Spinal and bulbar muscular atrophy, also known as Kennedy disease, is a disorder of specialized nerve cells that control muscle movement (motor neurons). These nerve cells originate in the spinal cord and the part of the brain that is connected to the spinal cord (the brainstem).

Spinal and bulbar muscular atrophy mainly affects males and is characterized by muscle weakness and wasting (atrophy) that usually begins in adulthood and worsens slowly over time. Muscle wasting in the arms and legs results in cramping; leg muscle weakness can also lead to difficulty walking and a tendency to fall. Certain muscles in the face and throat (bulbar muscles) are also affected, which causes progressive problems with swallowing and speech. Additionally, muscle twitches (fasciculations) are common. Some males with the disorder experience unusual breast development (gynecomastia) and may be unable to father a child (infertile).

Kennedy's disease is an inherited motor neuron disease that affects males. It is one of a group of disorders called lower motor neuron disorders, which involve disruptions in the transmission of nerve cell signals in the brain to nerve cells in the brain stem and spinal cord.

Onset of the disease is usually between the ages of 20 and 40, although it has been diagnosed in males from their teens to their 70s.

Early symptoms include:

• Tremor of the outstretched hands
• Muscle cramps with exertion
• Fasciculations (fleeting muscle twitches visible under the skin)

Eventually, individuals develop limb weakness which usually begins in the pelvic or shoulder regions. Weakness of the facial and tongue muscles may occur later in the course of the disease and often leads to dysphagia (difficulty in swallowing), dysarthria (slurring of speech), and recurrent aspiration pneumonia. Some individuals develop gynecomastia (excessive enlargement of male breasts) and low sperm count or infertility. Others develop non-insulin-dependent diabetes mellitus.

Kennedy's disease is an x-linked recessive disease, which means the female parent carries the defective gene on one X chromosomes. Female children of people with Kennedy's disease are also carriers and have a 50 percent chance of having a male child affected with the disease. Parents with concerns may wish to talk to a genetic counselor.

Currently, there is no known cure for Kennedy's disease. Treatment is symptomatic and supportive. Physical therapy and rehabilitation to slow muscle weakness and atrophy may prove helpful.

Kennedy's disease is slowly progressive. Individuals tend to remain ambulatory until late in the disease, although some may use mobility devices such as wheelchairs during later stages. The life span of individuals with Kennedy's disease is usually normal.

Spinal and bulbar muscular atrophy results from a particular type of mutation in the AR gene. This gene provides instructions for making a protein called an androgen receptor. This receptor attaches (binds) to a class of hormones called androgens, which are involved in male sexual development. Androgens and androgen receptors also have other important functions in both males and females, such as regulating hair growth and sex drive.

The AR gene mutation that causes spinal and bulbar muscular atrophy is the abnormal expansion of a DNA segment called a CAG triplet repeat. Normally, this DNA segment is repeated up to about 36 times. In people with spinal and bulbar muscular atrophy, the CAG segment is repeated at least 38 times, and it may be two or three times its usual length. Although the extended CAG region changes the structure of the androgen receptor, it is unclear how the altered protein disrupts nerve cells in the brain and spinal cord. Researchers believe that a fragment of the androgen receptor protein containing the CAG segment accumulates within these cells and interferes with normal cell functions. The nerve cells gradually die, leading to the muscle weakness and wasting seen in this condition. People with a higher number of CAG repeats tend to develop signs and symptoms of spinal and bulbar muscular atrophy at an earlier age.

Normal Function

The AR gene provides instructions for making a protein called an androgen receptor. Androgens are hormones (such as testosterone) that are important for normal male sexual development before birth and during puberty. Androgen receptors allow the body to respond appropriately to these hormones.

The receptors are present in many of the body's tissues, where they attach (bind) to androgens. The resulting androgen-receptor complex then binds to DNA and regulates the activity of androgen-responsive genes. By turning the genes on or off as necessary, the androgen receptor helps direct the development of male sexual characteristics. Androgens and androgen receptors also have other important functions in both males and females, such as regulating hair growth and sex drive.

In one region of the AR gene, a DNA segment known as CAG is repeated multiple times. This CAG segment is called a triplet or trinucleotide repeat. In most people, the number of CAG repeats in the AR gene ranges from fewer than 10 to about 36.

