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Kennedy disease

This is part of Rare diseases.

Diagnosis: Kennedy disease

Synonyms: Spinal bulbar muscular atrophy, X-linked; SBMA

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Publication date: 2012-11-30
Version: 3.0 

The disease

Kennedy disease is an inherited neuromuscular disease characterised by slowly progressive wasting and weakening of the muscles. The disease almost exclusively affects males. The disorder was first described in 1968 by American neurologist William R. Kennedy. Since then, some thirty different names have been used to describe the condition, including spinobulbar muscular atrophy (SBMA) and X-linked spinobulbar neuronopathy.

Kennedy disease in many ways resembles another neurodegenerative disease known as amyotrophic lateral sclerosis or ALS (see separate information in the Rare Disease Database of the Swedish Board of Health and Welfare). However, Kennedy disease has a significantly slower progression, and it is therefore important to distinguish between the two diagnoses.

Occurrence

In Sweden only a few dozen individuals have been diagnosed with Kennedy disease. According to the international medical literature the prevalence is approximately 3 individuals per 100,000 population. A relatively high prevalence of Kennedy disease (15 per 100,000) has been reported from Vaasa in Western Finland. As the disease is rare and the symptoms may be mild, it is likely that there are more individuals with the condition who have not yet received an accurate diagnosis.

Cause

The cause of Kennedy disease is a mutation in a gene known as AR on the X chromosome (11q11-q12). It controls the formation of (codes for) the androgen receptor (AR) protein. In individuals with the disease, a section of the AR gene is unstable. This instability is due to an excessive number of repetitions of a certain DNA-sequence, CAG, in the AR gene. Normally there are 17-34 CAG repeats. If there are more than 37 repeats the individual will develop Kennedy disease, and the severity of the disease increases with the number of excessive repetitions. Individuals with 35-37 CAG repeats may remain asymptomatic or develop a mild form of the disease.

Androgen receptors reside in the cell (in the cytoplasm), where they respond to signals from male sex hormones (androgens). The receptors are present in many tissues in the body, including the central nervous system and the motor neurons (the nerve cells that regulate muscle activity) in the spinal cord and brain stem. When an androgen binds to the receptor, it relocates to the cell nucleus, where it signals to genes that respond by increasing the production of proteins involved in many reactions.

In Kennedy disease the androgen receptor is defective, so that activated but damaged androgen receptors accumulate in cells, particularly in the cell nuclei. As a result, electrical and chemical signals that are exchanged between the motor neurons and the muscles are disturbed, and the muscles atrophy.

Since the cell nucleus does not receive normal signals from the androgen receptor, the effects of the male sex hormones may be reduced. The defective receptors also accumulate in muscle tissue and in the pancreas, which may lead to diabetes. Sensory nerves and nerves (autonomous nerves) that control involuntary actions such as sweating are also affected.

Another mutation in the AR gene causes androgen insensitivity syndrome (see separate information text in the rare disease database).

Heredity

Kennedy disease is caused by a mutated gene located on the X chromosome, which is one of the chromosomes determining sex. Men have one X chromosome and one Y chromosome, while women have two X chromosomes. Inherited X-linked recessive disorders usually occur only in men, being passed down via a healthy female carrier who has one normal and one mutated gene. Sons of female carriers of a mutated gene run a 50 per cent risk of inheriting the disease and daughters run the same risk of being healthy carriers of a mutated gene. A man with an inherited X-linked recessive disease can not pass it on to his sons, but all his daughters will be carriers of the mutated gene.

There is a risk that daughters of a man with Kennedy disease will be carriers of a higher number of CAG repeats than their father (anticipation), which in turn increases the risk that their sons will have a more severe form of the disease than their grandfather.

