Spinal and Bulbar Muscular Atrophy

Spinal and bulbar muscular atrophy (Kennedy disease) is an X-linked recessive, slowly progressive lower motor neuron disease caused by a CAG repeat expansion in the androgen receptor gene. It causes proximal limb and bulbar weakness, fasciculations, and signs of androgen insensitivity in men.

The prevalence is about 1 in 40,000 males, and it is probably under diagnosed. Onset is usually between 30 and 50 years, and women who carry the gene are almost always asymptomatic or mildly affected.

Genetics. The disease is caused by 38 or more CAG repeats in the androgen receptor gene on the X chromosome. Longer repeats are linked with earlier onset, and repeats grow slightly on transmission.

Course. Slow progression over decades. Life expectancy is near normal, but falls, dysphagia and aspiration can occur in later stages, and many patients need a wheelchair after 15 to 20 years.

Pathophysiology.

The mutant androgen receptor is toxic when it binds testosterone, and it moves into the nucleus where it forms aggregates and disrupts transcription in motor neurons and muscle.

Muscle itself is also affected, and this helps explain the raised creatine kinase and the androgen insensitivity features.

• Slowly progressive proximal weakness and wasting of the limbs, with cramps, fasciculations and tremor.
• Bulbar involvement: facial and perioral fasciculations, tongue atrophy, dysarthria and dysphagia.
• Gynaecomastia, testicular atrophy, reduced fertility, erectile dysfunction and reduced libido.
• Sensory neuropathy with reduced vibration sense, and diabetes in some.
• Absent or reduced reflexes; laryngospasm in some.

Red flags.

• Rapid progression, upper motor neuron signs or respiratory failure (motor neurone disease).
• Aspiration pneumonia, weight loss or recurrent choking.
• Cardiac conduction abnormality (Brugada type changes have been reported).

• Genetic testing for CAG repeat expansion in the androgen receptor gene is diagnostic.
• Creatine kinase is raised (usually 2 to 10 times normal); serum testosterone is normal or raised.
• Nerve conduction studies show a sensory axonal neuropathy; electromyography shows chronic denervation.
• Swallowing assessment, spirometry, glucose, lipids and liver function tests, and ECG.
• Genetic counselling for the family.

Differential diagnosis. Amyotrophic lateral sclerosis, spinal muscular atrophy, Pompe disease, myositis, hereditary motor neuropathy, myasthenia gravis and inclusion body myositis.

• No treatment halts the disease; care is multidisciplinary and supportive.
• Avoid androgens (testosterone), which can worsen the disease.
• Physiotherapy: gentle exercise, stretching, cramp management and falls prevention; avoid overexertion.
• Speech and swallowing therapy, nutrition review and modified diets; gastrostomy for severe dysphagia.
• Respiratory review: spirometry yearly, sleep studies and non-invasive ventilation when indicated.
• Manage cramps with stretching and hydration.
• Screen and treat diabetes, hyperlipidaemia and fatty liver; endocrine review of gynaecomastia and fertility.
• Mobility aids, orthoses and occupational therapy.
• Androgen lowering therapy is under study and is not established.
• Genetic counselling: daughters of affected men are obligate carriers; sons are not affected.

Monitoring. Review every 6 to 12 months with strength testing, swallowing, spirometry, glucose and ECG.

Referral and escalation. Neuromuscular specialist and clinical genetics; speech and language therapy; respiratory and endocrine services.

Special groups. Women carriers: counselling and rare mild symptoms. Reproductive planning: preimplantation genetic testing is available.