• Credits
  • Section Writer: Dr. Om J Lakhani
  • Section Editor: Dr. Om J Lakhani

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• Q. Give the diagnostic criteria for suspecting MODY.
  • Autosomal dominant transmission across three generations
  • Onset before age 25 in one of the affected members of the pedigree
  • Non-ketotic presentation
  • Non-obese body habitus.
• Q. How many forms of MODY exist as of today?
  • 11 forms of MODY exist
  • A recent review also included ABCC8 and KCNJ11 in the MODY list – hence 13 forms of MODY are now enlisted
• Q. How is insulin released in the body?
  • Basal insulin secretion
    • Transcription factors play a role in the release of basal insulin
      • HNF 4alpha
      • HNF1 alpha
      • IPF1
      • HNF 1 beta
      • NeuroD1
  • Nutrient-mediated insulin release
    • Glucose  (GLUT2) → pancreatic beta cell → (glucokinase) → Glucose 6 phosphatase → glucolysis → Mitochondria → ATP
    • ATP → closes ATP sensitive potassium channel → prevents Potassium to flux out → depolarize the cell → Open of calcium channel → influx of calcium → movement of insulin containing granules → release of insulin
  • Basal insulin release
• #Pearl
  • Closure/inhibition of K+ Channel releases insulin ….
  • If it remains open- neonatal diabetes
  • If it remains closed – hypoglycemia
• Q. What are the pools of insulin collection in the beta cells?
  • Two pools
  • One is close to the plasma membrane  release → 1st phase insulin secretion
  • 2nd is more interior → 2nd phase insulin secretion
• Q. What are the features of MODY?
• Autosomal dominant
  • Single gene defects
  • History in 2-3 generation
  • Onset before 25-35 years of age
  • Lean
  • Non-ketotic, non-insulin-dependent
  • Most present around puberty
• Q. Enlist the various MODY.
  • 
• Q. Which is the commonest MODY?
  • MODY 3- HNF 1 alpha
  • This is present in 58% of MODY cases
• Q. Which is more common in children and which is more common in adults?
  • Glucokinase – MODY- more common presentation in children
  • MODY3- more common presentation in adults
• #pearl
  • MODY2 – mild – no treatment required except in pregnancy
  • MODY1 and MODY3- can be treated with SU
• Q. Give a perspective of how common is MODY in children.
  • 15% of children presenting with diabetes are antibody negative
  • 15% of these will be MODY
  • So pretty rare
  • About 1.2% according to the SEARCH study
• MODY 3
• Q. Which cells express HNF 1alpha?
  • Liver and pancreas
• Q. What is the link between MODY 1 and MODY 3?
  • HNF 4 alpha regulates the action of HNF 1 alpha
  • Hence there is a link between MODY 1 and MODY 3
• Q. Does insulin levels decline in MODY3?
  • Yes
  • There is a progressive insulinopenia in MODY3 with age
• MODY 2
• Q. What is the main defect that occurs here?
  • There is reduced sensitivity to glucose by the beta cells
  • insulin is released at a higher level of glucose compared to normal
• Q. What happens if there is a homozygous mutation in GCK?
  • Then you develop neonatal diabetes
• #Pearl
• GCK
  • Homozygous mutation- Neonatal diabetes
  • Heterozygous mutation -  MODY2
• Q. How much glucose must be phosphorylated by glucokinase in normal conditions to release insulin?
  • At least 30% of the glucose must be phosphorylated to release insulin
  • This occurs at blood glucose of around 90 mg/dl
  • In MODY2 – there is reduced phosphorylation of glucose – hence glucose rises to more level before it is 30% phosphorylated
  • In NDM due to GCK- there is no phosphorylation of glucose and hence no release of insulin
• Q. How common is a microvascular complication in GCK?
  • They don’t develop microvascular complications
  • Risk of these complications is the same as the general population without diabetes
• Q. How common is GCK mutation in the general population?
  • 1 in 1000
• Q. When does the hyperglycemia start?
  • It starts in childhood itself
• Q. When are these patients recognized?
  • Often by routine screening especially during pregnancy
• Q. Is treatment recommended?
