• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

Spinal and Bulbar Muscular Atrophy

Synonyms: Kennedy's Disease, SBMA, X-Linked Spinal and Bulbar Muscular Atrophy
, MD, PhD
University of California, San Diego School of Medicine
La Jolla, California

Initial Posting: ; Last Update: July 3, 2014.

Summary

Disease characteristics. Spinal and bulbar muscular atrophy (SBMA) is a gradually progressive neuromuscular disorder in which degeneration of lower motor neurons results in muscle weakness, muscle atrophy, and fasciculations. SBMA occurs only in males. Affected individuals often show gynecomastia, testicular atrophy, and reduced fertility as a result of mild androgen insensitivity.

Diagnosis/testing. All males with SBMA have expansion of a CAG trinucleotide repeat (>35 CAGs) in the androgen receptor gene (AR). Molecular genetic testing identifies the CAG trinucleotide repeat expansion.

Management. Treatment of manifestations: Use of braces and walkers for ambulation as needed as the disease progresses; breast reduction surgery for gynecomastia as needed.

Surveillance: Annual assessment of strength; annual assessment of pulmonary function in advanced cases.

Other: Clinical trials of drugs that produce pharmacologic castration (e.g., leuprorelin) did not reveal significant efficacy. Based on animal studies, administration of testosterone and its analogs may make the motor neuron disease worse.

Genetic counseling. SBMA is inherited in an X-linked manner. Affected males who are fertile pass the disease-causing allele to each daughter. Carrier females have a 50% chance of transmitting the CAG trinucleotide repeat expansion to each child; males who inherit it will be affected; females who inherit it will be carriers and will not be affected. Carrier testing for at-risk female relatives and prenatal testing for pregnancies at increased risk are possible if the disease-causing allele in the family is known.

Diagnosis

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, such as gynecomastia
  • Post-adolescent onset of:
    • Spinal lower motor neuron disease with 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 pathogenic variants are known to cause SBMA.

Allele sizes. All individuals with SBMA have an expansion in the number of CAG trinucleotide repeats in exon 1 of AR.

  • Normal alleles. 34 or fewer CAG trinucleotide repeats
  • Mutable normal alleles. None reported to date
  • Reduced penetrance alleles. Kuhlenbäumer et al [2001] suggested that an allele of 37 CAG trinucleotide 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 trinucleotide 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

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

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by this Method
Affected MalesCarrier Females
ARTargeted mutation analysis 2100%100% 3

1. See Table A. Genes and Databases for chromosome locus and protein name. See Molecular Genetics for information on allelic variants.
2. CAG repeat number can be determined by fragment length analysis of amplicons from polymerase chain reaction (PCR) amplification of the CAG repeat region within AR.
3. Sequence analysis of genomic DNA cannot detect deletion of one or more exons or the entire X-linked gene in a heterozygous female.

Testing Strategy

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

Clinical Description

Natural History

Spinal and bulbar muscular atrophy (SBMA, or Kennedy's disease, named for the neurologist who published an early clinical description) 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 30 and 50 years [Atsuta et al 2006, Rhodes et al 2009]. Onset of neurologic symptoms does not usually occur in childhood or adolescence.

Early signs are difficulty with walking and a tendency to fall. Many 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 and distal 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 aspiration pneumonia and ventilatory failure because of weakness of the bulbar and respiratory musculature [Kennedy et al 1968, Atsuta et al 2006]. This complication is the main life-threatening problem in SBMA, and likely becomes an issue for only a minority of individuals. Therefore, the 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 a mean age of 65 years.

Affected males may also have degeneration of the dorsal root ganglia, leading to mild (usually subclinical) 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].

Histopathology. 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]. Changes in muscle include evidence of myopathy [Sorarù et al 2008], in addition to neurogenic muscle atrophy. Immunohistochemistry shows inclusions 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). Males with SBMA may not be able to grow a thick beard and may have difficulty conceiving.

