Clinical Diagnosis

The clinical diagnosis of spinal and bulbar muscular atrophy (SBMA) is suspected in males with the following:

• Adolescent-onset signs of androgen insensitivity including gynecomastia and/or small testes with oligospermia or azoospermia
• Post-adolescent onset of
  • Spinal lower motor neuron disease with proximal muscle weakness of the limbs or muscle cramps
  • Bulbar lower motor neuron disease with fasciculations of the tongue, lips, or perioral region; dysarthria and difficulty swallowing
• No signs of upper motor neuron disease such as hyperreflexia or spasticity
• Family history consistent with X-linked inheritance

Molecular Genetic Testing

Gene. AR, the gene encoding the androgen receptor, is the only gene in which mutation is currently known to cause SBMA.

Allele sizes. All individuals with SBMA have expansion of a CAG trinucleotide repeat in exon 1 of AR.

• Normal alleles. 34 or fewer CAG repeats
• Mutable normal alleles. None reported to date
• Reduced penetrance alleles. Kuhlenbäumer et al [2001] suggest that an allele of 37 CAG repeats can manifest reduced penetrance. Therefore, the clinical significance of alleles with 36-37 CAG repeats should be interpreted within the context of family history, consultand's clinical presentation, and genotype-phenotype correlations in other family members.
• Full penetrance alleles. 38 or more CAG repeats
• Alleles of questionable significance. There is no consensus as to the clinical significance of alleles of 35 CAG repeats. Interpretation of alleles of this size may require consideration of the affected individual's clinical presentation and reconciliation with repeat sizes in family members.

Clinical testing

• Targeted mutation analysis. CAG repeat number can be determined by polymerase chain reaction (PCR) amplification of the CAG repeat region within AR.

Table 1. Summary of Molecular Genetic Testing Used in Spinal and Bulbar Muscular Atrophy

View in own window

Gene Symbol	Test Method	Mutation Detected	Mutation Detection Frequency 1	Test Availability
AR	Targeted mutation analysis	CAG repeat expansion in exon 1	100%	Clinical

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.
1. The ability of the test method used to detect a mutation that is present in the indicated gene

Testing Strategy

To confirm/establish the diagnosis in a proband. Any individual suspected of having SBMA should undergo AR molecular diagnostic testing to determine CAG repeat length. Such testing is 100% sensitive and specific.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutation in the family.

Note: (1) Carriers are heterozygotes for this X-linked disorder and are almost always clinically unaffected (see Clinical Description). (2) Identification of female carriers requires prior identification of the disease-causing mutation in the family.

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing expansion in the family.

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

Mutations in AR also cause the androgen insensitivity syndrome.

Natural History

Spinal and bulbar muscular atrophy (SBMA, or Kennedy's disease, named for the neurologist who originally recognized it) is a disorder of slowly progressive muscle weakness associated with mild androgen insensitivity [Kennedy et al 1968, Harding et al 1982]. Only males are affected.

Neurologic findings. Neurologic symptoms typically begin between age 20 and 50 years [Atsuta et al 2006]. Onset of neurologic symptoms does not occur in childhood or adolescence.

Early signs are difficulty with walking and a tendency to fall. Some individuals have muscle cramps, while others complain of an action tremor [Nagashima et al 1988]. Deep tendon reflexes are decreased.

After one to two decades of symptoms, most affected individuals have difficulty climbing stairs. With time, atrophy of the proximal musculature becomes evident. About one third of affected individuals require a wheelchair 20 years after the onset of symptoms.

Most individuals eventually show involvement of the bulbar muscles and have difficulty with speech articulation and swallowing. Severely affected individuals (many of whom are non-ambulatory) are at risk for asphyxiation or aspiration pneumonia because of weakness of the bulbar musculature [Kennedy et al 1968, Atsuta et al 2006]. This complication is the only life-threatening problem in SBMA, and probably only becomes important for about 10% of elderly individuals. Therefore, the vast majority of individuals with SBMA have a normal life expectancy and do not die from direct complications of their motor neuron disease. Fifteen of 223 persons in the Atsuta et al [2006] study died at the mean age of 65 years.

