AR – Kennedy Disease

X‐linked spinal and bulbar muscular atrophy (SBMA), also known as Kennedy disease, is an adult‐onset neuromuscular disorder caused by a CAG trinucleotide repeat expansion in the first exon of the androgen receptor gene (AR). Affected males develop progressive distal limb and bulbar muscle weakness, fasciculations, sensory neuropathy, gynecomastia and testicular atrophy. Female carriers are typically asymptomatic or show subclinical features, reflecting X‐linked recessive inheritance and variable penetrance ([PMID:12445917]; [PMID:14999487]).

Genetic analyses across more than 30 unrelated families have identified expanded CAG repeats (38–68 repeats) in over 200 male probands, with full segregation in multiple pedigrees and founder effects in Scandinavian populations ([PMID:2222245]; [PMID:10951525]). Segregation studies confirmed co-segregation of the expanded allele with disease in at least 45 affected males and demonstrated meiotic instability of the repeat ([PMID:9010714]).

The mode of inheritance is X-linked recessive, with obligate carrier mothers and clinically affected hemizygous males. Carrier females rarely manifest mild symptoms, and anticipation has been observed in successive generations. Recurrent founder haplotypes have been documented in northern European populations, consistent with a single ancestral event approximately 20 generations ago ([PMID:10951525]).

Functional studies in cell and animal models demonstrate that polyglutamine expansions in AR cause protein misfolding, intraneuronal aggregation and motor neuron toxicity. Transgenic mice expressing polyQ-expanded AR recapitulate motor deficits, neuronal pathology and sexual phenotype, and preventing the N/C terminal interaction delays disease onset ([PMID:14636160]; [PMID:26673324]). Cellular assays reveal that mutant AR exhibits abnormal ligand binding, reduced transcriptional activity and altered protein clearance, supporting a toxic gain-of-function mechanism.

No studies have refuted the role of AR CAG expansions in SBMA; clinical heterogeneity is attributed to repeat length and modifying factors. To date, no pathogenic missense or loss-of-function variants in AR outside the repeat tract have been linked to Kennedy disease, underscoring the specificity of the CAG expansion mechanism.

In summary, the association between AR and Kennedy disease is Definitive based on >30 families, >200 affected probands, consistent X-linked segregation and concordant functional data. The diagnostic utility of CAG repeat analysis is well established, enabling carrier detection, genetic counseling and prenatal diagnosis.

Key Take-home: AR CAG repeat expansion testing provides a definitive molecular diagnosis for Kennedy disease, guiding clinical management and familial risk assessment.

References

• Archives of neurology • 1990 • X-linked spinal muscular atrophy (Kennedy's syndrome). A kindred with hypobetalipoproteinemia. PMID:2222245
• Hormone research • 1997 • Molecular analysis of the androgen receptor gene in Kennedy's disease. Report of two families and review of the literature. PMID:9010714
• Neuropathology and applied neurobiology • 2003 • Protein aggregation in motor neurone disorders. PMID:14636160
• Cell reports • 2015 • Preventing the Androgen Receptor N/C Interaction Delays Disease Onset in a Mouse Model of SBMA. PMID:26673324

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