Kennedy disease is an adult form of spinal muscular atrophy, the distinctive feature of which is a slow and relatively favorable course. It is manifested by a combination of sluggish paresis of the proximal muscle groups of the extremities, bulbar syndrome and endocrine disorders. Diagnostic search is carried out using electroneuromyography, muscle biopsy studies, genealogical analysis, DNA diagnostics, androgen profile assessment. Symptomatic therapy: metabolic, hormonal agents, beta-agonists, therapeutic gymnastics, massage.
G12.1 Other hereditary spinal muscular atrophy
Kennedy disease (bulbospinal muscular atrophy) is a genetically determined rare pathology of the nervous system, accompanied by endocrine disorders. It owes its name to the American neurologist V. Kennedy, who first described it in detail in 1968. It is inherited recessively linked to the X chromosome. Along with scapuloperoneal, distal, monomelic, oculopharyngeal muscular atrophy, in clinical neurology Kennedy disease refers to adult forms of spinal amyotrophy. Her debut takes place after the age of 40.
According to world statistics, the prevalence is at the level of 25 cases per 1 million people. At the end of the twentieth century, only 10 verified familial cases of bulbospinal amyotrophy were registered in the USA. Such a rarity may be associated with insufficiently accurate diagnosis, as a result of which the disease is treated as amyotrophic lateral sclerosis.
The genetic substrate of the disease is the expansion (increase in the number of repeats) of the CAG triplet (cytosine-adenine-guanine) in the androgen receptor gene localized at the Xq21-22 site of the long arm of the X chromosome.
The inheritance of bulbospinal amyotrophy linked to the X chromosome causes the incidence of predominantly male individuals. A woman can get sick if she inherits one defective X chromosome from her mother, and the second one from her father. However, in women, Kennedy disease has a milder course, severe cases are rare, a subclinical form is possible.
The core of pathogenesis consists of degenerative changes in the nuclei of the brainstem and the anterior horns of the spinal cord. As a result of a genetic mutation, the pathologically altered androgen receptor protein is located not in the cell nucleus, but in the cytoplasm. Due to the resistance of the mutant protein to the action of proteolytic enzymes of lysosomes, it begins to accumulate in large quantities, has a cytotoxic effect and disrupts the function of mitochondria, thereby causing the death of motor neurons of the spinal cord and neurons of the nuclei of the medulla oblongata.
Due to the defect of innervation and neurotrophy of muscles, their gradual atrophy occurs a second time. The lesion of the trunk leads to the development of bulbar syndrome and occurs 10-20 years after the appearance of peripheral paresis associated with damage to the spinal motor neurons of the anterior horns. Also, mutations in the receptor lead to a decrease in its sensitivity to male sex hormones (testosterone, dihydrotestosterone) – changes in reproductive function develop (testicular atrophy, fertility decline), disorders of lipid and protein metabolism (decrease in muscle mass, obesity, decrease in bone mineral density).
The manifestation of the disease usually occurs in the period from 40 to 50 years. It is characterized by a beginning with slowly progressive weakness in the proximal parts of the limbs: in the shoulders and hips. Paresis is accompanied by fascicular twitching, muscle hypotension, atrophy of muscle tissue, extinction of tendon reflexes; gradually spread somewhat distally. The sensitive sphere remains intact. There are no pathological pyramidal signs.
10-20 years after the debut, perioral fasciculations, bulbar manifestations (dysphagia, dysphonia, dysarthria), fasciculations and atrophic changes in the language occur. Joint contractures may form. Fasciculations of the perioral musculature act as a marker of bulbospinal amyotrophy. They are rapid involuntary contractions of the muscles located around the mouth, leading to twitching of the corners of the mouth or pulling the lips with a tube.
Kennedy disease is often accompanied by endocrine pathology. Gynecomastia, decreased libido, impotence, testicular atrophy are observed in sick men. About a third are diagnosed with male infertility associated with azoospermia. Diabetes mellitus is noted in 30% of cases. Symptoms of hypogonadism and signs of feminization are manifested against the background of normal blood testosterone levels and are most likely due to a defect in androgen receptors, which consists in their insensitivity to male hormones.
