Presentation: Clinical suspicion of motor neurone disease

A 37-year-old woman attends clinic with a one-year progressive history of motor impairment. To begin with, she had difficulty opening jars and dropped objects easily; more recently, she has experienced episodes of tripping on stairs. Her partner reports that she becomes apathetic and impulsive at times. Examination reveals a right foot drop, weakness and wasting of the small muscles of the hands, fasciculations in her right triceps and symmetrical hyperreflexia and extensor plantar reflexes.

• Genetic testing for motor neurone disease (MND), also known as amyotrophic lateral sclerosis (ALS), is increasingly sought after by both patients and clinicians. A relative minority of affected individuals will have a genetic variant that confers a high risk of disease, typically in c9orf72, which is strongly associated with a frontotemporal dementia (FTD), and less commonly in SOD1. Careful consideration of the relevance of an individual gene variant is important. This is particularly true in the context of predictive testing which is often sought by relatives of those affected.
• The National Genomic Test Directory includes ‘ALS with or without frontotemporal dementia’ as a criteria for genomic testing with no age limit recommendation. All patients with confirmed MND are eligible.
• Genomic testing should be considered for individuals presenting with symptoms of MND, with or without FTD, who fulfil all of the following criteria:
  • lower motor neurone degeneration evident during clinical, electrophysiological or neuropathological examination;
  • upper motor neurone degeneration evident during clinical examination;
  • a progressive disease course; and
  • no evidence of another aetiology, such as myeloradiculopathy or spinal and bulbar muscular atrophy (also known as Kennedy 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. For some genetic conditions, rapid testing is available for the purposes of pregnancy management. Assessment of symptoms during pregnancy and discussion of the patient’s choices regarding prenatal testing may be offered. If the patient or a close relative is pregnant, you may wish to offer them a referral to the local clinical genetics service for further discussion.

• 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 containing details of all available tests.
  • For information about how to arrange testing in Wales, Scotland or Northern Ireland, see Genomic testing in the devolved nations.
• To find out which genes are included on different gene panels, see the NHS Genomic Medicine Service Signed Off Panels Resource.
• Decide which of the tests best suits the needs of your patient and/or their family. For early onset MND there is one panel to select:
  • R58 Adult-onset neurodegenerative disorders. This panel investigates single-gene causes of adult-onset neurodegenerative conditions. It uses whole genome sequencing (WGS), though only genes known to cause adult-onset neurodegenerative conditions (including those associated with early-onset MND, such as SOD1, TARDBP and FUS) will be analysed. It also includes short tandem repeat (STR) testing for genes associated with a range of neurodegenerative conditions, notably the C9orf72 and AR genes.
• For tests that are undertaken using WGS, such as R58, you will need to:
  • complete an NHS GMS test order form with details of the affected individual (proband) and their parents, if available. Include 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 RoD 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.
• When testing in children, parental samples may be helpful for interpretation of the proband’s result but are not typically required for either of the tests recommended above. Parental samples can be taken alongside that of the proband, and their DNA stored, or can be requested at a later date if needed.
• 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 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: Amyotrophic lateral sclerosis
• NHS England: National Genomic Test Directory
• NHS Health A to Z: Motor neurone disease

References:

• Dharmadasa T, Edmond E, Scaber J and others. ‘Genetic testing in motor neurone disease’. Practical Neurology 2022: volume 22, issue 2, pages 107–116. DOI: 10.1136/practneurol-2021-002989

For patients

• Motor Neurone Disease Association: Inherited MND
• MyMNDgenetest: Genomic testing decision aids
• Oxford University Hospitals NHS Foundation Trust: Is MND hereditary?