Kennedy disease is an X-linked recessive form of spinal muscular atrophy. It occurs only in men. Age at onset is usually in the third to fifth decade of life, but earlier involvement has been reported. The disorder is ... Kennedy disease is an X-linked recessive form of spinal muscular atrophy. It occurs only in men. Age at onset is usually in the third to fifth decade of life, but earlier involvement has been reported. The disorder is characterized by slowly progressive limb and bulbar muscle weakness with fasciculations, muscle atrophy, and gynecomastia (Harding et al., 1982). The disorder is clinically similar to, but genetically distinct from, classic forms of autosomal spinal muscular atrophy (see, e.g., SMA1; 253300).
Georgiou et al. (2001) developed a single-cell PCR assay for the AR gene and described the application of this assay for preimplantation genetic diagnosis in a couple at risk, where the female partner ... - Prenatal Diagnosis Georgiou et al. (2001) developed a single-cell PCR assay for the AR gene and described the application of this assay for preimplantation genetic diagnosis in a couple at risk, where the female partner was a carrier of 47 repeats. Diagnosis was based on the detection of both normal and expanded alleles. Allele dropout of the expanded allele was observed. Neither expansions nor contractions were observed in the blastomeres biopsied from 11 embryos. Two embryos were unaffected, 8 were female carriers, and 1 was an affected male embryo.
Kennedy et al. (1968) described spinal-bulbar muscular atrophy in 9 males from 2 unrelated kindreds. Patients had onset of fasciculations followed by muscle weakness and wasting at approximately 40 years of age. Characteristic features included bulbar signs, facial ... Kennedy et al. (1968) described spinal-bulbar muscular atrophy in 9 males from 2 unrelated kindreds. Patients had onset of fasciculations followed by muscle weakness and wasting at approximately 40 years of age. Characteristic features included bulbar signs, facial fasciculations, and dysphagia. Three patients had gynecomastia. Pyramidal, sensory, and cerebellar signs were absent, suggesting lower motor neuron involvement. The disorder was compatible with a long life. Early reports of Japanese families may have referred to the same disorder (Takikawa, 1953; Murakami, 1957; Kurland, 1957; Tsukagoshi et al., 1965). Quarfordt et al. (1970) described 4 brothers with adult-onset proximal spinal muscular atrophy. Type II hyperlipoproteinemia was present in all 4 and was absent from their 1 unaffected sib, a sister. Some children of affected males, too young to show the neurologic abnormality, also showed hyperlipoproteinemia. Schoenen et al. (1979) listed the clinical hallmarks of Kennedy disease as onset in the third decade, slow progression, involvement of facial and bulbar muscles, and wasting of the proximal and, in some cases, the distal musculature. Clinical signs were usually asymmetric, and there were consistent and abundant fasciculations predominantly in the perioral muscles. Other features included intention tremor and gynecomastia. The disorder shows X-linked recessive inheritance. Endocrinologic studies suggested an anatomic defect in the hypothalamus leading to androgen deficiency and estrogen excess. Punnett and Schotland (1979) studied a family with 7 affected males in 4 generations. Pearn and Hudgson (1978) described a spinal muscular atrophy syndrome characterized by adolescent onset, gross hypertrophy of the calves, and a slowly progressive clinical course. They proposed X-linked inheritance for the family of 1 of their patients who had an affected brother and 2 affected maternal uncles. In a study of 100 patients with SMA, Bouwsma and Van Wijngaarden (1980) found 23 cases with hypertrophied calves, elevated serum creatine kinase and onset between 1 and 20 years of age. All were male and many were brothers. Harding et al. (1982) reported 10 men with SBMA from 8 families. Proximal limb muscle weakness developed in the third to fifth decades of life, often preceded by muscle cramps on exertion and tremor of the hands. Weakness and fasciculation of the facial muscles and tongue were also prominent. All had gynecomastia and some were infertile. Plasma creatine kinase levels were increased and muscle biopsies showed neurogenic atrophy with secondary myopathic changes. In 4 Italian males in 3 sibships related as first cousins and by history in their maternal grandfather, Guidetti et al. (1986) described an X-linked adult-onset neurogenic muscular atrophy, mainly proximal, with late distal and bulbar involvement. All patients had essential tremor, gynecomastia, and impotence, although all affected males had children. One patient had hyperlipidemia. Hausmanowa-Petrusewicz et al. (1983) studied 8 of 12 male patients with X-linked spinal muscular atrophy. Six had had gynecomastia. First muscle symptoms began between 21 and 44 years of age, at which time the patients also noted disturbances in their sexual function. Some were reported to have sterility. Biopsy showed