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.
In males, the disease slowly progresses over decades with bulbar and lower motor neuron loss, muscle denervation, and direct skeletal muscle involvement. 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. Supportive care is focused on preventing disease complications and maintaining independence.
Signs and symptoms Neuromuscular symptoms include muscle weakness and wasting of the limb, bulbar and respiratory muscles, tremor, fasciculations, muscle cramps, speech and swallowing difficulties, decreased or absent deep tendon reflexes, and sensory neuropathy. Other manifestations of SBMA include androgen insensitivity (gynecomastia, erectile dysfunction, reduced fertility, testicular atrophy), and metabolic impacts (glucose resistance, hyperlipidemia, fatty liver disease).
Neuromuscular effects SBMA patients develop limb weakness which often begins in the pelvic or shoulder regions between 30 and 50 years of age. 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. Fasciculation, or fleeting muscle twitches visible under the skin, is a spontaneous, involuntary muscle contraction and relaxation, and is especially noticeable in the face and tongue of SBMA patients. Lingual atrophy occurs later in the course of the disease, but the tongue may develop an unusual shape due to coexisting denervation and reinnervation. A cramp is a sudden, involuntary, painful skeletal muscle contraction of skeletal muscle, and common in motor neuron disorders.
Bulbar symptoms (weakness of the facial and tongue muscles) typically follow limb manifestations and may start with difficulty with speech articulation (dysarthria) before swallowing difficulty (dysphagia). 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. Signs of dysphagia include difficulty controlling solids, liquids or saliva in the mouth, coughing and choking. As the disease progresses, there is increased risk of aspiration pneumonia, which is the leading cause of death in SBMA patients. 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. Laryngospasms are often followed by a high-pitched breathing sound (stridor) due to rapid and vigorous contraction of the laryngeal sphincters. This is a frightening and hugely distressing experience, but rarely escalates to prolonged or serious episodes.
In SBMA, deep tendon reflexes are diminished or absent. Sensory involvement results in degeneration of dorsal root ganglion cells with reduced vibratory sensation (distally in the legs), neuropathic pain, and numbness. 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.
Androgen insensitivity Loss of AR function in SBMA patients results in partial androgen insensitivity, including gynecomastia, erectile dysfunction, decreased libido, infertility and testicular atrophy. Patients with complete androgen insensitivity syndrome do not show symptoms of SBMA, indicating neuromuscular symptoms are not caused by a loss of AR function.
Gynecomastia, excessive enlargement of male breasts, is observed in about three quarters of SBMA patients. It typically becomes apparent after puberty, and is often the first evidence of this disease. Erectile dysfunction, decreased libido, infertility and testicular atrophy are common. 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.
Metabolic disturbances Metabolic disturbances have also been reported in SBMA patients, with increased risk of insulin resistance, fatty liver disease, hyperlipidemia, and electrocardiogram (ECG) abnormalities. Impaired glucose homeostasis is a common feature of SBMA, and recent study found a significant correlation between insulin resistance and motor dysfunction in SBMA. 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.
Natural history Progression of muscle weakness is slow, with an approximately 2% decrease in muscle strength by quantitative muscle testing (QMT) per year.
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. 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. Hand tremor was noticed first (median age: 33 years), followed by muscular weakness (median = 44 years), need for handrail to ascend stairs (49 years), dysarthria (50 years), dysphagia (54 years), use of a cane (59 years), and wheelchair use (61 years). Twenty-one patients developed pneumonia (median age: 62 years) and 15 of them died (median = 65 years). The most common cause of death in these cases was pneumonia and respiratory failure. There was considerable variation in the age of onset for each milestone, often varying by 25 to 30 years between the 10th to 90th percentile ranges. The ages at onset of each ADL milestone were strongly correlated with the length of CAG repeats in the AR gene. However CAG-repeat length did not correlate with the time intervals between each ADL milestone, suggesting that the rate of disease progression does not correlate with CAG-repeat length. The average time interval between muscle weakness and handrail use was 5–6 years, between weakness and cane use was 9–11 years, between weakness and wheelchair use was 12–13 years, and between weakness and death was 10–20 years.
Mechanism
Molecular mechanism SBMA is caused by a trinucleotide repeat expansion in the first exon of the androgen receptor (AR) gene. The AR gene, located in the X chromosome, contains a CAG repeat that encodes a polyglutamine tract in the androgen receptor protein. The tract normally varies from about 11 to 33 repeats; however, in SBMA patients, the tract contains 38 to 68 CAG repeats. The expanded series of CAG repeats in SBMA results in production of a toxic androgen receptor protein with an expanded polyglutamine tract called polyQ-AR. 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.
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. CAG repeat numbers account for about 60% of the observed variation in motor disability, indicating other factors may play important roles disease progression.
The mechanisms which lead to neurodegeneration in SBMA are not fully understood. In SBMA, polyQ-AR misfolds and aggregates, leading to formation of nuclear inclusions (NIs) and diffuse accumulation of AR in the nucleus. This aggregation of the mutant protein is dependent on the presence of testosterone, the ligand for the androgen receptor. Female carriers of SBMA express polyQ-AR are generally asymptomatic or manifest only mild symptoms, due to lower levels of testosterone. Similarly, in animal models of SBMA castration dramatically reduces disease phenotype. Toxicity is believed to occur through multiple cellular mechanisms including transcriptional dysregulation, mitochondrial dysfunction, disruption of protein homeostasis and cellular signaling pathways, as well as autophagy.
SBMA is member of a group of diseases caused by polyglutamine expansion, including Huntington's disease and six types of spinocerebellar ataxia. Common characteristics of polyglutamine (or polyQ) diseases is the accumulation of polyQ proteins and the progressive degeneration of nerve cells, usually affecting people later in life. However different polyQ-containing proteins damage different subsets of neurons, leading to different symptoms.
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. Myogenic abnormalities in patient muscle include atrophic and morphologically abnormal muscle fibers, fiber-type grouping, and centralized nuclei. Serum creatine kinase (CK) levels are much higher than would be expected for a purely neurogenic disease.
In animal studies, 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. 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. However, when administered intrathecally into the CNS, disease was not rescued.
Inheritance