Spinal and bulbar muscular atrophy (SBMA), popularly known as Kennedy's disease, is a rare, adult-onset, X-linked recessive lower motor neuron disease caused by trinucleotide CAG repeat expansions in exon 1 of the androgen receptor (AR) gene, which results in both loss of AR function and toxic gain of function.

Other manifestations of SBMA include androgen insensitivity (gynecomastia, erectile dysfunction, reduced fertility, testicular atrophy), and metabolic impacts (glucose resistance, hyperlipidemia, fatty liver disease).

In SBMA patients, tremor is most common in the hands, but also occur in the head, voice and lower limbs, and may be observed ten years prior to muscle weakness.

[3][5][11] Dysarthria is common, with hypernasality due to incomplete lifting of soft palate, but typically remains relatively mild and seldom leads to the loss of oral communication.

[3] Up to half of all patients experience laryngospasm, an uncontrolled contraction (spasm) of the vocal folds, with a sense of choking, and feel that the air cannot enter or exit the airways for long seconds.

Sensory involvement results in degeneration of dorsal root ganglion cells with reduced vibratory sensation (distally in the legs), neuropathic pain, and numbness.

[11] There are sporadic reports of certain psychological traits (lack of self-confidence, emotional flattening, and poor concentration), but detailed neuropsychological examination of 64 SBMA patients did not detect any abnormalities.

[3][14] Loss of AR function in SBMA patients results in partial androgen insensitivity, including gynecomastia, erectile dysfunction, decreased libido, infertility and testicular atrophy.

[3][15] Metabolic disturbances have also been reported in SBMA patients, with increased risk of insulin resistance, fatty liver disease, hyperlipidemia, and electrocardiogram (ECG) abnormalities.

In a second group, liver dome magnetic resonance spectroscopy measurements were increased in participants with SBMA relative to age- and sex-matched controls.

[11][12] The most extensive dataset on disease progression is a study of 223 Japanese patients where milestones in nine activities of daily living (ADL) was observed for up to 20 years.

[20] Multiple studies have demonstrated that in SBMA, CAG repeat length inversely correlates with the age of symptom onset, but not with the rate of disease progression.

[3][11][21][18][22] Individuals with longer CAG expansions reach ADL milestones earlier (handrail, cane, wheelchair-bound, death) and eventually develop more severe disease manifestations.

[8] CAG repeat numbers account for about 60% of the observed variation in motor disability, indicating other factors may play important roles disease progression.

Female carriers of SBMA express polyQ-AR are generally asymptomatic or manifest only mild symptoms, due to lower levels of testosterone.

[11] In animal studies, mice which express the polyglutamine androgen receptor in all tissues were shown to develop progressive neuromuscular degeneration mimicking SBMA.

[24] Further, treatment of mouse models of SBMA with antisense oligonucleotides targeting the polyglutamine androgen receptor reduced disease burden when administered subcutaneously though they could not cross the blood brain barrier.

Levels of creatine kinase (CK), a biomarker of muscle degeneration, were found to increase during intense exercise, indicating primary myopathy.

[11] In a third study, high-intensity interval training (HIIT) for less than one hour per week, improved both VO2max and performed workload, without increasing CK levels, self-rated fatigue and pain.

[27][30] Overall, these results suggest that exercise programs should be individually tailored, and SBMA patients must be carefully monitored for maladaptive biomarkers (increasing CK levels) to prevent muscle damage and worsening of disease phenotypes.

[24] Several proteins key to normal cellular function have been found to be sequestered[clarification needed] within these aggregates, including CREB-BP, Hsp70, Hsp40, and components of the ubiquitin proteasome system.

[24] Following its transcription and translation, the androgen receptor is modified with a number of post-translational modifications, including phosphorylation, methylation, acetylation, and SUMOylation.

[11] Leuprorelin, a GnRH agonist which blocks the synthesis of testosterone when given continuously, was initially shown to be effective at improving motor function in mouse models of SBMA.

[11][10] At the forty-eight week mark, there was no significant difference in the ALS functional rating scale, the primary outcome measure of the study, between placebo and leuprorelin treated groups.

[28] A larger, multi-center, placebo-controlled, double blind study was then conducted which contained 199 SBMA patients who were randomized to either placebo or leuprorelin treatment.

[28] Other secondary measures, such as number of AR positive scrotal cells and serum CK level were significantly different in the treatment group.

Fifty patients were recruited to a randomized, placebo controlled trial spanning two years, with a primary endpoint of quantitative muscle assessment.

[11] The study found increased thigh muscle volume improved lean body mass following 12 weeks of treatment in the BVS857 group compared to placebo.

[11] In 2000, the Kennedy's Disease Association[32][33][34] was founded by Susanne and Terry Waite and Patrick Griffin to help find effective treatments and a cure for SBMA.

[35] The KDA website states that they focus on providing "seed-money" to post-doc and other young researchers to start working on SBMA, collecting preliminary data that can be used to support larger proposals to governmental and philanthropic organizations.