Some affected males also experience degeneration of the dorsal root ganglia, leading to mild abnormalities in sensory function in the distal extremities [Sobue et al 1981, Nagashima et al 1988, Antonini et al 2000].

Electrodiagnostic studies are consistent with diffuse denervation atrophy, anterior horn cell loss, and sensory neuronopathy [Olney et al 1991, Ferrante & Wilbourn 1997].

Neuropathology. Degeneration of anterior horn cells in the spinal cord of affected individuals is observed [Kennedy et al 1968, Amato et al 1993, Ogata et al 1994]. Immunohistochemistry shows widespread accumulation of mutant androgen receptor (AR) protein [Adachi et al 2005].

Androgen insensitivity. Symptoms of androgen insensitivity typically begin in adolescence with gynecomastia, which is observed frequently in affected males [Warner et al 1992, Sinnreich et al 2004]. Variability in disease severity and progression occurs both within and between families [La Spada et al 1992, Doyu et al 1993, Lee et al 2005]. This is especially true of the androgen insensitivity signs of testicular atrophy and oligospermia/azoospermia with reduced fertility (see Androgen Insensitivity Syndrome). Many males with SBMA are not able to grow a thick beard and claim that they have had difficulty conceiving.

The androgen insensitivity can be more bothersome to affected individuals than the motor neuron disease, especially early in the course of the disorder [Warner et al 1992].

Genotype-Phenotype Correlations

Studies of CAG repeat length in males with SBMA have established a correlation between expansion size and disease severity. In general CAG repeat length inversely correlates with the age of onset of muscle weakness, difficulty climbing stairs, and wheelchair dependence [La Spada et al 1992]. Thus, males with SBMA with longer CAG repeat expansions tend to have earlier disease onset and more rapid progression [Doyu et al 1992, Igarashi et al 1992]. For example, early onset (age 8-15 years) and rapid progression have been described in a family with 50-54 CAG repeats [Echaniz-Laguna et al 2005].

However, these correlations are only generalizations and exceptions have been reported. For example, a male from a family with SBMA with 37 CAG repeats (the average number of repeats in affected males) has been reported to be asymptomatic at age 46 years [Kuhlenbäumer et al 2001].

The genotype-phenotype correlation between expansion size and disease severity can only account for about 60% of the variability observed in clinical findings, indicating that other factors in addition to CAG repeat length determine disease onset and progression. Indeed, relatives with SBMA with identical CAG repeat lengths may have considerably different disease courses.

Nomenclature

In the past, SBMA has been called X-linked spinal muscular atrophy.

Prevalence

SBMA occurs in fewer than 1:150,000 live male births. It occurs in individuals of European or Asian racial background but has yet to be reported in individuals of African or aboriginal racial background.

European populations in which SBMA has been observed include English, Belgian, French, Italian, German, Polish, Spanish, Swiss, Moroccan, and Turkish [La Spada et al 1991]. A founder effect has been reported in Scandinavia [Lund et al 2000].

Asian populations in which SBMA has been observed include Chinese, Japanese, Korean, and Vietnamese. SBMA appears to be much more common in the Japanese population than in any other ethnic group because of a founder effect [Tanaka et al 1996].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with spinal and bulbar muscular atrophy (SBMA), assessment of/for the following is recommended:

• Neurologic findings; attention to distal muscle strength and deep tendon reflexes
• Speech
• Swallowing
• Androgen responsiveness: male pattern hair growth, testicular size and fertility
• Gynecomastia

Treatment of Manifestations

Physical therapy and rehabilitation approaches, including the use of braces and walkers, offer the best prospect for remaining ambulatory as the disease progresses.

Some individuals with SBMA have breast reduction surgery for gynecomastia [Sperfeld et al 2002].