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

Heterozygotes

Neurologic findings. Although females who are carriers of full penetrance alleles of greater than 38 CAG repeats in AR are usually asymptomatic, a number of carriers have experienced muscle cramps or occasional tremors; however, female carriers usually do not have significant motor neuron disease [Nance 1997, Mariotti et al 2000].

Females who are symptomatic may have an abnormal electromyography [Sobue et al 1993].

Androgen insensitivity. SBMA is a sex-limited disorder, with females protected by having low levels of circulating androgens leading to lower levels of androgen receptor stimulation. In addition, due to X-inactivation, females have only a portion of actively transcribed full penetrance alleles (CAG>37), but it is the low level of circulating androgen that likely accounts for limited to absent symptoms in female carriers or females homozygous for AR full penetrance alleles.

Genotype-Phenotype Correlations

Studies of the number of CAG repeats in AR alleles in males with SBMA have established a correlation between number of CAG repeats and disease severity. In general, CAG repeat number 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 whose alleles have a larger number of CAG repeats 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 in which affected individuals have alleles of 50-54 CAG repeats [Echaniz-Laguna et al 2005].

However, these correlations are only generalizations and exceptions have been reported. For example, a male in a family with SBMA with AR alleles of 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 allelic CAG repeat number 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 number determine age of disease onset and rate of disease progression. Indeed, relatives with SBMA with an identical CAG repeat number may have considerably different disease courses.

Nomenclature

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

Prevalence

SBMA prevalence has been estimated at 1:50,000 males. 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 is much more common in the Japanese population than in other ethnic groups because of a founder effect [Tanaka et al 1996].

Differential Diagnosis

A number of hereditary and acquired neuromuscular disorders can produce gradually progressive muscle weakness.

The disorder with which spinal and bulbar muscular atrophy (SBMA) is most often confused is amyotrophic lateral sclerosis (ALS). Probably about one in 25 individuals diagnosed with ALS actually has SBMA instead of ALS [Parboosingh et al 1997]. Differentiation of ALS from SBMA can usually be made based on history and physical examination. ALS involves upper as well as lower motor neurons; individuals with ALS usually display upper motor neuron signs including hyperreflexia and spasticity. Individuals with ALS typically show involvement of a wider range of muscle groups as well as a more rapid disease progression. An important feature of SBMA is androgen insensitivity, which often causes gynecomastia; thus evaluation of males with motor neuron disease should include an assessment of breast size to determine if gynecomastia is present [Nagashima et al 1988].

Other forms of spinal muscular atrophy (SMA) that show autosomal recessive, autosomal dominant, and even X-linked inheritance have been described [Zerres 1989]. Of these, autosomal recessive SMA is the most common, occurring as four different phenotypes according to age of onset. Types I-III are known respectively as Werdnig-Hoffman disease (acute), Werdnig-Hoffman disease (chronic), and Kugelberg-Welander disease; all three types present in infancy or childhood, allowing clear differentiation from SBMA. Type IV SMA, like SBMA, has adult onset, but is much rarer than types I-III [Trentin et al 2005].

Muscle atrophy and muscle weakness from loss of motor neurons in the spinal cord are seen in other inherited neurodegenerative disorders including spinocerebellar ataxia type 3 (SCA3 or Machado-Joseph disease), Friedreich ataxia (FRDA), Tay-Sachs disease, and the adrenomyeloneuropathy (AMN) variant of X-linked adrenoleukodystrophy (X-ALD), but these disorders are quite different from SBMA. Individuals with prominent sensory findings in addition to muscle weakness could have a peripheral neuropathy (see Charcot-Marie-Tooth Hereditary Neuropathy Overview).

Non-genetic causes for motor neuron disease include structural lesions (e.g., spinal cord arteriovenous malformations), infections (especially poliomyelitis), toxins (chronic lead poisoning), metabolic problems (thyrotoxicosis), and paraneoplastic syndromes. Individuals with SBMA have been misdiagnosed as having chronic inflammatory neuropathy, metabolic myopathy, polymyositis, and myasthenia gravis.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

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
  • Medical genetics consultation

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 Primary Manifestations

There are currently no effective treatments to prevent development of disease manifestations in an asymptomatic individual known to possess an expanded CAG repeat after presymptomatic diagnosis.

