Kennedy's disease

Definition

Kennedy's disease is a rare genetic neurodegenerative disorder that affects the motor neurons (cells that are important for normal function of the brain and spinal cord). It is a progressive disorder that leads to increasing severity of motor dysfunction and subsequent deterioration of muscle strength, muscle tone, and motor coordination. It was first described by the American physician William R. Kennedy in 1966.

Description

As Kennedy's disease is a progressive neurodegenerative disorder, affected individuals have physical, mental, and emotional impacts. Physically, the neurological degenerative process results in muscle weakness and eventual muscle wasting that can affect the patient's ability to walk or move. Kennedy's disease is also called spinal bulbar muscular atrophy, or SBMA, because both the spinal and bulbar neurons are affected.

Demographics

Kennedy's Disease is inherited through the X chromosome, and since males only have one X chromosome inherited from their carrier mother, they are usually affected while females are usually carriers. Therefore, sons of carrier mothers will be affected and all her daughters have a 50% chance of being a carrier. Although affected males often have a low sperm count or are infertile, if they are capable of reproducing, all male children will be unaffected and all female children will be unaffected carriers. In some cases, women who are carriers also exhibit clinical symptoms, although they are generally less severe. Kennedy's disease is a rare disease, with only one in 50,000 males affected and no particular pattern among various races or ethnic groups.

Causes and symptoms

Symptoms do not usually develop until between the second and fourth decades of life, although an earlier (and a later) age of onset have been documented. Symptoms initially are mild and include tremors while stretching hands, muscle cramps after exertion, and fasciculations (visible muscle twitches). Muscle weakness often develops in the arms and legs, beginning usually in the shoulder or midsection. It is most noticeable in the legs and the arms. Breathing, swallowing, and talking are functions that require bulbar muscles controlled by motor nerves that communicate with the brain. The effects of bulbar muscle dysfunction can be manifested by slurred speech and dysphagia (swallowing difficulties). In later stages, patients often develop aspiration pneumonia (pneumonia caused by food and fluids traveling down the bronchial tubes instead of the trachea due to poor ability to swallow).

Kennedy's disease is caused by a trinucleotide repeat expansion in the androgen receptor gene. This means that three letters in the DNA alphabet (cytosine-adenine-guanine, or CAG) that are normally repeated 10–36 times expand to produce a larger repeat size of approximately a 40–62 repeated trinucleotide sequence. This sequence is unstable and can change from one generation to the next leading to further expansions. The specific mechanism explaining how this trinucleotide repeat expansion (which leads to an increased length in the protein it encodes) causes the disease is unknown.

Diagnosis

Patients with Kennedy's disease usually receive a definitive diagnosis in a clinical molecular genetics laboratory. This requires DNA extraction from blood, followed by testing the gene that causes Kennedy's disease for a mutation. Kennedy's disease can be misdiagnosed as spinal muscular atrophy and Lou Gehrig's disease due to similar symptoms displayed.

Treatment team

The treatment team caring for a patient with Kennedy's disease includes a neurologist, physical therapists, occupational therapists, gastroenterologists, and genetic counselors.

Treatment

Although research efforts are underway, currently there is no treatment for Kennedy's disease. Medical treatment is based on lessening the symptoms. Physical therapy is useful in reducing the side affects from the progressive muscle weakness.

Recovery and rehabilitation

In the absence of a cure, patients usually do not recover and the symptoms progress during their lifetime. Lifestyle changes may become necessary, especially late in the disease. These changes, in more severe cases, can include (but are not limited to) help eating, wheelchair access at home, and help with using the restroom and changing clothes.

Prognosis

Kennedy's disease is a neurodegenerative disorder that is slow in its progression. It is likely that individuals will become wheelchair bound during the later stages of the disease. Although individuals will have certain difficulties in motor function and may have special needs, the lifespan of affected individuals is not thought to be shortened.

Special concerns

Genetic counseling is important in this disorder since the presence of one affected offspring means that it is likely the disease gene was inherited and that there is a risk that there will be affected offspring in subsequent generations. The possibility of infertility due to low sperm count should also be discussed during the counseling, especially in cases that develop early. Also, gynecomastia (enlarged breasts) in males due to reduced virilization can also have psychosocial consideration and need to be addressed. Erectile dysfunction and/or testicular atrophy may also affect males.

