Fig. 1: Phenotypic and dysmorphic features of patient 1 (A and B),...
Understanding MODY 5: A Rare Genetic Form Of Diabetes
IntroductionWhat Is MODY?How MODY Differs from T1DM and T2DMWhat is MODY 5?Diagnosis ChallengesWhy Diagnosis MattersTreatment and ManagementFuture Directions and AwarenessConclusionsReferences
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
IntroductionMaturity-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 T2DMMODY 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 ChallengesDiagnosing 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.
Professor Maggie Shepherd - impact of a genetic diabetes diagnosis on patients and their familiesPlay
Why Diagnosis MattersThe 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 ManagementTreatment 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 AwarenessFuture 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
ConclusionsMODY 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.
ReferencesNew Genetic Risk Factor For Both Autism And Schizophrenia
Researchers have uncovered a prominent genetic risk factor for autism spectrum disorders and schizophrenia. The study, published by Cell Press on Nov. 4 in the American Journal of Human Genetics, reports a small genomic deletion in patients with these neurological conditions. The region includes a gene in which mutations cause a kidney disease (renal cysts and diabetes syndrome, RCAD).
ASDs include a range of neurodevelopmental conditions that are being diagnosed at an increasing rate. The Center for Disease Control and Prevention estimates that ASD currently affects 1 in 110 people. The prevalence of schizophrenia, with a diagnostic rate of 1 in 100 to 1 in 20, is similar. ASD and schizophrenia affect males more often than females, and both are thought to have a strong and overlapping genetic component.
"The genetic overlap between ASD and schizophrenia, both of which have a high heritability, has been the focus of several recent studies; however, no single specific genetic cause accounts for more than 1%-2% of cases," says Dr. Daniel Moreno-De-Luca, the lead author of the study.
Dr. Moreno-De-Luca and colleagues analyzed genomic DNA from more than 23,000 patients with ASD, developmental delay, or schizophrenia. They were looking for DNA duplications or deletions referred to as copy-number variants (CNV). Remarkably, they found the same deletion on chromosome 17 in 24 separate patients. This CNV was absent in 52,448 controls, making the finding statistically significant.
"We calculate the risk for this combined sample (ASD and schizophrenia) to be at least 13.58, and probably much higher," says Dr. David H. Ledbetter of Emory University. An odds ratio of 13.58 means that someone with this deletion is 13.58 times more likely to develop ASD or schizophrenia than is someone lacking this CNV.
The gene highlighted in this study is one of 15 contained within the deletion. Mutations in HNF1B have been associated with RCAD, and a number of the studied ASD patients were found to have a family history of kidney disease and/or diabetes. Conversely, RCAD patients often present with neurodevelopmental disorders.
"The phenotypic spectrum of patients with the 17q12 deletion is consistent with a gene syndrome that extends beyond RCAD," says Dr. Moreno-De-Luca. "We have uncovered a recurrent pathogenic CNV that confers a very high risk for ASD, schizophrenia, and neorodevelopmental disorders."
These data suggest that one or more of the 15 genes are critical for neorocognitive development.
Clinical Spectrum Associated With Recurrent Genomic Rearrangements In Chromosome 17q12European Journal Of Human Genetics - Nature
Structural variation of the human genome is due to the occurrence of rearrangements such as deletions, duplications, insertions, and inversions. All of these genomic rearrangements, except for inversions, result in copy number variation (CNV) or deviation from the normal number of copies for a given genomic segment. Genomic rearrangements may convey phenotypes by changing the copy number of dosage-sensitive genes, disrupting genes, creating fusion genes, and other mechanisms.1 Recurrent genomic rearrangements of chromosome 17q12 are associated with varied clinical phenotypes. Deletions of 17q12, including the HNF1β (hepatocyte nuclear factor 1-beta also known as transcription factor 2, MIM 189907) gene, are associated with maturity onset diabetes of the young type 5 (MODY5), as well as with cystic renal disease, renal dilations, pancreatic atrophy, and liver abnormalities.2, 3, 4, 5, 6 Earlier reports of this contiguous gene deletion syndrome involving HNF1 β have suggested that cognitive impairment is not part of the phenotype conveyed by these deletions. Mefford et al6 have reported that recurrent deletions in this region spanning 1.8 Mb are one of the few examples of contiguous gene deletion syndromes that present without mental retardation. The reciprocal duplication in this genomic region is rare in the normal population, and its frequency is higher in patients with mental retardation and epilepsy.6 To understand the phenotype associated with CNV in chromosome 17q12, we conducted a detailed clinical and molecular characterization of four patients with deletion and five patients with duplication of this region. Three of the four patients with deletions in 17q12 presented with developmental delay. Patients with a duplication in 17q12 presented with developmental delay, but seizures and other neurological findings were absent. Our findings increase the repertoire of characteristics associated with deletions and reciprocal duplications of chromosome 17q12. Importantly, contrary to previous reports, we show that developmental delay may be associated with the deletion of 17q12.
