Monogenic Diabetes are caused when one or more mutation occurs in a single gene. This type of mutations are very rare but has a great impact and lead to diabetes, at early stage.
In children, almost all monogenic diabetes are caused due to the mutations in gene that regulate β-cell function causing the loss of β-cell or dysfunction of β cell. This in turn affects the insulin synthesis, packaging, glucose sensing and insulin secretion.
Diabetes, diagnosed before the age of 6 months is more likely to have a genetic cause, so further clinical testing is required. On testing 2 subgroups were recognized: Transient Neonatal Diabetes Mellitus (TNDM) that are resolved at median of 12 weeks and then did not require any treatment. The majority of patients with TNDM have an imprinting abnormality of the transcription factor ZAC gene and HYMAI gene, encoding an untranslated RNS chromosome 6q. While Permanent Neonatal Diabetes Mellitus (PNDM) requires lifelong insulin injections from diagnosis onwards, PNDM is caused due to the mutations in the KCNJ11 gene in minority of patients,.
The second commonest cause of the mutations in patients having diabetes before the age of 6 months are - mutations in the KCNJ11 gene encoding the Kir6.2 subunit of KATP channel and that can result in heterozygous mutation (either TNDM-10% or PNDM-90%). In most cases they don’t have family history as these are spontaneous mutations. Patients having mutations with Kir6.2 show dependency on insulin. This is because 30% have ketoacidosis and do not have detectable C peptide and thus, it is treated with insulin. It is recently been proved that, these patients can be successfully be treated by oral sulfonylureas and they can also get better glycemic control without an increase in hypoglycemia and neurological features.
The most severe is the DEND (Developmental delay early onset generalised Epilepsy and Neonatal Diabetes) syndrome. DEND is caused, due to the mutation of V59M. Another cause of Neonatal diabetes is activated mutations in ABCC8 gene encoding the SUR1 subunit of the KATP channel.
In case of children having diabetes due to family history (whether type 1 or type 2 diabetes), diagnosis of Maturity Onset Diabetes of the Young (MODY) should be considered. It comes in two subgroups: (1) the result of transcription factor mutations (IPF1-MODY4, HNF1β-MODY5, HNF1α-MODY3, HNF4α-MODY1, NeuroD1-MODY6 or CEL-MODY7) and (2) mutations reducing glucose sensing (glucokinase mutations-MODY2).
It is important to diagnose monogenic diabetes correctly because not only it will help elucidate the origin of the patients having diabetes and explain other associated clinical features, it can also predict the clinical course of the patient and guide the most appropriate treatment. For instance, patients might not need any treatment or might be able to switch from insulin injections to tablets such Assulfonylurea. Different molecular genetic tests are also available to do the diagnosis of Diabetes.
Source: Pub Med Central- “Monogenic diabetes in children and young adults: Challenges for researcher, clinician and patient”
Filed under Diabetes, IDDM, NIDDM | Tags: ABCC8, CEL-MODY7, DEND, HNF1α-MODY3, HNF1β-MODY5, HNF4α-MODY1, HYMAI, IPF1-MODY4, KATP, KCNJ11, Kir6.2, NeuroD1-MODY6, permanent neonatal diabetes mellitus, SUR1, transiet neonatal diabetes mellitus, ZAC | Comment Below