Kennedy disease

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Kennedy disease

Definition

Kennedy disease (KD) is a disorder characterized by degradation of the anterior horn cells of the spinal cord resulting in slow progressive muscle weakness and atrophy. Men with Kennedy disease often have breast enlargement (gynecomastia), testicular atrophy, and may have infertility.

Description

Kennedy disease, also referred to as spinobulbar muscular atrophy (SBMA), arises primarily from degradation of the anterior horn cells of the spinal cord, resulting in proximal weakness and atrophy of voluntary skeletal muscle. Anterior horn cells control the voluntary muscle contractions from large muscle groups such as the arms and legs. For example, if an individual wants to move his/her arm, electrical impulses are sent from the brain to the anterior horn cells to the muscles of the arm, which then stimulate the arm muscles to contract, allowing the arm to move. Degradation is a rapid loss of functional motor neurons. Loss of motor neurons results in progressive symmetrical atrophy of the voluntary muscles. Progressive symmetrical atrophy refers to the loss of function of muscle groups from both sides of the body. For example, both arms and both legs are equally affected by similar degrees of muscle loss and the inability to be controlled and used properly. Progressive loss indicates that muscle loss is not instantaneous, rather muscle loss occurs consistently over a period of time. These muscle groups include those skeletal muscles that control large muscle groups such as the arms, legs and torso. The weakness in the legs is generally greater than the weakness in the arms.

Proximal weakness is in contrast to distal weakness, and indicates that muscles such as the arms and the legs are affected rather than the muscles of the hands, feet, fingers, and toes. However, the motor neuron of the brainstem and sensory neurons of the dorsal root ganglia are also affected in KD. Motor neurons are the neurons that control large muscle groups (arms, legs, torso) of which anterior horn cells are a subgroup. Sensory neurons are a distinct class of neurons that control an individual's senses. An example would be pain receptors that cause an involuntary reaction to a stimuli such as when a person accidentally grasps a boiling hot kettle and immediately releases the kettle. Dorsal root ganglia are analogous to a headquarters for neurons, through which essentially all neuronal stimuli are processed.

Diagnosis

Kennedy disease is suspected clinically in a male with an early adulthood onset of proximal muscle weakness of the limbs, fasticulations (small local contractions of the musculature that is visible through the skin) of the tongue, lips or area around the mouth, absence of hyperactive reflexes and spasticity, and often evidence of enlarged breasts and/or small testes with few or no sperm.

The diagnosis is made by a specific molecular genetic test that measures the number of "repeats" in a particular part of the androgen receptor (AR) gene . The alteration of the AR gene that causes Kennedy disease is an expansion of a CAG trinucleotide repeat in the first PART of the gene. In unaffected individuals, between 11 to 33 copies OF the CAG trinucleotide are present. In patients with Kennedy disease, this number rises to 40 to 62. The greater the number of expanded repeats, the earlier the age of onset.

Genetic profile

Kennedy disease is an X-linked recessive disease, meaning the abnormal gene is found on the X chromosome and two copies of the abnormal gene must be present for the disorder to occur. Since males only inherit one X chromosome (the other is the Y chromosome) they will always express an X-linked disorder if the abnormal gene is on the X chromosome they receive. Females on the other hand inherit two X chromosomes . Even if one X chromosome contains the abnormal gene, the second X chromosome with a normal functioning gene can usually compensate for the other. Males lack the second X chromosome that may be able to mask the effect of the abnormal gene.

The disease was first characterized in 1968. The KD-determining gene, androgen receptor (AR), maps to the proximal long arm of the X-chromosome.

The AR protein is a member of the steroid-thyroid hormone receptor family and is involved in transcription regulation. Transcription regulation is the molecular process that controls the "reading" of the genetic DNA information and turning it into RNA which is the material which generates proteins.

Demographics

Because of the X-linked inheritance pattern of Kennedy disease, only males are affected by this disorder. Females may be carriers of the disease if they possess an abnormal gene on one of her X chromosomes. Due to the rare nature of this disease, and the fact that it may frequently be misdiagnosed as another form of neuromuscular disease, no particular race or ethnicity appears to be at greater risk than another.

Kennedy disease is primarily an adult disease, with an onset between the third and fifth decade of life. Once symptoms present, the disease is slowly progressive. In addition to neuronal cell loss, breast enlargement (gynecomatia), reduced fertility and testicular atrophy have also been reported in affected males.

Treatment and management

To date, there is not treatment for SBMA. However, there are possible mechanisms through which treatment could be developed. Gene therapy could be used for SBMA to replace the abnormal gene associated with SBMA with a copy carrying fewer CAG repeats. Currently this is not possible or available.

As the bulbar muscles of the face are affected, eating and swallowing can become difficult. Due to the weakening of the respiratory muscles, breathing can also be labored. It is therefore essential for patients to undergo chest physiotherapy (CPT). CPT is a standard set of procedures designed to trigger and aid coughing in patients. Coughing is important as it clears the patient's lungs and throat of moisture and prevents secondary problems, such as pneumonia.

As symptoms progress, patients may require a ventilator to aid breathing.

Prognosis

The majority of patients with SBMA have a normal life span. About 10% of older, severely affected patients with SBMA may die from pneumonia or asphyxiation secondary to weakness of the bulbar muscles.

Resources

BOOKS

Zajac, J.D., and H.E. MacLean. "Kennedy's Disease: Clinical Aspects." In Genetic Instabilities and Hereditary Neurological Diseases, edited by R.D. Wells and S.T. Warren. New York: Academic Press, 1998, pp. 87-100.

PERIODICALS

Crawford, T.O., and C.A. Pardo. "The Neurobiology of Childhood Spinal Muscular Atrophy." Neurobiology of Disease 3 (1996): 97-110.

Ferlini, A., et al. "Androgen Receptor CAG Repeat Analysis in the Differential Between Kennedy's Disease and Other Motoneuron Disorders." American Journal of Human Genetics 55 (1995): 105-111.

ORGANIZATIONS

Kennedy Disease (SBMA) Support Group. 1804 Quivira Road, Washington, KS 66968. (785) 325-2629. gryphon @grapevine.net. <http://www.geocities.com/HotSprings/Villa/1989>.

National Ataxia Foundation. 2600 Fernbrook Lane, Suite 119, Minneapolis, MN 55447. (763) 553-0020. Fax: (763) 553-0167. [email protected]. <http://www.ataxia.org/>.