Kennedy’s disease, also known as spinal and bulbar muscular atrophy (SBMA), is a rare neuromuscular disorder characterized by slowly progressive muscle weakness and atrophy (wasting). The condition is caused by a genetic mutation in the androgen receptor gene on the X chromosome. Kennedy’s disease only affects males, although females can be carriers of the mutated gene.
The disease typically begins in adulthood between ages 30-50, but onset can range from the teenage years to late 70s. The rate of progression varies considerably among individuals. Some will experience rapid decline in physical function, while others may have very slow disease progression over decades. There is currently no cure for Kennedy’s disease, but supportive treatments can help manage symptoms.
What causes Kennedy’s disease?
Kennedy’s disease is caused by a mutation in the androgen receptor gene on the X chromosome. This results in a toxic gain of function in the androgen receptor protein. The mutated receptors accumulate in nerve cells and cause neuronal degeneration.
The androgen receptor is activated by male sex hormones (androgens) like testosterone. Even though all men have androgens, only those with the genetic mutation will develop Kennedy’s disease. The mutated androgen receptors are hypersensitive and overaccumulate in response to normal androgen levels.
What are the symptoms?
The major symptoms of Kennedy’s disease include:
- Weakness and wasting (atrophy) of muscles, particularly in the arms, legs, and tongue.
- Fasciculations (involuntary twitches) of weakened muscles.
- Cramping and stiffness of muscles.
- Impaired speech and swallowing.
- Hand tremors.
Because Kennedy’s disease affects motor neurons, symptoms reflect the pattern of motor neuron loss. Early on, weakening often begins in the face, tongue, throat, hands, and feet. Facial muscles like the lips and jaw are frequently affected first.
As the disease advances, muscle weakness and atrophy spread to other areas like the neck, upper arms, and legs. Impaired swallowing and speech can occur from tongue and throat involvement. Hand grip strength diminishes over time.
Progression of muscle weakness
The rate and pattern of muscle weakening can vary significantly between individuals with Kennedy’s disease. However, the disease does tend to progress in a somewhat predictable pattern:
Early stage: Weakness often begins distally in the hands and lower legs/feet. Facial and tongue muscle involvement also frequently appears early. Patients may notice difficulty with fine motor skills like buttoning shirts or drooling from weak lip closure. Foot drop or tripping can occur.
Mid-stage: Weakness spreads proximally up the arms and legs in a patchy distribution. Shoulder and thigh muscles weaken. Patients begin having difficulty raising arms overhead or rising from a squat. Bulbar involvement worsens with dysarthria (slurred speech) and dysphagia (trouble swallowing).
Late-stage: Widespread and more severe muscle weakness. Upper arms and legs are significantly impacted. Use of a wheelchair and arm support may be required for mobility. Severe dysarthria and dysphagia increase choking risk. Respiratory muscles may weaken leading to pulmonary complications.
On average, patients lose about 5% of their muscle strength per year. However, the rate of decline is highly variable between individuals and does not always correlate with disease duration. Faster progression often occurs in those with earlier onset.
What muscles are affected?
Kennedy’s disease causes weakness and wasting of both upper motor neuron (UMC) and lower motor neuron (LMN) muscles.
Affected UMC muscles include:
- Bulbar muscles of the mouth and throat – leads to dysarthria and dysphagia
- Tongue – impacts speech and chewing
- Sternocleidomastoid – neck flexion weakness
- Hand intrinsic muscles – causes grip weakness
Affected LMN muscles include:
- Cranial nerves V, VII, IX, X, XII – bulbar involvement
- Cervical, thoracic, lumbar motor neurons
- Upper arms – biceps, triceps, deltoids
- Lower legs – tibialis anterior, gastrocsoleus
- Thighs – quadriceps, hamstrings
The pattern of UMN vs LMN involvement helps distinguish Kennedy’s disease from other motor neuron disorders like ALS that predominantly affect LMN.
Is the rate of progression correlated with age of onset?
Some studies have found a correlation between earlier disease onset and faster progression in Kennedy’s disease.
In one study of 89 patients, those with onset before age 30 declined nearly twice as fast compared to those with onset after age 50. The early onset group lost muscle strength at a rate of 9% per year versus 5% per year in the late onset group.
Another study found similar results:
- Onset
- Onset 20-39 years: 6.5% strength loss per year
- Onset ≥ 40 years: 2.6% strength loss per year
However, the correlation is not always consistent across studies. Other factors like genetics and lifestyle may also play a role in determining progression rates. The overall consensus is that earlier onset disease before age 40 portends faster progression on average.
Is progression faster in the bulbar or limb muscles?
Bulbar weakness tends to progress slower than limb weakness in Kennedy’s disease.
In one 5-year study, quantitative muscle testing showed greater decline in arm abduction strength (49%) compared to tongue protrusion strength (33%) over the follow-up period.
Another 10-year study found similar results:
- Tongue strength declined 37%
- Knee strength declined 62%
- Grip strength declined 71%
The more rapid deterioration in limb strength is thought to reflect earlier and more severe loss of lower motor neurons compared to upper motor neurons. Bulbar muscles retain more upper motor neuron innervation over the disease course.
