Kennedy disease
Kennedy disease, also known as spinobulbar muscular atrophy (SBMA), is a progressive neuromuscular disorder primarily affecting males and caused by a specific genetic mutation involving a CAG repeat expansion in the androgen receptor gene on the X chromosome. This disorder is characterized by symptoms such as proximal muscle weakness, muscular atrophy, and mild androgen insensitivity, with onset typically occurring between the ages of 20 and 50. Although female carriers of the gene mutation usually remain asymptomatic, some may experience mild symptoms like muscle cramps and fatigue.
The inheritance pattern is X-linked recessive, meaning that males with a family history of Kennedy disease are at the highest risk for developing symptoms, while females generally do not exhibit the disease but can be carriers. Diagnosis is confirmed through clinical evaluation and genetic testing to assess the number of CAG repeats in the androgen receptor gene.
Management of Kennedy disease often involves physical therapy, rehabilitation services, and psychosocial counseling to help individuals cope with the progressive nature of the condition. While there are no known cures, ongoing research is exploring potential therapeutic agents aimed at mitigating symptoms and managing the disease's impact. Life expectancy for those affected is typically not significantly reduced, although they may require mobility assistance as the condition advances.
Kennedy disease
ALSO KNOWN AS: Kennedy’s disease; SBMA; spinobulbar muscular atrophy; spinal and bulbar muscular atrophy; X-linked spinobulbar muscular atrophy
DEFINITION Kennedy disease is a progressive neuromuscular disorder caused by a trinucleotide repeat expansion (CAG) on the X chromosome. Features include proximal muscle weakness, muscular atrophy, and mild androgen insensitivity.
Risk Factors
Since Kennedy disease is inherited in an X-linked recessive pattern, the largest risk factor for showing symptoms of disease is a male having a maternal history of Kennedy disease. Some families have passed the exclusively through the maternal line and have never had a liveborn male affected. De novo (spontaneous) mutations have not been observed; therefore, risks to families without a family history are very low.
Kennedy disease is described as a sex-limited disease, meaning that female carriers are not expected to be symptomatic. There have been reports of some female carriers having an increased occurrence of muscle cramps and fatigue.
Etiology and Genetics
Kennedy disease is caused by a polyglutamine (CAG) expansion in the androgen receptor (AR) gene on the X chromosome, at location Xq11-Xq12. Kennedy disease results when a male has more than thirty-five CAG repeats in the AR gene. The CAG expansion is believed to alter the AR protein structure to cause neuromuscular degeneration. The mechanism of expansion causing disease is not well understood. The AR protein is expressed in the brain, spinal cord, and muscle tissue.
Only males will be affected with Kennedy disease. Females carrying one X chromosome with the CAG expansion in the AR gene are unaffected carriers. All daughters of men with Kennedy disease will be unaffected carriers. All sons of men with Kennedy disease will be unaffected noncarriers. Daughters of carrier women will have a 50 percent risk of being carriers themselves, whereas sons of carrier women will have a 50 percent risk of being affected with Kennedy disease.
The CAG expansion seen in the AR protein in Kennedy disease is not believed to significantly expand in gametogenesis, as seen in other CAG repeat disorders. However, some cases of expansion have been documented. In general, the number of CAG repeats inversely correlates with the age of onset of symptoms including muscle weakness, difficulty climbing stairs, and wheelchair dependence. Therefore, a small amount of anticipation (increasing severity with subsequent generations) is expected. Also, males with more CAG repeats are expected to have an earlier age of diagnosis, as well as a more rapid progression of symptoms. However, this association can account for only 60 percent of the clinical variation in affected individuals. Therefore the number of CAG repeats in the AR gene cannot be used to predict age of onset or clinical severity of symptoms.
Symptoms
Neurologic symptoms typically begin between the ages of twenty and fifty. The first symptoms are usually difficulty walking, muscle cramps, and an intention tremor. As the disease progresses, symptoms worsen to include involvement of the bulbar muscles, and affected individuals typically have difficulty with speech articulation and swallowing. Approximately one-third of affected individuals will require a wheelchair as the disease progresses. Symptoms of androgen insensitivity are also seen, including gynecomastia, testicular atrophy, and reduced fertility. Some affected males have reported difficulty having children and inability to grow facial hair.
Screening and Diagnosis
Diagnosis is made by clinical exam and evaluation of family history. Functional muscle testing may help to make a diagnosis of Kennedy disease. A pattern of X-linked inheritance should be considered and other inheritance methods ruled out. Molecular to evaluate the number of repeats in the AR gene will confirm or rule out the diagnosis. Predictive testing of children and are generally not performed due to ethical implications of diagnosing a young person for an adult-onset condition.
Treatment and Therapy
Treatment includes physical therapy and rehabilitation services for the neuropathic and muscular symptoms. Strength testing and pulmonary function testing can be used as surveillance of disease progression. Psychosocial counseling may be helpful to affected individuals and family to learn coping skills for dealing with a diagnosis of a degenerative neuromuscular genetic disease. Genetic counseling is recommended for families with Kennedy disease to discuss natural history, surveillance, and risk to family members.
Most patients will require aid with walking as the disease progresses, including braces, walkers, or wheelchairs. Breast reduction surgery for gynecomastia is performed as needed. Supplementation of testosterone does not appear to overcome the androgen insensitivity; however, research studies are under way to determine its effectiveness.
Clinical trials have been undertaken on therapeutic agents that may help patients with Kennedy disease. One is a curcumin-based product called AJ201, which is designed to active cellular pathways and degrade the protein that causes Kennedy disease. The other is NIDO-361, which targets the gene mutation that leads to the androgen receptor issues responsible for Kennedy disease.
Prevention and Outcomes
Surveillance of disease progression and intervention services such as physical therapy may help alleviate symptoms or progression of disease. There are no other known risk factors that will mitigate the effect of the disease. Life expectancy is not expected to be reduced.
Bibliography
Jorde, Lynn B., John C. Carey, Michael J. Bamshad, and Raymond L. White. Medical Genetics. 3d ed. Philadelphia: Mosby, 2006.
"KD Research: Clinical Trials." Kennedy's Disease Association, kennedysdisease.org/kd-research/clinical-trials.html. Accessed 2 Sept. 2024.
Nance, M. A. “Clinical Aspects of CAG Repeat Diseases.” Brain Pathology 7 (1997): 881–900.
Nussbaum, Robert L., Roderick, R. McInnes, and Huntington F. Willard. Thompson and Thompson Genetics in Medicine. 7th ed. New York: Saunders, 2007.