Prevention of Secondary Complications

The most worrisome complications in SBMA result from bulbar weakness, as these complications (asphyxiation and aspiration pneumonia) can be life threatening. Individuals with bulbar weakness must be counseled in the importance of carefully cutting their food into small pieces for eating and avoiding items that may be difficult to chew and then swallow.

Surveillance

Appropriate measures include:

• Strength testing (annually)
• Pulmonary function tests (annually in advanced cases)

Agents/Circumstances to Avoid

Individuals with a tendency to fall should avoid slippery or rough walking surfaces.

Testing of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

There is no consensus or clear evidence as to whether androgen or anti-androgen therapy is an effective form of treatment for the neurologic complications.

• At least one clinical trial of high-dose oral testosterone has been undertaken; no significant benefit was derived for the androgen treatment group [Goldenberg & Bradley 1996]. Based on research in Drosophila and mouse models of SBMA, many investigators believe that androgen treatment can be harmful.
• Anti-androgen therapy shows promise based upon numerous studies in Drosophila and mouse models as well as knowledge of the molecular basis of SBMA. For these reasons, a Japanese group [Banno et al 2009] performed a clinical trial of leuprorelin in individuals with SBMA who were followed over 48 weeks: significant improvement was observed in cricopharyngeal opening duration, but in no other outcome measures. Although the trial was continued as an open label extension, and encouraging results were reported, the conclusion was that this clinical trial did not establish efficacy for anti-androgen therapy in SBMA [Fischbeck & Bryan 2009]. Hence, the utility of anti-androgen therapy as a treatment for SBMA remains unclear. Furthermore, it is possible that anti-androgen therapies, even if effective, would need to be administered prior to or early on in the neurodegenerative process. More importantly, the side effects of anti-androgen therapies would probably far outweigh the therapeutic benefit for most individuals, and likely should be reserved for people with SBMA who are wheelchair bound or exhibit pronounced bulbar weakness.
• Another anti-androgen therapy approach was recently attempted [Fernández-Rhodes et al 2011]: individuals with SBMA were randomized to placebo or dutasteride, a drug that blocks the conversion of testosterone to dihydrotestosterone (DHT). The rationale was that DHT may mediate many of the toxic effects, and this drug would permit affected individuals to retain the anabolic effects of testosterone, thereby diminishing the side effects of anti-androgen therapy. However, this study did not show a significant effect of dutasteride on the progression of muscle weakness in SBMA.

Recent studies of amyotrophic lateral sclerosis (ALS) suggest that creatine supplementation may temporarily enhance muscle strength and exercise performance in this motor neuron disease [Mazzini et al 2001], prompting speculation that it may offer a similar benefit to individuals with SBMA.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

Administration of male hormones (testosterone and its analogs) is not effective in overcoming the androgen insensitivity.

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

Mode of Inheritance

Spinal and bulbar muscular atrophy (SBMA) is inherited in an X-linked recessive manner.

Risk to Family Members

Parents of a male proband

• The father of a male proband is not affected, nor is he a carrier.
• To date, all mothers of men with SBMA who have been tested have been shown to carry the CAG expansion. However, SBMA is a late-onset disorder and mothers may not always be available for testing.
• The true incidence of de novo mutations in men with SBMA is not presently known; no de novo mutations have been observed.

Sibs of a proband

• Based on the observation that all tested mothers of affected males are carriers, the chance of transmitting the expanded allele in each pregnancy is 50%.
• Male sibs who inherit the mutation will be affected; female sibs who inherit the mutation will be carriers and will usually not be affected.

Offspring of a proband. All daughters of affected males are obligate carriers. None of the sons are affected.

Other family members of a proband. The proband's maternal aunts may be at risk of being carriers and the aunt's offspring, depending on their gender, may be at risk of being carriers or of being affected.

Carrier Detection

Carrier testing of at-risk female relatives is possible.

