Presentation: Clinical suspicion of mitochondrial neuro-gastrointestinal encephalopathy (MNGIE)

A 19-year-old male is admitted with vomiting and is diagnosed with severe pseudo-obstruction. He becomes increasingly encephalopathic during admission. On examination, you note ptosis and ophthalmoparesis. Nerve conduction studies show a demyelinating peripheral neuropathy, and a brain MRI shows white matter changes.

• Genomic testing should be considered if the patient has a history of worsening gastrointestinal symptoms (such as cachexia, abdominal distension, upper gastrointestinal symptoms and/or diarrhoea) accompanied by neurological features (such as chronic progressive external ophthalmoplegia, encephalopathy or peripheral neuropathy).
• In addition, testing should be considered if the patient presents with raised plasma thymidine and deoxyuridine on biochemical testing.
• 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.
• 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.
  • R394 Mitochondrial neuro-gastrointestinal encephalopathy: This panel looks for variants in the TYMP gene, the main cause of mitochondrial neuro-gastrointestinal encephalopathy (MNGIE). This is a targeted test undertaken by single gene sequencing.
  • R300 Possible mitochondrial disorder – whole mitochondrial genome sequencing: Mitochondrial DNA variants, especially m.3243A>G, can also cause pseudo-obstruction, though this is often accompanied by features of mitochondrial encephalopathy lactic acidosis and stroke-like episodes (MELAS).
• For tests that do not include whole genome sequencing, including R349, you should use your local Genomic Laboratory Hub test order and consent (record of discussion) forms.
• For diagnostic testing in children with symptoms of MNGIE, parental samples are not always required. If they are required, they can be taken alongside that of the child (proband), and their DNA stored, or can be requested at a later date if needed.
• For blood-derived DNA-based tests, an EDTA sample (typically a purple-topped tube) is required.
• Muscle biopsy may be performed as part of the clinical investigations. Your laboratory can arrange transfer of muscle samples to your local mitochondrial laboratory. If you require further advice on testing, including choice of tissue, please contact your local highly specialised service for mitochondrial disease.
• 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

For patients

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