Introduction
Diabetes is most commonly classified into Type 1 or Type 2, however now, it is understood that MORE THAN JUST 2 FORMS OF DIABETES EXIST !(although hybrid forms occur much less frequently).
Maturity-onset diabetes of the young (MODY) is a type of monogenic diabetes first described as a mild and asymptomatic form of diabetes that was observed in non-obese children, adolescents, and young adults. MODY is distinct in both genetics and management and many genes linked to MODY have now been sequenced and described.
Why is MODY Significant? .
Recognizing it is essential, as misdiagnosis can lead to overtreatment and neglect due to unnecessary insulin therapy( as many MODY patients are treated as Type 1 )and missed genetic counselling opportunities.
Correct identification is essential as it not only improves quality of life in patients but also allows screening in other family members and reducing complications by optimizing therapy .
Understanding this syndrome is important in knowing whom to test.
Background
First described in the 1970s, MODY is caused by single-gene mutations that impair pancreatic beta-cell function.
MODY is non ketotic ,non-autoimmune and non-obesity-related. It typically presents before age 25, and often has a strong family history of diabetes across generations.
Epidemiology and Genetics
• MODY accounts for 1–5% of all diabetes cases. Almost 6.5% of children with antibody-negative diabetes have a form of MODY.
• Autosomal dominant pattern of inheritance.
• MODY 1–3 are the most common types however a total of 14 types have now been recognised .
• Patients with MODY share genotypic features of both type 1 and type 2 diabetes and are often misdiagnosed as having either type 1 diabetes or type 2 diabetes. Therefore, as the frequency of MODY diagnoses increases, the prevalence may prove to be higher. It is predominantly prevalent in Caucasian populations, but has also been reported in Asian Indians, in South Africa and other races.
MODY Types and Features :
| MODY Type | Gene Mutation | Description |
| MODY 1 | HNF4A | Responsive to Sunfonylureas . May later require insulin |
| MODY 2 | GCK( Glucokinase) | Mild , stable hyperglycemia. Often asymptomatic and may not require treatment. |
| MODY 3 | HNF1A | Most common type in many regions . Responds well to Sulfonylureas. |
| MODY 4 | PDX1 | Very rare . Can cause pancreatic agenesis in homozygous form. |
| MODY 5 | HNF1B | Associated with renal cysts , uterine anomalies , and multisystem involvement . |
History and Physical
Personal medical history should be thorough .
The diagnosis of MODY occurs in adolescence or early adulthood therefore details from the period around the time of diagnosis is highly important.
Birth history should be obtained if known .
Clues from birth history :
MODY 1 patients may have a history of a higher birth weight generally more than 800gr above normal, as well as transient neonatal hyperinsulinemic hypoglycaemia.
MODY 2 patients may have had a history of mild fasting hyperglycaemia at birth.
MODY 3 patients may have had transient neonatal hyperinsulinemic hypoglycaemia .Some forms of MODY can be associated with extra-beta cell manifestations, including renal, hepatic, genitourinary, exocrine pancreatic, or intestinal effects.
IUGR is seen in those with MODY 5 in addition to some congenital abnormalities such as renal and urogenital tract anomalies as well as pancreatic hypoplasia.
Family history : Family history provides some of the most crucial information. As MODY is inherited in an autosomal dominant pattern patients often have a strong family history of diabetes spanning at least 3 generations. Details surrounding the diabetes diagnosis for each family member should include the age of onset, their body habitus at diagnosis, and history of insulin use. Information on prior genetic testing in the family can be very helpful.
Physical examination : Does not provide any specific information guiding one to the diagnosis of MODY or a specific subtype. Even though MODY patients are characteristically of normal weight, obesity in these patients can coexist.
Clinical Clues
• Younger individuals , presenting before 25 years of age but not insulin dependent
• Non-ketotic hyperglycaemia . Hyperglycemia is stable / mild.
• Negative for autoantibodies (e.g., GAD, IA-2)
• Strong family history (diabetes in multiple generations)
• Absence of insulin resistance features (e.g., acanthosis nigricans, obesity)
• Lacking typical features of both type 1 and 2 Diabetes
Who should be tested for MODY ?
Patients with isolated diabetes should be tested if they have:
a) Diabetes diagnosed young (≤35 years in White Europeans and ≤30 years in high prevalence ethnic groups like South Asians). AND
b) Unlikely to have Type 1 diabetes because:
They are not on insulin treatment.
OR
They are on insulin treatment with all autoantibodies tested negative (minimum testing of GADA and IA2A) and a random non-fasting C peptide value ≥200pmol/L. AND
c) Have features suggestive of MODY:
An HbA1c at diagnosis of diabetes <7.5% (58mmol/mol), if diagnosed under 18 years of age,
OR
BMI <30kg/m2 adult (child BMI <95th centile) and a parent with diabetes (if White) or BMI <27kg/m2 (child BMI <95th centile) and a parent with diabetes (if high prevalence type 2 diabetes ethnic group).
OR
Have a MODY probability score ≥20% if not insulin treated and ≥10% if insulin treated (see the MODY calculator)
Investigations and Diagnosis :
Genetic testing is the gold standard.
C-peptide levels can help assess endogenous insulin production.
Genetic testing for MODY mutations is recommended in case of family history of DM in a parent and first-degree relatives of the affected parent, absence of pancreatic islets autoimmunity, detectable C-peptide level in serum and/or urine at least 3–5 years after diagnosis, and absence of consistent severe obesity, acanthosis nigricans and/or other markers of the metabolic syndrome among affected family members.Genetic testing should also be considered if a patient is not obese or has unusual fat distribution.Laboratory testing should include serum and urine glucose, glycated haemoglobin (HbA1c), lipid profile, liver enzymes, markers of renal function as well as the measurement of high-sensitivity CRP.
Management
•MODY 2 : often no treatment needed except during pregnancy.
•MODY 1 & 3 : respond well to low-dose sulfonylureas.
•Avoid insulin unless clearly needed.
•Genetic counselling is essential for family planning.
Conclusion
MODY is a rare but important form of diabetes that requires clinical suspicion, especially in young patients with a family history.
As future clinicians we must remain vigilant for atypical presentations and consider genetic testing when appropriate to ensure proper patient care .
References
• Shields BM et al. Diabetologia, 2010.
• Fajans SS, Bell GI. New England Journal of Medicine, 2011.
• NICE Guidelines – Diabetes in children and young people.
• https://www.ncbi.nlm.nih.gov/books/NBK532900/
• https://www.sciencedirect.com/science/article/abs/pii/S0033062024000495
• https://www.diabetesgenes.org/tests-for-diabetes-subtypes/guidelines-for-genetic-testing-in-mody/