Kennedy's Disease Pathophysiology

Kennedy’s disease is a rare genetic disease that affects the spinal and bulbar neurons. It causes muscle weakness and atrophy in the body, particularly in the legs and legs, arms, face and throat. Initial symptoms typically present between the ages of 30 and 50, and males tend to be more prone to symptoms of the condition than females.

In individuals with the disease, the motor neurons that extend from the spinal cord to the muscular cells become dysfunctional and necrotic, disabling the ability to contract the muscles as normal.

Androgen Receptor Protein

The androgen receptor protein is a ligand-dependent transcriptional factor that is found abundantly on motor neurons, in addition to many other areas of the body. Kennedy’s disease is thought to be associated with a mutation in the polyglutamine repeat expansion of the receptor. The exact mechanism of how this mutation causes motor dysfunction and other symptoms of the disease is not currently known, although both loss and gain of function is capable of leading to symptoms.

Animal models of the androgen receptor protein mutation have suggested that androgen hormones play a role in the neurotoxic mechanisms of the disease. In particular, the testosterone hormone is thought to be pivotal as females are affected to a lesser degree and the symptoms of males tend to improve upon castration.

Androgen receptor antagonists, such as leuprorelin, inhibit the accumulation of mutant androgen receptors and have been shown to prevent motor dysfunction in studies of mice. Supporting this notion, a case study of a male patient that was prescribed testosterone therapy for osteoporosis prevention initiated symptoms with treatment and subsided when the medication was ceased.

As a result of this research, it is believed that testosterone is necessary for the pathophysiology of Kennedy’s disease and the development of neurotoxic effect. This is likely to occur via translocation of the mutated receptor into the cell nucleus where is aggregates or changes the transcriptional activity.

Nerve Transmission and Symptoms

A disruption in the transmission of nerve cell signals is responsible for the symptoms exhibited in individuals with Kennedy’s disease. Initial symptoms include tremor when the hands and arms are extended, muscle cramps and muscle twitching. This occurs due to the abnormality in the signal transmission of the motor neurons that are responsible for the movement of these areas of the body.

As the disease progresses, limb weakness can develop in the pelvic region, shoulders, facial muscles and tongue. This is caused by the progressive changes in the nerve transmission, specifically related to the androgen receptor protein.

Recessive Inheritance

Kennedy’s disease is an x-linked genetic disease that follows a recessive inheritance pattern. The mother of affected individuals is thought to carry the defective gene on one of the X chromosomes.  

Although female children may be carriers of the gene mutation and disease, they do not usually experience symptoms due to the low levels of androgen receptor protein on their motor neurons. On the other hand, male children may inherit the gene mutation if the mother is a genetic carrier and are likely to experience symptoms.

References

• http://www.medmerits.com/index.php/article/kennedy_disease/P5
• http://emedicine.medscape.com/article/1172604-overview#a5
• http://www.kennedysdisease.org/index.php/about-kennedys-disease/what-is-kennedys-disease
• http://www.ninds.nih.gov/disorders/kennedys/kennedys.htm