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.

Evaluation of Relatives at Risk

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

Therapies Under Investigation

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

  • Anti-androgen therapy shows promise based on 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. In particular, there was no effect on the primary outcome measure (the ALS Functional Rating Scale or ALSFRS) in the period of randomization. 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].
  • A larger subsequent study with swallow function as the primary outcome measure also did not show an overall benefit, except in post hoc analysis of subjects in whom disease duration was less than ten years [Katsuno et al 2010].
  • 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.

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 disease onset 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.

Creatine supplementation. 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, but this remains to be tested.

Experimental therapies in animal models

  • Other interventions that have been shown to have benefit in mouse models of SBMA include the HSP-90 inhibitors 17-AAG and 17-DMAG, the synthetic curcumin dervative ASC-J9, and insulin-like growth factor 1 [reviewed in Fischbeck 2012].
  • Very recently, one group directly examined the role of muscle expression of mutant AR in SBMA disease pathogenesis by developing a BAC transgenic mouse model featuring a floxed first exon to permit cell-type specific excision of a human AR transgene [Cortes et al 2014]. They engineered the human AR transgene to carry 121 CAG repeats (BAC fxAR121), and found that BAC fxAR121 mice develop a gender-restricted, progressive neuromuscular phenotype, characterized by weight loss, motor deficits, muscle atrophy, myopathy, and shortened life span. By terminating expression of mutant AR in the skeletal muscles of BAC fxAR121 male mice, this study revealed a crucial role for muscle expression of mutant AR in SBMA disease pathogenesis. Hence, this work predicts that muscle-directed therapies hold great promise as definitive treatments for SBMA motor neuron degeneration.
  • Another recent study sought to ameliorate toxicity in mouse models of SBMA by suppressing polyQ-AR expression using antisense oligonucleotides (ASOs) [Lieberman et al 2014]. This investigation developed compounds to specifically target mutant AR expression in the periphery, and using two mouse models, found that peripheral gene suppression of mutant AR rescues deficits in muscle weight, fiber size, and grip strength; reverses changes in muscle gene expression; and extends the life span of mutant males. Interestingly, delivery of an anti-AR ASO to the CNS also elicited a modest improvement in these disease read-outs in a SBMA mouse model. Hence, this report, together with the genetic rescue study of SBMA [Cortes et al 2014], strongly suggests that peripheral administration of therapies directed to muscle should be explored in humans 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

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 one AR allele with an abnormal number of CAG repeats. 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 disease-causing CAG repeat allele in each pregnancy is 50%.
  • Male sibs who inherit the disease-causing CAG repeat allele will be affected; female sibs who inherit the allele 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. Such testing determines the number of CAG repeats and is 100% sensitive and specific.

Related Genetic Counseling Issues

CAG repeat instability. Disease-causing AR alleles with abnormally large numbers of CAG repeats have the property of genetic instability, meaning that the numbers of CAG repeats often change when transmitted from parent to offspring. In SBMA, a slight tendency toward expansion (an increase in number) of CAG repeats exists, although the number of CAG repeats is relatively stable with only small increases in repeat length and frequent small decreases in repeat number (i.e., contractions). Repeat instability with male transmission of a disease-causing allele has been described. Although a correlation exists between CAG repeat number and disease onset and severity in individuals with SBMA, prediction of disease course cannot be based on measured CAG repeat number.

Testing of at-risk asymptomatic adults. Testing of at-risk asymptomatic adults for SBMA is possible 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 position statement on genetic testing of minors for adult-onset conditions 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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the pathogenic variant has been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing for this disease/gene or custom prenatal testing.