Resources

BOOKS

Cooper, D. N., M. Krawczak, and S. E. Antonarakis. "The Nature and Mechanisms of Human Gene Mutation." In The Metabolic and Molecular Basis of Inherited Disease, 7th ed. Edited by C. R. Scriver, A. L. Beaudet, W. S. Sly, and D. Valle. NY: McGraw-Hill, 1995.

Icon Group Publications. The Official Parent's Sourcebook on Spinal Muscular Atrophy: A Revised and Updated Directory for the Internet Age. San Diego: Icon Group International, 2002.

Panzarino, Connie. Me in the Mirror. Seal Press, 1994.

OTHER

"NINDS Kennedy's Disease Information Page." National Institute of Neurological Disorders and Stroke. (April 24, 2004). http://www.ninds.nih.gov/health_and_medical/disorders/kennedy's.htm.

"What Is Kennedy Disease?" Kennedy Disease Association. (April 24, 2004). http://www.kennedysdisease.org/about.html.

ORGANIZATIONS

National Organization of Rare Disorders. PO Box 8923, New Fairfield, CT 06812-8925. (203) 746-6518 or (800) 999-6673; Fax: (203) 746-6481. orphan@rarediseases.org. http://www.rarediseases.org.

Kennedy's Disease Association. PO Box 2050, Simi Valley, CA 93062-2050. (805) 577-9591. tswaite@pacbell.net. http://www.kennedysdisease.org/about.html.

Bryan Richard Cobb, PhD

Kennedy's disease
Classification and external resources
ICD-10	G12.1
ICD-9	335.1
OMIM	313200
DiseasesDB	7144
eMedicine	neuro/421
MeSH	D055534

Kennedy's disease (KD) or X-linked spinal and bulbar muscular atrophy (SBMA) or spinobulbar muscular atrophy^[1] or X-Linked bulbo-spinal atrophy^[2] is a neuromuscular disease associated with mutation of the androgen receptor (AR).^[3][4] Because of its endocrine manifestations related to the impairment of the AR, it can be viewed as a variation of the disorders of the androgen insensitivity syndrome (AIS). It is also related to other neurodegenerative diseases caused by similar mutations, such as Huntington's disease and the spinocerebellar ataxias. Kennedy's disease is named after W. R. Kennedy, a neurologist who was among the first to describe this disease.^[5]

Contents 1 Genetics 2 Pathophysiology 3 Signs and symptoms 3.1 Neuromuscular 3.2 Homozygous females 4 History 5 References 6 External links

Genetics

Kennedy's disease is inherited in an X-linked recessive pattern.

The androgen receptor gene that is mutated in Kennedy's disease is located on the X chromosome, and the effects of the mutation may be androgen-dependent, thus only males are fully affected. Females are rarely affected; female carriers tend to have a relatively mild expression of the disease if they show symptoms at all.

Pathophysiology

As reported in 1991, Kennedy's disease is caused by expansion of a CAG repeat in the first exon of the androgen receptor gene (trinucleotide repeats).^[6] The CAG repeat encodes a polyglutamine tract in the androgen receptor protein. The greater the expansion of the CAG repeat, the earlier the disease onset and more severe the disease manifestations. The repeat expansion likely causes a toxic gain of function in the receptor protein, since loss of receptor function in androgen insensitivity syndrome does not cause motor neuron degeneration. KD may share mechanistic features with other disorders that are caused by polyglutamine expansion, such as Huntington's disease. There is currently no treatment or cure for Kennedy's disease.

It is a lower motor neuron disease.^[7]

Signs and symptoms

Kennedy's disease patients have muscle cramps and progressive weakness due to degeneration of motor neurons in the brain stem and spinal cord.

Ages of onset and severity of manifestations in affected males vary from adolescence to old age, but most commonly develop in middle adult life. The latest onset was described in a male of 84 years of age. KD does not usually compromise longevity. The syndrome has neuromuscular and endocrine manifestations.

