Understanding MODY 5: A Rare Genetic Form of Diabetes

By Vijay Kumar MalesuReviewed by Benedette Cuffari, M.Sc.

Introduction
What Is MODY?
How MODY Differs from T1DM and T2DM
What is MODY 5?
Diagnosis Challenges
Why Diagnosis Matters
Treatment and Management
Future Directions and Awareness
Conclusions
References

MODY 5 isn’t just another diabetes; it’s a genetic disorder with wide-ranging effects, requiring vigilant diagnosis and multidisciplinary management.

Image Credit: Kateryna Novikova / Shutterstock.com

Introduction

Maturity-Onset Diabetes of the Young  (MODY) 5 is a rare genetic form of diabetes caused by mutations in the hepatocyte nuclear factor 1-beta (HNF1B) gene. MODY 5 accounts for approximately 2–6% of all MODY cases, with HNF1B mutations or whole-gene deletions (including 17q12 deletion syndrome) being the primary causes. Up to 50% of MODY 5 cases result from de novo mutations, so a positive family history may be absent. This article explores the distinctions between MODY and other forms of diabetes, the advantages of genetic testing, and the significance of early diagnosis for personalized care and family screening.

What Is MODY?

MODY is a rare form of monogenic diabetes, which refers to diabetes caused by a mutation in a single gene. MODY typically develops before the age of 25 and is often misdiagnosed as either type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM). Unlike T1DM, MODY is not an autoimmune condition, nor is it associated with obesity or insulin resistance like T2DM.^1,2 Initially described in a seminal publication by Tattersall and Fajans in 1975, MODY has a reported prevalence ranging from 1 to 5% among all patients diagnosed with diabetes mellitus.

MODY is inherited in an autosomal dominant pattern, which indicates that a single copy of the mutated gene from one parent can cause the disorder. However, for MODY 5, up to half of cases are due to de novo mutations or whole gene deletions, so family history may not always be present. To date, over 20 genes have been linked to MODY, all of which are involved in insulin production and glucose sensing in pancreatic beta cells. The most commonly implicated genes in MODY include glucokinase (GCK), hepatocyte nuclear factor 1-alpha (HNF1A), hepatocyte nuclear factor 4-alpha (HNF4A), and HNF1B.

Diagnosis of MODY requires genetic testing, which helps guide personalized treatment. Some types of MODY respond well to oral sulfonylureas, whereas others, such as GCK-MODY, may not require any treatment at all.^1,2

How MODY Differs from T1DM and T2DM

MODY is a monogenic form of diabetes that differs significantly from T1DM and T2DM, especially in terms of cause, presentation, and treatment. Unlike T1DM, which is autoimmune in origin and commonly presents with ketoacidosis in younger patients, MODY is not associated with an autoimmune process. In fact, MODY typically manifests as non-ketotic hyperglycemia and frequently goes undetected due to its mild symptoms.

As compared to T2DM, MODY is not associated with obesity, insulin resistance, or metabolic syndrome. Instead, MODY typically develops in lean individuals with a strong family history of diabetes. However, in MODY 5, family history may be absent due to frequent de novo mutations.

Genetic confirmation is crucial, as many patients with MODY can be managed without insulin. Correct classification ensures appropriate treatment and avoids unnecessary medication or insulin use, especially during pregnancy.³

What is MODY 5?

MODY 5, which is caused by mutations in the HNF1B gene, presents as a multisystem disorder due to the widespread activity of HNF1B in multiple organs. MODY 5 often manifests as early-onset diabetes; however, it can be distinguished by additional abnormalities affecting the kidneys, liver, pancreas, and reproductive organs.⁴

Patients with MODY 5 frequently exhibit renal abnormalities such as bilateral kidney cysts, hydronephrosis, or structural malformations like multicystic dysplasia due to impaired proximal tubule differentiation and abnormal glomerulotubular connections. Renal disease, often cystic dysplasia, hypoplasia, or structural anomalies, may precede the onset of diabetes and is a key diagnostic clue. HNF1B mutations can also cause electrolyte imbalance as a result of reduced function of key transporters in the renal tubules, which can lead to disturbances in magnesium, sodium, and calcium excretion.^4. Electrolyte imbalances, particularly hypomagnesemia and hypokalemia, are common.

Genitourinary defects, including malformations of the uterus, epididymis, or seminal vesicles, may occur in MODY 5; however, they are not common. Pancreatic hypoplasia or agenesis may occur, causing both endocrine (diabetes) and exocrine pancreatic insufficiency. Liver dysfunction and pancreatic issues, such as glucose intolerance or pancreatitis, have also been observed. In some cases, particularly with whole gene deletions at 17q12, neurodevelopmental abnormalities may be present. The phenotypic spectrum of MODY 5 is broad, ranging from isolated diabetes to complex syndromes with renal, hepatic, pancreatic, and neurodevelopmental manifestations.

