Providing information for patients and professionals on research and clinical care in genetic types of diabetes.

Guidelines for Genetic Testing in MODY

Diagnostic testing for maturity-onset diabetes of the young (MODY) should be performed where it is going to change clinical management. This is likely to be in cases where there is uncertainty either in the diagnosis or in how a patient should be treated. As with any other laboratory test it is important that there is selection on clinical grounds to make the test appropriate. These are guidelines to the situations where we think testing would be helpful.

Children and young adults with mild hyperglycaemia: testing for glucokinase gene mutations

The finding of a raised fasting blood glucose in the range of 5.5 – 8 mmols/l is unusual in children and young adults. This always raises concern that they may be about to develop type 1 diabetes. However a considerable proportion of these patients will have a mutation in the glucokinase gene which is associated with stable hyperglycaemia throughout life which does not require treatment and indeed responds very poorly to either tablets or insulin. This is very rarely associated with any microvascular complications. The following features suggest a diagnosis of a glucokinase mutation:-

1. the fasting hyperglycaemia is persistent and stable over a period of months or years
2. in an oral glucose tolerance test the increment (2hr glucose – fasting glucose) is small (typically <3.5 mmol/l) although because of the variability of the oral glucose tolerance test this should not be considered an absolute criteria.
3. Parents may have mild type 2 diabetes or may not be diabetic. On testing one parent will have a mildly raised fasting blood glucose, in the range of 5.5 – 8 mmol/l, as this is an autosomal dominant condition.

Gestational diabetes: testing for glucokinase gene mutations

As glucokinase patients have mild fasting hyperglycaemia throughout life this often presents during pregnancy when routine testing is performed. Since these patients have a consistently raised fasting blood glucose they will have macrosomic children (as long as their child does not have the mutation). The diagnosis of a glucokinase mutation is important not only as the child may subsequently be picked up as having a raised fasting blood glucose and this may lead to concern about type 1 diabetes but also because the guidelines given to the mother are different from the normal “pre-type 2” diabetic phenotype as they will not deteriorate with time. The following criteria identify when glucokinase testing is appropriate:-

1. Persistently raised fasting blood glucose in the range of 5.5 – 8 mmol/l both before, during and after pregnancy.
2. An increment of <4.6 mmol/l on at least one oral glucose tolerance test (either during or after pregnancy).
3. A parent may have mild type 2 diabetes but often this has not been detected and so the absence of family history should not exclude the diagnosis.

Children and young adults with diabetes and a strong family history of diabetes: testing for hepatocyte nuclear factor 1A (HNF1A) gene mutations

The identification of an HNF1A gene mutation establishes that a patient is likely to be non insulin-dependent throughout life, although approximately 1/3 will ultimately require insulin treatment. These patients are extremely sensitive to sulphonylureas and as long as they do not have problems with hypoglycaemia can be maintained on these for many decades. Interestingly glycaemic control in sulphonylureas is often better than that achieved on insulin. Making a diagnosis also allows the high heritability of diabetes in these families to be explained and allows genetic counselling of the risk to their offspring (50%). Diagnostic testing should be considered in the following situations:

1. Good glycaemic control outside a normally expected honeymoon period not on insulin (usually <3 years).
2. Young-onset diabetes that shows characteristics of not being insulin-dependent e.g. not developing ketoacidosis in the absence of insulin, good glycaemic control on a small dose of insulin, or detectable C-peptide measured when on insulin.
3. Family history of diabetes. This may be insulin treated and considered to be “type 1” diabetes. This would typically be diagnosed in the 20s, 30s or 40s. There may also be an affected grandparent although often these are diagnosed after 45 yrs.
4. Oral glucose tolerance tests in early stages tend to show a very large glucose increment usually >5 mmol/l. Some subjects may have a normal fasting value but still rise into the diabetic range at 2hrs.
5. Glycosuria and relatively normal blood glucose levels are often seen as these patients also have a low renal threshold.
6. Marked sensitivity to sulphonylureas resulting in hypoglycaemia despite apparently poor control before starting OHA.

Children and young adults with diabetes and a strong family history of diabetes: testing for hepatocyte nuclear factor 4A (HNF4A) gene mutations

MODY diabetes due to mutations of the HNF4A gene is considerably less common that other MODY diabetes due to mutations of the HNF1A gene but has similar characteristics, although the age of diagnosis may be later.

The Molecular Genetics Laboratory at the Royal Devon & Exeter NHS Healthcare Trust is able to offer a range of diagnostic and predictive molecular genetic tests for MODY which are listed below. The laboratory has a complement of ten scientific staff covering a commitment to diagnostic work and research. A state of the art DNA Sequencer (ABI PRISM 377) has enabled the department to establish a sequencing service for research, diagnostic testing and external users.

The following tests are available:

Glucokinase analysis in mild fasting hyperglycaemia and maturity-onset diabetes of the young (MODY)

HNF1A and HNF4A gene analysis in maturity-onset diabetes of the young (MODY)

For further information, please contact Prof. Sian Ellard, Clinical Molecular Geneticist at:

Molecular Genetics Laboratory
Royal Devon & Exeter Hospital
Barrack Road
Exeter
EX2 5DW

Tel: +44 (0) 1392 408259
Fax: +44 (0) 1392 406121
Email: Sian.Ellard@nhs.net