Presentation: Patient with suspected maternally inherited diabetes and deafness (MIDD)

A 22-year-old female presents to a neurology clinic complaining of migraine with aura. She admits to some hearing loss and has recently been diagnosed with diabetes. There is a family history on her mother’s side of both deafness and diabetes.

• The combination of adult-onset hearing loss and diabetes with a family history consistent with a maternal inheritance pattern indicates a possible diagnosis of maternally inherited diabetes and deafness (MIDD). The variant that causes this condition is also responsible for mitochondrial encephalopathy lactic acidosis and stroke-like episodes (MELAS), which is related.
• Genomic testing for this common variant should be undertaken in any patient who presents with a possible mitochondrial condition.
• Unaffected individuals may present with a family history of a mitochondrial condition. Where signs and/or symptoms suggestive of that condition are not present in the patient, it is usually recommended that the patient is not tested and is instead referred to a local clinical genetics service for predictive (also known as pre-symptomatic) testing. This will allow discussion about the management implications for their own health including reproductive options.

• Consult the National Genomic Test Directory. From here you can access the rare and inherited disease eligibility criteria document for information about individual tests and their associated eligibility criteria. You can also access a spreadsheet containing details of all available tests.
  • For information about how to arrange testing in Wales, Scotland or Northern Ireland, see Genomic testing in the devolved nations.
• For more information about the genes that are included on different gene panels, see the NHS Genomic Medicine Service (GMS) Signed Off Panels Resource.
• Useful tests undertaken on DNA extracted from blood include the below.
  • R64 MELAS or MIDD: This panel will test for the common MT-TL1 variant (m.3243A>G) associated with MIDD. The level of this variant found in blood DNA can fall over time (that is, with increasing age), though levels may be maintained in DNA extracted from urine or muscle. It is recommended that the testing clinician contacts the testing laboratory prior to sending these additional samples.
• If R64 MELAS or MIDD testing is negative, consider other testing available for mitochondrial conditions, hearing loss or monogenic diabetes.
• For tests that do not use whole genome sequencing, including R64:
  • you should use your local Genomic Laboratory Hub test order and consent (record of discussion) forms;
  • most tests are DNA based, and an EDTA sample (typically a purple-topped tube) is required. There are a few tests for which a different type of tube is used; see Samples for genomic testing in rare disease;
  • urine samples should contain 50ml of first-pass morning urine, which should be stored in a sterile container and refrigerated to avoid bacterial DNA contamination. It is advisable to contact your local mitochondrial laboratory to ensure that this sample is requested, collected and processed correctly.
• If you are discussing genomics concepts with your patients, you may find it helpful to use the visual communication aids for genomics conversations.
• Information about patient eligibility and test indications was correct at the time of writing. When requesting a test, please refer to the National Genomic Test Directory to confirm the right test for your patient.

For clinicians

• NHS England: National Genomic Test Directory
• NHS Rare Mitochondrial Disorders Service: Care guidelines

References:

• Bindoff LA, Gorman GS, Yi Shiau N and others. ‘Consensus-based statements for the management of mitochondrial stroke-like episodes’. Wellcome Open Research 2019: volume 4, issue 201. DOI: 10.12688/wellcomeopenres.15599.1
• Labrum R, Mavraki E, Sergeant K and others. ‘Genetic testing for mitochondrial disease: The United Kingdom best practice guidelines’. European Journal of Human Genetics 2022: volume 31, pages 148–163. DOI: 10.1038/s41431-022-01249-w

For patients

• NHS Rare Mitochondrial Disorders Service: What is mitochondrial disease?
• The Lily Foundation