Clinical reports Patient 1This male patient was born at 34 weeks of gestation to a gravida 3, para 1 woman with no significant medical history. A prenatal ultrasound revealed the presence of multicystic dysplastic kidneys. His birth weight was 2.2 kg (50th centile), whereas measurements of his length and FOC were not available. During the first 2 years, it was noted that he had developmental delay, as evidenced by walking only by 2 years of age, and a vocabulary of 10 words at 3 years. Evaluation of speech was remarkable for significant expressive and receptive speech delays. At 5 years and 6 months, his weight (14.8 kg, z-score=−2.43) and height (96 cm, z-score=−3.41) were well below normal, whereas his FOC (49.6 cm, 10th centile) was normal. The physical examination revealed plagiocephaly, but no other craniofacial dysmorphisms were observed. His systemic examination was normal. MRI of the brain did not show any structural defects, whereas the imaging of kidneys showed multicystic renal dysplasia and a nonfunctioning right kidney. A peripheral blood karyotype revealed normal chromosome constitution, 46, XY.
Patient 2The proband was born at 39 weeks of gestation. Prenatal ultrasounds were remarkable for cystic renal disease and oligohydramnios. His birth weight was 2179 gm (z-score=−2.8), length was 43 cm (z-score=−4), and head circumference was 34.5 cm (9th centile, z-score=−1.4). He had a large anterior fontanel, a shawl scrotum, and a significant coarctation of the aorta that required urgent surgical correction. He had significant failure to thrive and had not regained his birth weight by 7 weeks; however, his weight gain improved after 2 months of age and at the 4-month evaluation, his growth parameters were remarkable with a weight of 4100 gm (z-score=−4.1), length of 50 cm (z-score=−7.6), and a head circumference of 41.5 cm (54th centile, z-score=0.1). He did not have any facial dysmorphic features and his systemic examination was unremarkable. He developed a social smile at 3 months, but did not attain head control. An ultrasound of the head showed no structural abnormalities and renal imaging showed the presence of multiple small cysts.
Patient 3This female patient was born to nonconsanguineous Caucasian parents. The maternal history was significant for generalized tonic–clonic seizures being treated with phenytoin, phenobarbitol, carbamazapine, and sodium valproate. Carbamazapine was discontinued during the latter half of the second trimester. A prenatal ultrasound showed the presence of multiple renal cysts. The proband was delivered by emergent cesarean section at 30 weeks because of maternal seizures. She developed complex partial seizures in the first year of life. Her attainment of motor milestones was initially delayed, as evident by rolling over at 9 months of age, but her subsequent motor development was normal and she walked by 15 months of age. She had difficulties in language development and showed learning difficulties, and is enrolled in special education classes. She was referred to a genetics clinic for the evaluation of learning difficulties and short stature at 13 years of age. Her growth parameters were remarkable for a height of 135 cm (z-score=−3.18), weight of 33.5 kg (z-score=−1.86), and a normal FOC of 52 cm (40th percentile). Her physical examination was unremarkable. Testing for fragile X syndrome and galactosemia were unremarkable. MRI of the brain showed hyperintensities in the hippocampi (Figure 1a), but no other structural abnormalities were observed. The results of evaluation for hormonal causes of short stature, including thyroid hormone, thyroid-stimulating hormone, follicle-stimulating hormone, luteinizing hormone, and insulin-like growth factor-1, were within normal limits.
Figure 1MRI in two patients with a deletion of 17q12. (a) Patient 3 with hyperintensities in hippocampi (arrow). (b) Patient 4 with mild cerebral atrophy, substantial atrophy in the left hippocampus (arrow), and non-specific findings of increased FLAIR intensities in the subcortical white matter of the left superior frontal gyrus.