Health Conditions Related to Genetic Changes

Androgen insensitivity syndrome

Hundreds of different variants (also called mutations) in the AR gene have been identified in people with androgen insensitivity syndrome, a condition that affects sexual development before birth and during puberty. Most of these variants are changes in single DNA building blocks (base pairs). Other variants insert or delete multiple base pairs in the gene or affect how the gene is processed into a protein. Some variants lead to an abnormally short version of the androgen receptor protein, while others result in the production of an abnormal receptor that cannot bind to androgens or to DNA.

As a result of these changes, cells that are normally sensitive to androgens become less responsive to these hormones or unable to use these hormones at all. People with this condition are genetically male, with one X chromosome and one Y chromosome in each cell. Because their bodies are unable to respond to androgens, they may have mostly female sex characteristics or signs of both male and female sexual development.

Variants that eliminate the function of the androgen receptor cause complete androgen insensitivity syndrome. Genetic changes that significantly reduce but do not eliminate the receptor's activity cause partial androgen insensitivity syndrome. Variants that only slightly reduce the activity of the receptor cause mild androgen insensitivity syndrome.

Spinal and bulbar muscular atrophy

Spinal and bulbar muscular atrophy, a disorder of specialized nerve cells that control muscle movement (motor neurons), results from an expansion of the CAG trinucleotide repeat in the AR gene. Instead of the typical 10 to 36 repeats, CAG is repeated from 38 to more than 60 times in people with this disorder. Although the extended CAG region changes the structure of the androgen receptor, it is unclear how the altered protein damages nerve cells. Researchers believe that a fragment of the androgen receptor protein containing the CAG repeats accumulates within these cells and interferes with normal cell functions. This buildup leads to the gradual loss of motor neurons, which results in muscle weakness and wasting (atrophy).

Androgenetic alopecia

Changes in the AR gene are associated with an increased risk of androgenetic alopecia, a form of hair loss also known as male pattern baldness in men and female pattern hair loss in women. The variations change the number or order of DNA building blocks (base pairs) that make up the AR gene. These genetic changes appear to be most frequent in men with hair loss that begins at an early age. Researchers believe that AR gene variations may increase the activity of androgen receptors in the scalp. Although androgenetic alopecia is related to the effects of androgens on hair growth, it remains unclear how changes in the AR gene increase the risk of hair loss in people with this condition.

Polycystic ovary syndrome

MedlinePlus Genetics provides information about Polycystic ovary syndrome

Prostate cancer

MedlinePlus Genetics provides information about Prostate cancer

Other Names for This Gene

• AIS
• ANDR_HUMAN
• androgen receptor (dihydrotestosterone receptor; testicular feminization; spinal and bulbar muscular atrophy; Kennedy disease)
• DHTR
• HUMARA
• KD
• NR3C4
• SBMA
• SMAX1
• TFM

Genomic Location

This condition is inherited in an X-linked pattern. A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome, one of the two sex chromosomes. In males (who have only one X chromosome), a mutation in the only copy of the gene in each cell causes the disorder. In most cases, males experience more severe symptoms of the disorder than females (who have two X chromosomes). Females with a mutation in one copy of the AR gene in each cell are typically unaffected. 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. Researchers believe that the milder signs and symptoms in females may be related to lower androgen levels.

A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

Yes. Therapies for Kennedy disease under investigation have included:

• High-dose testosterone - At least one clinical trial of high-dose oral testosterone has been undertaken, and no significant benefit was seen for the androgen treatment group. Based on research in Drosophila and mouse models, many researchers believe that androgen treatment can be harmful.
• Anti-androgen therapy - There is no consensus or clear evidence as to whether anti-androgen therapy is an effective treatment for the neurologic complications of Kennedy disease. However, anti-androgen therapy shows promise based on studies in Drosophila and mouse models as well as knowledge of the molecular basis of Kennedy disease.
• Creatine supplementation - Recent studies of amyotrophic lateral sclerosis (ALS) suggest that creatine supplementation may temporarily enhance muscle strength and exercise performance, prompting speculation that it may offer a similar benefit to people with Kennedy disease; however, this remains to be tested.
• Experimental therapies in animal models - Some interventions have been shown to be beneficial in mouse models; these studies have suggested that muscle-directed therapies hold great promise as treatments for Kennedy disease.

This condition affects fewer than 1 in 150,000 males and is very rare in females.