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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #152: Monogenic Disorders of the Beta Cell Part 2

Nov 20, 2018


Maturity-onset diabetes of the young (MODY) refers to group of monogenic subtypes of diabetes characterized by young onset (usually before 25 years) of non-insulin-dependent diabetes, beta-cell dysfunction that is inherited as an autosomal dominant trait. Mutations in at least 10 genes have been found to cause MODY; (see Figure 28.3) the common subtypes are due to mutations in GCK, Hepatocyte nuclear factor 1-alpha (HNF1A), HNF4A, and HNF1B. The definition of the underlying genes has resulted in the recognition of distinct clinical and physiologic subgroups of MODY with varying clinical course, prognosis, and treatment requirements. Classifications of diabetes by the ADA and the WHO recognize these discrete subtypes.


Diagnosis of MODY

Table 28.2 shows the key differences between type 1 and type 2 diabetes and MODY in young adults. Over 80% of people with MODY will initially be misdiagnosed with type 1 or type 2 MODY [1]. MODY subjects tend to be (but are not exclusively) non-obese, lack features of the insulin resistance syndrome, and be GAD and IA-2 antibody negative. The strict classic criteria for MODY: (i) age of onset diabetes <25, (ii) non-insulin-dependent diabetes, (iii) family history of diabetes (due to autosomal dominant inheritance), have been successfully applied to genetic studies. However, they have poor sensitivity, missing 50% of patients with a diagnosis of MODY [1]. Recently, an online clinical prediction model has been developed for MODY (a MODY calculator: www.diabetesgenes.org/content/mody-probability-calculator). This allows clinicians to identify those patients that are most likely to benefit from genetic testing based on a pretest probability of MODY, taking into account a patient’s age of diagnosis, treatment, BMI, and family history [1]. The importance of a genetic diagnosis of MODY is that these patients often do not need insulin treatment and an appropriate switch of therapy can lead to an improvement in well-being and glucose control.

Prevalence of MODY subtypes

MODY accounts for approximately 1% of non-insulin dependent diabetes in Europe [1]. Large national collections allow assessment of the relative prevalence of the different subgroups of MODY as shown in Figure 28.3 [2]. The relative prevalence varies, by country, according to how patients are identified. As glucokinase mutations are common (≅0.1% population) but asymptomatic, their frequency will be higher in populations where there is wider screening for and follow-up of abnormal glucose levels in children and young adults.

The MODY phenotypes

The MODY phenotypes can essentially be divided into two distinct clinical groups: glucokinase MODY (GCK-MODY) and transcription factor MODY (TF-MODY). The phenotypes in these two groups are completely different (see Table 28.1), and it is confusing that they both fall under the same group name of MODY. GCK-MODY is characterized by stable fasting hyperglycemia that is present from birth, nonprogressive, does not require treatment (except in pregnancy), and is not associated with serious vascular complications. TF-MODY diabetes, on the other hand, is not present at birth but usually develops in adolescents/young adults. The two commonest forms are due to mutations in HNF1A and HNF4A. They are progressive with increasing treatment requirements and are associated with the full range of diabetes-associated microvascular complications [3].

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