Patient 4This female patient was born with a dysplastic right kidney and left renal agenesis. She developed complex partial seizures at 8 months of age and had been on treatment with various antiseizure medications. At the age of 3 years, she underwent her first cadaveric renal transplant that was rejected because of poor compliance with medications, and the patient was maintained on continuous cycling peritoneal dialysis for 7 years. At the age of 11 years, she underwent a second renal transplant and received long-term treatment with steroids that resulted in the development of diabetes mellitus. She was diagnosed with moderate mental retardation and had significant learning difficulties. She is enrolled in special education classes that train her in vocational skills. A physical examination at 20 years was remarkable for a height of 150 cm (z-score=−2.05) and a weight of 54.7 kg (35th centile, z-score=−0.39). The physical examination was remarkable for mild hirsutism and cushingoid habitus, and for bilateral punctuate cataracts of the lens. There were no facial dysmorphisms. Neurological examination showed normal muscle tone with no focal deficits. MRI of the brain revealed mild cerebral atrophy, substantial atrophy in the left hippocampus, and non-specific findings of increased FLAIR intensities in the subcortical white matter of the left superior frontal gyrus (Figure 1b)
Patient 5This male patient was evaluated at 4 years and 6 months of age. His prenatal history was significant for maternal polyhydramnios. His birth weight was 2.66 kg (2nd centile, z-score=−2.1), whereas his length was 48.5 cm (5th centile, z-score=−1.7). Soon after birth, a tracheoesophageal fistula (TEF) with esophageal atresia, along with butterfly vertebra at the ninth thoracic vertebra, were noted. There were no associated renal, cardiac, or genitourinary abnormalities. He underwent a surgical correction of the TEF. When examined by a geneticist at 4 years and 6 months of age, his weight (16.4 kg, 32nd centile, z-score=−0.47), height (104 cm, 34th centile, z-score=−0.42), and FOC (50 cm, 10–25th centile) were normal. He had no craniofacial dysmorphisms and the systemic examination was unremarkable. His developmental parameters were age appropriate.
Patients 6 and 7Patient 6 was born at 33 weeks of gestation by emergent cesarean section performed for placental abruption in the mother (Patient 7). He was large for gestational age, with a weight of 2.4 kg (97th centile) and length of 46.5 cm (97th centile). The immediate perinatal period was complicated by respiratory distress that required mechanical ventilation for 2 weeks. The first 3 years were characterized by delayed attainment of motor developmental milestones, as evidenced by rolling over at 9 months, sitting unsupported by 12 months, and walking by 32 months. His language development was delayed, and the proband spoke his first words by 2 years. He was noted to have significant behavioral abnormalities including aggressive and self-injurious behaviors. When examined at 4 years and 6 months of age, his weight (20.8 kg, 82nd centile, z-score=0.93), FOC (49.5 cm, 10–25th centile), and height (110 cm, 90th centile, z-score=1.32) were normal. His physical examination was remarkable for synophrys and mild syndactyly of the second and third fingers and toes bilaterally. A developmental evaluation revealed global developmental delay, receptive and expressive language deficits, and oppositional defiant behavior. MRI of the brain and echocardiography were normal.
The proband's mother (patient 7) was also found to have learning difficulties and required special education classes throughout her schooling. On examination at 45 years of age, she showed no craniofacial dysmorphisms, but shared the mild syndactyly of the second and third toes.
Patient 8This female patient was referred for a genetics evaluation at 4 years and 4 months of age. The patient was in the care of foster parents because of social reasons. The details of her prenatal and birth history were unavailable, but there was concern for intrauterine exposure to alcohol and drugs. The mother of the proband was reported to have cognitive impairment. The patient was noted to have behavioral abnormalities including aggressive and self-injurious behaviors such as biting and hitting others, use of inappropriate language, and auditory hallucinations. Her developmental evaluation was remarkable for expressive speech delay. Her weight (15.56 kg, 11th centile) and height (98 cm, 32nd centile) were normal, whereas FOC (48 cm) measured below the 2nd centile. Her physical examination revealed no significant facial dysmorphisms, except for small palpebral fissures and a thin upper lip. Her systemic examination was normal.
Patient 9This 3-year-old male patient, half-sibling of patient 8, was evaluated by genetics for developmental delay. The mother apparently had cognitive impairment, and abused alcohol and drugs during pregnancy. When transferred to the care of foster parents at 2 years of age, the proband was nonverbal. At 3 years, he had developed a vocabulary of around 50 words and spoke in several word phrases with around 50 percent intelligibility. His weight (13.4 kg, 25th centile), height (91 cm, 13th centile), and FOC (48.6 cm, ∼10th centile) were normal. His physical examination showed minor facial dysmorphic features including a triangular face, small palpebral fissures, epicanthal folds, and small mouth. His systemic examination was unremarkable.
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