Kennedy disease is caused by a change (mutation) in the AR gene that encodes for a protein known as the androgen receptor on the X chromosome. The instructions within every gene consist of different arrangements of four basic chemicals (nucleotide bases) called adenine (A), cytosine (C), guanine (G), and thymine (T). Individuals with the disease have an abnormal section in the AR gene, which is due to an excessive number of CAG trinucleotide repetitions in the DNA sequence. An unaffected individual has 10-35 CAG repeats in the AR gene while a person with Kennedy disease has more than 36 CAG repeats in the gene.
The androgen receptor is in the cytoplasm of a cell where it responds to signals from male sex hormones (androgens). These receptors are abundant in many body tissues such as the skin, kidney, prostate, skeletal muscle, and the central nervous system motor neurons in the spinal cord and brainstem. In an unaffected person, the androgen hormone will bind to the receptor, and then the hormone-receptor complex will translocate into the nucleus, where it will signal genes to increase protein production for various functions.
In Kennedy disease, the exact mechanism for neuronal impairment is unknown, but it has to do with an altered functioning of the mutant androgen receptor.
Kennedy disease is an X-linked genetic disorder that occurs primarily in males. Very rarely, female carriers of the abnormal gene may show symptoms.
Normal females have two X chromosomes, in which one is an activated chromosome and the other is inactivated. Female carriers for Kennedy disease typically do not show symptoms because the androgen receptor must bind to its ligand, testosterone, to translocate to the nucleus and perform its functions. As females have low circulating levels of testosterone, Kennedy disease female carriers do not activate their mutant androgen receptors, thus rendering the mutant state of the androgen receptor protein innocuous. Males have only one X chromosome and will develop Kennedy disease if they inherit the X chromosome containing the disease gene. Affected males with X-linked disorders will always pass the gene to their daughters, but will only pass their normal Y chromosome to their sons. Therefore, all of the daughters of an affected male will be carriers for the disease, while sons of an affected male will not have the disease. Sons of female carriers have a 50 percent chance of inheriting the disease, while daughters have a 50 percent chance of becoming carriers.