pronounced involutional changes in Leydig cells, and plasma testosterone level was decreased. Muscle involvement was most marked proximally in the limbs. Fasciculations in the muscles of the trunk and limbs and fibrillation and atrophy of the tongue were noted. Bulbar muscle involvement was less striking than in reports by others. Warner et al. (1990) reported 4 affected brothers and an affected maternal uncle. In addition to typical neurologic features including early muscle cramps, visible fasciculation and weakness of oropharyngeal and limb muscles, dysarthria, and areflexia, the patients showed facial asymmetry, gynecomastia, testicular atrophy, and infertility. All 5 affected males had hypobetalipoproteinemia. Warner et al. (1990) pointed to other reported cases of lipid abnormalities, but concluded that the relationship to the neurologic disorder was unclear. They stated that Fischbeck had informed them in 1989 of linkage between the disorder in this family (Fischbeck et al., 1986) and markers on Xq13.21. Amato et al. (1993) reported 17 SBMA patients from 7 families. One was a 71-year-old man. Weakness in all patients was usually slowly progressive, but they described 1 exception: a man who rapidly progressed from being a healthy firefighter to wheelchair-dependency in less than 1.5 years. Four carrier females had no clinical features of the disorder. Doyu et al. (1993) reported a case of extraordinarily late onset of this disorder in an 84-year-old Japanese man, with no family history of any related disease, who noted mild difficulty in climbing stairs when he was in his mid-seventies. At the age of 83, painful muscle cramps in the calves and difficulty in walking were more apparent, although he could ride a bicycle and work in the field. At age 84, he showed diffuse muscular weakness and striking amyotrophy in the 4 limbs as well as in the truncal and facial muscles. The tongue was mildly atrophic, but there was no dysphagia. Fasciculation was striking in his face, tongue, neck, anterior chest, and arm and leg muscles, and was enhanced by mild voluntary contractions. There was no gynecomastia. The number of tandem CAG repeats in the first exon of the AR gene was 40, which was the shortest in the authors' series of patients with SBMA; 45 of their cases showed a range from 40 to 55, and the normal range was 17 to 24. No statement was made about children of the patient. This is likely one of the oldest and most mildly affected patients reported. In studies of 34 patients with Kennedy disease, Sperfeld et al. (2002) found that onset was in adolescence, which is earlier than previously thought. Most frequently, early symptoms were gynecomastia, muscle pain, and premature muscle exhaustion. Weakness was not a typical initial symptom and was frequently found in distal limbs if present early. They found a correlation between the number of CAG repeats and the age at onset of weakness, but not to the age at onset of Kennedy disease. Echaniz-Laguna et al. (2005) reported an Italian family in which 7 boys had early-onset, rapidly progressive SBMA. Molecular analysis detected expanded CAG repeats ranging from 50 to 54, in the intermediate range. The mean age at onset was 13 years (range 8 to 15) of proximal upper and lower limb atrophy and weakness, which was associated with postural upper limb tremor in 4 patients. All patients developed fasciculations and dysarthria in their teens, and 3 patients had loss of independent ambulation in their mid-twenties. All the boys had prepubertal gynecomastia before age 8, without being overweight. EMG tests in 4 patients showed widespread denervation in all four limbs and bulbar muscles. Echaniz-Laguna et al. (2005) noted that 3 patients had been diagnosed with nonspecific limb-girdle muscular dystrophy in childhood. - Female Homozygotes Schmidt et al. (2002) described 2 sisters, aged 34 and 42 years, homozygous for the CAG expansion in the AR gene causing Kennedy disease, in whom symptoms were limited to occasional muscle cramps and twitches. Both sibs had mild hand tremor, and the elder had rare perioral fasciculations and mild motor axonal loss in the sternocleidomastoid muscle. Both parents were deceased, but each was thought to have contributed an X chromosome containing the CAG expansion to the sibs. This was supported by a history of muscle disease in the father and the diagnosis of Kennedy disease in a maternal cousin. Women heterozygous for the Kennedy disease gene are generally asymptomatic; however, Kennedy et al. (1968) noted in their original report that 'several female siblings of affected males had muscle cramps.' One of the remarkable features of the homozygous sisters reported by Schmidt et al. (2002) was the mildness of their manifestations. The authors suggested that the increased severity of Kennedy disease in men is due to higher levels of androgen receptor stimulation compared to women, which may produce higher levels of abnormal transcriptional regulation. Blockade of androgen receptor may thus offer some therapeutic benefit in Kennedy disease.
