Diagnosis and management of maturity onset diabetes of the young (MODY)

What is MODY and who gets it?

Case reports in the 1970s described a familial form of non-insulin dependent diabetes that presented before the age of 25 years.3 The molecular genetic basis of MODY was recognised in the 1990s,^w1-w6 and diagnostic genetic testing for common subtypes followed rapidly. Mutations in the genes encoding the enzyme glucokinase (GCK) and the nuclear transcription factors hepatocyte nuclear factor 1α (HNF1A) and hepatocyte nuclear factor 4α (HNF4A) are the most common causes of MODY, and in the United Kingdom they represent 32%, 52%, and 10% of MODY cases, respectively.4 The prevalence of MODY subtypes differs across countries: GCK mutations are more commonly diagnosed in countries where glucose testing of asymptomatic people is routine (such as France, Spain, and Italy), whereas in countries where random blood glucose tests are seldom done HNF1A-MODY is more commonly diagnosed.^w7-w12

To date, mutations in 10 different genes have been associated with a MODY phenotype (table 1⇓).^{w1-w6 w13-w15} On the basis of referrals to the UK diagnostic testing centre, the minimum UK population prevalence of all MODY subtypes is estimated as 68-108 cases per million.4 This figure is comparable with population based cross sectional studies in Oxfordshire, UK, and Nord-Trondelag, Norway, which estimated minimum prevalences for HNF1A-MODY of 84 and 63 cases per million respectively.^{w16 w17}

Although cases of MODY have been described in most ethnic groups, only 0.5% of people referred for MODY testing in the UK were of Asian origin.^w18 This low referral rate may reflect poor uptake of genetic testing by Asian patients, or that Asian patients, even with clinical features suggestive of MODY, are more readily assumed to have type 2 diabetes.

How does MODY present clinically?

Patients with MODY typically display one or more of the following features: a strong family history of diabetes (of any type), onset of diabetes in the second to fifth decade, insulin independence (although insulin may be needed for optimal control), absence of features of insulin resistance, and absence of β cell autoimmunity. The specific genetic subtype of MODY determines the clinical presentation, prognosis, and treatment response.

The recognition of MODY is challenging because of its relatively low prevalence and the overlap in presentation and clinical features between patients with MODY and those with other subtypes of diabetes. Table 2⇓ summarises the similarities and differences between common MODY subtypes and type 1 and type 2 diabetes. The box lists the features to consider when assessing the cause of diabetes.

How is the condition diagnosed?

Diagnostic genetic testing for MODY, by direct sequencing of the genes, is widely available. The sequencing technique used in the UK diagnostic testing centre has greater than 99% sensitivity to detect a heterozygous base substitution.^w22 Genetic testing should be performed after informed consent, with the implications of both a positive or negative result discussed with the patient. Predictive and diagnostic genetic testing for MODY was welcome to most adults,^w23 but less satisfactory to adolescents, despite previous counselling.^w24 General practitioners may prefer to refer patients to the local diabetes or clinical genetics team to discuss MODY genetic testing rather than to organise testing themselves. In general, we recommend genetic counselling before predictive genetic testing (when the person does not have diabetes), especially for children.^{w24 w25} Offer diagnostic genetic testing to relatives of patients with MODY who have diabetes. Do not assume that all family members will have MODY, because different types of diabetes can occur within the same family.^w26

Why is diagnosis often delayed?

Currently, testing for MODY is largely opportunistic. The UK diagnostic testing centre recently reported an average delay of 13 years from diagnosis of diabetes to establishing a definitive genetic diagnosis in patients with MODY, and it reported considerable variation in referral rates for MODY testing across the UK.4 It also estimated that more than 80% of MODY cases in the UK are currently misdiagnosed as type 1 or type 2 diabetes.4 Explanations for this variation include financial restraints on accessing genetic testing and differences in local clinical expertise in MODY. Knowledge and experience of MODY is limited outside of specialist diabetes centres; a diagnosis of MODY is therefore rarely considered in most patients with diabetes who are managed in primary care.

Can diagnosis of MODY be improved?

Genetic testing is too expensive for indiscriminate use in all patients with diabetes. In 2008 best practice guidelines were produced for the diagnosis of MODY secondary to mutations in the GCK, HNF1A, and HNF4A genes.10 These guidelines recommend genetic testing for people who match specific clinical criteria: diabetes presenting before the age of 25 years, a strong family history of diabetes, and evidence of insulin independence. The extent of underdiagnosis described above suggests that genetic testing is not routinely offered to patients meeting these testing criteria. Furthermore, more than half of patients with confirmed mutations identified in European countries do not meet these clinical criteria for referral, so even adherence to current guidelines will continue to miss a large proportion of patients with MODY.4 11

Which patients diagnosed with type 1 diabetes should be referred for genetic testing?

Patients with MODY who present at a young age may be misdiagnosed as having type 1 diabetes and inappropriately treated with insulin.

