Presentation: Patient with adult-onset ataxia

A 52-year-old man attends a neurology clinic with a two-to-three-year history of instability and falls. Examination reveals hypometric horizontal saccades, dysarthria, bilateral upper and lower limb dysmetria and impaired tandem gait. Blood tests including thyroid function, vitamin B12, alpha-fetoprotein, caeruloplasmin, coeliac antibodies, vitamin E and anti-GAD antibodies are normal. Brain MRI imaging reveals mild cerebellar atrophy.

• Genomic testing should be considered for patients presenting with:
  • an adult-onset, slowly progressive or episodic cerebellar ataxia, where history and standard initial investigations have been unable to identify a cause; and/or
  • a family history of cerebellar ataxia, where the features in the patient closely resemble those of other affected family members.
• Where there is a likely diagnosis of an acquired or functional neurological condition, genomic testing should only be considered with caution, and referrals should clearly indicate which signs and/or symptoms indicate a likely genetic diagnosis.
• 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.

• 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.
• Decide which of the panels best suits the needs of your patient and/or their family. Because ataxia is a symptom reported in a large number of conditions, more than one test indication may be relevant in patients with signs that encompass more than one neurological domain. For patients with an unexplained adult-onset cerebellar ataxia, there is one panel to select.
  • R54 Hereditary ataxia with onset in adulthood: This panel includes whole genome sequencing (WGS) and short tandem repeat (STR) testing for a panel of genes associated with hereditary cerebellar ataxias, including spinocerebellar ataxia, fragile X-associated tremor ataxia syndrome and Friedreich ataxia. Please note that if cerebellar ataxia with neuropathy and vestibular areflexia syndrome is suspected, this must be specifically stated on the request form and be accompanied by the supporting clinical findings. STR testing for RFC1 will then be activated following a negative WGS result.
• For patients in whom there is a clinical suspicion of a mitochondrial condition, a different diagnostic pathway with early involvement of specialist services may be required.
  • The R54 panel includes testing of some genes known to cause mitochondrial conditions, including POLG1 and MT-ATP6 (which causes neurogenic muscle weakness, ataxia and retinitis pigmentosa (NARP)). See also: Adult with suspected POLG-related disease and Clinical suspicion of neurogenic muscle weakness, ataxia and retinitis pigmentosa (NARP). If a specific mitochondrial condition is suspected, please contact the Rare Mitochondrial Disorders Service for further advice.
• For tests that are undertaken using WGS, including R54, you will need to:
  • complete an NHS GMS test order form with details of the affected individual (proband) and their parents where available, including details of the phenotype (using human phenotype ontology (HPO) terms) and the appropriate panel name(s) with associated R number (see How to complete a test order form for WGS for support);
  • 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 individual and their parents, you will need three RoD forms (see How to complete a record of discussion form for support); and
  • obtain a consultee form signed by an appropriate relative or advocate if an adult patient does not have capacity to consent to genomic testing.
• 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.
• 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 was 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

• Ataxia UK: Medical guidelines
• GeneReviews: Hereditary ataxia
• Genomics England: NHS GMS Signed Off Panels Resource
• NHS England: National Genomic Test Directory

References:

• de Silva RN, Greenfield J, Vallortigara J and others. ‘Diagnosis and management of progressive ataxia in adults’. Practical Neurology 2019: volume 19, issue 3, pages 196–207. DOI: 10.1136/practneurol-2018-002096

Patients

• Ataxia UK