  • No except in pregnancy
• *Other MODY
• Q. What is the mutation in MODY 1?
  • HNF 4 alpha
• Q. How do they present?
  • The same as MODY 3
• MODY 5
• Q. What is a mutation in MODY 5?
  • HNF 1 beta
  • It also controls HNF 4 alpha
• Q. What are the clinical features of MODY5?
  • Hyperglycemia
  • Renal dysplasia
  • Pancreatic atrophy on CT scan
  • Genital tract abnormalities- bicornuate uterus
  • Increased AST/ALT
  • Hypomagnesemia
  • Sensorineural deafness
• Q. Do patients with MODY 5 have a family history?
  • 30-40% of MODY5 mutations are spontaneous and hence family history may not be present!
  • Even with the same mutation- there is a difference in phenotype observed even in the same family
• Q. Do MODY5 have insulin resistance?
  • Compared to other MODY- MODY-5 tends to have more insulin resistance
• Q. What happens to the pancreas in this patient?
  • They have pancreatic atrophy - may also have exocrine dysfunction
• #pearl- Renal dysfunction is more common in MODY-5 and hence may present to a nephrologist before they go to an endocrinologist
• Q. How does MODY differ from type 1 diabetes?
  • Nonketotic
  • Antibodies negative
  • No relation with high-risk alleles – HLA
• Q. How does MODY differ from type 2?
  • Insulinopenic
  • Lean
  • Normal insulin sensitivity
• Q. Is it more common in Caucasians?
  • No
  • It is common in all races
• Q. How long do MODY patients maintain SU sensitivity?
  • Rule of thumb is 1/3rd or ½ lose their SU sensitivity over time
• Pearl
  • Transition of NDM patient from insulin to SU should be done only after hospitalization and not on an OPD basis
• Q. How do you treat MODY5?
  • Initially respond to SU
  • Eventually require insulin
• Q. Can insulin gene mutation also cause transient NDM?
  • Yes
  • However, most cases are permanent
  • It is an important cause of permanent neonatal diabetes
• Q. Which is the most common monogenic form of diabetes?
  • MODY
• Q. Which is the most common form of MODY?
  • HNF 1 alpha- MODY3 = 50%
  • GCK – MODY 2- 25%
  • HNF 4 alpha- MODY 1 = 10%
• Q. What are the defects in HNF 4 alpha?
  • It is an insulin secretory defect
• Q. Do patients with MODY 1 develop microvascular complications?
  • Yes
• Q. Does a patient with GCK defect (MODY 2 develop microvascular complications)?
  • No they don’t
• Q. How can MODY 3 (HNF 1 alpha) be detected early?
  • There is a reduction of renal threshold (mainly due to defect in SGLT)
  • Hence glycosuria may develop before hyperglycemia
  • Hence test for urine glucose 2 hours after glucose load can be used to detect an early defect in relatives of a patient with HNF 1 alpha
  • Similarly, 1,5 Anhydroglucitol can help diagnose MODY 3 early
• Q. Do they have an increased risk of CV mortality (MODY3)?
  • Yes
• Q. What is the Drug of choice in the treatment of MODY 3?
  • They have marked sensitivity to Sulphonylureas and hence that is the drug of choice
• Q. Which mutation leads to MODY 4?
  • Mutation in insulin promoter factor 1 (IPF1)
• Q. Which mutation leads to MODY 5?
  • HNF 1 beta
• Q. What leads to MODY 6?
  • Defect in NeuroD1 (Neurogenic differentiation factor D1)
• Q. How is MODY diagnosed?
  • Only by genetic testing
• Q. A young patient with diabetes and antibodies positive..can it be MODY?
  • Less likely
• Q. What is MIDD?
  • Maternally inherited diabetes with deafness
  • It is a mitochondrial form of diabetes
  • They have a defect in insulin secretion and the onset of deafness is around 30-40 years
• Q. Can metformin be used in these patients?
  • No
  • Increase risk of lactic acidosis
• Wolfram syndrome (DIDMOAD syndrome)
• Q. What are the features of Wolfram syndrome (DIDMOAD syndrome)?
  • Diabetes insipidus, Diabetes mellitus, optic atrophy, and deafness
• Q. What is the gene defective in Wolfram’s syndrome?
