Monogenic diabetes

MONOGENIC DIABETES
Dr.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

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

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

Monogenic diabetes

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