Maturity-onset diabetes of the young (MODY)

MODY is a clinically and genetically heterogeneous group of monogenic, non-autoimmune diabetes disorders, typically manifesting before 35 years of age. The phenotype varies markedly by causal gene.

GCK-MODY presents with mild, stable fasting hyperglycaemia (5.5-8.0 mmol/L) present from birth; affected individuals are usually asymptomatic, the abnormality is often detected during routine examinations or pregnancy screening, and diabetes-related complications are extremely uncommon.

HNF1A-MODY and HNF4A-MODY are characterised by progressive β-cell dysfunction with onset of overt diabetes in late adolescence or early adulthood, accompanied by glycosuria and, in HNF4A-MODY, transient neonatal hyperinsulinaemic hypoglycaemia in a subset.

HNF1B-MODY (renal cysts and diabetes syndrome) is a multisystem disorder in which kidney involvement frequently predominates over diabetes and may include structural anomalies, renal cysts, hepatobiliary abnormalities, exocrine pancreatic hypoplasia, and genital tract anomalies in females. Inter- and intra-familial variability in age of onset and severity is substantial.

Less common MODY subtypes (e.g. those caused by variants in genes such as PDX1, NEUROD1, KLF11, ABCC8, KCNJ11, INS and others) generally present with variable degrees of β‑cell dysfunction and age of onset, sometimes accompanied by additional features such as pancreatic exocrine insufficiency or neurological abnormalities. The clinical expression of these rarer forms is often heterogeneous and can overlap with both type 1 and type 2 diabetes, making genetic testing essential for accurate diagnosis. Inter- and intra-familial variability in age of onset and severity is substantial.

MODY is estimated to account for approximately 1-6% of all diabetes cases in European populations. A general-population prevalence has not been established, and the majority of cases remain clinically undiagnosed. However, rare disease registries such as estimate an overall prevalence in the range of approximately 1–5 per 10,000 individuals, highlighting both its rarity and likely underrecognition in routine clinical practice.

MODY is associated with heterozygous germline pathogenic variants in at least 14 genes. The principal causative genes encode β-cell transcription factors, the glucose-sensing enzyme glucokinase, and components of the insulin-secretion machinery. The most frequently implicated genes are HNF1A (30-65% of MODY, MODY3), GCK (30-50%, MODY2), HNF4A (5-10%, MODY1), HNF1B (<5%, MODY5/RCAD syndrome), and PDX1 (~1%, MODY4); further rare causes include ABCC8, KCNJ11, and INS. The unifying molecular consequence is impaired insulin secretion in the absence of autoimmunity or significant insulin resistance.

MODY is inherited in an autosomal dominant manner. Each child of an affected individual has a 50% risk of inheriting the pathogenic variant. Prenatal molecular testing is technically possible once the familial pathogenic variant has been identified.

The diagnosis of MODY is established in a proband with non-autoimmune diabetes, preserved endogenous insulin production, and an autosomal dominant family history by identification of a heterozygous pathogenic variant in a MODY-related gene on molecular genetic testing. Supportive biochemical findings include absent pancreatic islet autoantibodies, a measurable C-peptide ≥ 0.60 ng/mL (0.2 nmol/L) in the presence of hyperglycaemia, and a low high-sensitivity C-reactive protein (< 0.75 mg/L) suggestive of HNF1A-MODY. In HNF1B-MODY, kidney imaging frequently demonstrates bilateral hyperechogenic kidneys, renal cysts, or structural anomalies.

Main differential diagnoses include:

• Type 1 diabetes mellitus: presence of pancreatic islet autoantibodies, loss of endogenous insulin production, ketoacidosis when insulin is omitted, and absence of an autosomal dominant family pattern; polygenic.
• Type 2 diabetes mellitus: onset typically after 45 years in association with obesity, acanthosis nigricans, dyslipidaemia, and insulin resistance; polygenic, with familial clustering reflecting shared risk alleles and environment.
• Permanent neonatal diabetes mellitus: diabetes onset within the first 6 months of life; commonly caused by heterozygous variants in KCNJ11, ABCC8, or INS, or biallelic variants in GCK.

• Establishing the molecular diagnosis enables precise classification and informs prognosis.
• Specific and individualised surveillance and clinical management – including subtype-tailored therapy and monitoring for microvascular and macrovascular complications – are guided by the molecular diagnosis and are determined by the treating physicians in consultation with the affected individual.
• Once a pathogenic variant has been identified in an index case, predictive genetic testing can be offered to at-risk family members.

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