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.

MELAS should be suspected in individuals with:

• stroke-like episodes before the age of 40;
• encephalopathy with seizures and/or dementia;
• high plasma or CSF lactate;
• muscle weakness and exercise intolerance;
• recurrent or cyclical vomiting; and/or
• recurrent migrainous headaches (though in isolation this is not specific to MELAS).

MELAS may also be suspected based on characteristic MRI brain imaging findings, or from muscle biopsy findings.

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 as 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 predictive 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 for information about individual tests and their associated eligibility criteria. You can also access a spreadsheet 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 information about the genes that are included on different gene panels, see the NHS Genomic Medicine Service (GMS) Signed Off Panels Resource.
• Consult the Rare Mitochondrial Disorders Service website. Here you can find advice about testing from your closest centre (London, Oxford or Newcastle), including specific test request forms.
• Decide which of the tests best suits the needs of your patient and/or their family. The relevant test directory panels, which are undertaken on DNA extracted from blood, include:
  • 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 test directory 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 R98 Likely inborn error of metabolism and R63 Possible mitochondrial disorder – nuclear genes. 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 are undertaken using whole genome sequencing (WGS), including R98, you will need to:
  • complete an NHS GMS test order form with details of the affected individual (proband) and their parents, including details of the phenotype (using human phenotype ontology (HPO) terms) and the appropriate panel name(s) with associated R number(s) (see How to complete a test order form for WGS for support); and
  • complete an NHS GMS record of discussion (RoD) form for each person being tested – for example, if you are undertaking trio testing of an affected patient and their parents, you will need three RoD forms (see How to complete a RoD form for support).
• For tests that do not include WGS, such as R300, R352, R299 and R63:
  • you should use your local Genomic Laboratory Hub (GLH) test order and consent (record of discussion) forms.
• When testing in children, parental samples may be helpful for interpretation of the proband’s result. Parental samples can be taken alongside that of the proband, and their DNA stored, or can be requested at a later date if needed.
• 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.
• 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.
• 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 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