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Spinal and Bulbar Muscular Atrophy

Synonyms: Kennedy's Disease, SBMA, X-Linked Spinal and Bulbar Muscular Atrophy

, MD, PhD.

Author Information

Initial Posting: ; Last Update: January 26, 2017.

Estimated reading time: 23 minutes


Clinical 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.


The diagnosis of SBMA is established in a male proband by the identification of a hemizygous expansion of a CAG trinucleotide repeat (>35 CAGs) in AR by molecular genetic testing.


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 anti-androgen drugs (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 expanded CAG repeat to each daughter. Carrier females have a 50% chance of transmitting the CAG trinucleotide 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 a pregnancy at increased risk are possible if the expanded CAG repeat has been identified in an affected family member.


Suggestive Findings

Spinal and bulbar muscular atrophy (SBMA) should be suspected in males with the following clinical features and family history.

Clinical features

  • Adolescent-onset signs of androgen insensitivity (e.g., 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 (e.g., hyperreflexia, spasticity)

Family history is consistent with X-linked inheritance. Lack of a family history consistent with X-linked inheritance does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of SBMA is established in a male proband by identification of a hemizygous expansion of a CAG trinucleotide repeat (>35 CAGs) in AR by molecular genetic testing (see Table 1).

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, the 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.

Molecular genetic testing approaches include targeted testing for the CAG repeat size in AR.

Table 1.

Molecular Genetic Testing Used in Spinal and Bulbar Muscular Atrophy

Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method
AR Targeted analysis 3100%

See Molecular Genetics for information on allelic variants detected in this gene.


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.

Clinical Characteristics

Clinical Description

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 [Grunseich et al 2014b]. 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 nonambulatory) are at risk for aspiration pneumonia and ventilatory failure because of weakness of the bulbar and respiratory musculature [Mariotti et al 2000, 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 [Antonini et al 2000, Grunseich et al 2014b].

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 mutated 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].


Neurologic findings. Females who are carriers of full-penetrance alleles of greater than 38 CAG repeats in AR are usually asymptomatic. While number of carriers have experienced muscle cramps or occasional tremors, 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-chromosome 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 heterozygous female carriers or in females with biallelic full-penetrance AR 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 largest AR repeat expansion reported in a person with SBMA is 68 [Grunseich et al 2014a].

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.


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


SBMA has an estimated prevalence of 1:300,000 males. It only occurs in individuals of European or Asian racial background; it 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 five different phenotypes based on age of onset and maximum function attained. Types 0-III are known respectively as congenital SMA, Werdnig-Hoffman disease (acute), Dubowitz disease (chronic), and Kugelberg-Welander disease; all four 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 0-III.

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); however, 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.


Evaluations Following Initial Diagnosis

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

  • Assessment of/for:
    • Neurologic findings; attention to distal muscle strength and deep tendon reflexes
    • Speech
    • Swallowing
    • Androgen responsiveness: male pattern hair growth, testicular size, and fertility
    • Gynecomastia
  • Consultation with a clinical geneticist and/or genetic counselor

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.


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 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. 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; 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 derivative ASC-J9, and insulin-like growth factor 1 (reviewed in Fischbeck [2012]).
  • More recently, one group directly examined the role of muscle expression of mutated 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 male sex-restricted progressive neuromuscular phenotype, characterized by weight loss, motor deficits, muscle atrophy, myopathy, and shortened life span. By terminating expression of mutated AR in the skeletal muscles of BAC fxAR121 male mice, this study revealed a crucial role for muscle expression of mutated 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 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 AR expression in the periphery, and using two mouse models, found that peripheral gene suppression of mutated AR rescues deficits in muscle weight, fiber size, and grip strength; reverses changes in muscle gene expression; and extends the life span of mutated 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, but was much less effective than peripheral delivery. 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. Preparations are underway to initiate a clinical trial of anti-AR ASO therapy via peripheral delivery in males with SBMA.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.


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, mode(s) of 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; it is not meant to address all personal, cultural, or ethical issues that may arise 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 manner.

Risk to Family Members

Parents of a male proband

  • The father of an affected male will not have the disorder nor will he be hemizygous for a pathogenic CAG trinucleotide expansion in AR; therefore, he does not require further evaluation/testing.
  • 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 CAG trinucleotide expansion in men with SBMA is not presently known; no de novo expansions have been observed thus far.

Sibs of a male proband

  • The risk to sibs depends on the genetic status of the mother.
  • Based on the observation that all tested mothers of affected males are heterozygotes (carriers), the chance of transmitting the pathogenic CAG trinucleotide expansion in each pregnancy is 50%.
  • Male sibs who inherit the pathogenic CAG trinucleotide expansion will be affected; female sibs who inherit the expansion will be heterozygotes (carriers) and will usually not be affected.

