Spinal and Bulbar Muscular Atrophy

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 in affected males. Affected individuals often show gynecomastia, testicular atrophy, and reduced fertility as a result of mild androgen insensitivity.

Diagnosis/testing.

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.

Management.

Treatment of manifestations: Use of braces and walkers for ambulation as needed as the disease progresses; standard treatments for dysarthria and dysphagia; breast reduction surgery for gynecomastia as needed; standard treatment per cardiologist and/or endocrinologist for cardiac manifestations and metabolic syndrome; psychosocial support and education to decrease stress and burden on caregivers.

Surveillance: Annual assessment of strength, mobility, activities of daily living, speech, and feeding issues; annual assessment of pulmonary function in those with advanced disease; annual assessment of cholesterol and triglycerides, with hepatic function testing if elevated; annual assessment of cardiovascular health per cardiologist; assessment of need for family and caregiver support.

Other: Clinical trials of anti-androgen drugs (e.g., leuprorelin) did not consistently reveal significant efficacy, but leuprorelin was efficacious as a treatment for dysphagia in a follow-up clinical trial in Japan, leading to its approval in Japan but not elsewhere. Based on animal studies, administration of testosterone and its analogs may worsen motor neuron disease.

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 usually 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 (e.g., no male-to-male transmission). Absence of a known family history 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 proband'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

Clinical Description

Spinal and bulbar muscular atrophy (SBMA) is a disorder of slowly progressive muscle weakness associated with mild androgen insensitivity.

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, while the average number of CAG repeats in affected males is 37, Kuhlenbäumer et al [2001] reported a male in a family with SBMA with AR alleles of 37 CAG repeats who was asymptomatic at age 46 years. 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.

Nomenclature

SBMA has been called Kennedy's disease, named for the neurologist who published an early clinical description. In the past, SBMA has also been called X-linked spinal muscular atrophy.

Prevalence

SBMA has an estimated prevalence of 1:300,000 males. To date, SBMA has only been reported in individuals of European or Asian ethnic 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 population groups 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), the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 3.

Recommended Evaluations Following Initial Diagnosis in Individuals with Spinal and Bulbar Muscular Atrophy

Treatment of Manifestations

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 4).

Table 4.

Treatment of Manifestations in Individuals with Spinal and Bulbar Muscular Atrophy

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations in Table 5 are recommended.

Table 5.

Recommended Surveillance for Individuals with Spinal and Bulbar Muscular Atrophy

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 reported for the androgen treatment group [Goldenberg & Bradley 1996]. Based on research in Drosophila and mouse models of SBMA, many investigators believe that androgen treatment may 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, 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 (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 in Japan 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]. Because leuprorelin was efficacious as a treatment for dysphagia in this clinical trial, it has been approved as a treatment for individuals with SBMA in Japan but not elsewhere.
• In another anti-androgen therapy study [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, the 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 controversial. 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 hypothesis remains to be tested.

AJ201. AnnJi Pharmaceuticals intends to move forward with a Phase II clinical trial of AJ201, a small molecule capable of inducing Nrf1, Nrf2, and possibly Hsf1, based on encouraging results obtained in preclinical trails performed in SBMA model mice [Bott et al 2016] and acceptable safety/toxicity testing in a Phase I clinical trial. Recruitment for the Phase II clinical trial will begin in 2023.

Experimental therapies in animal models

• Other interventions 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]).
• Cortes et al [2014] directly examined the role of muscle expression of mutated androgen receptor (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. 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 central nervous system also elicited a modest improvement in these disease readouts in an 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. There is interest in pursuing a clinical trial of anti-AR ASO therapy via peripheral delivery in SBMA, but this is not yet being planned.

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.

Other

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

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 CAG trinucleotide repeat expansion in AR; therefore, he does not require further evaluation/testing.
• To date, all mothers of affected males who have undergone molecular genetic testing have been shown to be heterozygous for a CAG trinucleotide repeat expansion.
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and if the CAG trinucleotide repeat expansion cannot be detected in her leukocyte DNA, she most likely has germline mosaicism.
• If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier) or, theoretically, the affected male may have a de novo CAG trinucleotide repeat expansion (in which case the mother is not a carrier) or the mother may have somatic/germline mosaicism.
  The true incidence of de novo CAG trinucleotide repeat expansion in males with SBMA is not presently known; no de novo expansions have been reported thus far.
• Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. (Note: Because SBMA is a late-onset disorder, mothers may not always be available for testing.)

Sibs of a male proband. The risk to sibs depends on the genetic status of the mother.

