1. Dr.Karthik Balachandran

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  Lipoatrophic diabetes  Mutations in the PPARγ gene

11. 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)

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 acanthosis nigricans  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 (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

16. 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

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. Rabson mendenhall 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/l sensorineural 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, mucocutaneous candidiasis, 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