Related Genetic Counseling Issues

CAG repeat expansion instability. CAG repeat expansions that cause disease in SBMA have the property of genetic instability, meaning that they often change length when transmitted from parent to offspring. In SBMA, a slight tendency toward CAG repeat expansion exists, although the CAG repeat size is relatively stable with only small repeat length shifts and frequent small contractions. Repeat instability with male transmission of the expanded allele has been described. Although a correlation exists between CAG repeat length and disease onset and severity in individuals with SBMA, prediction of disease course cannot be based on measured CAG repeat length.

Testing of at-risk asymptomatic adults. Testing of at-risk asymptomatic adults for SBMA is available using the techniques described in Molecular Genetic Testing. Such testing is not useful in accurately predicting age of onset, severity, type of symptoms, or rate of disease progression in asymptomatic individuals. When testing at-risk individuals for SBMA, an affected family member should be tested first to confirm the molecular diagnosis in the family.

Molecular genetic testing of asymptomatic individuals younger than age 18 years who are at risk for adult-onset disorders for which no treatment exists is not considered appropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause. Children who are symptomatic, however, usually benefit from having a specific diagnosis established.

See also the National Society of Genetic Counselors resolution on genetic testing of children and the American Society of Human Genetics and American College of Medical Genetics points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents.

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal testing is possible for pregnancies of women who are carriers if the CAG repeat expansion has been identified in a family member. The usual procedure is to determine the sex by performing chromosome analysis on fetal cells obtained by chorionic villus sampling (CVS) at about ten to 12 weeks' gestation or by amniocentesis usually performed at about 15 to 18 weeks' gestation. If the karyotype is 46,XY, DNA from fetal cells can be analyzed for the CAG repeat expansion.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for adult-onset conditions which (like SBMA) do not affect intellect or life span are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified in an affected family member. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Published Guidelines/Consensus Statements

1. American Society of Human Genetics and American College of Medical Genetics. Points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents. Available online. 1995. 10-2-12. [PMC free article: PMC1801355] [PubMed: 7485175]
2. National Society of Genetic Counselors. Resolution on prenatal and childhood testing for adult-onset disorders. Available online. 1995. 10-2-12.

