Spinal and bulbar muscular atrophy (SBMA), popularly known as Kennedy's disease, is a debilitating neurodegenerative disorder resulting in muscle cramps and progressive weakness due to degeneration of motor neurons in the brainstem and spinal cord and muscle wasting.[5][6]
The condition is associated with mutation of the androgen receptor (AR) gene[7][8] and is inherited in an X-linked recessive manner. As with many genetic disorders, no cure is known, although research continues. Because of its endocrine manifestations related to the impairment of the AR gene, patients with SBMA develop partial symptoms of androgen insensitivity syndrome (AIS) in addition to neuromuscular degeneration. SBMA is related to other neurodegenerative diseases caused by similar mutations, such as Huntington's disease.[9] The prevalence of SBMA has been estimated at 2.6:100,000 males.[10]
Signs and symptoms
Individuals with SBMA have muscle cramps and progressive weakness due to degeneration of motor neurons in the brain stem and spinal cord. Ages of onset and severity of manifestations in affected males vary from adolescence to old age, but most commonly develop in middle adult life. The syndrome has neuromuscular and endocrine manifestations.[6]
Neuromuscular
Early signs often include weakness of tongue and mouth muscles, fasciculations, and gradually increasing weakness of limb muscles with muscle wasting. Neuromuscular management is supportive, and the disease progresses very slowly, but can eventually lead to extreme disability.[11] Further signs and symptoms include:
- Bulbar signs: bulbar muscles are those supplied by the motor nerves from the brain stem, which control swallowing, speech, and other functions of the throat.[4]
- Lower motor neuron signs: lower motor neurons are those in the brainstem and spinal cord that directly supply the muscles, loss of lower motor neurons leads to weakness and wasting of the muscle.[4]
- Respiratory musculature weakness[4]
- Action tremor[4]
- Babinski response: when the bottom of the foot is scraped, the toes bend down (an abnormal response would be an upward movement of the toes indicating a problem with higher-level (upper) motor neurons).[12]
- Decreased or absent deep tendon reflexes [4]
Muscular
- Cramps: muscle spasms[4]
- Muscular atrophy: loss of muscle bulk that occurs when the lower motor neurons do not stimulate the muscle adequately[4]
Endocrine
- Gynecomastia: male breast enlargement[13]
- Erectile dysfunction[13]
- Reduced fertility[13]
- Testicular atrophy: testicles become smaller and less functional[14]
Other
- Late onset: individuals usually develop symptoms in their late 30s or afterwards (rarely is it seen in adolescence) [4]
Homozygous females
Homozygous females, both of whose X chromosomes have a mutation leading to CAG expansion of the AR gene, have been reported to show only mild symptoms of muscle cramps and twitching. No endocrinopathy has been described.[14]
Genetics
SBMA is a hereditary syndrome, inherited in an X-linked recessive manner.[7] The AR gene, located in the X chromosome, contains a tract of CAG repeats within the region coding for the N-terminal domain.[6] The number of repeats varies among individuals. Healthy males carry up to 34 repeats. From 35 to around 46 repeats, penetrance (the possibility that the individual manifests the disease) gradually increases, approaching a maximum value (full penetrance).[10] Therefore, males bearing 35 to 46 CAG repeats are at intermediate but increasing risk for developing SBMA. Males bearing 47 or more repeats have nearly 100% risk of developing SBMA.[10] Other, still unidentified genetic factors may also play a role in disease manifestation and symptoms’ severity. Genetic founder effects are likely to be responsible for the higher prevalence of SBMA observed in certain geographic regions.[15]
Pathophysiology
SBMA is caused by expansion of a CAG repeat in the first exon of the androgen receptor gene (trinucleotide repeats).[16][17] The CAG repeat encodes a polyglutamine tract in the androgen receptor protein.[18][16] Patients with longer CAG expansions tend to develop more severe disease manifestations and earlier disease onset. The repeat expansion likely causes a toxic gain of function in the receptor protein, since loss of receptor function in androgen insensitivity syndrome does not cause motor neuron degeneration.[19]
