Presentation: Clinical suspicion of young-onset 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.

• Genomic testing should be considered for individuals presenting with symptoms of motor neurone disease (MND) with or without frontotemporal dementia (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).
• The National Genomic Test Directory includes ‘age of onset under 50 years or a familial history of ALS/MND or FTD’ as a current criteria for genomic testing. This may change on review and may be interpreted according to individual patient needs. Some clinicians choose to offer genomic testing to all patients with confirmed MND.
• 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 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. 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 most commonly 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, 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.
• R58 is DNA-based, and an EDTA sample (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: 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
• Oxford University Hospitals NHS Foundation Trust: Is MND hereditary?