Pathophysiological Mechanisms and Clinical Phenotypes of Kennedy Syndrome

Review Article

Abstract

Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy syndrome, is a rare X-linked neuromuscular disorder characterized by the progressive degeneration of lower motor neurons in the brainstem and spinal cord. The disease etiology originates from an unstable CAG trinucleotide repeat expansion within the first exon of the androgen receptor (AR) gene, resulting in an elongated polyglutamine tract. This mutation confers a toxic gain-of-function to the androgen receptor protein, which aggregates within the nucleus of motor neurons and muscles in a ligand-dependent manner, necessitating the presence of circulating androgens for phenotypic expression. Clinical presentation typically manifests in adult males during the fourth or fifth decade of life, encompassing proximal muscle weakness, bulbar palsy, fasciculations, and distinct endocrine disturbances such as gynecomastia and reduced fertility, reflecting a state of mild androgen insensitivity. Recent investigations have shifted the paradigm from a purely neuron-centric view to a broader neuromuscular perspective, implicating skeletal muscle as a primary site of toxicity. Current therapeutic options remain largely supportive, though elucidating the molecular cascades of transcriptional dysregulation, mitochondrial dysfunction, and impaired axonal transport has identified novel targets for disease-modifying interventions. This review discusses about molecular advances with clinical observation to delineate the current state of SBMA research