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. SBMA occurs only in 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; 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 pregnancies 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 consistent with X-linked inheritance

Note: 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 the 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.

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].

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.

Nomenclature

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

Prevalence

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].

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.

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 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 gender-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.

Other

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