La Spada et al. (1991) observed a correlation between CAG length and disease severity. In an analysis of 26 Japanese SBMA patients from 21 families, Doyu et al. (1992) found the same results: the greater the number of ... La Spada et al. (1991) observed a correlation between CAG length and disease severity. In an analysis of 26 Japanese SBMA patients from 21 families, Doyu et al. (1992) found the same results: the greater the number of CAG repeats, the lower the age of onset of limb muscular weakness and the higher the age-adjusted disability score. La Spada et al. (1992) concluded that although there was a correlation between disease severity and CAG repeat length, other factors seemed to contribute to the phenotypic variability. They found that expanded (CAG)n alleles underwent alteration in length when transmitted from parent to offspring. Of 45 meioses examined, 12 (27%) demonstrated a change in CAG repeat number. Both expansions and contractions were observed, although their magnitude was small. There was a greater rate of instability in male meiosis than in female meiosis. The findings of Amato et al. (1993) in 17 patients from 7 families appeared to be at variance with the findings of others: no large expansion of the mutation was observed in transmission through 3 generations of 1 family, and phenotypic expression, although variable between and within families, was not related to the size of the mutation. The authors stated that anticipation had not clearly been observed in Kennedy disease.
In 35 unrelated patients with SBMA, La Spada and Fischbeck (1991) and La Spada et al. (1991) identified an expanded CAG repeat in the first exon of the AR gene (313700.0014). The abnormality was not observed in 263 ... In 35 unrelated patients with SBMA, La Spada and Fischbeck (1991) and La Spada et al. (1991) identified an expanded CAG repeat in the first exon of the AR gene (313700.0014). The abnormality was not observed in 263 normal persons. The AR CAG repeat is normally polymorphic, with an average repeat number of 22 +/- 3. SBMA patients had 11 different (CAG)n alleles, with repeat numbers ranging from 40 to 52, more than 6 standard deviations above the normal mean. The AR gene abnormality segregated with the disease in 15 SBMA families, with no recombination in 61 meioses (lod score = 13.2 at theta = 0.0). The CAG repeat encodes a polyglutamine tract in a portion of the AR protein that is not directly involved in hormone- or DNA-binding. There was no correlation between the size of the CAG repeat and the presence of altered in vitro androgen binding. However, there was correlation between CAG repeat length and disease severity; the mildest clinical manifestations were associated with the smallest CAG repeat. Ferlini et al. (1995) identified a CAG repeat expansion in the AR gene in 3 of 25 sporadic patients with heterogeneous motor neuron diseases. By in vitro examination of different tissues from 2 SBMA patients, Spiegel et al. (1996) did not find somatic instability of the CAG repeat expansion. Jedele et al. (1998) found no evidence of somatic mosaicism in multiple tissues from a fetus with SBMA.
