the genetic change affecting the potassium channel the more likely developmental problems are and the more severe they are if they occur. The commonest genetic change causing developmental problems in KCNJ11 is ‘V59M’ where most patients have moderate to severe difficulties. There is some variability between children with the same genetic change so it is not possible to predict exactly how severely a child will be affected.
What type of developmental delay is seen ?
The developmental delay varies from children who are very mildly affected and attend normal schools to severe effects where individuals are unable to walk or talk. Some of the difficulties that have been identified include the following:
- Being slow to walk or being ‘clumsy’
- Being slow to talk
- Having difficulty concentrating which may be diagnosed as attention deficit disorder or hyperactivity
- Doing less well at school, especially with numeracy/maths
- Difficulty in social situations which may be diagnosed as Asperger’s syndrome or Autism
- Epilepsy – this may be present in the first year of life when patients have severe genetic changes causing DEND syndrome. With iDEND due to the KCNJ11 V59M they may develop epilepsy later, typically between 3-10 years of age, these are usually ‘absence’ seizures that do not require prolonged treatment
Can sulphonylureas help delayed development as well as the diabetes?
Some improvement has been noted in most children with developmental delay when they are treated with high doses of glibenclamide (we recommend a minimum 0.5mg/kg/day, many patients require 1mg/kg/day and some take up to 2mg/kg/day). In patients with established learning problems this will result in small improvements in areas such as concentration and speech but their development will still be delayed compared to other children of the same age.
There is clear evidence suggesting there are considerable benefits in treating the child with glibenclamide immediately the diagnosis of a potassium channel mutation is made. The best outcome is if they are treated with sulphonylureas in the first 6 months of life. Early treatment is likely to help the brain develop correctly in the crucial first months of life.
Developmental delay affects approximately 20% of children with KCNJ11 or ABCC8 neonatal diabetes. It is important to identify those patients whose genetic change means they are at high risk of developmental delay since early treatment with high dose sulphonylureas (around 1mg/kg/day) is likely to achieve the best outcome.
For further information or support please contact Professor Andrew Hattersley on +44 (0) 1392 40 8260 or email@example.com or Dr Maggie Shepherd on +44 (0) 1392 40 8261 or firstname.lastname@example.org
June 2014 - PDF