Bulbospinal Muscular Atrophy Congenital

Kennedy’s disease, SBMA, spinal-bulbar muscular atrophy, X-linked bulbospinal muscular atrophy, X-linked spinal and bulbar muscular atrophy, SMAX1, X-linked BSMA, X-linked bulbospinal amyotrophy.

Bulbospinal muscular atrophy is a rare genetic condition that primarily affects adult men, causing slow but steady muscle weakness that develops over decades.

Table of contents

• What is bulbospinal muscular atrophy?
• Signs and symptoms
• What causes this condition
• Who is affected
• How the condition is diagnosed
• Disease progression and life expectancy
• Treatment and management

What is bulbospinal muscular atrophy?

Bulbospinal muscular atrophy, also known as Kennedy’s disease, is a genetic disorder that affects the nerve cells that control muscle movement. These nerve cells, called motor neurons, are found in the spinal cord and in a part of the brain called the brainstem. When these motor neurons break down, the muscles they control become weak and waste away over time.^[1]

The name “Kennedy disease” honors Dr. William Kennedy, who first described this condition in 1968.^[1] The term “bulbospinal” refers to the specific areas affected. The word bulbar describes a bulb-like structure in the lower part of the brain that contains nerve cells controlling muscles in the face, mouth, and throat.^[1]

The condition is also sometimes called spinal-bulbar muscular atrophy, or SBMA for short. This disorder particularly affects the facial muscles, swallowing muscles, and the arm and leg muscles, especially those nearest the center of the body.^[1]

Signs and symptoms

Men with bulbospinal muscular atrophy typically begin experiencing symptoms between the ages of 30 and 50, though the disease may appear earlier or later in some people.^[3] Early signs often include difficulty walking, a tendency to fall, muscle cramps, muscle twitching, fatigue, and slurred speech.^[3]

As the disease progresses, affected people develop weakness and wasting in their limb muscles, particularly in muscles near the center of the body. Many will have difficulty climbing stairs.^[8] Muscle twitches, called fasciculations, are common and can be visible under the skin, especially in the face and tongue.^[2]

Most people with this condition eventually show problems with their bulbar muscles, which results in difficulty with speaking and swallowing. This can manifest as dysarthria (difficulty speaking clearly), dysphonia (voice problems), hanging jaw, tongue wasting, and chewing difficulty.^[3] Progressive problems with swallowing and speech develop as the facial and throat muscles become affected.^[4]

Tremor is an involuntary, rhythmic muscle contraction and relaxation. In people with this condition, tremor is most common in the hands but can also occur in the head, voice, and lower limbs. Tremor may be noticeable up to ten years before muscle weakness appears.^[6]

This condition also causes hormonal issues in men. Many affected men develop enlarged breasts, known as gynecomastia, and may experience reduced fertility, shrinking of the testicles, and difficulties with sexual function.^[2] These symptoms are related to abnormal processing of male hormones called androgens, which include testosterone.^[8]

In severe cases, affected people may be at risk for aspiration pneumonia, a lung infection caused by food or liquid entering the airways or lung. Lung failure due to weakness of the bulbar and breathing muscles is uncommon but can be life-threatening.^[8] In the terminal stages of the disease, some people may be unable to swallow or breathe without assistance.^[3]

What causes this condition

Bulbospinal muscular atrophy is caused by a genetic defect in the androgen receptor (AR) gene, which is located on the X chromosome.^[3] The AR gene contains a repeated sequence of DNA known as a CAG triplet repeat. Most people have fewer than 36 CAG repeats in their AR gene, leading to production of normal androgen receptor proteins.^[8]

People with this condition have an abnormal expansion of the number of CAG repeats in their AR gene, with at least 38 CAG repeats present. In affected individuals, the CAG segment may be repeated 40 to 62 times.^[3] This change is referred to as a “trinucleotide repeat expansion.”^[8]

The normal function of the androgen receptor is to help cells process male hormones like testosterone. The abnormally increased repetition of this CAG triplet leads to an expanded stretch of glutamines within the androgen receptor protein. This causes the protein to misfold and break down improperly.^[3]

These defective androgen receptor proteins cannot transport male hormones correctly. Additionally, fragments of the mutated protein accumulate in nerve cells and interfere with normal cell functions.^[4] The aggregates are believed to cause problems with how other proteins are produced, ultimately leading to motor neuron death.^[3]

Without a sufficient number of motor neurons, the body cannot properly start and maintain muscle contractions, leading to progressive muscle wasting.^[3] People with a higher number of CAG repeats tend to develop signs and symptoms at an earlier age.^[4]

Who is affected

This condition is inherited in an X-linked pattern, which means the defective gene is located on the X chromosome. Because males have only one X chromosome, they need only one copy of the mutated gene to develop the disease. Females have two X chromosomes, so they are rarely affected.^[4]