Tanaka et al. (1996) investigated the origin of the SBMA mutations in the Japanese population by analyzing the (CAG)n and (GGC)n repeats of the AR gene locus in unrelated SBMA and normal X chromosomes in Japanese males. They ... Tanaka et al. (1996) investigated the origin of the SBMA mutations in the Japanese population by analyzing the (CAG)n and (GGC)n repeats of the AR gene locus in unrelated SBMA and normal X chromosomes in Japanese males. They found linkage disequilibrium between the (GGC)n haplotype and the (CAG)n mutation. Their results demonstrated a founder effect for SBMA in a Japanese population, indicating that de novo pathologic expansion of the CAG repeat is probably rarer in SBMA than in other diseases due to triplet repeat expansion. Udd et al. (1998) estimated the prevalence of Kennedy disease in the Vasa region of western Finland to be 13 per 85,000 male inhabitants. Kennedy disease was the most common motor neuron disorder in the Vasa region, exceeding the prevalence of ALS by a factor of 2. None of the patients, despite previous examinations, had correct diagnoses before 1995. Nine of the 10 families belonged to the Swedish-Finnish language group, yielding a 1.75 times higher prevalence within that specific part of the population. All cases were confirmed by DNA tests. The range of CAG-repeat expansions in the patients was 41 to 47 repeats (normal up to 35). There was no clear correlation between the repeat number and the clinical severity of the disease. One heterozygous female alive in her eighties had a movement disability beginning at age 60. Her diagnosis remained unclassified progressive encephalopathy with myoclonus leading to a bedridden state. It was uncertain whether the heterozygous AR mutation had any causal connection with her CNS disorder. Lund et al. (2000) haplotyped 13 Finnish, 10 Swedish, 12 Danish, and 2 Norwegian SBMA families with a total of 45 patients and 7 carriers for multiple microsatellite markers spanning a 25.2-cM region around the AR gene in search of a genetic founder effect. All the Scandinavian SBMA families shared the same 18-repeat microsatellite allele for the intragenic GGC repeat, which was present in only 24% of the controls. Linkage disequilibrium was also seen for the closest microsatellite markers. In addition, extended haplotypes of the Finnish, Swedish, and Danish SBMA families revealed country-specific common founder haplotypes, which over time became gradually shortened by recombinations. No common haplotype was found among the controls. The data suggested that the SBMA mutation was introduced into western Finland 20 generations earlier. Haplotype analysis implied a common ancestor for most Scandinavian SBMA patients. Lund et al. (2001) haplotyped 123 SBMA families (from Finland, Sweden, Norway, Denmark, Germany, Belgium, Italy, Japan, Australia, and Canada) for the intragenic SNP marker ARd12, the intragenic GGC repeat, and 16 microsatellite markers spanning a 25.2 cM region around the AR gene. All the Finnish, Swedish, and Norwegian patients carried the same kind of haplotype with absent intragenic ARd12 StuI site, while the patients from all other countries, including Denmark, harbored the StuI site, suggesting that the Danish patients derived their disease chromosome from another ancestor than the previously reported common Scandinavian founder (Lund et al., 2000). The haplotype analysis showed 2 founder haplotypes in German, 3 in Italian, 2 in Japanese, and 2 in Australian patients, while no common haplotype was detected among the Canadian patients. These results implied that the CAG repeat expansion mutation in SBMA is not a unique event. No particular expansion-prone haplotype could be detected. Among 95 SBMA patients with defined ages at onset, the authors found a weak negative correlation between the CAG repeat length and the age of onset.
The clinical diagnosis of spinal and bulbar muscular atrophy (SBMA) is suspected in males with the following:...