Neuromuscular

Early signs often include weakness of tongue and mouth muscles, fasciculations, and gradually increasing weakness of limb muscles with muscle wasting. In some cases, premature muscle fatigue begins in adolescence. Neuromuscular management is supportive, and the disease progresses very slowly and often does not lead to extreme disability.

Neurological:

• Bulbar signs: The bulbar muscles are those supplied by the motor nerves from the brain stem, which control swallowing, breathing, speech, and other functions of the throat. Bulbar signs are problems with these muscles.
• Lower motor neuron signs: The lower motor neurons are those in the brainstem and spinal cord that directly supply the muscles. Loss of lower motor neurons leads to weakness and wasting of the muscle.
• Primary sensory neuropathy: Loss of sensation and numbness, usually not noticeable.
• Intention tremor: Hand tremor with volitional effort.
• Normal Babinski (plantar) response: When the bottom of the foot is scraped, the toes bend down. An abnormal response would be an upward movement of the toes indicating a problem with higher level (upper) motor neurons.
• Decreased or absent deep tendon reflexes: When a doctor taps the knee with his hammer little or nothing happens.

Muscular:

• Fasciculations: Twitching of muscles when at rest.
• Cramps: Large muscle spasms.
• Muscular atrophy: Loss of muscle bulk that occurs when the lower motor neurons do not stimulate the muscle adequately.

Endrocrine

• Gynecomastia: Breast enlargement.
• Impotence
• Erectile dysfunction
• Reduced fertility
• Low sperm count
• Testicular atrophy: Testicles become smaller and less functional.

Miscellaneous Characteristics:

• Late onset: Patients usually develop symptoms in the late 30's or later.
• Slow progression: Nearly normal lifespan
• Symmetry of clinical signs: Muscles are usually affected symmetrically.

Homozygous females

Homozygous females, both of whose X chromosomes have a mutation leading to CAG expansion of the AR gene, have been reported to show only mild symptoms of muscle cramps and twitching. No endocrinopathy has been described.

History

This disorder was first described by Dr. William R. Kennedy in 1968.^[5] In 1991 it was recognized that the AR is involved in the disease process. The disease is probably more common than originally thought. A study in Scandinavia suggested a prevalence of 1.3/8,500 making KD the most common form of motor neuron disease in the specific area studied; nobody had been diagnosed before 1995. It has been suggested that some men with KD may be misdiagnosed to have amyotrophic lateral sclerosis (ALS, also Lou Gehrig's disease).

References

1. ^ spinobulbar muscular atrophy at Dorland's Medical Dictionary
2. ^ MeSH Bulbo-Spinal+Atrophy,+X-Linked
3. ^ Fischbeck KH, Lieberman A, Bailey CK, Abel A, Merry DE (June 1999). "Androgen receptor mutation in Kennedy's disease". Philos. Trans. R. Soc. Lond., B, Biol. Sci. 354 (1386): 1075–8. doi:10.1098/rstb.1999.0461. PMID 10434308. 
4. ^ Chen CJ, Fischbeck KH (2006). "Chapter 13: Clinical aspects and the genetic and molecular biology of Kennedy's disease". in Tetsuo Ashizawa; Wells, Robert V.. Genetic Instabilities and Neurological Diseases (Second ed.). Boston: Academic Press. pp. 211–222. ISBN 0-12-369462-0. 
5. ^ ^{a b} Kennedy WR, Alter M, Sung JH (July 1968). "Progressive proximal spinal and bulbar muscular atrophy of late onset. A sex-linked recessive trait". Neurology 18 (7): 671–80. PMID 4233749. 
6. ^ La Spada AR, Wilson EM, Lubahn DB, Harding AE, Fischbeck KH (July 1991). "Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy". Nature 352 (6330): 77–9. doi:10.1038/352077a0. PMID 2062380. 
7. ^ Merry DE (July 2005). "Animal models of Kennedy disease". NeuroRx 2 (3): 471–9. PMID 16389310. 