• If the mother of the proband has a CAG trinucleotide repeat expansion, the chance of transmitting it in each pregnancy is 50%.
• Males who inherit:
  • An expansion of 38 or more CAG trinucleotide repeats will be affected;
  • A CAG trinucleotide repeat expansion in the reduced-penetrance range are at risk for SBMA. (The clinical significance of alleles with 36-37 CAG repeats should be interpreted within the context of family history and genotype-phenotype correlations in other family members; see Establishing the Diagnosis.)
• Intrafamilial clinical variability is observed in SBMA; affected male family members with identical CAG repeat numbers may have considerably different disease courses (see Genotype-Phenotype Correlations).
• Females who inherit a full-penetrance allele of 38 or more CAG repeats are usually asymptomatic or may have mild symptoms (see Clinical Description, Heterozygous Females).

Offspring of a male proband

• Affected males who are fertile transmit the CAG trinucleotide repeat expansion to all of their daughters (who will be heterozygotes and will usually not be affected) and none of their sons.
• Repeat instability with male transmission of a CAG trinucleotide repeat expansion has been described (see Related Genetic Counseling Issues, CAG repeat instability).

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

Heterozygote (Carrier) Detection

Identification of female heterozygotes requires prior identification of the AR CAG trinucleotide repeat expansion in an affected family member.

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.

Predictive testing (i.e., testing of asymptomatic at-risk individuals)

• Predictive testing for at-risk relatives is possible once the AR CAG trinucleotide expansion has been identified 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.
• Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.

Predictive testing in minors (i.e., testing of asymptomatic at-risk individuals age <18 years)

• For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, 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.
• For more information, see 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.

In a family with an established diagnosis of SBMA, it is appropriate to consider testing of symptomatic individuals regardless of age.

Family planning

• The optimal time for determination of genetic risk 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 an AR CAG trinucleotide repeat expansion has been identified in an affected family member, prenatal 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. For more information, see the National Society of Genetic Counselors position statement on prenatal testing in adult-onset conditions.

Molecular Pathogenesis

AR encodes a member of the steroid receptor superfamily. The androgen receptor (AR) protein is expressed in the brain, spinal cord, and muscle [Matsuura et al 1993, Ogata et al 1994]. 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. Expansion beyond the normal range of CAG trinucleotide repeats within the coding region of AR causes spinal and bulbar muscular atrophy (SBMA) [La Spada et al 1991]. CAG expansions produce an AR protein with an abnormally long polyglutamine stretch at the N-terminal end [La Spada et al 1991]. A model for how polyglutamine tract expansion in the AR protein leads to neurodegeneration in SBMA has been established over the course of the last three decades. The AR protein is in complex with co-actors and chaperones in the cytosol, and upon binding to its ligand testosterone (or metabolites thereof), the AR protein enters the nucleus, where it functions as a transcription factor. Heterozygous females do not display fulminant motor neuron disease because of their low levels of circulating testosterone, thereby preventing nuclear entry of mutated AR protein. Polyglutamine-expanded AR protein misfolds and interferes with transcription regulation. Once in the nucleus, polyglutamine-expanded AR protein may cause pathology by interfering with transcriptional coactivators such as the CREB-binding protein [McCampbell et al 2000, Sopher et al 2004].

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 the AR protein and its coactivators and corepressors may underlie disease pathogenesis [Nedelsky et al 2010]. The polyglutamine tract region is also proteolytically processed and a polyglutamine-containing peptide fragment is retained in the nucleus, where it forms neuronal intranuclear inclusions (NIIs) [Young et al 2009]. NIIs have been found in spinal cord and skeletal muscle sections from deceased individuals with SBMA [Li et al 1998]. The expression of mutated AR protein in skeletal muscle appears to be a major driver of the disease process, based on the presence of myopathy in individuals with SBMA and experiments in SBMA mouse models [Cortes et al 2014].

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.

Mechanism of disease causation. The 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.

AR-specific laboratory technical considerations. About 98% of females have AR alleles with different numbers of CAG repeats on their two X chromosomes. The high degree of heterozygosity in females makes the AR CAG repeat a useful marker for studying X-chromosome inactivation. 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.

Table 6.

Notable AR Variants

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 and Asians" [Sun & Lee 2013].

Author Notes

Dr La Spada is a Distinguished Professor at UC Irvine , where he maintains a research program focused on neurodegenerative proteinopathies. Spinal and bulbar muscular atrophy (SBMA) remains a major focus of his research efforts.

Acknowledgments

Dr La Spada's SBMA research is supported by a R35 award (NS122140) from the NINDS at the National Institutes of Health.

Revision History

• 15 December 2022 (sw) Comprehensive update posted live
• 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

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 12-6-22.
• National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available online. 2019. Accessed 12-6-22.

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