DiagnosisClinical DiagnosisThe clinical diagnosis of spinal and bulbar muscular atrophy (SBMA) is suspected in males with the following:Adolescent-onset signs of androgen insensitivity including gynecomastia and/or small testes with oligospermia or azoospermia Post-adolescent onset of Spinal lower motor neuron disease with proximal muscle weakness of the limbs or muscle cramps Bulbar lower motor neuron disease with fasciculations of the tongue, lips, or perioral region; dysarthria and difficulty swallowing No signs of upper motor neuron disease such as hyperreflexia or spasticity Family history consistent with X-linked inheritance Molecular Genetic TestingGene. AR, the gene encoding the androgen receptor, is the only gene in which mutation is currently known to cause SBMA. Allele sizes. All individuals with SBMA have expansion of a CAG trinucleotide repeat in exon 1 of AR. Normal alleles. 34 or fewer CAG repeats Mutable normal alleles. None reported to date Reduced penetrance alleles. Kuhlenbäumer et al [2001] suggest that an allele of 37 CAG repeats can manifest reduced penetrance. Therefore, the clinical significance of alleles with 36-37 CAG repeats should be interpreted within the context of family history, consultand's clinical presentation, and genotype-phenotype correlations in other family members. Full penetrance alleles. 38 or more CAG repeats Alleles of questionable significance. There is no consensus as to the clinical significance of alleles of 35 CAG repeats. Interpretation of alleles of this size may require consideration of the affected individual's clinical presentation and reconciliation with repeat sizes in family members. Clinical testingTargeted mutation analysis. CAG repeat number can be determined by polymerase chain reaction (PCR) amplification of the CAG repeat region within AR. Table 1. Summary of Molecular Genetic Testing Used in Spinal and Bulbar Muscular AtrophyView in own windowGene SymbolTest MethodMutation DetectedMutation Detection Frequency 1Test AvailabilityARTargeted mutation analysis CAG repeat expansion in exon 1 100%Clinical 1. The ability of the test method used to detect a mutation that is present in the indicated geneTesting Strategy To confirm/establish the diagnosis in a proband. Any individual suspected of having SBMA should undergo AR molecular diagnostic testing to determine CAG repeat length. Such testing is 100% sensitive and specific.Carrier testing for at-risk relatives requires prior identification of the disease-causing mutation in the family.Note: (1) Carriers are heterozygotes for this X-linked disorder and are almost always clinically unaffected (see Clinical Description). (2) Identification of female carriers requires prior identification of the disease-causing mutation in the family.Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing expansion in the family.Genetically Related (Allelic) DisordersMutations in AR also cause the androgen insensitivity syndrome.
Spinal and bulbar muscular atrophy (SBMA, or Kennedy's disease, named for the neurologist who originally recognized it) is a disorder of slowly progressive muscle weakness associated with mild androgen insensitivity [Kennedy et al 1968, Harding et al 1982]. Only males are affected....
Natural HistorySpinal and bulbar muscular atrophy (SBMA, or Kennedy's disease, named for the neurologist who originally recognized it) is a disorder of slowly progressive muscle weakness associated with mild androgen insensitivity [Kennedy et al 1968, Harding et al 1982]. Only males are affected.Neurologic findings. Neurologic symptoms typically begin between age 20 and 50 years [Atsuta et al 2006]. Onset of neurologic symptoms does not occur in childhood or adolescence. Early signs are difficulty with walking and a tendency to fall. Some individuals have muscle cramps, while others complain of an action tremor [Nagashima et al 1988]. Deep tendon reflexes are decreased. After one to two decades of symptoms, most affected individuals have difficulty climbing stairs. With time, atrophy of the proximal musculature becomes evident. About one third of affected individuals require a wheelchair 20 years after the onset of symptoms.Most individuals eventually show involvement of the bulbar muscles and have difficulty with speech articulation and swallowing. Severely affected individuals (many of whom are non-ambulatory) are at risk for asphyxiation or aspiration pneumonia because of weakness of the bulbar musculature [Kennedy et al 1968, Atsuta et al 