External links

• "Kennedy's Disease Association". http://www.kennedysdisease.org/index.html. Retrieved 2008-06-12. "for more information on Kennedy's disease" 
• "Taylor Lab Home". University of Pennsylvania. http://www.med.upenn.edu/taylor/. Retrieved 2008-06-12. "for information on Kennedy's Disease research" 
• Spinal Muscular Atrophy - Fight SMA

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v • d • e Sex linkage: X-linked disorders X-linked recessive Immune Chronic granulomatous disease (CYBB) · Wiskott-Aldrich syndrome · X-linked severe combined immunodeficiency · X-linked agammaglobulinemia · Hyper-IgM syndrome type 1 · IPEX · X-linked lymphoproliferative disease Hematologic Haemophilia A · Haemophilia B · X-linked sideroblastic anemia Endocrine Androgen insensitivity syndrome/Kennedy disease · KAL1 Kallmann syndrome · X-linked adrenal hypoplasia congenita Metabolic amino acid: Ornithine transcarbamylase deficiency · Oculocerebrorenal syndrome dyslipidemia: Adrenoleukodystrophy carbohydrate metabolism: Glucose-6-phosphate dehydrogenase deficiency · Pyruvate dehydrogenase deficiency · Danon disease/glycogen storage disease Type IIb lipid storage disorder: Fabry's disease mucopolysaccharidosis: Hunter syndrome purine-pyrimidine metabolism: Lesch-Nyhan syndrome mineral: Menkes disease Nervous system X-Linked mental retardation: Coffin-Lowry syndrome · Fragile X syndrome · MASA syndrome · X-linked alpha thalassemia mental retardation syndrome eye disorders: Color blindness (red and green, but not blue) · Ocular albinism (1) · Norrie disease · Choroideremia other: Charcot-Marie-Tooth disease (CMTX2-3) · Pelizaeus-Merzbacher disease · SMAX2 Skin and related tissue Dyskeratosis congenita · Hypohidrotic ectodermal dysplasia (EDA) · X-linked ichthyosis · X-linked endothelial corneal dystrophy Neuromuscular Becker's muscular dystrophy/Duchenne · Centronuclear myopathy (MTM1) · Conradi-Hünermann syndrome Urologic Alport syndrome · Dent's disease · X-linked nephrogenic diabetes insipidus No primary system Barth syndrome · McLeod syndrome · Simpson-Golabi-Behmel syndrome X-linked dominant X-linked hypophosphatemia · Focal dermal hypoplasia · Aicardi syndrome · Incontinentia pigmenti · Rett syndrome · CHILD syndrome · Lujan-Fryns syndrome

v • d • e Non-Mendelian inheritance: anticipation Trinucleotide repeat disorders Polyglutamine (PolyQ) Dentatorubral-pallidoluysian atrophy · Huntington's disease  · Kennedy disease · Spinocerebellar ataxia 1, 2, 3, 6, 7, 17 (Machado-Joseph disease) Non-Polyglutamine Fragile X syndrome · Friedreich's ataxia · Myotonic dystrophy type 1 · Spinocerebellar ataxia 8, 12 Four nucleotides Myotonic dystrophy type 2

v • d • e Genetic disorder: Receptor deficiencies Growth factor receptor FGFR1 Pfeiffer syndrome · KAL2 Kallmann syndrome FGFR2 Apert syndrome · Antley-Bixler syndrome · Pfeiffer syndrome · Crouzon syndrome · Jackson-Weiss syndrome FGFR3 Achondroplasia · Hypochondroplasia · Thanatophoric dysplasia TGF beta receptors Endoglin (Hereditary hemorrhagic telangiectasia) · TGFBR1/TGFBR2 (Loeys-Dietz syndrome) Hormone receptor Thyroid hormone receptor Thyroid hormone resistance Thyrotropin receptor CHNG1 congenital hypothyroidism Parathyroid hormone receptor Jansen's metaphyseal chondrodysplasia · Pseudohypoparathyroidism Androgen receptor Androgen insensitivity syndrome · Kennedy disease Estrogen receptor Estrogen insensitivity syndrome Growth hormone receptor Laron syndrome Mineralocorticoid receptor PHA1AD pseudohypoaldosteronism Anti-Müllerian hormone receptor Persistent Mullerian duct syndrome II · Familial hypocalciuric hypercalcemia Other Robinow syndrome

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