MONOGENIC DIABETESDr.Karthik Balachandran

Agenda

Introduction Monogenic diabetes

What? Why to? How?-pathogenesis When ? How?-diagnosis Where?

Individual types-in brief Conclusion

Introduction

Human genome contains more than 3 billion base pairs

20-25000 genes are believed to code for proteins

Single gene defects can lead to diabetes –independent of environmental influences

Monogenic diabetes

Inheritance of mutation in single gene Dominant ,recessive or denovo Most are due to mutations in genes which

regulate βcell function Rare cases due to insulin resistance Can mimic type 1 or type 2 diabetes

Why diagnose monogenic diabetes?

To elucidate the pathophysiology Changes the treatment For example

NO need of drugs- GCK mutations insulin injections being replaced by tablets ( low

dose in HNFα or high dose in potassium channel defects -Kir6.2 and SUR1)

tablets in addition to insulin ( metformin in insulin resistant syndromes)

Insulin synthesis and secretion

Pathophysiologic classification

ASSOCIATED WITH INSULIN RESISTANCE Mutations in the insulin receptor gene

• Type A insulin resistance • Leprechaunism • Rabson-Mendenhall syndrome

Lipoatrophic diabetes Mutations in the PPARγ gene

ASSOCIATED WITH DEFECTIVE INSULIN SECRETION Mutations in the insulin or proinsulin genes Mitochondrial gene mutations Maturity-onset Diabetes of the Young (MODY)

HNF-4α (MODY 1) Glucokinase (MODY 2) HNF-1α (MODY 3) IPF-1 (MODY 4) HNF-1β (MODY 5) NeuroD1/Beta2 (MODY 6)

When to suspect?

1. Neonatal diabetes and diabetes diagnosed within the first 6 months of life

2. Familial diabetes with an affected parent

3. Mild (5.5–8.5 mmol/l) fasting hyperglycaemia especially if young or familial

4. Diabetes associated with extra pancreatic features

When to suspect?

Diagnosis of type 1 may be wrong when A diagnosis of diabetes before 6 months Family history of diabetes with a parent affected Evidence of endogenous insulin production

outside the ‘honeymoon’ phase (after 3 years of diabetes)

When pancreatic islet autoantibodies are absent,especially if measured at diagnosis

When to suspect?

The diagnosis of type 2 DM in young may be wrong when Not obese/family members normal weight No acanthosis nigricans Ethnic background with low prevalence No e/o insulin resistance with fasting C peptide in

the normal range

How to diagnose?

Molecular testing for mutations Costly – some (eg Kir 6.2 –done free of cost) Forms are downloadable(diabetesgenes.org,

mody.no) Costs ~ $600 Careful patient selection – perform C peptide

level and autoantibody testing UCPCR >0.53 rules out insulinopenia

Specific causes

Mutations in the insulin receptor Type A insulin resistance Leprechaunism Rabson Mendelhall syndrome

All have acanthosis nigricans,androgen excess,absence of obesity and massively raised insulin concentrations

Leprechaunism -intrauterine growth retardation, fasting hypoglycemia, and death within the first 1 to 2 years of life

Rabson-Mendenhall syndrome short stature protuberant abdomen abnormalities of teeth and nails Pineal hyperplasia

Leprechaunism –Donahue syndrome

Rabson mendenhall syndrome

Neonatal diabetes

Insulin requiring diabetes diagnosed before 3 months of age

Two types Transient (resolves within 12 weeks) Permanent

Difficult to predict at the time of diabetes Associated clinical features can help

simplified approach

Transient is more likely when h/o consanguinity No extrapancreatic features(except macroglossia)

Presence of characteristic extra pancreatic features –in specific gene defects

USG abd/KUB and pancreatic autoantibodies(seen in IPEX) before molecular testing

Wolcott Rallison syndrome

AR DM +

Epiphyseal dysplasia Renal impairment Acute hepatic failure Developmental delay No autoantibodies

Should be suspected within 3 years

Wolcott Rallison syndrome

Wolfram syndrome

AR Progressive optic atrophy before 16 years b/l sensorineural deafness DI Dilated renal tracts Truncal ataxia No autoantibodies Death by 30 years

Roger s syndrome

Thiamine responsive megaloblastic anemia Sensorineural deafness Mutation in SLC9A2 Deafness doesn’t respond to thiamine

Mitochondrial diabetes

Maternally inherited Usually don’t present in pediatric age group as

diabetes unlike other forms MELAS MIDD Progressive non autoimmune beta cell failure

Monogenic Forms of Type 1A Diabetes

Autoimmune Polyendocrine Syndrome Type I (AIRE Gene)

T1DM, mucocutaneous candidiasis, hypoparathyroidism, Addison's disease, and hepatitis

XPID-polyendocrinopathy, immune dysfunction, and diarrhea

Mutation in Fox P3 gene-BMT cures

Newer MODY s

MODY 7- KLF 11 MODY 8- CEL MODY9 -PAX4 gene MODY 10-INS (PROINSULIN) gene MODY 11 –BLK gene None have any specific phenotypic markers or

management different from routine DM

Summary

Consider monogenic diabetes in young patients /those not fitting the original diagnosis

Molecular testing available free for some-but careful patient selection is the key

Diagnosing monogenic DM can free the patient from “shots”

It is also cost effective to the system