NORD gratefully acknowledges Joseph Kim, NORD Editorial Intern from the University of Notre Dame, and Albert La Spada, MD, PhD, FACMG, Professor of Neurology, Neurobiology, and Cell Biology; Director, Duke Center for Neurodegeneration & Neurotherapeutics; and Vice Chair, Department of Neurology; Duke University School of Medicine, for assistance in the preparation of this report.
Kennedy disease is a rare, X-linked slowly progressive neuromuscular disorder. Kennedy disease is typically an adult-onset disease, where symptoms occur mainly between the ages of 20 and 50. The disease is characterized by symptoms such as muscle weakness and cramps in the arms, legs, and facial area, enlarged breasts, and difficulty with speaking and swallowing (dysphagia). Kennedy disease affects fewer than 1 in 350,000 males and does not typically occur in females, who are protected by their low levels of circulating testosterone, accounting for the sex-limited inheritance pattern in this disorder. Treatment is symptomatic and supportive, and life expectancy is normal, though a small percentage of patients (~ 10%) succumb to the disease in their 60’s or 70’s due to swallowing complications (aspiration pneumonia, asphyxiation) resulting from the bulbar weakness. Kennedy disease is named after William R. Kennedy, MD, who described this condition in an abstract in 1966 and a full report in 1968.
Affected individuals begin to develop neurological symptoms between 20 to 50 years of age. These early symptoms include:
· Weakness/cramps in arm and leg muscles (proximal > distal)
· Face, mouth, and tongue muscle weakness
· Difficulty with speaking and swallowing (dysphagia)
· Twitching (Fasciculations)
· Tremors and trembling in certain positions
· Enlarged breasts (gynecomastia)
· Testicular atrophy
The disease affects the lower motor neurons that are responsible for the movement of many muscles in the legs, arms, mouth, and throat. Affected individuals will show signs of twitching, often in the tongue and/or hand, followed by muscle weakness and problems with facial muscles. These neurons, which connect the spinal cord to the muscles, become defective and die, so the muscles cannot contract. The destruction of these nerves is the main reason for the numbness, muscle weakness, and inability to control muscle contraction. With lack of normal neuromuscular function, a patient may experience hypertrophied calves in which the calf muscles thicken due to muscle cramps. In some cases, patients may also have one side of the body more affected than the other side.
The disease also affects nerves that control the bulbar muscles, which are important for breathing, speaking, and swallowing. Androgen insensitivity can also occur, sometimes beginning in adolescence and continuing through adulthood, characterized by enlarged breasts, decreased masculine appearance, and infertility. Patients may experience problems such as low sperm count and erectile dysfunction.
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.
Kennedy disease affects fewer than 1 in 350,000 males and is very rare in females. Kennedy disease has been diagnosed in the USA, Europe, Asia, South America, and Australia. The Japanese population appears to have a very high prevalence of Kennedy Disease because of a founder effect.
A diagnosis of Kennedy disease is suspected based on physical signs and symptoms, and sometimes family history. Diagnosis can be confirmed by molecular genetic testing on a blood sample for CAG trinucleotide repeat expansion in the AR gene. Individuals with greater than 36 CAG trinucleotide repeats in the AR gene are diagnosed with the condition.
Clinical Testing and Work-Up
Annual examinations to assess muscle strength may be appropriate.
Currently, there is no known treatment or cure for Kennedy disease. Physical therapy, occupational therapy, and speech therapy are commonly used to adapt to the progressing disease and maintain an individual’s skills. Braces, walkers, and wheel chairs are used for ambulation. Breast reduction surgery is sometimes used as needed in patients with gynecomastia. Testosterone is not an appropriate treatment, as it can make the disease worse.
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Contact for additional information about Kennedy disease:
Albert La Spada, MD, PhD, FACMG
Professor of Neurology, Neurobiology, and Cell Biology
Director, Duke Center for Neurodegeneration & Neurotherapeutics
Vice Chair, Department of Neurology
Duke University School of Medicine
Bryan Building, Room 401-E, DUMC 2900
Durham, NC 27710
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Barkhaus PE, Verman S. Kennedy Disease. Medscape. http://emedicine.medscape.com/article/1172604-overview Updated Jun 08, 2016. Accessed July 31, 2018.
NINDS Kennedy’s Disease Information Page. National Institute of Neurological Disorders and Stroke (NINDS). https://www.ninds.nih.gov/Disorders/All-Disorders/Kennedys-Disease-Information-Page Last updated June 15, 2018. Accessed July 31, 2018.
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Spinal and Bulbar Muscular Atrophy, X-Linked 1; SMAX1. Entry No: 313200. Last Edited 09/23/2010. Available at: http://omim.org/entry/313200 Accessed July 31, 2018.
Spinal and bulbar muscular atrophy . Genetics Home Reference. http://ghr.nlm.nih.gov/condition/spinal-and-bulbar-muscular-atrophy Reviewed December 2012. Accessed July 31, 2018.
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