Spinal and bulbar muscular atrophy may share mechanistic features with other disorders caused by polyglutamine expansion, such as Huntington's disease.[18] For example, the polyglutamine expanded androgen receptor is known to misfold and aggregate.[20] This aggregation of the mutant protein is dependent on the presence of testosterone, the ligand for the androgen receptor.[20] As a result, though female carriers of the CAG repeat expansion express the polyglutamine androgen receptor protein, due to lower levels of testosterone they do not develop disease.[16] Similarly, in animal models of SBMA castration dramatically reduces disease phenotype.[20] Polyglutamine expansion of the androgen receptor has a number of known cellular and molecular consequences, including disrupting cellular signaling pathways, protein homeostasis, and cellular trafficking.[21][20]
Diagnosis
Diagnosis of SBMA is based on identifying the number of CAG repeats in the AR gene using molecular techniques such as PCR. The accuracy of such techniques is nearly 100%.[7]
Prognosis
A 2006 study followed 223 patients for up to twenty years. Of these, 15 died, with a median age of 65 years. The authors tentatively concluded that this is in line with a previously reported estimate of a shortened life expectancy of 10–15 years (12 in their data).[22] Greater than fifty percent of individuals with SBMA develop lower limb weakness.[23] Weakness most often begins between the age of 30 and 60.[16] Weakness typically becomes severe enough to necessitate a wheelchair about twenty years following the onset of symptoms.[16]
Management
In terms of the management of spinal and bulbar muscular atrophy, no cure is known and treatment is supportive. Rehabilitation to slow muscle weakness can prove positive, though the prognosis indicates some individuals will require the use of a wheelchair in later stages of life.[24] Preferred nonsurgical treatment occurs due to the high rate of repeated dislocation of the hip.[13] No cure for SBMA is known.[25][17][16]
History
SBMA was first described in Japanese literature in 1897 by Hiroshi Kawahara in a case report detailing progressive bulbar palsy in two brothers.[23][16] Information on the clinical course, X-linked inheritance patterns, and key pathologic features was later documented by William R. Kennedy in 1968.[5] Onset of disease in mid-life and lack of symptoms in heterozygous female carriers was further described by Anita Harding in 1982.[16] In 1986, the causative gene of SBMA was shown to be present on the proximal arm of the X chromosome by Kurt Fischbeck,[23] though the exact gene causing SBMA had not yet been characterized. In 1991, it was discovered that the AR gene is involved in the disease process, and that expansion of a CAG repeat in the AR gene causes disease.[7]
Research
Research in SBMA is broad, and covers a number of aspects of the disorder. Below is a summary of a few areas of ongoing research in SBMA:
Aggregation
The polyglutamine androgen receptor does not fold properly, and subsequently forms protein aggregates with other proteins. This is a gain of new function conferred by the polyglutamine tract, as the non-polyglutamine expanded androgen receptor does not form these aggregates.[26] 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.[20] It is thought that loss of sufficient supply of these and other key proteins contributes to the pathogenesis of the disease, though further research is ongoing.[26]
Post-Translational Modifications
Following it's transcription and translation, the androgen receptor is modified with a number of post-translational modifications, including phosphorylation, methylation, acetylation, and SUMOylation. The polyglutamine androgen receptor has been found to have different levels of some these post-translational modifications.[20] Further, altering the levels of certain post-translational modifications of the mutant androgen receptor has altered the degree of toxicity in cellular and animal models, suggesting they may be a target for further research and therapeutic development.[20]
Role of Skeletal Muscle in Disease
Several studies have suggested skeletal muscle plays an important role in the pathophysiology of SBMA in animal models.[26] Mice which express the polyglutamine androgen receptor in all tissues were shown to develop progressive neuromuscular degeneration mimicking SBMA, however, when the mice were genetically manipulated to express the protein in all tissues except skeletal muscle, muscle atrophy, neuromuscular degeneration, and survival were significantly improved.[26] 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.[26] However, when administered intrathecally into the CNS, disease was not rescued.[26]
Clinical trials
Leuprorelin
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.[20] A small pilot study was performed in which five SBMA patients were given subcutaneous injections of leuprorelin every four weeks for six months, with serial scrotal skin biopsies performed.[27] 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.[27] Notably, in this study patients were not randomized to treatment groups or placebo controlled.[27]
