monogenic diabetes
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Dr.Karthik Balachandran. Monogenic diabetes. 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 - PowerPoint PPT PresentationTRANSCRIPT
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