Figure: X-linked recessive inheritance  via a healthy female carrier

Figur: X-kromosombunden recessiv nedärvning från sjuk, anlagsbärande man

Symptoms

The symptoms of Kennedy disease usually present between the ages of 20 and 50 years. The muscles weaken and slowly atrophy, but muscle cramps and hand tremors (postural tremors) may present several years before muscle weakness has developed. The muscle weakness is proximal, meaning that the muscles closest to and in the trunk tend to be most affected. Small muscle contractions (fasciculations) in the musculature of the arms, legs, and trunk are also common. Muscle stretch responses are often weak or absent. The condition is slowly progressive and life expectancy is not affected.

The disease also affects the medulla oblongata (the bulbar region of the brain), which is usually noticed 5 to 10 years after the onset of arm and leg symptoms. Bulbar symptoms include weakening of the facial muscles and more pronounced twitches in the face and tongue. Swallowing difficulties (dysphagia) and speech difficulties (dysarthria) are other common symptoms. Drooling may occur as a consequence of difficulties in swallowing saliva. Individuals with the disorder are at increased risk of recurring pneumonia, as the cough and gag reflexes are weakened, which makes it easier for bacteria to spread from the upper respiratory tract down to the lungs.

Weakened leg muscles make walking more difficult and increase the risk of falling. Many people with Kennedy disease retain their ability to walk throughout their whole lives, while others may need a wheelchair.

Insensitivity to male sexual hormones presents as enlarged breast glands (gynaecomastia) and impaired sexual function. Reduced sex drive, infertility, impotence, and shrunken testicles are symptoms that affect approximately half of all individuals with Kennedy disease. Fertility problems associated with impaired sperm production may develop as the disease progresses. In mild cases of the disease, sexual function and fertility may be normal.

Diabetes is associated with the disease in approximately ten per cent of all cases.

Diagnosis

The characteristic symptoms in combination with test results of neurological examinations should raise the suspicion of Kennedy disease.

A neurophysiological examination will show essentially normal peripheral nerve conduction. The sensory nerve conduction may, however, be slightly impaired. An EMG test (electromyography) may detect chronic denervation, indicating that the pathway between the spinal cord motor neurons and the muscle fibres is partially blocked.

In some cases, a muscle biopsy is performed. Like the EMG, it will show signs of denervation.

The diagnosis can be confirmed by DNA analysis. At the time of diagnosis the family should be offered genetic counselling. Carrier and prenatal diagnostics, as well as pre-implantation genetic diagnostics (PGD) in association with IVF (in vitro fertilization), are available in families where the mutation is known.

Treatment/interventions

There is currently no intervention that prevents the development of the disease. The treatment is therefore directed at easing the symptoms and compensating for functional limitations.

Enlarged breast glands can be treated surgically.

Testosterone or other forms of androgen replacement therapy should never be prescribed as there is a risk of exacerbating the disease.

Men with Kennedy disease should be in contact with specialists in neurology and endocrinology.

Speech and swallowing difficulties are treated by a speech therapist. The major hospitals in Sweden have specialist teams (dyshagia and nutrition teams) for assessing and treating eating and swallowing difficulties.

A physiotherapist will provide advice on suitable exercises to retain as much function as possible. Breathing exercises are sometimes needed.

Depending on the degree of the functional disability, assistance devices, new routines and individualized adaptations facilitate activities of daily living, such as ambulation, hygiene, dressing and undressing, and eating. If necessary, the home, the car, and the workplace can be adapted to individual needs. An occupational therapist, from the hospital or the patient’s local district, should assist in determining what measures need to be taken.

It is important for young people and adults with Kennedy disease to be well informed about their condition. Professional psychological and social support should also be offered, and is normally provided by a psychologist or a rehabilitation counsellor. The rehabilitation counsellor also handles information about the provision of national and regional support, for example personal assistance services, home help services, and residential care facilities. A sex therapist may provide support and assistance in cases of sexual dysfunction.

Practical advice

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National and regional resources in Sweden

Swedish neurologists are familiar with Kennedy disease. However, the resources needed to confirm the diagnosis are not available at all clinics.

Resource personnel

Chief physician Björn Lindvall, Muscle Centre, Örebro University Hospital, SE-701 85 Örebro, Sweden. Tel: +46 19 602 10 00. Email: bjorn.lindvall@orebroll.se.