A subsequent larger study consisted of fifty SBMA patients randomized to either leuprorelin treatment or placebo. This trial spanned 48 weeks of treatment with treatment occurring every four weeks initially. Following treatment, thirty-four patients had an open-label follow-up spanning an additional ninety-six weeks with treatment continuing every twelve weeks.[20][28] 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.[27][28] There was improvement in swallowing a barium contrast marker, a secondary endpoint of the study, at forty-eight weeks.[27] Further, there was improvement in the ALS functional rating scale at the 96 and 144 week marks, suggesting a longer period may be needed to see effects of leuprorelin.[27]
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. The study spanned forty-eight weeks with leuprorelin treatment every 12 weeks, with ability to swallow a barium contrast marker as the primary endpoint.[27][20] In this study, there was not a significant difference in barium swallow at forty-eight weeks.[27][28] There was also no difference in other videofluorography measurements, supporting the lack of improvement in swallow function in the treatment group.[27] Other secondary measures, such as number of AR positive scrotal cells and serum CK level were significantly different in the treatment group.[27] Though the primary endpoint of the study did not show an effect of leuprorelin on SBMA patients, a subgroup analysis performed on patients who had symptoms for ten years or less did show improved swallowing function, and it was suggested that treatment may be more effective in patients who have shown symptoms for shorter periods of time or with less advanced disease.[27]
A recent follow-up open-label study compared thirty-six patients treated with leuprorelin to nontreated controls over eighty four months, and found that the treated group showed slower decline in motor function than the non-treated group.[20] Significantly differing endpoints of this study included the ALS Functional Rating Scale, the Limb Norris Score, and the Norris Bulbar Score.[20]
Dutasteride
Dutasteride is a 5α-reductase inhibitor which blocks the conversion of testosterone into dihydrotestosterone. Dihydrotestosterone binds to androgen receptor more avidly, and inhibiting conversion of testosterone into dihydrotestosterone reduces overall androgen receptor activation. Fifty patients were recruited to a randomized, placebo controlled trial spanning two years, with a primary endpoint of quantitative muscle assessment.[27] No significant difference was found in quantitative muscle assessment between the placebo and dutasteride groups at the two year mark.[27] Secondary outcomes including barium swallow and manual muscle testing also showed no significant difference between groups.[20]
Exercise
A small pilot study was performed on eight SBMA patients evaluating the effects of exercise.[27][29] Patients performed thirty minute training sessions on a stationary bicycle with increasing frequency per week (two sessions per week in weeks 1–2, three sessions per week in weeks 3–4, and five sessions per week for weeks 5–12).[27] No significant changes in the primary endpoint VO2max, the maximum oxygen uptake which is a marker of endurance and fitness, were found following the exercise regimen.[27]
A larger study was conducted in 2015 including 50 SBMA patients randomized to exercise or a stretching-only program for twelve weeks.[20][29] The adult myopathy assessment tool was used as the primary endpoint of the study.[20] Secondary endpoints included muscle strength, quality of life score, balance, and IGF-1 levels.[20] No significant differences were found between the primary endpoint or secondary endpoints of the study.[27] However, subgroup analysis did show benefit for low-functioning groups, suggesting there may be a role for exercise in these patients.[20]
BVS857
IGF-1, a signaling molecule downstream of growth hormone, has well established functions promoting skeletal muscle growth.[20] In preclinical studies on mouse models of ALS, IGF-1 was shown to be protective against motor neuron death.[20] A double blind, placebo-controlled clinical trial was performed with eighteen SBMA patients receiving BVS857, a mimetic of IGF-1, with nine placebo controls.[20] The study found increased thigh muscle volume improved lean body mass following 12 weeks of treatment in the BVS857 group compared to placebo.[20] However, eleven of eighteen patients were found to have an immune response against BVS857, with five patients developing neutralizing antibodies, posing a challenge for long-term treatment.[20]