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 an option for some families in which the pathogenic allelic variant has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Kennedy's Disease Association, Inc.
    PO Box 1105
    Coarsegold CA 93614-1105
    Phone: 559-658-5950
    Email: info@kennedysdisease.org
  • National Library of Medicine Genetics Home Reference
  • Muscular Dystrophy Association - USA (MDA)
    3300 East Sunrise Drive
    Tucson AZ 85718
    Phone: 800-572-1717
    Email: mda@mdausa.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Spinal and Bulbar Muscular Atrophy: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Spinal and Bulbar Muscular Atrophy (View All in OMIM)

313200SPINAL AND BULBAR MUSCULAR ATROPHY, X-LINKED 1; SMAX1
313700ANDROGEN RECEPTOR; AR

Gene structure. AR comprises eight exons and spans 180 kb [UCSC Genome Browser]. The longest transcript variant NM_000044.3 has 10,661 bp with a coding region of 2,763 bp. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Benign allelic variants. A highly polymorphic CAG repeat starting at amino acid codon number 58 is found within the AR coding domain. Unaffected individuals have five to 34 CAG trinucleotide repeats; some may have the reduced penetrant alleles with 36-37 repeats (See Molecular Genetic Testing).

About 98% of females are heterozygous and have AR alleles with different numbers of CAG repeats on their two X chromosomes. The most common alleles number from 18 to 25 CAG repeats. Variation in mean CAG repeat length occurs within different racial populations, with Africans having the smallest mean CAG repeat length and Asians having the largest mean CAG repeat length; the CAG repeat length in white European populations is intermediate to these two.

The high degree of heterozygosity in females make the AR CAG repeat a useful marker for studying X-chromosome inactivation. Epidemiologic evidence showing that shorter CAG repeat lengths correlate with more aggressive prostate cancers in males has been presented.

Pathogenic allelic variants. Expansion beyond the normal range of CAG trinucleotide repeat within the coding region of AR was found to be clearly associated with the spinal bulbar muscular atrophy (SBMA) phenotype [La Spada et al 1991].

Genetic testing of sperm of an affected male showed that 20% of the sperm had a CAG repeat number equal to that in the DNA from somatic cells, whereas 56% had further expansion of the CAG repeat number, and 24% had contraction of the CAG repeat number. Most of the allelic expansions and contractions were between one and three CAG repeats.

Normal gene product. AR is a member of the steroid receptor superfamily and therefore displays a typical protein structure, consisting of a highly conserved DNA-binding domain at the center of the protein and a highly conserved ligand-binding domain at the C-terminal end. AR transcript NM_000044.3 encodes a 920-amino acid protein with molecular mass of approximately 110 kd. A second isoform of approximately 87 kd is found in most cell types and likely reflects translation initiation at methionine 188 [Gao & McPhaul 1998]. The N-terminal region of the androgen receptor (AR) protein is relatively poorly conserved and is thought to mediate transcriptional activation of target genes [Zhou et al 1995]. The AR protein contains a nuclear localization signal (NLS) at amino acids 627-658.

Abnormal gene product. Because CAG repeats encode the amino acid glutamine, individuals with SBMA produce an AR protein that contains an abnormally long polyglutamine stretch at the N-terminal end [La Spada et al 1991]. This expanded polyglutamine tract presumably alters the conformation of the AR protein (or an N-terminal peptide fragment from the AR protein) resulting in neurodegeneration in SBMA. The presence of the abnormal polyglutamine denotes a new function on the AR protein; in general, this mechanism of disease pathogenesis is called a gain of function. The AR protein is expressed in the brain, spinal cord, and muscle [Matsuura et al 1993, Ogata et al 1994].