Associate Professor Lars-Olof Ronnevi, Neurology Clinic, Karolinska University Hospital, SE-171 76 Stockholm, Sweden. Tel: +46 8 517 700 00.

Courses, exchanges of experience, recreation

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Organizations for the disabled/patient associations etc.

Rare Diseases Sweden, Box 1386, SE-172 27 Sundbyberg, Sweden. Tel: +46 8 764 49 99, email: info@sallsyntadiagnoser.se, www.sallsyntadiagnoser.se. Rare Diseases Sweden is a national association promoting the interests of people with rare diseases.

NHR, The Swedish Association for Persons with Neurological Disabilities, St Eriksgatan 44, Box 490 84, SE-100 28 Stockholm, Sweden. Tel: +46 8 677 70 10, fax: +46 8 24 13 15, email: nhr@nhr.se, www.nhr.se.

There is an American Kennedy´s Disease Association, email: info@kennedysdisease.org, www.kennedysdisease.org.

Courses, exchanges of experience for personnel

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Research and development

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Information material

An information leaflet on Kennedy disease that summarises the information in this database text is available free of charge from the customer service department of the Swedish National Board of Health and Welfare (in Swedish only, article number 2012-8-24). Address: SE-120 88 Stockholm, Sweden. Tel: +46 75 247 38 80, fax: +46 35 19 75 29, email: publikationsservice@socialstyrelsen.se. Postage will be charged for bulk orders.

Literature

Adachi H, Katsuno M, Minamiyama M, Waza M, Sang C, Nakagomi Y et al. Widespread nuclear and cytoplasmic accumulation of mutant androgen receptor in SBMA patients. Brain 2005; 128: 659-670.

Antonini G, Gragnani F, Romaniello A, Pennisi EM, Morino S, Ceschin V et al. Sensory involvement in spinal-bulbar muscular atrophy (Kennedy’s disease). Muscle Nerve 2000; 23: 252-258.

Atsuta N, Watanabe H, Ito M, Banno H, Suzuki K, Katsuno M et al. Natural history of spinal and bulbar muscular atrophy (SBMA): a study of 223 Japanese patients. Brain 2006; 129: 1446-1455.

Banno H, Katsuno M, Suzuki K, Tanaka F, Sobue G. Pathogenesis and therapy of spinal and bulbar muscular atrophy (SBMA). Cell Tissue Res 2012; 349: 313-320.

Chahin N, Klein C, Mandrekar J, Sorenson E. Natural history of spinal-bulbar muscular atrophy. Neurology 2008; 70: 1967-1971.

Ferrante MA, Wilbourn AJ. The characteristic electrodiagnostic features of Kennedy’s disease. Muscle Nerve 1997; 20: 323-329.

Finsterer J. Perspectives of Kennedy’s disease. J Neurol Sci 2010; 298: 1-10.

Hanajima R, Terao Y, Nakatani-Enomoto S, Hamada M, Yugeta A, Matsumoto H et al. Postural tremor in X-linked spinal and bulbar muscular atrophy. Mov Disord 2009; 24: 2063-2069.

Hashizume A, Katsuno M, Banno H, Suzuki K, Suga N, Mano T et al. Longitudinal changes of outcome measures in spinal and bulbar muscular atrophy. Brain 2012 Jul 6. [Epub ahead of print]

Hsiao PW, Lin DL, Chang C. The linkage of Kennedy’s neuron disease to ARA24, the first identified androgen receptor polyglutamine regionassociated coactivator. J Biol Chem 1999; 274: 20229-20234.

Kennedy WR, Alter M, Ho Sung J. Progressive proximal spinal and bulbar muscular atrophy of late onset. Neurology 1968; 18: 671-680.

Lee JH, Shin JH, Park KP, Kim IJ, Lim JG, Choi YC et al. Phenotypic variability in Kennedy’s disease: implication of the early diagnostic features. Acta Neurol Scand 2005; 112: 57-63.

