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  Disease summary:

  
  
  
  
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    MODY is estimated to explain 0.2% to 2% of adult diabetes diagnosed before 45 years of age, and is frequently misdiagnosed as either type 1 or type 2 diabetes.

    
    
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    The correct diagnosis of MODY is important to inform therapeutic interventions, disease prognosis, presymptomatic screening, and genetic counseling.

    
    
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    American Diabetes Association diagnostic categories of diabetes include type 1 diabetes, type 2 diabetes, gestational diabetes, and other specific types of diabetes. The various forms of maturity-onset diabetes of the young (MODY) are classified as “genetic defects of beta-cell function” within the “other specific types” category.

  
  

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  Hereditary basis:

  
  
  
  
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    All forms of MODY are inherited in an autosomal dominant fashion.

    
    
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    Penetrance: Overall estimated at 80% to 95% lifetime; however, lower penetrance diabetes loci such as HNF1B (50%) contribute to MODY.

    
    
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    Prevalence of MODY is approximately 50 to 200 per million individuals.

  
  

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  Genetic differential diagnosis:

  
  
  
  
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    It is important to distinguish MODY from mitochondrial diabetes and deafness (MIDD), neonatal diabetes mellitus (NDM), and syndrome-related diabetes.

    
    
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    MIDD represents up to 1% of diabetes and is characterized by maternal inheritance and deafness as the name suggests. The most common mitochondrial mutation (m.3243A>G) is also causative of several other mitochondrial syndromes including mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes syndrome (MELAS) and therefore has phenotypic overlap.

    
    
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    NDM is diagnosed before 6 months and may be transient (TNDM) or permanent (PNDM) in nature. TNDM is caused by an imprinting defect in the 6q24 region that leads to excessive paternally derived expression of the PLAGL1 and HYMAJ genes in approximately 70% of cases. PNDM, and less commonly TNDM, may be caused by a mutation in the constituents of the beta-cell K-ATP channel (KCNJ11 or ABCC8). PNDM may also result from homozygous or compound heterozygous loss of function mutations in the GCK or INS genes. Mutations in the K-ATP channel are important to identify because they may be treated with high-dose sulfonylureas. Patients with TNDM are at increased risk for diabetes in adulthood.

    
    
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    Diabetes is associated with several genetic syndromes: Down syndrome, Klinefelter syndrome, Turner syndrome, Wolfram syndrome, Friedreich ataxia, Huntington disease, Laurence-Moon-Biedl syndrome, myotonic dystrophy, porphyria, Prader-Willi syndrome, lipodystrophy, and many others.

  
  

Diagnostic Criteria for MODY

Historic diagnostic criteria for MODY are (1) hyperglycemia typically before age 25 years, (2) an autosomal dominant inheritance pattern affecting three generations, (3) absence of insulin therapy at least 5 years after diagnosis or significant C-peptide levels in a patient on insulin therapy indicating a beta-cell function defect, (4) absence of obesity or evidence of peripheral resistance. Families diagnosed with MODY frequently violate the historic diagnostic criteria: They may present at a later age, have fewer affected generations, progress rapidly, and have an elevated body mass index (BMI).

MODY is a clinically heterogeneous group of disorders consequent to genetic heterogeneity, allelic heterogeneity, variable expressivity, and incomplete penetrance.

Clinical criteria is expected to have a high specificity but a relatively low sensitivity

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  Nonketotic hyperglycemia

  
  
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  Age less than 25 in at least one affected member

  
  
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  Autosomal dominant inheritance pattern affecting three generations

  
  
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  Evidence of a beta-cell secretion defect, retained C-peptide production

And the absence of

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  Maternal inheritance with deafness, autoantibodies characteristic of type 1 diabetes

Patients that fail to meet these diagnostic criteria in the context of high clinical suspicion may still be appropriate for genetic evaluation. The 2008 best practice guidelines recommended HNF4A, GCK, and HNF1A gene analysis in patients demonstrating diabetes before age 25 years, a strong family history, and evidence of insulin independence.

Clinical Characteristics

The clinical phenotype of MODY is variable (Table 56-1). Even family members with the same mutation may display variable disease severity. MODY is characterized by a defect in insulin secretion capacity even in presymptomatic affected individuals. Presentation may be precipitated by factors that unmask an underlying beta-cell defect by reducing insulin sensitivity. Precipitants include infections, medications such as steroids, puberty, pregnancy, and obesity. However, the most common presentation is asymptomatic hyperglycemia. MODY should be suspected in young hyperglycemic patients who lack characteristic features of type 2 diabetes (obesity, acanthosis nigricans, polycystic ovarian syndrome) or type 1 diabetes.