Literature Cited

1. Adachi H, Katsuno M, Minamiyama M, Waza M, Sang C, Nakagomi Y, Kobayashi Y, Tanaka F, Doyu M, Inukai A, Yoshida M, Hashizume Y, Sobue G. Widespread nuclear and cytoplasmic accumulation of mutant androgen receptor in SBMA patients. Brain. 2005;128:659–70. [PubMed: 15659427]
2. Amato AA, Prior TW, Barohn RJ, Snyder P, Papp A, Mendell JR. Kennedy's disease: a clinicopathologic correlation with mutations in the androgen receptor gene. Neurology. 1993;43:791–4. [PubMed: 8469342]
3. Antonini G, Gragnani F, Romaniello A, Pennisi EM, Morino S, Ceschin V, Santoro L, Cruccu G. Sensory involvement in spinal-bulbar muscular atrophy (Kennedy's disease). Muscle Nerve. 2000;23:252–8. [PubMed: 10639619]
4. Atsuta N, Watanabe H, Ito M, Banno H, Suzuki K, Katsuno M, Tanaka F, Tamakoshi A, Sobue G. Natural history of spinal and bulbar muscular atrophy (SBMA): a study of 223 Japanese patients. Brain. 2006;129:1446–55. [PubMed: 16621916]
5. Beitel LK, Scanlon T, Gottlieb B, Trifiro MA. Progress in Spinobulbar muscular atrophy research: insights into neuronal dysfunction caused by the polyglutamine-expanded androgen receptor. Neurotox Res. 2005;7:219–30. [PubMed: 15897156]
6. Brown CJ, Goss SJ, Lubahn DB, Joseph DR, Wilson EM, French FS, Willard HF. Androgen receptor locus on the human X chromosome: regional localization to Xq11-12 and description of a DNA polymorphism. Am J Hum Genet. 1989;44:264–9. [PMC free article: PMC1715398] [PubMed: 2563196]
7. Buchanan G, Yang M, Cheong A, Harris JM, Irvine RA, Lambert PF, Moore NL, Raynor M, Neufing PJ, Coetzee GA, Tilley WD. Structural and functional consequences of glutamine tract variation in the androgen receptor. Hum Mol Genet. 2004;13:1677–92. [PubMed: 15198988]
8. Doyu M, Sobue G, Mitsuma T, Uchida M, Iwase T, Takahashi A. Very late onset X-linked recessive bulbospinal neuronopathy: mild clinical features and a mild increase in the size of tandem CAG repeat in androgen receptor gene. J Neurol Neurosurg Psychiatry. 1993;56:832–3. [PMC free article: PMC1015073] [PubMed: 8331366]
9. Doyu M, Sobue G, Mukai E, Kachi T, Yasuda T, Mitsuma T, Takahashi A. Severity of X-linked recessive bulbospinal neuronopathy correlates with size of the tandem CAG repeat in androgen receptor gene. Ann Neurol. 1992;32:707–10. [PubMed: 1449253]
10. Echaniz-Laguna A, Rousso E, Anheim M, Cossée M, Tranchant C. A family with early-onset and rapidly progressive X-linked spinal and bulbar muscular atrophy. Neurology. 2005;64:1458–60. [PubMed: 15851746]
11. Fernández-Rhodes LE, Kokkinis AD, White MJ, Watts CA, Auh S, Jeffries NO, Shrader JA, Lehky TJ, Li L, Ryder JE, Levy EW, Solomon BI, Harris-Love MO, La Pean A, Schindler AB, Chen C, Di Prospero NA, Fischbeck KH. Efficacy and safety of dutasteride in patients with spinal and bulbar muscular atrophy: a randomised placebo-controlled trial. Lancet Neurol. 2011;10:140–7. [PMC free article: PMC3056353] [PubMed: 21216197]
12. Ferrante MA, Wilbourn AJ. The characteristic electrodiagnostic features of Kennedy's disease. Muscle Nerve. 1997;20:323–9. [PubMed: 9052811]
13. Gao T, McPhaul MJ. Functional activities of the A and B forms of the human androgen receptor in response to androgen receptor agonists and antagonists. Mol Endocrinol. 1998;12:654–63. [PubMed: 9605928]
14. Goldenberg JN, Bradley WG. Testosterone therapy and the pathogenesis of Kennedy's disease (X-linked bulbospinal muscular atrophy). J Neurol Sci. 1996;135:158–61. [PubMed: 8867072]
