Australian Doctor 8th Nov Issue | Page 40

8 NOVEMBER 2024 ausdoc . com . au

PAGE 38

C-peptide levels less than 200pmol / L as having type 1 diabetes , if the diagnosis was ever in doubt .

In contrast , patients with MODY usually maintain sufficient beta cell function and usually have serum C-peptide concentrations consistently exceeding 200pmol / L ; they thus do not require chronic insulin therapy . Because a clinical diagnosis of MODY is challenging in primary care , specialist referral is appropriate to assist in making a diagnosis in autoantibody-negative young individuals with diabetes . Most major centres have speciality clinics that manage adolescents or young adults with diabetes ; these are more appropriate than routine type 2 diabetes clinics that are dominated by older patients .

A systematic approach to the diagnosis of MODY appears in figure 6 .

GENETIC SCREENING FOR MODY

AT present , MODY is a diagnosis of exclusion in Australia ( that is , it is not type 1 diabetes or type 2 diabetes , so it must be something else ). As discussed earlier , there are no clinical criteria to accurately identify all patients with monogenic diabetes . Consequently , international guidelines recommend that the correct diagnosis of MODY and determination of subtype should be based on genetic testing . 5 It has been suggested that genetic screening for MODY be considered for all adolescents / young adults with diabetes without auto antibodies , irrespective of other clinical characteristics , because of the challenge of a clinical diagnosis . 24

Molecular genetic testing is now available as a routine diagnostic service in some countries , but this is clearly costly or impractical in many others . There are no recommendations for genetic testing for MODY in Australia , although a position statement is currently being developed by the Australian Diabetes Society , Endocrine Society of Australia , Human Genetics Society of Australasia , and Royal College of Pathologists of Australasia .

In young individuals where there is a suspicion of MODY ( see box 1 ), it is reasonable to inform them of the availability of genetic testing and its potential to facilitate predictions of the likely clinical course , response to treatment and prognosis , as well as the identification of potentially affected family members . The RACGP handbook Genomics in General Practice provides recommendations regarding the best approach to genetic testing in general practice . 20

The only commercially available MODY-targeted gene panel in Australia is performed at Mater Pathology in Brisbane . This DNA test aims to identify the common mutations causing MODY with an expected diagnostic yield of 80-90 %. This test is not covered by Medicare and costs $ 1100 for the full panel , with a routine turnaround time of 4-6 weeks .

In most forms of MODY , the mutation is inherited in an autosomal dominant fashion . This means there is a 50 % chance of a parent with MODY passing this mutated gene to their child . It is therefore also reasonable to consider and discuss the

Figure 4 . Acanthosis nigricans .

Box 3 . Criteria listed on the MODY risk calculator developed by the University of Exeter

• Age in years at diagnosis .

• Sex .

• Currently treated with insulin or tablets .

• Time to insulin treatment ( if currently treated with insulin ): — Not currently treated with insulin . — Within six months of diagnosis . — Longer than six months after diagnosis .

• BMI in kg / m ².

• HbA1c in %.

• Current age .

• Parent affected with diabetes .

• Ethnicity .

• Other features : — Renal cysts . — Deafness . — Partial lipodystrophy . — Severe insulin resistance in absence of obesity .

• Severe obesity with other syndromic features .

Source : University of Exeter 23B

potential risk to any children they have or plan to have . Genetic testing can be offered to other family members . The testing costs are lower ( about $ 200 ) for predictive studies in family members where the specific MODY mutation is already known . The development of newer and faster techniques to sequence genes , in particular next-generation sequencing platforms , will likely facilitate a more accurate and comprehensive diagnosis . 18

Table 2 . Some clinical features that may assist in distinguishing MODY from type 1 diabetes or type 2 diabetes

Clinical features Type 1 diabetes Type 2 diabetes MODY

Age of diagnosis ( years )

Weight

Autoantibodies

The peak incidence of type 1 diabetes occurs in children and adolescents , leading to its previous designation as ‘ juvenile diabetes ’

Similar to general population at first presentation or reduced weight due to acute hyperglycaemia

Multiple anti-islet cell antibodies in more than 90 % of cases

Non-invasive prenatal testing ( NIPT ) may be used to determine fetal genotype and guide antenatal management of women with a known GCK-MODY mutation . 25 Many of the thousands of providers of DNA testing across the globe also report on MODY genes , making it even more important that practitioners are aware of MODY and can counsel their patients appropriately .

If a family member is identified as a carrier of a mutated MODY gene ,

Typically , type 2 diabetes presents in mature age adults older than 40 years However , type 2 diabetes has become the most common cause of diabetes in adolescents and young adults

Most people with type 2 diabetes are overweight or obese

Uncommon , rarely multiple autoantibodies

Insulin sensitivity

Family history of diabetes

History of diabetic ketoacidosis

Presenting features

Normal , once blood glucose concentrations are controlled

Reduced Associated stigmata of insulin resistance ( eg , acanthosis nigricans , skin tags , PCOS )

it is currently not possible to prevent the onset of diabetes , although diet and lifestyle optimisation ( that should routinely be undertaken by most young Australians ) is appropriate and may delay the onset of diabetes and the subsequent risk of diabetes-associated complications . 4 Regular testing of a patient ’ s blood glucose blood levels is also appropriate , and pre-conception planning for pregnancy in female carriers should also considered .

Typically , MODY first presents in young people aged 10-25

Similar to general population at first presentation

Uncommon , rarely multiple autoantibodies

Sometimes , depending on mutation

Normal , once blood glucose concentrations are controlled

Common

Acute onset of hyperglycaemia

Rare unless treated with SGLT2 inhibitors

Slow onset of hyperglycaemia

Rare unless treated with SGLT2 inhibitors

Slow onset of hyperglycaemia

TREATMENT OF MODY

IN the absence of a genetic diagnosis , most individuals with MODY can initially be managed using standard oral glucose-lowering agents as required , in combination with appropriate diet and lifestyle modification . In MODY3 , the most common subtype of MODY , increased sensitivity to sulfonylurea ( SU ) therapy has been reported , leading many endocrinologists to consider a trial of