2006]. This complication is the only life-threatening problem in SBMA, and probably only becomes important for about 10% of elderly individuals. Therefore, the vast majority of individuals with SBMA have a normal life expectancy and do not die from direct complications of their motor neuron disease. Fifteen of 223 persons in the Atsuta et al [2006] study died at the mean age of 65 years.Some affected males also experience degeneration of the dorsal root ganglia, leading to mild abnormalities in sensory function in the distal extremities [Sobue et al 1981, Nagashima et al 1988, Antonini et al 2000].Electrodiagnostic studies are consistent with diffuse denervation atrophy, anterior horn cell loss, and sensory neuronopathy [Olney et al 1991, Ferrante & Wilbourn 1997]. Neuropathology. Degeneration of anterior horn cells in the spinal cord of affected individuals is observed [Kennedy et al 1968, Amato et al 1993, Ogata et al 1994]. Immunohistochemistry shows widespread accumulation of mutant androgen receptor (AR) protein [Adachi et al 2005]. Androgen insensitivity. Symptoms of androgen insensitivity typically begin in adolescence with gynecomastia, which is observed frequently in affected males [Warner et al 1992, Sinnreich et al 2004]. Variability in disease severity and progression occurs both within and between families [La Spada et al 1992, Doyu et al 1993, Lee et al 2005]. This is especially true of the androgen insensitivity signs of testicular atrophy and oligospermia/azoospermia with reduced fertility (see Androgen Insensitivity Syndrome). Many males with SBMA are not able to grow a thick beard and claim that they have had difficulty conceiving. The androgen insensitivity can be more bothersome to affected individuals than the motor neuron disease, especially early in the course of the disorder [Warner et al 1992].Heterozygotes Neurologic findings. Although females who are carriers of an abnormal CAG expansion in AR are usually asymptomatic, a number of carriers have experienced muscle cramps or occasional tremors; however, no reported female carriers have had significant motor neuron disease [Nance 1997, Mariotti et al 2000]. Females who are symptomatic may have an abnormal electromyogram [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, heterozygotes only have a portion of active mutant alleles, but it is the low level of circulating androgen that principally accounts for limited to absent symptoms in female carriers or females homozygous for AR repeat expansion alleles.
Studies of CAG repeat length in males with SBMA have established a correlation between expansion size and disease severity. In general CAG repeat length inversely correlates with the age of onset of muscle weakness, difficulty climbing stairs, and wheelchair dependence [La Spada et al 1992]. Thus, males with SBMA with longer CAG repeat expansions tend to have earlier disease onset and more rapid progression [Doyu et al 1992, Igarashi et al 1992]. For example, early onset (age 8-15 years) and rapid progression have been described in a family with 50-54 CAG repeats [Echaniz-Laguna et al 2005]....
Genotype-Phenotype CorrelationsStudies of CAG repeat length in males with SBMA have established a correlation between expansion size and disease severity. In general CAG repeat length inversely correlates with the age of onset of muscle weakness, difficulty climbing stairs, and wheelchair dependence [La Spada et al 1992]. Thus, males with SBMA with longer CAG repeat expansions tend to have earlier disease onset and more rapid progression [Doyu et al 1992, Igarashi et al 1992]. For example, early onset (age 8-15 years) and rapid progression have been described in a family with 50-54 CAG repeats [Echaniz-Laguna et al 2005].However, these correlations are only generalizations and exceptions have been reported. For example, a male from a family with SBMA with 37 CAG repeats (the average number of repeats in affected males) has been reported to be asymptomatic at age 46 years [Kuhlenbäumer et al 2001].The genotype-phenotype correlation between expansion size and disease severity can only account for about 60% of the variability observed in clinical findings, indicating that other factors in addition to CAG repeat length determine disease onset and progression. Indeed, relatives with SBMA with identical CAG repeat lengths may have considerably different disease courses.
A number of hereditary and acquired neuromuscular disorders can produce gradually progressive muscle weakness....
