Monogenic diabetes

1. Dr.KarthikBalachandran Monogenic diabetes

2. Agenda • Introduction • Monogenic diabetes • What? • Why to? • How?-pathogenesis • When ? • How?-diagnosis • Where? • Individual types-in brief • Conclusion

3. 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

4. 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

5. 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)

6. Insulin synthesis and secretion

10. Pathophysiologic classification ASSOCIATED WITH INSULIN RESISTANCE • Mutations in the insulin receptor gene • Type A insulin resistance • Leprechaunism • Rabson-Mendenhall syndrome • Lipoatrophicdiabetes • Mutations in the PPARγ gene

11. ASSOCIATED WITH DEFECTIVE INSULIN SECRETION • Mutations in the insulin or proinsulingenes • 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)

12. 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

13. 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

14. When to suspect? • The diagnosis of type 2 DM in young may be wrong when • Not obese/family members normal weight • No acanthosisnigricans • Ethnic background with low prevalence • No e/o insulin resistance with fasting C peptide in the normal range

15. How to diagnose? • Molecular testing for mutations • Costly – some (egKir 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

16. Specific causes • Mutations in the insulin receptor • Type A insulin resistance • Leprechaunism • RabsonMendelhall syndrome • All have acanthosisnigricans,androgenexcess,absence of obesity and massively raised insulin concentrations

17. 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

18. Leprechaunism –Donahue syndrome

19. Rabsonmendenhall syndrome

21. 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

23. 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

24. Wolcott Rallison syndrome • AR • DM + • Epiphyseal dysplasia • Renal impairment • Acute hepatic failure • Developmental delay • No autoantibodies • Should be suspected within 3 years

25. Wolcott Rallison syndrome

26. Wolfram syndrome • AR • Progressive optic atrophy before 16 years • b/lsensorineural deafness • DI • Dilated renal tracts • Truncal ataxia • No autoantibodies • Death by 30 years

27. Roger s syndrome • Thiamine responsive megaloblastic anemia • Sensorineural deafness • Mutation in SLC9A2 • Deafness doesn’t respond to thiamine

28. 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

29. Monogenic Forms of Type 1A Diabetes • Autoimmune Polyendocrine Syndrome Type I (AIRE Gene) • T1DM, mucocutaneouscandidiasis, hypoparathyroidism, Addison's disease, and hepatitis • XPID-polyendocrinopathy, immune dysfunction, and diarrhea • Mutation in Fox P3 gene-BMT cures

30. 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

31. 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