Presentation: Clinical suspicion of myoclonic epilepsy with ragged red fibres (MERRF)

A 28-year-old male is referred to a neurology clinic by his GP with myoclonic jerks and mild ataxia. His history is suggestive of myoclonic epilepsy. He has two large lumps on his neck, which you suspect to be lipomas, and there is a family history of lipomas in his mother and maternal uncle. His maternal uncle is now experiencing cognitive decline.

• Genomic testing should be considered in all patients presenting with clinical features suggestive of myoclonic epilepsy with ragged red fibres (MERRF), including:
  • a history of myoclonus and/or myoclonic epilepsy with a maternal family history; and
  • myoclonus associated with multisystemic features (such as fatigue, ataxia, cardiac arrhythmias, lipomas, hearing loss, optic atrophy and peripheral neuropathy), which should prompt consideration of a diagnosis of MERRF.
• 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 or highly specialised service to discuss testing as part of a predictive (presymptomatic) testing pathway.
• A genetic diagnosis may have implications for other family members, and can be particularly relevant during a pregnancy. Testing for mitochondrial conditions during pregnancy can be particularly complex. If the patient or a close relative is pregnant, please discuss the case with your local clinical genetics service.

• 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 our dedicated Knowledge Hub resource.
• 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.
  • R350 MERRF syndrome: This will test for the most common cause of MERRF, which is the m.8344A>G variant in the MT-TK gene. It is a targeted test and does not use whole genome sequencing (WGS).
  • R300 Possible mitochondrial disorder: This panel uses whole mitochondrial genome sequencing. It will identify single nucleotide variants, which are less common causes of MERRF. It is a mitochondria-specific DNA-based test, and does not involve WGS.
  • R352 Mitochondrial DNA maintenance disorder: Mitochondrial DNA maintenance conditions have very rarely been reported to present with a MERRF phenotype. This panel is mitochondria-specific DNA based, and does not involve WGS.
• For tests that do not include WGS, you should use your local Genomic Laboratory Hub test order and consent (record of discussion) forms.
• For diagnostic testing in children with symptoms of MERRF, parental testing is not usually required. If it is required, samples can be taken alongside that of the child (proband), and their DNA stored, or can be requested at a later date if needed.
• For DNA-based tests, an EDTA sample (typically a purple-topped tube) is required. Other samples may be recommended by the testing laboratory. A muscle biopsy is typically not necessary to establish a diagnosis of MERRF, but where recommended 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 these samples are 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

• GeneReviews: MERRF
• NHS England: National Genomic Test Directory
• NHS Rare Mitochondrial Disorders Service

For patients

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