In all the CAG trinucleotide repeat diseases involving the central nervous system, the CAGs encode the amino acid glutamine [La Spada & Taylor 2010]. These so-called "polyglutamine tract expansion diseases" all produce unrelated proteins, without obvious similarities in function or subcellular localization. How polyglutamine tract expansion leads to neurodegeneration in SBMA and these other diseases is still unknown [La Spada & Taylor 2010]. One possible pathogenic cascade posits that the polyglutamine tract region is proteolytically processed and a polyglutamine-containing peptide fragment is retained in the nucleus, where it forms neuronal intranuclear inclusions (NIIs) [Young et al 2009]. Once in the nucleus, polyglutamine-expanded AR peptide fragments may cause pathology by interfering with transcriptional coactivators such as the CREB-binding protein [McCampbell et al 2000, Sopher et al 2004]. NIIs have been found in spinal cord sections from deceased individuals with SBMA [Li et al 1998]. In addition to gain-of-function polyglutamine proteotoxicity, recent research work has focused on the role of altered normal function in dictating cell type specificity in SBMA, and this work suggests that altered protein complex interactions between AR and its coactivators and corepressors may underlie disease pathogenesis [Nedelsky et al 2010].

References

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. 6-30-14. [PMC free article: PMC1801355] [PubMed: 7485175]
  2. National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset disorders. Available online. 2012. Accessed 6-30-14.

