Monogenic Causes of Diabetes: Maturity- onset diabetes of the young
المؤلف:
Holt, Richard IG, and Allan Flyvbjerg
المصدر:
Textbook of diabetes (2024)
الجزء والصفحة:
6th ed , page 275-279
2025-12-14
37
MODY is autosomal dominantly inherited diabetes that, despite a young age of onset, is not insulin dependent. It results from β- cell dysfunction rather than insulin resistance. The underlying genetic aetiology has now been defined, allowing MODY to be sub classified according to the gene involved. Variants in at least 11 genes have been linked to MODY. These include variants in the gene encoding the glucose- sensing enzyme glucokinase (GCK) and variants in several transcription factors that affect β- cell development and function, the frequencies of which are summarized in Figure 1. Clinical presentation varies greatly depending on the underlying genetic variant. Table 1 summarizes the clinical features of glucokinase and transcription factor diabetes. The strikingly different subtypes of MODY mean it is important to define the underlying genetic aetiology. We recommend the use of clinical categories based on underlying genetic cause, for example familial mild fasting hyperglycaemia resulting from glucokinase gene variants (GCK MODY), familial young- onset progressive diabetes resulting from HNF1A and HNF4A variants (transcription factor MODY), and renal cysts and diabetes syndrome (RCAD) resulting from HNF1B variants.
Fig1. The different genetic aetiologies in a UK maturity- onset diabetes of the young (MODY) series from the Exeter Molecular Genomics Laboratory at the Royal Devon and Exeter NHS Foundation Trust, UK, from 2015 to 2020. Other includes WFS1, INSR, PPARG, INS, LMNA, PDX1, KCNJ11, NEUROD1, GATA6, SLC19A2, and TRMT10A subtypes. Source: Personal communication from Kevin Colclough.
Table1. Comparison of the clinical characteristics of glucokinase and transcription factor maturity- onset diabetes of the young (MODY).
Variants in the genes associated with MODY should be considered in people with diabetes diagnosed under 25 years of age who do not fully fit the phenotypes of type 1 diabetes or type 2 diabetes and who have a strong family history of diabetes (Table 2). Differentiating from apparent type 1 diabetes is particularly important, as these individuals can often be most effectively treated without the use of injected insulin. The differentiation of MODY from other types of diabetes is challenging and attention has turned to strategies that will enable better stratification of those requiring genetic testing, which include the use of a probability calculator (available at www.diabetesgenes.org to view and to download as a phone application), measurement of C- peptide and autoantibodies, as well as advances in genetic testing that allow panels of genes to be tested simultaneously using targeted next- generation sequencing.
Table2. Differentiating β- cell monogenic diabetes from type 1 diabetes and 2 diabetes.
Prevalence of MODY variants
MODY was previously indicated to have a minimum population prevalence of 108 cases per million, but this was recognized as an underestimate. Prevalence estimates from large systematic surveys are between 1% and 3% of young- onset diabetes; in the UK Using pharmacogeNetics to Improve Treatment in Early- onset Diabetes (UNITED) study, 3.6% of all diabetes diagnosed <30 years of age and 2.5% of all diabetes diagnosed <20 years of age were MODY, while the SEARCH for Diabetes in Youth study undertaken in the USA found that 1.2% of all cases diagnosed under 20 years of age were MODY. A population study based on screening pregnant women estimated the glucokinase prevalence to be 1.1 in 1000 population prevalence (or 1100 cases/million population), suggesting that most people with glucokinase variants are not coming to medical attention or are not being diagnosed. Based on previous estimates of MODY prevalence, 80–90% of cases were likely to be misdiagnosed or unrecognized, highlighting the need for improved case finding.
Strategies to improve case finding
The key approach to diagnosing MODY is to consider whether there are clinical features that are unusual for type 1 diabetes and type 2 diabetes and to undertake genetic testing in these individuals to confirm monogenic diabetes (Figure 2). Though the cost of molecular testing continues to fall, it is still relatively expensive and it is therefore recommended that testing is restricted to those individuals with a moderate to high possibility of a positive result. Traditional clinical features, such as age at onset, a parental history of diabetes, and non- insulin treatment, overlap considerably between MODY and other types of diabetes and therefore independently have poor discriminatory value.
Fig2. An approach to genetic testing in people with suspected MODY mutations. BMI, body mass index; GAD, glutamic acid decarboxylase; HbA1C, glycated haemoglobin; IA- 2, islet antigen 2. Source: Shields et al. and De Franco et al..
A MODY probability calculator (available at www.diabetesgenes. org) offers an excellent way to establish if a diagnosis of MODY is likely: it combines clinical information to predict the probability of testing positive for MODY. The calculator markedly improved the sensitivity and specificity of identifying MODY compared with standard criteria of diagnosis age <25 years with an affected parent.
Biomarkers such as C- peptide measurement, pancreatic autoantibodies, lipid profiles, and high- sensitive C- reactive protein (CRP) all have some discriminatory value in differentiating cases of MODY from other subtypes; however, they are not without limitations. Pancreatic autoantibodies are positive close to diagnosis in approximately 90% of people with type 1 diabetes if glutamic acid decarboxylase (GAD), islet antigen 2 (IA2), and zinc transporter 8 (ZnT8) antibodies are measured, compared to only 1% of those with MODY. A negative test does not exclude type 1 diabetes, especially as with increasing duration of diabetes anti body positivity is lost. Testing pancreatic autoantibodies in people treated with insulin is therefore of value, if positive, in excluding MODY. The presence of preserved C- peptide secretion in a person with type 1 diabetes of long duration may also help stratify those in whom MODY testing should be considered; however, 8% of people with long- term type 1 diabetes have stimulated C- peptide levels of >200 pmol/l. Utilization of non- invasive urinary C- peptide to creatinine ratios assists in differentiating MODY from type 1 diabetes and avoids the need for blood samples. In the paediatric population, the Swedish Better Diabetes Diagnosis (BDD) study found that absence of all pancreatic autoantibodies and modest hyperglycaemia (glycated haemoglobin [HbA1c] 58 mmol/mol; <7.5 %) at diagnosis of diabetes were discriminatory clinical features of MODY from type 1 diabetes and should lead to genetic testing. This again emphasizes that antibody testing is helpful since a positive result excludes MODY.
New discriminatory tools have been developed to aid differentiation of MODY from type 1 diabetes, including the type 1 diabetes genetic risk score. The type 1 diabetes genetic risk score is generated by genotyping common genetic variants associated with an increased risk of type 1 diabetes and summing their effective weight into a numerical score.
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