  • WFS1
• Q. Why is it called DIDMOAD syndrome?
  • DI- diabetes insipidus
  • DM- Diabetes mellitus
  • OA- Optic atrophy
  • D- Deafness (Sensorineural deafness)
• Q. What are the two types of Wolfram syndrome (DIDMOAD syndrome)?
  • Type 1
    • Homozygous or compound heterozygous individuals
    • Have all the classical features of the syndrome
    • It is caused by a mutation in the WFS1 gene
  • Type 2
    • It is caused by a mutation in the CISD2 gene
    • They have all other features except Diabetes insipidus
    • They tend to develop a gastrointestinal ulcer
• Q. What is the pathogenesis seen in this condition?
  • the children have a mutation in the WFS1 gene which encodes for a protein Wolfarmin
  • This is present in the Endoplasmic reticulum and deficiency of this leads to increase Endoplasmic reticulum stress leading to early apoptosis of cells
• Q. What are the features of diabetes seen in this condition?
  • Diabetes seen here is associated with Beta-cells apoptosis
  • Hence presents like Type 1 Diabetes - may also have ketoacidosis
  • However, the long-term course is milder compared to type 1 and may also have fewer microvascular complications
  • This is generally the first manifestation
• Q. What is a useful marker progression of optic atrophy?
  • Retinal thinning
• Q. When is deafness seen?
  • It occurs in 2nd decade of life
• Q. Do these children have other urinary abnormalities other than just having Diabetes insipidus?
  • Yes
  • A spectrum of urological abnormalities has been described in WS, such as a large atonic bladder, a low capacity, a high-pressure bladder with sphincter dyssynergia, and hydroureteronephrosis.
  • Yearly assessment of renal function, measurement of postvoid residual urine volume by renal ultrasound, and urodynamic testing are recommended
• Q. What are the other abnormalities seen?
  • Progressive neurological deterioration
  • Hypogonadotropic hypogonadism
  • Cerebellar ataxia
  • Peripheral neuropathy
  • Central apnea
  • Usually leads to early mortality by age of 30 years
• Neonatal diabetes mellitus
• Q. What is the definition of neonatal diabetes?
  • Diabetes occurs in the first 6 months of life
  • #Pearl
  • Type 1 diabetes rarely occurs before 6 months of life
• Q. What are the diseases associated with the potassium channel remaining open (gain of function mutation)?
  • Potassium channel has 4 subunits
  • Depending on how many subunits are affected you can develop a different degree of severity of diabetes. Ranging from
    • Permanent neonatal diabetes
    • Transient neonatal diabetes
• Q. Classify neonatal diabetes?
  • Transient form
  • Permanent form
  • Syndromic form
• Q. A child presents with neonatal diabetes with macroglossia and umbilical hernia. Which mutation would you suspect?
  • Uniparental Paternal disomy / paternal duplication in the region of 6q24 encoding gene PLAG1 or HYMAI
  • Neonatal diabetes is generally transient in these cases
  • This is the most common form of transient neonatal diabetes
• Q. Which mutation most commonly leads to permanent neonatal diabetes?
  • KCNJ11 mutation – associated with DEND mutation
• pearl
  • With neonatal diabetes- KCNJ11 mutation dominant
  • In hyperinsulinemic hypoglycemia – ABCC8 mutation dominates
• Q. What is the typical pattern of clinical presentation in NDM?
  • They have mild intrauterine growth retardation at birth
  • Failure to thrive with hyperglycemia at birth
  • Remission at about 3-4 months of age
  • Again recurrence in about 50% of cases
• Q. How commonly does KCNJ11 mutation respond to SU?
  • 90% of cases respond to SU- DEND can be prevented by giving SU
• Q. Name 3 other rare genetic syndromes associated with diabetes?
  • Wolfram’s syndrome
  • Maternally (mitochondrial) inherited diabetes and deafness – MIDD
• Q. Should you do Sanger sequencing based on Phenotype or Next generation sequencing?
  • MODY- do 3 important genes first – MODY1,2, 3 and then move to other genes
  • In NDM- it is better to do next-generation sequencing