15. Grewal RP, Leeflang EP, Zhang L, Arnheim N. The mutation properties of spinal and bulbar muscular atrophy disease alleles. Neurogenetics. 1998;1:249–52. [PubMed: 10732798]
16. Harding AE, Thomas PK, Baraitser M, Bradbury PG, Morgan-Hughes JA, Ponsford JR. X-linked recessive bulbospinal neuronopathy: a report of ten cases. J Neurol Neurosurg Psychiatry. 1982;45:1012–9. [PMC free article: PMC491638] [PubMed: 6890989]
17. Igarashi S, Tanno Y, Onodera O, Yamazaki M, Sato S, Ishikawa A, Miyatani N, Nagashima M, Ishikawa Y, Sahashi K. et al. Strong correlation between the number of CAG repeats in androgen receptor genes and the clinical onset of features of spinal and bulbar muscular atrophy. Neurology. 1992;42:2300–2. [PubMed: 1461383]
18. Kennedy WR, Alter M, Sung JH. Progressive proximal spinal and bulbar muscular atrophy of late onset. A sex-linked recessive trait. Neurology. 1968;18:671–80. [PubMed: 4233749]
19. Kuhlenbäumer G, Kress W, Ringelstein EB, Stögbauer F. Thirty-seven CAG repeats in the androgen receptor gene in two healthy individuals. J Neurol. 2001;248:23–6. [PubMed: 11266016]
20. La Spada AR, Paulson HL, Fischbeck KH. Trinucleotide repeat expansion in neurological disease. Ann Neurol. 1994;36:814–22. [PubMed: 7998766]
21. La Spada AR, Roling DB, Harding AE, Warner CL, Spiegel R, Hausmanowa-Petrusewicz I, Yee WC, Fischbeck KH. Meiotic stability and genotype-phenotype correlation of the trinucleotide repeat in X-linked spinal and bulbar muscular atrophy. Nat Genet. 1992;2:301–4. [PubMed: 1303283]
22. La Spada AR, Wilson EM, Lubahn DB, Harding AE, Fischbeck KH. Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature. 1991;352:77–9. [PubMed: 2062380]
23. Lee JH, Shin JH, Park KP, Kim IJ, Kim CM, Lim JG, Choi YC, Kim DS. Phenotypic variability in Kennedy's disease: implication of the early diagnostic features. Acta Neurol Scand. 2005;112:57–63. [PubMed: 15932358]
24. Li M, Miwa S, Kobayashi Y, Merry DE, Yamamoto M, Tanaka F, Doyu M, Hashizume Y, Fischbeck KH, Sobue G. Nuclear inclusions of the androgen receptor protein in spinal and bulbar muscular atrophy. Ann Neurol. 1998;44:249–54. [PubMed: 9708548]
25. Lund A, Udd B, Juvonen V, Andersen PM, Cederquist K, Ronnevi LO, Sistonen P, Sörensen SA, Tranebjaerg L, Wallgren-Pettersson C, Savontaus ML. Founder effect in spinal and bulbar muscular atrophy (SBMA) in Scandinavia. Eur J Hum Genet. 2000;8:631–6. [PubMed: 10951525]
26. Mariotti C, Castellotti B, Pareyson D, Testa D, Eoli M, Antozzi C, Silani V, Marconi R, Tezzon F, Siciliano G, Marchini C, Gellera C, Donato SD. 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;10:391–7. [PubMed: 10899444]
27. Matsuura T, Ogata A, Demura T, Moriwaka F, Tashiro K, Koyanagi T, Nagashima K. Identification of androgen receptor in the rat spinal motoneurons. Immunohistochemical and immunoblotting analyses with monoclonal antibody. Neurosci Lett. 1993;158:5–8. [PubMed: 8233073]
28. Mazzini L, Balzarini C, Colombo R, Mora G, Pastore I, De Ambrogio R, Caligari M. Effects of creatine supplementation on exercise performance and muscular strength in amyotrophic lateral sclerosis: preliminary results. J Neurol Sci. 2001;191:139–44. [PubMed: 11677005]
29. McCampbell A, Taylor JP, Taye AA, Robitschek J, Li M, Walcott J, Merry D, Chai Y, Paulson H, Sobue G, Fischbeck KH. CREB-binding protein sequestration by expanded polyglutamine. Hum Mol Genet. 2000;9:2197–202. [PubMed: 10958659]
30. Nagashima T, Seko K, Hirose K, Mannen T, Yoshimura S, Arima R, Nagashima K, Morimatsu Y. Familial bulbo-spinal muscular atrophy associated with testicular atrophy and sensory neuropathy (Kennedy-Alter-Sung syndrome). Autopsy case report of two brothers. J Neurol Sci. 1988;87:141–52. [PubMed: 3210030]