The condition primarily affects adult males. The estimated prevalence is approximately 1 in 30,000 to 1 in 40,000 males.^[3][7] It is very rare in females.^[4]

Females with a mutation in one copy of the AR gene in each cell are typically unaffected. However, a few females with mutations in both copies of the gene have had mild features related to the condition, including muscle cramps and occasional tremors. Female carriers who have one copy of this mutation can experience a mild form of the disease, particularly as they get older, around 60 to 70 years of age.^[2][4]

Affected males who are fertile pass the expanded CAG repeat to each daughter. Carrier females have a 50% chance of transmitting the genetic change to each child. Males who inherit it will be affected; females who inherit it will be carriers and will usually not be affected.^[2] A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.^[4]

How the condition is diagnosed

The condition should be suspected in adult males who show slowly progressive muscle weakness affecting the limbs or muscle cramps, along with bulbar problems like fasciculations of the tongue, lips, or around the mouth, difficulty speaking, and difficulty swallowing.^[2] Signs of androgen insensitivity, such as gynecomastia appearing during adolescence, are also suggestive.^[2]

A family history consistent with X-linked inheritance supports the diagnosis, though absence of a known family history does not rule it out.^[2] There is a general impression that the condition may be underdiagnosed, partly due to misdiagnosis and the mild symptoms some people show.^[5]

A standard physical examination can help diagnose a generalized neuromuscular disorder. A blood test for an enzyme called creatine kinase, which is found in deteriorating muscles, can determine the presence of muscle damage. Creatine kinase levels are usually elevated two to five times above normal.^[3][7]

Testing of nerve function, called electromyography, typically shows diffuse motor neuron involvement, often with sensory changes that may not cause symptoms.^[2] Blood tests may reveal elevated levels of testosterone, progesterone, follicle-stimulating hormone, and luteinizing hormone, along with reduced nerve conduction velocities.^[3]

Genetic testing confirms the diagnosis by identifying the expanded CAG repeat (more than 35 CAGs) in the AR gene.^[2] This testing can definitively identify the specific cause of muscle impairment.^[8]

The multidisciplinary assessment should check for involvement beyond the nervous system, such as heart rhythm abnormalities (including Brugada syndrome), signs of androgen resistance, problems with the urinary and reproductive systems, and metabolic changes like glucose intolerance and high cholesterol.^[15]

Disease progression and life expectancy

Bulbospinal muscular atrophy progresses very slowly, over the course of decades.^[1] The disease is gradually progressive, and muscle strength declines slowly, at a rate of approximately 2% per year based on muscle testing.^[6]

By one to two decades after symptom onset, most affected people will experience muscle weakness and wasting in their arm and leg muscles. About one-third of affected people will require a wheelchair 20 years after symptom onset.^[8]

Most people with this condition have a normal life expectancy, as the disease begins late in life and progresses relatively slowly compared to other forms of muscular atrophy.^[8] However, with earlier diagnoses and thorough supportive care, rehabilitation of muscle weakness is possible and can help prevent or delay muscle wasting. These factors are important for increasing the amount of time a person can walk as the disease progresses.^[8]

Treatment and management

There is currently no cure for bulbospinal muscular atrophy.^[1] Management is supportive and involves multiple healthcare specialists, with the goal of maintaining function, managing bulbar and breathing symptoms, and improving quality of life.^[10]

As the disease progresses, people may need braces and walkers to help with movement. Standard treatments are used for speech difficulties and swallowing problems. Some people with significant swallowing difficulties may require a feeding tube inserted into the stomach, called a gastrostomy.^[2][10]

Physical therapy is important to preserve strength and mobility. Speech and swallow therapy helps with bulbar problems. Nutritional support becomes necessary as needed.^[10] Respiratory function should be monitored, particularly in later stages of the disease.^[2]

For gynecomastia, breast reduction surgery may be performed if needed. Heart problems and metabolic syndrome are treated according to standard approaches by specialists. Annual assessment should include checking strength, mobility, daily activities, speech, and feeding issues.^[2]

Several anti-androgen therapies have been investigated, but clinical trials have not demonstrated consistent or meaningful benefits, and these therapies are not recommended for routine use.^[10] Importantly, testosterone therapy is not recommended, as research has shown that increasing male hormone levels can make disease progression worse.^[10]

Psychosocial support and education are important to decrease stress and burden on caregivers. Assessment of the need for family and caregiver support should be ongoing.^[2]

Carrier testing for at-risk female relatives and prenatal testing for a pregnancy at increased risk are possible if the expanded CAG repeat has been identified in an affected family member.^[2] Antenatal diagnosis is possible for mothers carrying the mutation.^[3]