Spinal Bulbar Muscular Atrophy (Kennedy Disease, AR CAG, XR)
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stethoscope Medicine
A 46-year-old man presents with a 5-year history of progressive proximal leg weakness, muscle cramps, and hand tremor. On examination, he has fasciculations over the chin, lips, and tongue, with tongue atrophy and dysarthria. He also reports erectile dysfunction and notes bilateral gynecomastia with small testes. Neurological examination reveals lower motor neuron signs with absent reflexes but NO upper motor neuron signs. Genetic testing reveals a CAG repeat expansion (46 repeats) in the androgen receptor gene on the structure marked **A** in the diagram. Which of the following best describes the chromosomal location and pathogenic mechanism of this mutation?
A. Chromosome Xq12; polyglutamine-expanded androgen receptor misfolds and aggregates in lower motor neurons when ligand-bound, causing toxic gain-of-function and neurodegeneration
B. Chromosome 5q13; deletion of SMN1 gene leads to loss of survival motor neuron protein and selective motor neuron degeneration in childhood
C. Chromosome 4; CAG expansion in HTT gene causes polyglutamine aggregation in striatal neurons with prominent movement disorder
D. Chromosome 9; GAA repeat expansion in FXN gene causes frataxin deficiency with cerebellar ataxia and cardiomyopathy
Explanation
Why option 1 is correct
The structure marked A is Chromosome Xq12, the location of the androgen receptor (AR) gene. Kennedy disease (spinal and bulbar muscular atrophy, SBMA) is caused by a CAG repeat expansion (≥38 repeats) in exon 1 of the AR gene. The pathogenic mechanism involves a polyglutamine-expanded androgen receptor that misfolds in the presence of testosterone or DHT. Ligand binding triggers nuclear translocation, aggregation, and toxic gain-of-function specifically in lower motor neurons of the brainstem and spinal cord, leading to the characteristic clinical picture of bulbar fasciculations, tongue atrophy, proximal weakness, and androgen insensitivity features (gynecomastia, erectile dysfunction, testicular atrophy). This is the only polyQ disease that is X-linked recessive. [Harrison 21e Ch 442; La Spada GeneReviews SBMA 2023]
Why each distractor is wrong
Option 2 (Chromosome 5q13; SMN1 deletion): This describes spinal muscular atrophy (SMA), an autosomal recessive condition with childhood or adolescent onset, not the X-linked Kennedy disease. SMA presents with proximal weakness but lacks the bulbar fasciculations, androgen insensitivity features, and adult-onset progressive course seen in this patient.
Option 3 (Chromosome 4; HTT CAG expansion): This describes Huntington disease, which is caused by CAG expansion in the HTT gene on chromosome 4. While both are polyQ diseases, Huntington presents with prominent movement disorder (chorea), cognitive decline, and psychiatric symptoms—not the lower motor neuron weakness, bulbar fasciculations, and androgen insensitivity seen here.
Option 4 (Chromosome 9; FXN GAA expansion): This describes Friedreich ataxia, caused by GAA repeat expansion in the frataxin gene on chromosome 9. It presents with cerebellar ataxia, cardiomyopathy, and scoliosis—not the motor neuron disease phenotype or androgen insensitivity features of Kennedy disease.
High-YieldNEET PG
Kennedy disease is the ONLY X-linked polyQ disease; it uniquely combines lower motor neuron weakness with androgen insensitivity (gynecomastia, ED, testicular atrophy) because the mutant AR protein misfolds in the presence of testosterone.
[Harrison 21e Ch 442; La Spada GeneReviews SBMA 2023]
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