In type 1 diabetes, autoimmune destruction of the β cells results in complete insulin deficiency within three to five years of diagnosis (the “honeymoon period”), whereas some β cell function is maintained in MODY.12 13 14 15 Consider MODY in patients with evidence of continued endogenous insulin secretion (for example, persistent C peptide production, low insulin dose (<0.5 units/kg/day), and no tendency to ketoacidosis when insulin is omitted) three to five years after diagnosis with apparent type 1 diabetes.

C peptide is co-secreted with insulin from the β cell and can be measured in blood or urine. Urinary C peptide to creatinine ratio can be measured in urine with boric acid preservative that has been sent by post.^w27 A case-control study found that this test provided excellent discrimination between 97 patients with MODY and 69 patients with long duration type 1 diabetes.15 However, assessment of C peptide is less useful for distinguishing MODY from type 1 diabetes close to diagnosis, when endogenous insulin production is still present.

At diagnosis of type 1 diabetes, most patients have pancreatic autoantibodies, including antibodies to glutamic acid decarboxylase and to islet cells. Patients with MODY are not thought to have pancreatic autoantibodies, and their absence is often part of the selection strategy for genetic testing. A recent case-control study reported that less than 1% of 508 patients with a confirmed genetic diagnosis of MODY had antibodies to β cells.16 A paediatric survey, however, found that 17% of patients with confirmed MODY mutations had positive antibodies.9 The difference between the studies probably relates to different laboratories and methods of antibody testing used, but the results suggest that the presence of pancreatic antibodies should not preclude genetic testing in cases where there is high clinical suspicion.

Parental history of diabetes is more common in MODY than in type 1 diabetes, although family history alone does not discriminate well between type 1 diabetes and MODY.^w28

Which patients diagnosed with type 2 diabetes should be referred for genetic testing?

In contrast to type 2 diabetes, patients with MODY have β cell dysfunction that typically occurs in the absence of insulin resistance. Thus, patients with young onset (<45 years) of apparent type 2 diabetes, who do not have features of insulin resistance, may have MODY. Clinical features such as acanthosis nigricans, central obesity, hypertension, and dyslipidaemia can be used as surrogate markers of insulin resistance in everyday clinical practice. In a cross sectional study of patients with a clinical diagnosis of type 2 diabetes, two of 15 patients without insulin resistance were found to have HNF1A mutations.^w29 In a second cross sectional study, 12 of 291 (4%) patients with young adult onset type 2 diabetes were found to have a mutation in the HNF1A or HNF4A genes using age of diagnosis of diabetes 30 years or less or absence of metabolic syndrome as a strategy to identify subjects for genetic testing.14 Type 2 diabetes in adolescents is almost always associated with obesity and features of insulin resistance, so the clinical contrast with MODY is more distinct than in adults with type 2 diabetes.^w30

A family history of diabetes is common in people with young onset type 2 diabetes.^w31 Parental history of diabetes does not discriminate well between patients with type 2 diabetes and those with MODY; a case-control study of 44 patients with HNF1A-MODY and 44 age matched patients with type 2 diabetes found no difference in reported parental diabetes.17

Another clinical clue is marked sensitivity to sulfonylurea agents (see below); patients who have hypoglycaemia on low or normal doses of sulfonylureas may have an HNF1A or HNF4A mutation.

How are patients with MODY treated?

Future strategies for diagnosing MODY

A cost effective biomarker that could be used to screen all patients with young onset diabetes to pick out those most likely to have MODY would improve rates of diagnosis. Most candidate biomarkers investigated so far have had insufficient sensitivity and specificity to be useful for screening.^w36-w40 High sensitivity C reactive protein, which is under transcriptional control by HNF1A, has recently been reported to be significantly lower in patients with HNF1A mutations than in those with other types of diabetes.27 This finding has now been replicated in two large European studies of around 1500 patients with MODY.28 29 Low concentrations of this protein (<0.25-0.75 mg/L, depending on the assay used) discriminated well between patients with HNF1A-MODY and those with young onset type 2 diabetes, with receiver operator characteristic curve derived C statistics of more than 0.8. Given its wide availability and modest costs, this test could be readily incorporated into diagnostic pathways to facilitate the identification of patients with HNF1A-MODY.

Conclusion

Despite the wide availability of molecular genetic testing, identification of patients with MODY remains a challenge for clinicians. An accurate genetic diagnosis of MODY has important clinical implications for individual patients and their relatives. Therefore, clinicians should be aware of the rarer causes of diabetes, particularly MODY, and should not be afraid to challenge existing diabetes diagnostic labels. We propose that a systematic assessment of the underlying cause of diabetes is incorporated into diabetes care plans for patients with diabetes diagnosed between the ages of 10 and 45 years, using a simple diagnostic algorithm such as that outlined in the figure⇓. Otherwise most patients with MODY will continue to be misdiagnosed and forgo the opportunity of individualised care, tailored to the underlying genetic causes.

Algorithm to aid diagnosis of maturity onset diabetes of the young (MODY) in patients with young adult onset diabetes

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