Spinal and bulbar muscular atrophy (SBMA / Kennedy disease)
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A 45-year-old man presents with several years of progressive proximal leg weakness, muscle cramps, and tongue fasciculations with mild dysarthria. He notes longstanding gynecomastia and reduced fertility. Reflexes are diminished without spasticity. Repeat-sizing of the AR gene shows a CAG expansion of 47 repeats.
X-linked recessive; CAG trinucleotide expansion in exon 1 of the androgen receptor gene AR (Xq12). Pathogenic ≥38 repeats; longer expansions correlate weakly with earlier onset. The expanded polyglutamine tract makes a toxic, gain-of-function AR protein that aggregates in motor neurons. The same gene, when carrying loss-of-function variants instead, causes androgen insensitivity syndrome, a clean teaching example of allelic heterogeneity, where the mechanism (gain vs loss) determines a completely different phenotype.
- Adult-onset (typically 30-60), slowly progressive lower-motor-neuron-only disease: no spasticity, no Babinski
- Bulbar involvement: dysarthria, dysphagia, tongue atrophy and fasciculations
- Proximal limb weakness, cramps, and contraction fasciculations
- Endocrine signs of mild androgen insensitivity: gynecomastia, testicular atrophy, reduced fertility
- Mildly elevated CK; sensory nerve action potentials often reduced (subclinical sensory neuronopathy)
- Heterozygous females are typically asymptomatic; rare mild manifesting carriers
- Molecular CAG repeat sizing of AR: diagnostic; no panel needed if the phenotype fits
- EMG/NCS show LMN denervation with the small-fiber sensory involvement noted above
- Distinguish from ALS (upper + lower motor neurons, faster), SMA (infant- or child-onset, SMN1), and myopathies (no fasciculations, no bulbar signs early)
- No disease-modifying therapy; care is supportive (PT, swallowing/speech evaluation, respiratory monitoring)
- Avoid androgen / testosterone supplementation: androgen binding drives the toxic AR protein into the nucleus where it aggregates, and clinical trials of androgen reduction (leuprolide, dutasteride) have shown only modest benefit
- Genetic counseling: X-linked transmission. All daughters of an affected man are obligate carriers; sons are unaffected. Maternal carriers transmit to 50% of sons (affected) and 50% of daughters (carriers).
- Same gene, opposite mechanism, opposite organ system. AR CAG expansion → motor neuron disease (gain-of-function polyQ toxicity). AR loss-of-function → androgen insensitivity syndrome (a 46,XY DSD). Useful prototype for explaining allelic heterogeneity to learners.
- A middle-aged man with slow LMN weakness, bulbar signs, and gynecomastia is the classic clinical picture: AR should come to mind before ALS.
- SBMA is one of the few X-linked CAG/polyQ disorders. Most polyQ disorders (Huntington, the SCAs) are autosomal dominant.
"Kennedy makes you Kinky, not Killer": Kennedy/SBMA is slowly progressive over decades (not rapidly fatal like ALS), with the distinctive Kinky endocrine clues (gynecomastia, infertility) plus tongue fasciculations.
"AR has two faces": A repeat expansion in AR kills motor neurons (SBMA). A loss-of-function variant in AR blocks androgen signaling (AIS). Same gene, opposite mechanism.