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. Banno H, Katsuno M, Suzuki K, Takeuchi Y, Kawashima M, Suga N, Takamori M, Ito M, Nakamura T, Matsuo K, Yamada S, Oki Y, Adachi H, Minamiyama M, Waza M, Atsuta N, Watanabe H, Fujimoto Y, Nakashima T, Tanaka F, Doyu M, Sobue G. Phase 2 trial of leuprorelin in patients with spinal and bulbar muscular atrophy. Ann Neurol. 2009;65:140–50. [PubMed: 19259967]
  6. Cortes CJ, Ling SC, Guo LT, Hung G, Tsunemi T, Ly L, Tokunaga S, Lopez E, Sopher BL, Bennett CF, Shelton GD, Cleveland DW, La Spada AR. Muscle expression of mutant androgen receptor accounts for systemic and motor neuron disease phenotypes in spinal and bulbar muscular atrophy. Neuron. 2014;82:295–307. [PMC free article: PMC4096235] [PubMed: 24742458]
  7. 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]
  8. 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]
  9. 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]
  10. 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]
  11. Ferrante MA, Wilbourn AJ. The characteristic electrodiagnostic features of Kennedy's disease. Muscle Nerve. 1997;20:323–9. [PubMed: 9052811]
  12. Fischbeck KH, Bryan WW. Anti-androgen treatment for spinal and bulbar muscular atrophy. Ann Neurol. 2009;65:119–20. [PubMed: 19259961]
  13. Fischbeck KH. Developing treatment for spinal and bulbar muscular atrophy. Prog Neurobiol. 2012;99:257–61. [PMC free article: PMC3460036] [PubMed: 22668795]
  14. 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]
  15. 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]
  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. Katsuno M, Banno H, Suzuki K, Takeuchi Y, Kawashima M, Yabe I, Sasaki H, Aoki M, Morita M, Nakano I, Kanai K, Ito S, Ishikawa K, Mizusawa H, Yamamoto T, Tsuji S, Hasegawa K, Shimohata T, Nishizawa M, Miyajima H, Kanda F, Watanabe Y, Nakashima K, Tsujino A, Yamashita T, Uchino M, Fujimoto Y, Tanaka F, Sobue G. Japan SBMA Interventional Trial for TAP-144-SR (JASMITT) study group. Efficacy and safety of leuprorelin in patients with spinal and bulbar muscular atrophy (JASMITT study): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2010;9:875–84. [PubMed: 20691641]
  19. 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]
  20. 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]
  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. La Spada AR, Taylor JP. Repeat expansion disease: progress and puzzles in disease pathogenesis. Nat Rev Genet. 2010;11:247–58. [PubMed: 20177426]
  24. 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]
  25. 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]
  26. Lieberman AP, Yu Z, Murray S, Peralta R, Low A, Guo S, Yu XX, Cortes CJ, Bennett CF, Monia BP, La Spada AR, Hung G. Peripheral androgen receptor gene suppression rescues disease in mouse models of spinal and bulbar muscular atrophy. Cell Rep. 2014;7:774–84. [PubMed: 24746732]
  27. 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]
  28. 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]
  29. 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]
  30. 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]
  31. 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]
  32. 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]
  33. Nance MA. Clinical aspects of CAG repeat diseases. Brain Pathol. 1997;7:881–900. [PubMed: 9217974]
  34. Nedelsky NB, Pennuto M, Smith RB, Palazzolo I, Moore J, Nie Z, Neale G, Taylor JP. Native functions of the androgen receptor are essential to pathogenesis in a Drosophila model of spinobulbar muscular atrophy. Neuron. 2010;67:936–52. [PMC free article: PMC3514079] [PubMed: 20869592]
  35. 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]
  36. Olney RK, Aminoff MJ, So YT. Clinical and electrodiagnostic features of X-linked recessive bulbospinal neuronopathy. Neurology. 1991;41:823–8. [PubMed: 2046924]
  37. 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]
  38. Rhodes LE, Freeman BK, Auh S, Kokkinis AD, La Pean A, Chen C, Lehky TJ, Shrader JA, Levy EW, Harris-Love M, Di Prospero NA, Fischbeck KH. Clinical features of spinal and bulbar muscular atrophy. Brain. 2009;132:3242–51. [PMC free article: PMC2792370] [PubMed: 19846582]
  39. 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]
  40. 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]
  41. 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]
  42. Sopher BL, Thomas PS, LaFevre-Bernt MA, Holm IE, Wilke SA, Ware CB, Jin LW, Libby RT, Ellerby LM, La Spada AR. Androgen receptor YAC transgenic mice recapitulate SBMA motor neuronopathy and implicate VEGF164 in the motor neuron degeneration. Neuron. 2004;41:687–99. [PubMed: 15003169]
  43. Sorarù G, D'Ascenzo C, Polo A, Palmieri A, Baggio L, Vergani L, Gellera C, Moretto G, Pegoraro E, Angelini C. Spinal and bulbar muscular atrophy: skeletal muscle pathology in male patients and heterozygous females. J Neurol Sci. 2008;264:100–5. [PubMed: 17854832]
  44. 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]
  45. 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]
  46. 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]
  47. 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]
  48. Young JE, Garden GA, Martinez RA, Tanaka F, Sandoval CM, Smith AC, Sopher BL, Lin A, Fischbeck KH, Ellerby LM, Morrison RS, Taylor JP, La Spada AR. Polyglutamine-expanded androgen receptor truncation fragments activate a Bax-dependent apoptotic cascade mediated by DP5/Hrk. J Neurosci. 2009;29:1987–97. [PMC free article: PMC2746676] [PubMed: 19228953]
  49. Zerres K. Classification and genetics of proximal spinal muscular atrophies. Prog Clin Biol Res. 1989;306:85–9. [PubMed: 2662215]
  50. 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. Rees JL. Spinobulbar muscular atrophy. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). Chap 161. New York, NY: McGraw-Hill. Available online. 2014. Accessed 7-1-14.
  2. Sinnreich M, Klein CJ. Bulbospinal muscular atrophy: Kennedy's disease. Arch Neurol. 2004;61:1324–6. [PubMed: 15313856]

Chapter Notes

Revision History

  • 3 July 2014 (me) Comprehensive update posted live
  • 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
Copyright © 1993-2014, University of Washington, Seattle. All rights reserved.

For more information, see the GeneReviews Copyright Notice and Usage Disclaimer.

For questions regarding permissions: ude.wu@tssamda.

Bookshelf ID: NBK1333PMID: 20301508
PubReader format: click here to try

Views

  • PubReader
  • Print View
  • Cite this Page
  • Disable Glossary Links

Tests in GTR by Gene

Tests in GTR by Condition

Related information

  • MedGen
    Related information in MedGen
  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to pubmed
  • Gene
    Gene records cited in chapters on the NCBI bookshelf. Links are provided by the authors or the NCBI Bookshelf staff.

Related citations in PubMed

See reviews...See all...