Professor Merlin Thomas ( left ) Professor and program leader , department of diabetes , Monash University , Melbourne , Victoria .

Dr Tomasz Block ( right ) Advanced trainee in endocrinology , Alfred Health ; PhD candidate , department of diabetes , Monash University , Melbourne , Victoria .

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This information was correct at the time of publication : 8 November 2024

BACKGROUND

DIABETES now affects over half a

billion people across the globe . 1 Most of these have type 2 diabetes , driven by excess ‘ out of place ’ ( ectopic ) fat that leads to a progressive decline in the insulin-producing capacity of the beta cells of the pancreas to meet the requirements for sustained glucose control . 2 More than 10 million people around the world have type 1 diabetes that results from the autoimmune destruction of the beta cells in their pancreatic islets . 3

In addition , some young people may develop diabetes because of a genetic mutation that results in the progressive ( non-autoimmune ) loss of the insulin-production capacity of the pancreas . 4 This is clinically known as maturity-onset diabetes of the young ( MODY ). 5 , 6 Because MODY is much less common than type 1 or type 2 diabetes , doctors may be unaware of MODY in their practice , unless alerted by a specialist referral or an established family history .

It has been suggested that 90 % of patients are initially misdiagnosed and managed as having type 1 or youth-onset type 2 diabetes . 7 , 8

MODY was originally described as a ‘ diagnosis of exclusion ’, in young individuals who had ‘ juvenile diabetes ’ ( that is , the onset of diabetes occurs during childhood , adolescence or adults aged younger than 25 ) but did not have type 1 diabetes .

However , the term MODY is a misnomer . Its pathogenesis and clinical features are very different from ( maturity onset ) type 2 diabetes , which although previously rare , is common and now possibly the dominant cause of youth-onset diabetes . 9

Although most patients with MODY present as teenagers , the same genetic mutations may sometimes also result in diabetes that first presents later in adulthood or during pregnancy ( see figure 1 ).

This How to Treat provides an overview of MODY , exploring when to think about MODY in patients with

diabetes , how to identify those individuals with diabetes who could have MODY , as well as when and how to consider screening for genetically determined diabetes .

It also discusses the management of MODY , considering genetic screening is becoming increasingly common in primary care . 7

EPIDEMIOLOGY

MODY is a rare disease . It is estimated that 1-5 % of all people worldwide with diabetes have MODY . 10 However , the true prevalence may be higher because of low rates of diagnosis and high rates of misdiagnosis . 11

Unbiased genetic screening studies undertaken on large Biobank samples ( of more than 300,000 individuals in the general population ) have suggested that one in every 1500-2100 individuals may carry a pathogenic variant in one of the MODY-associated genes . 12 This suggests that at least 10,000 Australians

may carry a diabetes-causing mutation of a MODY gene . However , fewer than 10 % of this number currently have this diagnosis . 7 Recent surveys estimate that about 1-5 % of women with gestational diabetes had undiagnosed MODY .

11 , 13

Overall , the documented prevalence of clinically diagnosed MODY varies widely according to the population and its ethnicity . The highest rates have been documented in Western European populations . A lower prevalence of MODY has been suggested in Asian populations , although this may partly reflect low rates of screening and different

14 , 15 mutation profiles .

PATHOGENESIS

MODY is caused by a change in the coding sequence ( mutation ) of a single gene ( that is , MODY is a monogenetic disorder ). MODY is the most common presentation of monogenic diabetes ; the others are ultra-rare neonatal diabetes and diabetes