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Maturity-onset diabetes of the young type 5
MODY5 is a genetic condition usually diagnosed before 25 years of age. It impacts the body's ability to produce insulin and often affects kidney development and other organs. It is inherited in an autosomal dominant manner.
Overview
Maturity-onset diabetes of the young type 5 (MODY5) is a specific type of diabetes that typically appears before the age of 25, even in individuals who are not overweight. Unlike type 1 or type 2 diabetes, MODY5 is caused by a change in a single gene, *HNF1B* [PMID:16335160]. This genetic alteration affects how the body produces insulin and can also lead to a range of other health issues, particularly involving the kidneys.
MODY5 is considered a rare condition, though its exact prevalence is not well established. It is important to distinguish MODY5 from other forms of diabetes because its diagnosis influences management strategies and provides important information about potential kidney and genitourinary complications [PMID:24074215]. Understanding the genetic basis of MODY5 can help individuals and families manage their health more effectively and anticipate potential associated conditions.
Symptoms & clinical features
The primary symptom of MODY5 is diabetes, which results from the pancreas not producing enough insulin. This can lead to high blood sugar levels. However, MODY5 often presents with a broader set of symptoms affecting various organ systems, making it distinct from other forms of diabetes.
Key features frequently include kidney abnormalities, which can range from structural problems like cysts or being smaller than typical, to functional issues that may lead to chronic kidney disease [PMID:24074215]. Individuals with MODY5 may also experience problems with the genitourinary system, such as uterine abnormalities in females or undescended testes in males. Other potential symptoms can include abnormalities in liver function, pancreatic dysfunction beyond insulin production (such as exocrine pancreatic insufficiency), and occasionally neurological issues or gout. The severity and combination of these symptoms can vary significantly among affected individuals.
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Affected organs
MODY5 primarily affects the kidneys and the pancreas. The kidneys are often structurally abnormal, with common findings including kidney cysts, kidney hypoplasia (underdevelopment), or even a single kidney. These kidney issues can sometimes progress to chronic kidney disease.
The pancreas is affected in its ability to produce insulin, leading to diabetes. Beyond insulin production, the pancreas can also be affected in its exocrine function, which involves producing digestive enzymes. Other organs that may be affected include the liver, leading to elevated liver enzymes, and the genitourinary system, causing conditions such as uterine malformations or undescended testes.
Risks & severity
MODY5 can present with a wide spectrum of severity, even within the same family. The age of diabetes onset is typically before 25 years, but can vary. The progression of kidney disease is also variable; some individuals may maintain good kidney function for many years, while others may develop end-stage renal disease requiring dialysis or kidney transplantation [PMID:24074215].
Other risks associated with MODY5 include complications related to diabetes, such as neuropathy, retinopathy, and nephropathy, if blood sugar levels are not well managed. There is also an increased risk of gout due to impaired magnesium reabsorption in the kidneys. Given the potential for multi-organ involvement, regular monitoring and a coordinated care approach are often recommended to manage the various potential health issues that may arise.
Genetic causes
MODY5 is caused by pathogenic variants in the *HNF1B* gene. This gene provides instructions for making a protein called hepatocyte nuclear factor 1-beta. This protein is a transcription factor, meaning it plays a crucial role in regulating the activity of other genes.
The *HNF1B* protein is particularly important for the normal development and function of various organs, including the kidneys, pancreas, liver, and genitourinary tract. When there is a pathogenic variant in *HNF1B*, the protein may not be produced correctly or may not function as it should. This disruption leads to the wide range of symptoms observed in MODY5, by affecting how these organs develop and operate [PMID:16335160].
- HNF1B HNF1 homeobox B
Inheritance pattern
MODY5 is inherited in an autosomal dominant pattern. This means that only one copy of the altered *HNF1B* gene in each cell is sufficient to cause the condition. An individual with MODY5 has a 50% chance of passing the altered gene, and therefore the condition, to each of their children, regardless of the child's sex.
In some cases, a new (de novo) pathogenic variant in the *HNF1B* gene can occur in an individual for the first time, meaning neither parent carries the altered gene. However, once an individual has the variant, they can then pass it on to their children as described above. Genetic counselling can provide more detailed information for families about inheritance risks and testing options.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
Diagnosis & testing
Diagnosing MODY5 typically involves a combination of clinical assessment and genetic testing. If a young person develops diabetes that does not fit the typical profile of type 1 or type 2 diabetes, especially if there are associated kidney problems or a family history of MODY, MODY5 might be suspected. Blood tests to assess kidney function, blood sugar levels, and sometimes pancreatic function may be performed.
