Kennedy’s disease is associated with a defect in the androgen receptor (AR) gene, which provides instructions for the androgen receptor protein. This protein is found throughout the body, but there are high levels in the motor neurons, which are those involved in the control of voluntary muscles.
The mutation results in a section of the gene, called a CAG trinucleotide repeat, to become abnormally expanded. This causes the gene to be much longer than normal and results in an abnormally large protein with an altered structure to be produced.
The exact mechanism of how this causes damage to the nerve cells and leads to Kennedy’s disease is not fully understood. But it is thought that the abnormal protein may build up inside the cells until it disrupts their normal function and triggers their death.
Everyone has two copies of every chromosome apart from the sex chromosomes (the X and Y chromosomes). Females have two X chromosomes, while males have one X and one Y chromosome.
Kennedy’s disease is an X-linked disease, as the affected AR gene is located on the X chromosome. This means that if a woman carries a defective AR gene on one of her X-chromosomes, she most likely will not show any symptoms because the gene on the other X-chromosome can compensate. However, she has a 50 percent risk of passing the defective gene to her children. She, therefore, will have a 50 percent risk of having a son with Kennedy’s disease, and a 50 percent risk of having a daughter who, like herself, also is a carrier. This is why the disease affects many more men than women.
Females who carry a copy of the mutated AR gene also are predicted to produce less of the androgen receptor protein.
Kenndey’s disease is mainly associated with progressive, adult-onset, muscle weakness and wasting in the arms and legs. This commonly results in frequent cramps, as well as leg weakness, leading to difficulty walking and increased risk of falls. In later stages of the disease, patients may need to use a wheelchair to move around.
Kennedy’s disease also can cause weakness in the muscles of the face and tongue, resulting in difficultly speaking or swallowing. However, this tends to develop later in the course of the disease.
As the mutated gene affects the body’s response to androgens, which are hormones such as testosterone involved in male sexual development, the disease can have other symptoms including infertility, testicular atrophy (shrinkage), enlarged breasts, a low sperm count, and erectile dysfunction.
Kennedy’s disease is frequently misdiagnosed, as the initial symptoms can mimic many other disorders such as amyotrophic lateral sclerosis (ALS). Moreover, as the disease is rare, it may not be the first suspected cause of the symptoms.
To confirm the diagnosis, a genetic test to assess the number of CAG trinucleotide repeats in the AR gene is recommended. In general, Kennedy’s disease is associated with more than 36 CAG repeats being present in the AR gene.
Prevalence and life expectancy
It is estimated that Kennedy’s disease affects one in 40,000 people worldwide, with most of them being undiagnosed or misdiagnosed for years. Patients’ life expectancy is similar to that of unaffected individuals.
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