Diagnosis Challenges

Diagnosing monogenic diabetes, especially MODY, remains a significant clinical challenge. Many patients with MODY are misdiagnosed due to overlapping symptoms, particularly when diabetes presents early in life or without classic features such as obesity or insulin resistance.

Standard diagnostic tests for diabetes, like glucose levels and autoantibody screens, do not distinguish MODY from other types. A family history of diabetes, especially across multiple generations in an autosomal dominant pattern, can raise clinical suspicion. However, in MODY 5, the absence of family history does not exclude the diagnosis, as up to 50% of cases arise de novo. A correct diagnosis requires genetic testing, which remains underutilized due to limited access, high costs, and a lack of awareness.⁵

Kidney cysts, renal dysfunction, or genitourinary abnormalities may be suggestive of MODY 5. However, these features may vary or be present only in some family members, thus making it difficult to make a definitive conclusion without comprehensive medical review. Tools like the MODY probability calculator and urinary C-peptide creatinine ratio can further assist in the diagnosis of this condition. Genetic testing is the gold standard for diagnosis, even in the absence of a family history.

Why Diagnosis Matters

The diagnosis of MODY is crucial because it directly influences treatment decisions, family health management, and long-term outcomes. Early diagnosis also allows for the timely implementation of lifestyle adjustments or treatment, which reduces the risk of complications.

Unlike T2DM, many MODY subtypes do not require lifelong insulin therapy. For example, individuals with HNF1A-MODY often respond well to sulfonylureas, which are oral medications. Thus, the misclassification of MODY as T1DM or T2DM can lead to unnecessary insulin use, increased costs, and potential side effects.

Accurate diagnosis also allows for targeted family screening, as MODY follows an autosomal dominant inheritance pattern. Identifying the causative mutation in one family member enables predictive testing in relatives, thereby facilitating early diagnosis, often before symptoms appear. In MODY 5, this is especially important for renal and extrapancreatic surveillance.

Genetic confirmation also reassures patients with mild subtypes, like GCK-MODY, who may not require treatment. In contrast, individuals with HNF1B-MODY may require additional monitoring for kidney or reproductive tract abnormalities. Recognition of neurodevelopmental risk is also necessary when whole-gene deletions are present.

Overall, a precise MODY diagnosis ensures personalized care, avoids unnecessary therapies, and empowers families with critical genetic insights for proactive healthcare planning.^1,2

Treatment and Management

Treatment for MODY depends on the specific genetic subtype, with management tailored to the patient's individual presentation. MODY 5, which is caused by mutations in the HNF1B gene, typically requires early initiation of insulin due to limited response to oral hypoglycemic agents. In some patients, sulphonylureas, repaglinide, and other therapeutics may help initially, but most patients eventually need insulin therapy.

MODY 5 often involves complications beyond glucose control, particularly affecting the kidneys and genitourinary system; therefore, regular monitoring of kidney and liver function is essential. Because of its multisystem involvement, management of MODY 5 should be multidisciplinary and involve input from endocrinologists, nephrologists, and other specialists as needed. This collaborative approach ensures comprehensive care that addresses both glycemic control and extra-pancreatic complications.

The use of precision medicine and molecular diagnosis plays a critical role in selecting the most appropriate treatment while minimizing unnecessary interventions.⁶

Future Directions and Awareness

Future directions in diabetes care emphasize broader access to genetic testing, greater physician education, and the use of precision medicine. As genetic testing becomes more affordable and widely available, clinicians can identify specific diabetes subtypes, such as monogenic forms, thereby allowing for targeted treatments.

Diagnosis remains underutilized due to limited awareness among healthcare providers; therefore, increasing physician training is essential to ensure accurate identification and personalized management of diabetes cases. Precision medicine offers the potential to personalize treatment plans based on a patient’s genetic profile, lifestyle, and environment, thereby leading to more effective therapies with fewer side effects.

Emerging technologies, such as patient-derived induced pluripotent stem cells (iPSCs) and CRISPR/Cas9 gene editing, are being used to model MODY subtypes in vitro and could inform the development of targeted therapies.

Ultimately, these innovations aim to improve patient outcomes, reduce healthcare costs, and ensure that advances benefit all populations equitably. Ongoing collaboration among clinicians, researchers, and policymakers is key to success.⁷

Conclusions

MODY 5 is a rare but significant form of diabetes, especially in young individuals with atypical presentations. The accurate diagnosis of MODY 5 is crucial, as it can profoundly change treatment plans and improve patient outcomes, thus avoiding unnecessary insulin use.

Genetic testing allows for targeted care and family screening to identify at-risk individuals before symptoms develop. Importantly, the misdiagnosis of MODY can lead to ineffective treatment and missed opportunities for managing related complications.

References

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