Offspring of a male proband. Affected males transmit the pathogenic CAG trinucleotide expansion to:

  • All of their daughters who will be heterozygotes (carriers) and will usually not be affected;
  • None of their sons.

Other family members. The proband's maternal aunts may be at risk of being heterozygotes (carriers) for the pathogenic CAG trinucleotide expansion and the aunt's offspring, depending on their sex, may be at risk of being carriers or of being affected.

Heterozygote Detection

Once the AR CAG repeat expansion has been identified in an affected family member, carrier testing of at-risk female relatives is possible.

Note: Females who are heterozygous (carriers) for this X-linked disorder will usually not be affected.

Related Genetic Counseling Issues

CAG repeat instability. Pathogenic AR alleles with abnormally large numbers of CAG repeats have the property of genetic instability, meaning that the number of CAG repeats often changes 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 pathogenic 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 adult relatives of individuals with SBMA is possible after molecular genetic testing has identified a pathogenic CAG trinucleotide expansion in an affected family member. Such testing is not useful in accurately predicting age of onset, severity, type of symptoms, or rate of disease progression in asymptomatic individuals.

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.

It is appropriate to consider testing symptomatic individuals regardless of age in a family with an established diagnosis of SBMA.

For more information, see also the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Academy of Pediatrics and American College of Medical Genetics and Genomics policy statement: ethical and policy issues in genetic testing and screening of children.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic 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.

Prenatal Testing and Preimplantation Genetic Testing

Once a pathogenic CAG trinucleotide expansion in AR has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for SBMA are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.


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 (MDA) - USA
    Phone: 800-572-1717
    Email: ResourceCenter@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 from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

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


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.

Benign 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 reduced-penetrance alleles with 36-37 repeats (see Establishing the Diagnosis).

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 makes the AR CAG repeat a useful marker for studying X-chromosome inactivation.

Pathogenic variants. Expansion beyond the normal range of CAG trinucleotide repeat within the coding region of AR causes 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. Similar studies on oocytes have not been possible.

Table 2.

Selected AR Variants

Variant ClassificationDNA Nucleotide ChangePredicted Protein ChangeReference Sequences
Benign c.172_174CAG(7_34)
(CAG ?-34 repeats)
See footnote 1. NM_000044​.3
Unknown c.172_174CAG(35)
(CAG 35 repeats)
Reduced-penetrance allele c.172_174CAG(36_37)
(CAG 36-37 repeats)
Pathogenic c.172_174CAG(38_68)
(CAG 38-? repeats)

Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.


Each CAG repeat results in the addition of a glutamine residue to the polymorphic polyglutamine repeat.

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 p.Met188 of the full-length protein [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. CAG encodes the amino acid glutamine, therefore, CAG expansions produce an AR protein with 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 via a gain-of-function mechanism. The AR protein is expressed in the brain, spinal cord, and muscle [Matsuura et al 1993, Ogata et al 1994].

SBMA and other CAG trinucleotide expansion diseases involving the central nervous system result from the abnormal glutamine expansion in the protein [La Spada & Taylor 2010]. Genes associated with these so-called "polyglutamine tract expansion diseases" produce unrelated proteins. 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].

Cancer and benign tumors. Dozens of epidemiologic and genetic association studies have examined a potential inverse relationship between AR CAG repeat length and the risk of developing prostate cancer. In 2013, a meta-analysis of published data up to that time concluded that "a shorter CAG repeat polymorphism may increase the risk of prostate cancer compared with the longer CAG repeat; in particular, the effect of shorter CAG repeats on the increased risk of prostate cancer was predominantly observed in Caucasians [i.e., persons of northern European background –ED.] and Asians" [Sun & Lee 2013].


Published Guidelines / Consensus Statements

  • Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available online. 2013. Accessed 2-23-22 [PubMed: 23428972]
  • National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available online. 2019. Accessed 2-23-22

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Chapter Notes

Revision History

  • 26 January 2017 (ma) Comprehensive update posted live
  • 3 July 2014 (me) Comprehensive update posted live
  • 13 October 2011 (me) Comprehensive update posted live
  • 28 December 2006 (me) Comprehensive update posted live
  • 1 July 2004 (me) Comprehensive update posted live
  • 29 August 2002 (me) Comprehensive update posted live
  • 26 February 1999 (pb) Review posted live
  • 15 December 1998 (als) Original submission
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