Presentation: Clinical suspicion of spinal and bulbar muscular atrophy (Kennedy disease)

A 42-year-old male comes to neurology clinic with a six-year history of slowly progressive muscle cramping, weakness and falls, and a more recent history of twitching of muscles around his mouth. His younger brother has started having similar symptoms. Examination reveals asymmetric proximal weakness in both upper and lower limbs with bilateral postural upper limb tremor, widespread fasciculations and depressed deep tendon reflexes. Peri-oral fasciculations, tongue wasting and gynaecomastia are also noted.

• Spinal and bulbar muscular atrophy (SBMA) should be suspected in males with the following clinical features, with or without a family history suggestive of X-linked inheritance:
  • post-adolescent onset of:
    • lower motor neurone limb weakness and/or lower motor neurone bulbar dysfunction; and
    • absence of upper motor neurone signs (for example, spasticity, extensor plantar responses or hyperreflexia); and
  • adolescent or adult-onset signs of androgen insensitivity (for example, gynaecomastia, testicular atrophy, reduced fertility and erectile dysfunction).
• 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 document for information about individual tests and their associated eligibility criteria. You can also access a spreadsheet containing details of all available tests.
  • For those working within NHS Wales, please consult the All Wales Medical Genomics Service website for information on how to arrange testing.
• 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. Initially only whole genome sequencing (WGS) will be undertaken for the panels listed below. If SBMA is highly likely to be the clinical diagnosis, please state this clearly on the test order form. This will allow the testing laboratory to allocate testing resources to the most appropriate first-line test, in this case short tandem repeat (STR) testing for the CAG triplet repeat expansion in the androgen receptor (AR) gene.
  • R78 Hereditary neuropathy or pain disorder (not PMP22 copy number). This panel is indicated if hereditary neuropathies are the main differential diagnosis. It includes WGS and singleton STR testing.
  • R381 Other rare neuromuscular disorders. This panel is aimed at a broad range of clinical phenotypes not covered by more specific indications such as congenital muscular dystrophy. Testing is undertaken by WGS and STR testing that includes the AR gene.
  • R58 Adult-onset neurodegenerative disorders. This panel investigates single-gene causes of adult-onset neurodegenerative conditions, including motor neurone disease. It encompasses potential differential diagnoses, such as lower-motor-neurone-onset motor neurone disease. It includes WGS and STR testing of a panel of genes known to cause adult-onset neurodegenerative conditions.
• For tests that are undertaken using WGS, including R78, R38 and R58, you will need to:
  • complete an NHS GMS test order form with details of the affected individual (proband) and their parents if 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 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.
• The tests outlined above are all 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: Spinal and bulbar muscular atrophy
• Genomics England: NHS GMS Signed Off Panels Resource
• NHS England: National Genomic Test Directory

For patients

• Kennedy’s Disease Association