Spinal and bulbar muscular atrophy (Kennedy disease)

Spinal and bulbar muscular atrophy (SBMA) is an X-linked genetic condition in which degeneration of lower motor neurones results in a slowly progressive neuromuscular disease in affected males. Affected individuals often show signs of androgen insensitivity.

Clinical features of SBMA include:

• • post-adolescent (typically between the ages of 30 and 50) onset of:
    • lower motor neurone limb weakness, often predominantly proximal and often asymmetric, with symptoms such as:
      • weakness, falls and muscle cramps; and
      • reduced power, fasciculations and depressed deep tendon reflexes;
    • lower motor neurone bulbar dysfunction (though this is rarely the presenting feature of SBMA), with symptoms such as:
      • speech and swallowing difficulty;
      • tongue wasting (especially midline) and fasciculations;
      • fasciculations-myokymia of the perioral region (‘quivering chin’); and
      • dysarthria.
  • absence of upper motor neurone signs (spasticity or hyperreflexia); and
  • adolescent- or adult-onset signs of androgen insensitivity (such as gynaecomastia, testicular atrophy, reduced fertility and erectile dysfunction).
• Additional supportive features may include:
  • postural or action limb tremor; most often in the upper limbs as a common early symptom and which may be alcohol responsive;
  • laryngospasm;
  • sensory neuropathy, typically presenting late in the course of the disease;
  • sleep conditions, especially obstructive sleep apnoea;
  • metabolic syndrome such as raised cholesterol and triglycerides, type 2 diabetes mellitus and fatty liver disease; and
  • moderately elevated creatine kinase (CK).
• Cardiac involvement is reported, associated cardiac rhythm disturbances typical of Brugada syndrome. Monitoring according to current cardiology guidelines is recommended.
• Heterozygous females:
  • are normally asymptomatic due to low levels of circulating androgens;
  • may experience muscle cramps and occasional tremors, but usually do not have significant lower motor neurone disease;
  • may have atypical electromyography (EMG) if they are symptomatic; and
  • are at risk of having affected children.

SBMA is caused by a hemizygous CAG trinucleotide repeat expansion in the androgen receptor (AR) gene located on the X chromosome. CAG expansion length (by number of repeats) should be clinically interpreted in the following ways.

• 34 CAG repeats or fewer: This result is normal. No symptoms would be expected to develop in males or females.
• 35 CAG repeats: This result is of questionable significance. Interpretation requires consideration of clinical features, as well as repeat sizes in other family members.
• 36 to 37 CAG repeats: This result indicates possible reduced penetrance, and should be interpreted in the context of clinical features and family history.
• 38 CAG repeats and over: This result can be interpreted as fully penetrant and disease causing. In general, the greater the number of repeats, the earlier the age of disease onset but with considerable variability.

There is variable expressivity in the clinical phenotype of SBMA patients with the same expansion length, even within the same family. It is not possible to predict disease severity or progression in an individual patient based on CAG expansion length.

SBMA is an X-linked condition.

• X-linked recessive conditions are usually only present in males.
• Males with X-linked conditions cannot pass the variant on to their sons, but they always pass their affected X chromosome to their daughters. If the condition is recessive, their daughters will be carriers for the condition.
• Female carriers of X-linked recessive conditions have a second, working copy of the gene and are therefore usually unaffected, or affected only mildly.
• Sons of female carriers of X-linked recessive conditions have a 1-in-2 (50%) chance of being affected by the condition, and their daughters have a 1-in-2 (50%) chance of being carriers.

Mothers of affected individuals are likely to be heterozygous carriers for the trinucleotide repeat expansion, especially if there is more than one affected family member. As such, genomic testing of the mother of an affected individual is recommended.

Female carriers may develop symptoms, as outlined above under ‘clinical features’. All males who inherit the variant will be expected to develop symptoms.

The number of CAG repeats is typically stable between generations, with only small changes to repeat length typically seen. For this reason, anticipation (earlier or more severe in successive generations) is relatively rare – though when it does occur, it is more common with male transmission. Onset in childhood is exceptionally rare.

If you are discussing genomics concepts with your patients, you may find it helpful to use the visual communication aids for genomics conversations.

Management of those with SBMA is best delivered via a multidisciplinary team, including (though not limited to) neurology, endocrinology, speech and language therapy and physiotherapy. In the UK, there are currently no licensed medications for SBMA.

For clinicians

• GeneReviews: Spinal and bulbar muscular atrophy
• NHS England: National Genomic Test Directory
• OMIM: #313200 Spinal and bulbar muscular atrophy

References:

• Araki A, Katsuno M, Suzuki K and others. ‘Brugada syndrome in spinal and bulbar muscular atrophy‘. Neurology 2014: volume 82, number 20, pages 1813-1821. DOI: 10.1212/WNL.0000000000000434
• Pradat PF, Bernard E, Corcia P and others. ‘The French national protocol for Kennedy’s disease (SBMA): consensus diagnostic and management recommendations‘. Orphanet Journal of Rare Disease 2020: volume 15, article number 90. DOI: 10.1186/s13023-020-01366-z
• Schellenberg KL, Caspar-Bell G, Ellis C and others. ‘Best practice recommendations for the clinical care of spinal bulbar muscular atrophy‘. Canadian Medical Association Journal 2025: volume 197, issue 31. DOI: 10.1503/cmaj.250180

For patients

• Kennedy’s Disease Association
• Kennedy’s Disease UK