Presentation: Adult with suspected POLG-related disease

A 40-year-old female is referred with a suspected sensory neuropathy. On examination, you also identify evidence of ophthalmoparesis and a sensory ataxia.

• Genomic testing should be considered in patients who present with:
  • a history of sensory ataxia and neuropathy;
  • progressive external ophthalmoplegia, especially when accompanied by additional neurological features such as neuropathy, ataxia, parkinsonism or hearing loss;
  • stroke-like episodes, especially if mitochondrial DNA testing has not delivered a diagnosis;
  • a combination of ataxia and epilepsy; and/or
  • a family history of symptoms suggestive of POLG-related disease, such as ophthalmoplegia, ataxia, childhood-onset seizures, regression and/or liver disease.
• 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.
  • R315 POLG-related disorder: This is a targeted test for POLG variants. The first stage of testing looks for the three known common variants, and testing is extended to full gene sequencing if no common variants are identified.
  • R352 Mitochondrial DNA maintenance disorder: This gene panel includes POLG and other nuclear encoded mitochondrial DNA maintenance genes. It may be more useful than targeted POLG testing if the phenotype is not highly specific but remains typical of a mitochondrial condition.
  • R299 Possible mitochondrial disorder – mitochondrial DNA rearrangement testing: This panel may be of particular use in patients with ophthalmoplegia. Adults with POLG-related disease typically have multiple mitochondrial deletions in skeletal muscle DNA. For this reason, muscle is the preferred tissue for this test, which looks for copy number variants and structural variation in the mitochondrial genome.
• If you require further advice on testing, including choice of tissue, please contact your local highly specialised service for mitochondrial disease.
• POLG is included in a number of other panels, including R54 Hereditary ataxia with onset in adulthood, R59 Early onset or syndromic epilepsy and R109 Childhood-onset leukodystrophy. Consideration should be given to the wider clinical differential diagnosis in the patient when choosing a testing strategy. Where the phenotype is not highly likely to be related to POLG, it may be relevant to request a broader panel (or panels) that includes other mitochondrial conditions.
• For tests that do not include whole genome sequencing, including R315:
  • you should use your local Genomic Laboratory Hub test order and consent (record of discussion) forms; and
  • parental samples, though not usually required, can be taken alongside that of the 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.
• 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: POLG-related disorders
• 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