Presentation: Clinical suspicion of neurogenic muscle weakness, ataxia and retinitis pigmentosa (NARP)

A 30-year-old female is referred to you with numbness, pins and needles and poor vision at night. On examination you note ataxia, sensory neuropathy and signs of retinitis pigmentosa. Her mother has similar symptoms, and the patient has a young child under investigation for severe developmental problems and seizures. You suspect a diagnosis of neurogenic muscle weakness, ataxia and retinitis pigmentosa (NARP).

• Genomic testing should be considered if:
  • the patient presents with a history of neurological symptoms (ataxia, neuropathy, muscle weakness and/or intellectual difficulties) accompanied by retinitis pigmentosa and/or optic atrophy;
  • a combination of neuropathy and/or ataxia and/or retinitis pigmentosa with very similar features is reported in a maternal relative;
  • the patient experiences episodic deterioration in the symptoms listed above, associated with intercurrent illness; or
  • there is a history of neuropathy, ataxia and/or retinitis pigmentosa in the mother of a child severely affected by Leigh syndrome.
• 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.
  • R351 NARP syndrome or maternally inherited Leigh syndrome: This panel involves single variant and small panel targeted testing. It looks for the most common cause of NARP, a heteroplasmic 8993T>G/C pathogenic variant in the MT-ATP6 gene. If this variant is not found, single gene sequencing is undertaken looking for other variants in the MT-ATP6 gene.
  • R300 Possible mitochondrial disorder – whole mitochondrial genome sequencing: This panel will identify other causes of NARP, including other variants in MT-ATP6 and other, less commonly involved mitochondrial DNA genes.
  • Nuclear-encoded mitochondrial genes do not typically present with NARP but are more commonly associated with Leigh syndrome, which presents in childhood. If mitochondrial DNA testing is negative, it is recommended that you seek advice from your local highly specialised service for advice on whether mitochondrial DNA testing from another tissue or nuclear gene testing could be relevant.
• For tests that do not include whole genome sequencing, including R351 and R300, you should use your local Genomic Laboratory Hub test order and consent (record of discussion) forms.
• Parental samples are not usually required for interpretation of the proband’s result. If they are required, they 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

• 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