Li M, Miwa S, Kobayashi Y, Merry DE, Yamamoto M, Tanaka F et al. Nuclear inclusions of the androgen receptor protein in spinal and bulbar muscular atrophy. Ann Neurol 1998; 44: 249-254.

Li M, Nakagomi Y, Kobayashi Y, Merry DE, Tanaka F, Doyu M et al. Non-neural nuclear inclusions of androgen receptor protein in spinal and bulbar muscular atrophy. Am J Pathol 1998; 153: 695-701.

Lund A, Udd B, Juvonen V, Andersen PM, Cederquist K, Davis M et al. Multiple founder effects in spinal an bulbar muscular atrophy (SBMA, Kennedy disease) around the world. Eur J Hum Genet 2001; 9: 431-436.

Manganelli F, Iodice V, Provitera V, Pisciotta C, Nolano M, Perretti A et al. Small-fiber involvement in spinobulbar muscular atrophy (Kennedy’s disease). Muscle nerve 2007; 36: 816-820.

Mariotti C, Castellotti B, Pareyson D, Testa D, Eoli M, Antozzi C et al. Phenotypic manifestations associated with CAG-repeat expansion in the androgen receptor gene in male patients and heterozygous females: a clinical and molecular study of 30 families. Neuromuscul Disord 2000; 10: 391-397.

Niesen AD, Sprung J, Prakash YS, Watson JC, Weingarten TN. Case series: anesthetic management of patients with spinal and bulbar muscular atrophy (Kennedy’s disease). Can J Anaesth 2009; 56: 136-141.

Priesler N, Andersen G, Thøgersen F, Crone C, Jeppesen TD, Wibrand F et al. Effect of aerobic training in patients with spinal and bulbar muscular atrophy (Kennedy disease). Neurology 2009; 72: 317-323.

Sinnreich M, Sorenson EJ, Klein CJ. Neurologic course, endocrine dysfunction and triplet repeat size in spinal bulbar muscular atrophy. Can J Neurol Sci 2004; 31: 378-382.

Shimada N, Sobue G, Doyu M, Yamamoto K, Yasuda T, Mukai E et al. X-linked recessive bulbospinal neuronopathy: clinical phenotypes and CAG repeat size in androgen receptor gene. Muscle Nerve 1995; 18: 1378-1384.

Suzuki K, Katsuno M, Banno H, Takeuchi Y, Atsuta N, Ito N et al. CAG repeat size correlates to electrophysiological motor and sensory phenotypes in SBMA. Brain 2008; 131: 229-239.

Udd B, Juvonen V, Hakamies L, Nieminen A, Wallgren-Pettersson C, Cederquist K et al. High prevalence of Kennedy’s disease in western Finland: is the syndrome underdiagnosed? Acta Neurol Scand 1998; 98: 128-133.

Database references

OMIM (Online Mendelian Inheritance in Man)
www.ncbi.nlm.nih.gov/omim 
Search: kennedy disease

GeneReviews (University of Washington)
www.genetests.org (select “GeneReviews”, then “Titles”)
search: spinal and bulbar muscular atrophy

Document information

The Swedish Information Centre for Rare Diseases produced and edited this information material.

The medical expert who wrote the draft of this information material is Associate Professor Göran Solders, Karolinska University Hospital, Stockholm,Sweden.

The relevant organisations for the disabled/patient associations have been given the opportunity to comment on the content of the text.

An expert group on rare diseases, affiliated with the University of Gothenburg, approved the material prior to publication.

Publication date: 2012-11-30
Version: 3.0
Publication date of the Swedish version: 2012-09-10

For enquiries contact The Swedish Information Centre for Rare Diseases, The Sahlgrenska Academy at the University of Gothenburg, Box 422, SE-405 30 Gothenburg, Sweden. Tel: +46 31 786 55 90, email: ovanligadiagnoser@gu.se.

 

About the database

This knowledge database provides information on rare diseases and conditions. The information is not intended to be a substitute for professional medical care, nor is it intended to be used as a basis for diagnosis or treatment.