Presentation: Patient with suspected mitochondrial encephalopathy lactic acidosis and stroke-like episodes (MELAS)

A 22-year-old female attends the emergency department with confusion, hallucinations and seizures. She is transferred to the intensive care unit with worsening seizures and raised lactate. An MRI shows posterior predominant lesions crossing the classical vascular territories, and her lactate is found to be significantly elevated.

Genomic testing for the common cause of mitochondrial encephalopathy lactic acidosis and stroke-like episodes (MELAS) is indicated for all patients in whom a mitochondrial condition is suspected. It is also indicated for maternally inherited diabetes and deafness (MIDD), which is a related condition.

Unaffected individuals may present with a family history of an adult-onset genetic condition. Where signs and/or symptoms suggestive of that condition are not present in the patient, they should be offered referral to a local clinical genetics service to discuss testing as part of a predictive (presymptomatic) testing pathway.

Due to the maternal inheritance pattern associated with some mitochondrial conditions, the patient and/or their close relatives may be offered testing even if they are unaffected because there may be significant management implications for their own health – including reproductive options. For this reason, if your patient or one of their close relatives wishes to discuss presymptomatic testing or pregnancy management, they should be offered referral to a local clinical genetics service.

• Consult the National Genomic Test Directory. From here you can access the rare and inherited disease eligibility criteria document, which provides information about individual tests and their associated eligibility criteria. You can also access a spreadsheet containing details of all available tests.
  • For those working within NHS Wales, please consult the All Wales Medical Genomics Service website for information on how to arrange testing.
• To find out which genes are included on different gene panels, see the NHS Genomic Medicine Service (GMS) Signed Off Panels Resource.
• Decide which of the panels best suits the needs of your patient and/or their family. Useful panels that are undertaken on DNA extracted from blood include the following.
  • R64 MELAS or MIDD. This panel will identify the common MT-TL1 variant (m.3243A>G) associated with MELAS. 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.
• Mitochondrial disease can be caused by variants in both mitochondrial DNA and nuclear DNA. Below is a list of some of the tests you might consider for patients whose clinical and biochemical phenotype indicates a mitochondrial condition but m.3243A>G testing is negative.
  • R300 Possible mitochondrial disorder. This panel involves whole mitochondrial genome sequencing. It will identify single nucleotide variants in the mitochondrial genome (less common causes of MELAS than m.3243A>G).
  • R352 Mitochondrial DNA maintenance disorder. This will identify variants in nuclear genes, such as in POLG.
  • R299 Possible mitochondrial disorder. This involves mitochondrial DNA rearrangement testing. Rearrangements are an uncommon cause of mitochondrial conditions like MELAS. In most adults, rearrangements can only be detected in muscle DNA, so this test should be considered in affected individuals under the age of 20.
  • Pathogenic variants found in the nuclear genome can sometimes present in a similar pattern to variants that cause mitochondrial conditions. For this reason, consideration should be given to other available panels and their indications – such as R59 Early onset or syndromic epilepsy and R98 Likely inborn error of metabolism – and your choice of additional panel should be guided by the clinical picture.
• In some circumstances, testing muscle DNA may be necessary to identify variants that are not present in the blood. Specific genomic testing may be guided by histological muscle analysis. Useful tests that are undertaken on DNA extracted from muscle include the following.
  • R299 Possible mitochondrial disorder. This involves mitochondrial DNA rearrangement testing, as described above.
  • R300 Possible mitochondrial disorder. This involves whole mitochondrial genome sequencing, as described above.
• For tests that do not include whole genome sequencing, such as R300, R352 and R299:
  • you should use your local Genomic Laboratory Hub test order and consent (record of discussion) forms; and
  • for DNA-based tests, an EDTA sample (purple-topped tube) is required. Your laboratory can arrange transfer of muscle samples to your local mitochondrial laboratory. 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 first to ensure that this sample is requested, collected and processed correctly.
• Information about patient eligibility and test indications were 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
• OMIM: #540000 Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS)

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