Genetic testing is used to confirm a diagnosis of MODY5. This involves analysing the *HNF1B* gene for pathogenic variants. In the UK, such testing is generally performed as part of the NHS Genomic Medicine Service. A clinician, often an endocrinologist or nephrologist, may refer individuals for genetic testing if MODY5 is suspected. The relevant NHS Genomic Medicine Service R-code for monogenic diabetes testing, which includes MODY5, is R157.
Management & lifestyle
Management for MODY5 is individualised and aims to address both the diabetes and any associated organ problems. For diabetes, treatment may involve diet modifications and medication, which can range from tablets to insulin injections, depending on the severity of insulin deficiency. Regular monitoring of blood sugar levels is important.
Kidney function is also carefully monitored, and management strategies may include blood pressure control and medications to protect the kidneys. If chronic kidney disease progresses, it may eventually require dialysis or a kidney transplant. Other associated conditions, such as gout or exocrine pancreatic insufficiency, are managed symptomatically. A multidisciplinary team, including diabetologists, nephrologists, and genetic counsellors, often provides comprehensive care.
UK care pathway
In the UK, individuals suspected of having MODY5 are typically referred through their GP to specialist services, such as endocrinology or nephrology. If a genetic cause for diabetes or kidney disease is suspected, a referral to a clinical genetics service may be made. Genetic counsellors within these services provide information, support, and help families understand the implications of genetic conditions.
Diagnostic genetic testing for MODY5 is available through the NHS Genomic Medicine Service (GMS). The testing for monogenic diabetes, which includes MODY5, is covered under NHS GMS R-code R157. Results from these tests help guide tailored management plans.
Frequently asked questions
Is MODY5 the same as type 1 or type 2 diabetes?
No, MODY5 is a distinct form of diabetes. Unlike type 1 diabetes, it is not an autoimmune condition, and unlike type 2 diabetes, it is not primarily caused by lifestyle factors or insulin resistance, although these can still play a role. MODY5 is caused by a pathogenic variant in a single gene, *HNF1B*.
If I have MODY5, will my children also have it?
If you have MODY5, there is a 50% chance that each of your children will inherit the altered *HNF1B* gene and therefore develop the condition. This is because MODY5 is inherited in an autosomal dominant pattern. Genetic counselling can provide more personalised risk information.
Can MODY5 affect other family members who do not have diabetes?
It is possible for family members to carry the *HNF1B* gene variant but not yet have been diagnosed with diabetes, especially if they are younger. However, MODY5 often presents with kidney abnormalities that can be present even before diabetes develops. If MODY5 is identified in a family, other relatives may be offered genetic testing and screening for associated conditions.
What kind of specialist doctor will manage my MODY5?
Managing MODY5 often involves a team of specialists. You will likely see an endocrinologist for your diabetes management and a nephrologist for kidney care. A genetic counsellor can also provide support and information about the genetic aspects of the condition.
References
- Adam MP, Bick S, Mirzaa GM. 17q12 Recurrent Deletion Syndrome. 1993. PMID: 27929632
- Verscaj CP, Velez-Bartolomei F, Bodle E. Characterization of the prenatal renal phenotype associated with 17q12, HNF1B, microdeletions. Prenatal diagnosis. 2024. PMID: 37632214
- Ge S, Yang M, Cui Y. The Clinical Characteristics and Gene Mutations of Maturity-Onset Diabetes of the Young Type 5 in Sixty-One Patients. Frontiers in endocrinology. 2022. PMID: 35846334
- Nurkolis F, Syahputra RA, Nugrahanto AP. Emerging phenotype: Maturity-onset diabetes of the young type 5 (MODY-5) - mechanisms, clinical spectrum, and unmet needs. Diabetology & metabolic syndrome. 2025. PMID: 40611325
- Fontana P, Costabile C, Falco M. MODY5 and 17q12 Microdeletion Syndrome: Phenotype Variability, Prenatal and Postnatal Counseling. Genes. 2025. PMID: 41009948
- Igarashi P, Shao X, McNally BT. Roles of HNF-1beta in kidney development and congenital cystic diseases. Kidney international. 2005. PMID: 16221171
- Hayakawa-Iwamoto A, Aotani D, Shimizu Y. Maturity-onset diabetes of the young type 5, presenting as diabetic ketoacidosis with alkalemia: A report of a case. Journal of diabetes investigation. 2022. PMID: 34931465
- Faguer S, Chassaing N, Bandin F. The HNF1B score is a simple tool to select patients for HNF1B gene analysis. Kidney international. 2014. PMID: 24897035