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. The disease causes progressive muscle loss with weakness, fasciculations, and cramps. Weakness of the bulbar muscles follows causing difficulties in speech (dysarthria) and swallowing (dysphagia). Female carriers do not show symptoms. Although there is no cure, supportive intervention can improve mobility and reduce complications. The prevalence of SBMA has been estimated at 2.6:100,000 males.
There is no known cure for SBMA. Muscle strength declines slowly, at a rate of approximately 2% per year based on quantitative muscle assessment. Muscle weakness often begins in proximal muscles, with most patients first noticing weakness in their lower limbs.
Tremor, fasciculations, and cramps are common early symptoms of SBMA. Tremor is an involuntary, somewhat rhythmic, muscle contraction and relaxation involving oscillations or twitching movements. 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.
Androgen insensitivity
Loss of AR function in SBMA patients results in partial androgen insensitivity, including gynecomastia, erectile dysfunction, decreased libido, infertility and testicular atrophy. One of the most disease-specific endocrine indices of SBMA is the androgen sensitivity index (luteinizing hormone / testosterone) which is elevated in 64% of cases, indicating both endocrine and exocrine testicular dysfunction. In a group of 22 patients with SBMA, evidence of fatty liver disease was detected in all individuals by magnetic resonance spectroscopy. In a second group, liver dome magnetic resonance spectroscopy measurements were increased in participants with SBMA relative to age- and sex-matched controls. SBMA patients may have higher frequency of Brugada syndrome and other electrocardiogram (ECG) abnormalities, which if not detected, can lead to sudden death. There are no reports of cardiomyopathy. However, there are indications that SBMA patients may be more likely to have high blood pressure and elevated total cholesterol and triglycerides. Muscle weakness was first noticed in the lower extremities (71%), upper extremities in (31%), bulbar symptoms (11%), and facial weakness (2%), with some patients observing initial muscle weakness simultaneously in two locations. The AR gene, located in the X chromosome, contains a CAG repeat that encodes a polyglutamine tract in the androgen receptor protein.
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. Individuals with longer CAG expansions reach ADL milestones earlier (handrail, cane, wheelchair, death) and eventually develop more severe disease manifestations.
Role of skeletal muscle in disease pathophysiology
SBMA has traditionally been considered primarily a disease of the motor neuron. Motor neurons degeneration is seen in the anterior horn of the spinal cord and brainstem, and electrophysiology studies show evidence of motor neuron dysfunction. However, several studies have suggested skeletal muscle plays an important role in SBMA pathophysiology.
Diagnosis
Diagnosis of SBMA is established by genetic testing that identifies a CAG trinucleotide repeat expansion in the AR gene.
Management
There is no known cure for SBMA. In a study with 8 SBMA patients, moderate-intensity exercise was not well tolerated, and exercise frequency was decreased prior to the end of the training program. Levels of creatine kinase (CK), a biomarker of muscle degeneration, were found to increase during intense exercise, indicating primary myopathy. In a study of home-based functional exercise with 50 SBMA patients, both the low-intensity exercise and stretching control groups tolerated exercise well, but there was no significant difference in primary and secondary outcomes between the two groups. 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. Onset of disease in mid-life and lack of symptoms in heterozygous female carriers was further described by Anita Harding in 1982. Several proteins key to normal cellular function have been found to be sequestered within these aggregates, including CREB-BP, Hsp70, Hsp40, and components of the ubiquitin proteasome system. Nuclear accumulation of polyglutamine androgen receptor was significantly reduced in patient scrotal biopsies. Additionally, serum CK, a marker of muscle deterioration, and testosterone levels were both reduced in patients receiving leuprorelin. 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. KDA has awarded grants and fellowships to researchers in the United States, Canada, Britain, Italy, and Japan to support both basic research and clinical trials on the causes and potential treatments for SBMA. 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. In 2022, the KDA Waite-Griffin Fellowship was established to encourage young researchers to include research on SBMA in their future career plans.