31. Nance MA. Clinical aspects of CAG repeat diseases. Brain Pathol. 1997;7:881–900. [PubMed: 9217974]
32. Ogata A, Matsuura T, Tashiro K, Moriwaka F, Demura T, Koyanagi T, Nagashima K. Expression of androgen receptor in X-linked spinal and bulbar muscular atrophy and amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 1994;57:1274–5. [PMC free article: PMC485506] [PubMed: 7931399]
33. Olney RK, Aminoff MJ, So YT. Clinical and electrodiagnostic features of X-linked recessive bulbospinal neuronopathy. Neurology. 1991;41:823–8. [PubMed: 2046924]
34. Parboosingh JS, Figlewicz DA, Krizus A, Meininger V, Azad NA, Newman DS, Rouleau GA. Spinobulbar muscular atrophy can mimic ALS: the importance of genetic testing in male patients with atypical ALS. Neurology. 1997;49:568–72. [PubMed: 9270598]
35. Sinnreich M, Sorenson EJ, Klein CJ. Neurologic course, endocrine dysfunction and triplet repeat size in spinal bulbar muscular atrophy. Can J Neurol Sci. 2004;31:378–82. [PubMed: 15376484]
36. Sobue G, Doyu M, Kachi T, Yasuda T, Mukai E, Kumagai T, Mitsuma T. Subclinical phenotypic expressions in heterozygous females of X-linked recessive bulbospinal neuronopathy. J Neurol Sci. 1993;117:74–8. [PubMed: 8410070]
37. Sobue G, Matsuoka Y, Mukai E, Takayanagi T, Sobue I, Hashizume Y. Spinal and cranial motor nerve roots in amyotrophic lateral sclerosis and X-linked recessive bulbospinal muscular atrophy: morphometric and teased-fiber study. Acta Neuropathol. 1981;55:227–35. [PubMed: 6891550]
38. Sperfeld AD, Karitzky J, Brummer D, Schreiber H, Häussler J, Ludolph AC, Hanemann CO. X-linked bulbospinal neuronopathy: Kennedy disease. Arch Neurol. 2002;59:1921–6. [PubMed: 12470181]
39. Tanaka F, Doyu M, Ito Y, Matsumoto M, Mitsuma T, Abe K, Aoki M, Itoyama Y, Fischbeck KH, Sobue G. Founder effect in spinal and bulbar muscular atrophy (SBMA). Hum Mol Genet. 1996;5:1253–7. [PubMed: 8872464]
40. Trentin AP, Scola RH, Teive HA, Raskin S, Germiniani FM, Werneck LC. Kennedy's disease phenotype with positive genetic study for Kugelberg-Welander's disease: case report. Arq Neuropsiquiatr. 2005;63:330–1. [PubMed: 16100985]
41. Warner CL, Griffin JE, Wilson JD, Jacobs LD, Murray KR, Fischbeck KH, Dickoff D, Griggs RC. X-linked spinomuscular atrophy: a kindred with associated abnormal androgen receptor binding. Neurology. 1992;42:2181–4. [PubMed: 1436532]
42. Zerres K. Classification and genetics of proximal spinal muscular atrophies. Prog Clin Biol Res. 1989;306:85–9. [PubMed: 2662215]
43. Zhou ZX, Lane MV, Kemppainen JA, French FS, Wilson EM. Specificity of ligand-dependent androgen receptor stabilization: receptor domain interactions influence ligand dissociation and receptor stability. Mol Endocrinol. 1995;9:208–18. [PubMed: 7776971]

Suggested Reading

1. Beitel LK, Pinsky L, Elhaji YA, Trifiro MA, Spinobulbar muscular atrophy. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York: McGraw-Hill; Chap 161. www​.ommbid.com. Accessed 10-6-11.
2. Sinnreich M, Klein CJ. Bulbospinal muscular atrophy: Kennedy's disease. Arch Neurol. 2004;61:1324–6. [PubMed: 15313856]

Revision History

• 13 October 2011 (me) Comprehensive update posted live
• 28 December 2006 (me) Comprehensive update posted to live Web site
• 1 July 2004 (me) Comprehensive update posted to live Web site
• 29 August 2002 (me) Comprehensive update posted to live Web site
• 26 February 1999 (pb) Review posted to live Web site
• 15 December 1998 (als) Original submission