What are the presentation, diagnosis, and management of Kennedy disease (spinal and bulbar muscular atrophy)?

Kennedy Disease (Spinal and Bulbar Muscular Atrophy)

Clinical Presentation

Kennedy disease is an X-linked recessive, adult-onset lower motor neuron disease characterized by progressive proximal limb weakness, bulbar dysfunction, sensory neuropathy, and androgen insensitivity manifesting as gynecomastia. 1

Motor Manifestations

• Proximal muscle weakness and atrophy develop in the limbs, typically beginning in the 4th-5th decade of life 1, 2
• Bulbar involvement presents as dysarthria, dysphagia, and tongue atrophy with fasciculations 1, 3
• Widespread fasciculations occur in skeletal muscles, particularly noticeable in the extremities 2, 3
• Tremor of the extremities may accompany the weakness 3
• Gait impairment develops as proximal weakness progresses 3

Sensory and Systemic Features

• Sensory disturbances are present but often subclinical, detected primarily on electrophysiological testing 1
• Gynecomastia is the most frequent systemic manifestation, related to androgen insensitivity 1, 3
• Sexual dysfunction including testicular atrophy occurs due to androgen receptor dysfunction 2, 3
• Cardiac rhythm disturbances and urinary dysfunction have been reported 1

Disease Course

• Slowly progressive with normal life expectancy, distinguishing it from more aggressive motor neuron diseases like ALS 1, 2
• Onset typically in the 4th-5th decade, though presentation can vary 1, 2

Diagnosis

Genetic testing demonstrating ≥38 CAG repeats in the androgen receptor gene on the X chromosome confirms the diagnosis of Kennedy disease. 1

Molecular Diagnosis

• CAG repeat expansion ≥38 in exon 1 of the androgen receptor gene is pathogenic 1
• Patients typically have >39 CAG repeats, with the expansion encoding an abnormal polyglutamine tract 4, 3
• Molecular genetic testing has 100% sensitivity in affected individuals 2

Electrophysiological Studies

• Electroneurography shows normal motor nerve conduction velocity but demonstrates axonal degeneration in sensory nerves 2
• Electromyography reveals chronic anterior horn cell degeneration in skeletal muscles, consistent with lower motor neuron disease 2
• EMG findings suggest spinal muscular atrophy pattern 3

Laboratory Findings

• Markedly elevated creatine kinase (CK) is characteristic, suggesting a primary myopathic component in addition to motor neuron involvement 1, 3

Imaging

• MRI may show tapering of the cervical and thoracic spinal cord in advanced cases 3

Muscle Biopsy

• Myopathic alterations on muscle biopsy support the presence of primary muscle involvement beyond pure motor neuron disease 1

Differential Diagnosis

Kennedy disease must be distinguished from amyotrophic lateral sclerosis (ALS), other forms of spinal muscular atrophy, and motor neuropathies, as the prognosis and management differ substantially. 2

Key Distinguishing Features from ALS

• Normal life expectancy in Kennedy disease versus rapid progression in ALS 2
• Presence of gynecomastia and androgen insensitivity is unique to Kennedy disease 1
• Sensory nerve involvement on electroneurography distinguishes Kennedy disease from pure motor neuron diseases 2
• X-linked inheritance pattern with male-only affected individuals 1

Management

No disease-modifying therapy is currently available for Kennedy disease; management focuses on symptomatic treatment of weakness, fatigue, and bulbar symptoms. 1

Symptomatic Treatment

• Physical therapy and rehabilitation are beneficial for managing progressive weakness 1
• Bulbar symptom management including speech therapy for dysarthria and dietary modifications for dysphagia 1
• Fatigue management strategies should be implemented 1

Investigational Approaches

• Androgen blockade has been explored as a potential therapeutic strategy, given the androgen-dependent nature of the disease 5
• Targeting androgen receptor function in muscles may provide neuroprotection, as androgens may trigger disease by acting in muscles that indirectly affect motor neurons 5
• Multiple therapeutic attempts in mouse models have not yet translated to effective human treatments 1

Monitoring

• Regular assessment of bulbar function to detect swallowing difficulties and aspiration risk 1
• Cardiac monitoring for rhythm disturbances 1
• Urological evaluation if urinary symptoms develop 1

Common Pitfalls

• Misdiagnosing Kennedy disease as ALS leads to unnecessary anxiety about prognosis, as Kennedy disease has normal life expectancy 2
• Overlooking the sensory component on clinical examination; electrophysiological testing is essential to detect subclinical sensory involvement 1, 2
• Failing to recognize gynecomastia as a diagnostic clue, especially if the patient has undergone prior surgical correction 3
• Not performing genetic testing when clinical and electrophysiological features suggest Kennedy disease, as molecular diagnosis is definitive and has 100% sensitivity 2