Despite the genetic nature of the disease and the damage to the central nervous system, due to the late manifestation and slow progression, serious life-threatening complications with Kennedy disease are rare. The most frequent adverse (erectile dysfunction, primary infertility) consequences are associated with low sensitivity to testosterone.
Frequent falls due to muscle weakness and osteoporosis increase the risk of pathological fractures. Extremely rarely, in severe situations, due to atrophy of the pharyngeal muscles and respiratory muscles, food may enter the respiratory tract (aspiration) and respiratory failure. Some people are diagnosed with breast cancer.
Patients with Kennedy disease are under the joint supervision of a neurologist and an endocrinologist. During the general examination of the patient, attention is drawn to a decrease in muscle tone, weakening of tendon reflexes, pseudohypertrophy of the calf muscles. Additional examination methods include:
- Laboratory tests. In the biochemical analysis of blood, an increase in the concentration of glucose, glycated hemoglobin, creatine phosphokinase, hepatic transaminases (ALT, AST) is noted. Despite the pronounced hypogonadism in the clinical picture, the level of testosterone in the blood is normal or even slightly elevated. In the analysis of urine, glucosuria and an increase in relative density are detected.
- EMG. During needle electromyography, an increase in the average duration, average and maximum amplitude of action potentials is detected. Muscle fibrillation potentials can be registered.
- Histology. Histological examination shows neuroaxonal degeneration in the spinal cord, necrosis of myofibrils in the muscles, proliferation of connective and adipose tissue.
- Genetic research. A DNA test is considered a verification diagnostic method. with the help of polymerase chain reaction, an increase in the number of repeats (CAG) is detected in the androgen receptor gene.
Differential diagnosis is performed with other neurodegenerative diseases affecting muscles:
- progressive becker muscular dystrophy;
- Werdnig-Hoffman amyotrophy;
- amyotrophic lateral sclerosis.
A distinctive feature of bulbospinal amyotrophy is a combination of motor neuron damage and endocrine pathology of the male genital sphere (hypogonadism).
All patients must be hospitalized in a neurological hospital. To date, there are no treatments that can prevent degenerative processes in nerve cells. All areas of therapy are symptomatic. Patients with impaired carbohydrate metabolism (diabetes mellitus, decreased glucose tolerance) are recommended to follow a carbohydrate-restricted diet.
Regular physical therapy and massage sessions help to slow the progression of atrophy in the muscles. The following medications are used for the treatment of bulbospinal amyotrophy of Kenned:
- Metabolic agents. To improve metabolism in nervous and muscular tissue, nootropics (piracetam, gamma-aminobutyric acid), L-carnitine, drugs that improve mitochondrial function (coenzyme Q10, succinic acid) are prescribed.
- Insulin and hypoglycemic drugs. In the case of diabetes mellitus, insulin and synthetic antidiabetic agents are added to the treatment – biguanides (metformin), sulfonylureas (glibenclamide) derivatives.
- Testosterone. The question of using testosterone as hormone replacement therapy remains open. On the one hand, it is necessary to combat hypogonadism, on the other hand, it can worsen the patient’s condition by increasing the stimulation of pathological receptors.
- Antiandrogens. Taking into account the probable role of testosterone in motor neurone damage, the appointment of drugs that reduce its production (leuprorelin, dutasteride) or blocking androgen receptors (flutamide) is pathogenetically justified.
- Clenbuterol. Recent studies have shown that the use of the beta-adrenergic receptor agonist Clenbuterol for the treatment of Kennedy disease has shown efficacy in reducing muscle weakness in patients.
The prognosis of Kennedy’s amyotrophy is relatively favorable. Due to the slow flow, patients retain the ability to move and self-care. Life expectancy is not less than in the general population. However, due to hormonal disorders, there is an increased likelihood of developing malignant neoplasms, in particular, breast cancer in men.