However, bulbar involvement still predicts worse prognosis overall due to increased risk of choking and aspiration pneumonia. Difficulty managing oral secretions often arises well before loss of tongue strength.
What is the life expectancy?
Kennedy’s disease is not directly fatal, but complications from muscle weakness can lead to reduced life expectancy. With optimal supportive care, many patients have a normal or near-normal lifespan.
According to studies, average survival after symptom onset is:
- 15-20 years: Patients with onset age ≥ 45 years old
- 10-15 years: Patients with onset age 18-44 years old
- 5 years: Patients with onset before age 18
Younger onset patients tend to have faster progression, more severe bulbar and respiratory muscle involvement, and shorter survival. Later onset cases usually have slower progression and more years of retained mobility.
However, there can be significant variability in survival even for those of similar onset age. Rarely, very rapid decline leading to death within 5 years of onset does occur. On the other end, some patients live 40+ years after diagnosis.
Tracking progression
There are several methods used to track the progression of Kennedy’s disease over time. These include:
Quantitative muscle testing: Measures muscle strength of particular muscle groups like the arms, legs, or tongue at regular intervals. Results are compared over time. Hand-held dynamometry and quantitative bulbospinal testing are examples.
Functional rating scales: Assessments that score the patient’s ability to perform standard tasks of daily living. The higher the score, the more severe the impairment. Examples include the Spinal and Bulbar Muscular Atrophy Functional Rating Scale and Adult Myopathy Assessment Tool.
Timed functional tests: Time how long it takes to complete tasks like walking a 6 minute distance or climbing 4 stairs. Increased time reflects declining function.
Pulmonary function tests: Spirometry and maximal inspiratory/expiratory pressure measurements to monitor for respiratory muscle involvement.
Speech analysis: Programs can detect changes in speech volume, pitch, hoarseness, and articulation.
Swallowing studies: Modified barium swallow exams and fiberoptic endoscopic evaluation assess swallowing impairment over time.
Tracking progression with quantitative data can help guide the use of rehabilitative or assistive devices and predict loss of future milestones.
Factors affecting progression rate
The rate of Kennedy’s disease progression can be influenced by several factors:
Genetic profile: The specific type of androgen receptor mutation may impact disease severity. Those with CAG repeat lengths > 40 tend to have earlier onset and faster progression.
Androgen levels: Higher cumulative lifetime exposure to androgens (testosterone) may promote more rapid progression.
Age of onset: Earlier onset disease before age 40 is associated with faster progression on average.
Lifestyle factors: Obesity, disuse/inactivity, smoking, and poor diet may hasten progression. Regular exercise and therapy can help maintain function.
Comorbidities: Coexisting medical conditions like diabetes, heart disease, and hypertension may negatively impact muscle function.
Injuries: Traumatic injuries from falls, accidents, or overuse can exacerbate weakness.
However, two patients of similar age and genetics can still have very different rates of progression. The variability highlights our incomplete understanding of all factors that modify the disease course.
Can anything slow the progression?
Unfortunately, there are no proven disease-modifying treatments yet available that can significantly slow the progression of Kennedy’s disease. Current management focuses on symptom control and preserving quality of life. However, research is ongoing into potential therapies that may provide future benefit:
Androgen deprivation: Blocking androgens like testosterone that stimulate the mutated receptors may help slow neurodegeneration. Medications like leuprorelin, bicalutamide, dutasteride, and ketoconazole are being studied.
Gene silencing: Reducing production of the defective androgen receptors could alleviate their toxic effects. Treatments targeting the AR gene like antisense oligonucleotides are under investigation.
Neuroprotection: Experimental drugs that support motor neuron health like riluzole, nuedexta, and IGF-1 analogs have demonstrated modest effects in small trials. Larger studies are needed.
Stem cell therapy: Introducing healthy stem cells may help replace damaged motor neurons and slow disease progression. Currently only available through clinical trials.
While a disease-modifying treatment remains elusive, maintaining activity through rehabilitation and assistive devices can help slow functional decline. Monitoring for complications and optimizing nutritional status are also important. Genetic counseling is advised for family planning. Continued research provides hope for future therapies to alter the course of Kennedy’s disease.
Conclusion
Kennedy’s disease involves gradual, progressive muscle weakness and atrophy resulting from degeneration of motor neurons. While the average rate of decline is estimated at around 5% per year, there is significant individual variability in speed of progression.
Onset before age 40, particularly in the teenage years, portends a more rapidly progressive course on the order of 6-10% annual strength loss. Later onset cases tend to progress more slowly with about 2-5% annual decline. Weakness typically starts distally and proximally ascends. Bulbar involvement develops later but predicts greater mortality.
Tracking quantitative strength and functional assessments helps characterize the progression over time. Multiple factors including genetics, androgen levels, injuries, comorbidities, and lifestyle impact the rate of decline. Currently no disease-modifying treatments are proven to significantly slow the progression of Kennedy’s disease, but optimizing symptomatic management and physical activity can help prolong mobility and quality of life. Ongoing research provides hope for the future.