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

A 42-year-old man 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 for those trying for a child or currently pregnant. 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 an expedited 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 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 tests best suits the needs of your patient and/or their family. Whole genome sequencing (WGS) will be undertaken for all the panels listed below. This includes short tandem repeat (STR) of the CAG triplet repeat expansion in the androgen receptor (AR) gene. If SBMA is highly likely to be the clinical diagnosis, please state this clearly on the test order form.
  • R460 Amyotrophic lateral sclerosis. This panel is indicated in patients who present with clinical features of motor neurone disease where a possible monogenic cause is suspected. Note that this panel is included in the Adult onset neurological disorders panel.
  • R78 Hereditary neuropathy or pain disorder (not PMP22 copy number): This panel is indicated if hereditary neuropathies are the main differential diagnosis.
  • 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.
• For tests that are undertaken using WGS, including R78, R381 and R460, 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 whole genome sequencing for support in completing WGS-specific forms); and
  • 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

• GeneReviews: Spinal and bulbar muscular atrophy
• Genomics England: NHS GMS Signed Off Panels Resource
• NHS England: National Genomic Test Directory

References:

• Devine H, Solomons M, Zampedri L and others. ‘Kennedy’s disease‘. Practical Neurology 2024: volume 24, issue 4, pages 302-305. DOI: 10.1136/pn-2023-004041

For patients

• Kennedy’s Disease Association