Differential DiagnosisA 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 with SBMA are misdiagnosed as having 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, is adult onset [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). 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.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
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:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease and needs of an individual diagnosed with spinal and bulbar muscular atrophy (SBMA), assessment of/for the following is recommended:Neurologic findings; attention to distal muscle strength and deep tendon reflexes Speech Swallowing Androgen responsiveness: male pattern hair growth, testicular size and fertility Gynecomastia Treatment of ManifestationsPhysical therapy and rehabilitation approaches, including the use of braces and walkers, offer the best prospect for remaining ambulatory as the disease progresses.Some individuals with SBMA have breast reduction surgery for gynecomastia [Sperfeld et al 2002].Prevention of Secondary ComplicationsThe 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.SurveillanceAppropriate measures include:Strength testing (annually) Pulmonary function tests (annually in advanced cases) Agents/Circumstances to AvoidIndividuals with a tendency to fall should avoid slippery or rough walking surfaces.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationThere is no consensus or clear evidence as to whether androgen or anti-androgen therapy is an effective form of treatment for the neurologic complications. At least one clinical trial of high-dose oral testosterone has been undertaken; no significant benefit was derived for the androgen treatment group [Goldenberg & Bradley 1996]. Based on research in Drosophila and mouse models of SBMA, many investigators believe that androgen treatment can be harmful. Anti-androgen therapy shows promise based upon numerous studies in Drosophila and mouse models as well as knowledge of the molecular basis of SBMA. For these reasons, a Japanese group [Banno et al 2009] performed a clinical trial of leuprorelin in individuals with SBMA who were followed over 48 weeks: significant improvement was observed in cricopharyngeal opening duration, but in no other outcome measures. Although the trial was continued as an open label extension, and encouraging results were reported, the conclusion was that this clinical trial did not establish efficacy for anti-androgen therapy in SBMA [Fischbeck & Bryan 2009]. Hence, the utility of anti-androgen therapy as a treatment for SBMA remains unclear. Furthermore, it is possible that anti-androgen therapies, even if effective, would need to be administered prior to or early on in the neurodegenerative process. More importantly, the side effects of anti-androgen therapies would probably far outweigh the therapeutic benefit for most individuals, and likely should be reserved for people with SBMA who are wheelchair bound or exhibit pronounced bulbar weakness.Another anti-androgen therapy approach was recently attempted [Fernández-Rhodes et al 2011]: individuals with SBMA were randomized to placebo or dutasteride, a drug that blocks the conversion of testosterone to dihydrotestosterone (DHT). The rationale was that DHT may mediate many of the toxic effects, and this drug would permit affected individuals to retain the anabolic effects of testosterone, thereby diminishing the side effects of anti-androgen therapy. However, this study did not show a significant effect of dutasteride on the progression of muscle weakness in SBMA. Recent studies of amyotrophic lateral sclerosis (ALS) suggest that creatine supplementation may temporarily enhance muscle strength and exercise performance in this motor neuron disease [Mazzini et al 2001], prompting speculation that it may offer a similar benefit to individuals with SBMA. Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.OtherAdministration of male hormones (testosterone and its analogs) is not effective in overcoming the androgen insensitivity.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDARXq12Androgen receptorThe Androgen Receptor Gene Mutations Database AR @ LOVD alsod/AR genetic mutationsARData 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) View in own window 313200SPINAL AND BULBAR MUSCULAR ATROPHY, X-LINKED 1; SMAX1 313700ANDROGEN RECEPTOR; ARNormal allelic variants. AR comprises eight exons and spans 80-100 kb [Brown et al 1989]. A highly polymorphic CAG repeat starting at amino acid codon number 58 is found within the AR coding domain. Normal individuals have nine to 34 CAG triplet repeats. About 98% of females show different AR CAG repeat lengths on their two X chromosomes, making 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 Europeans being intermediate to these two. Epidemiologic evidence showing that shorter CAG repeat lengths correlate with more aggressive prostate cancers in males has been presented. Pathologic allelic variants. Expansion of a variable 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 for a person affected with SBMA has shown that 20% of the cells had a CAG repeat number equal to the DNA from somatic cells, whereas 56% of the cells contained further expansion of the CAG repeat number, and 24% of the cells contained contraction of the CAG repeat number. Most of the expansions and contractions were between one and three CAG repeats. These results contrast with sperm analysis findings in individuals with Huntington disease in whom greater instability of CAG repeat number is observed [Grewal et al 1998].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. The AR cDNA is 2.8 kb in length and normally encodes a 919-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. Individuals with SBMA produce an AR protein that contains a polyglutamine tail at the N-terminal end [La Spada et al 1991]. This polyglutamine tail presumably alters the conformation of the AR protein (or an N-terminal peptide fragment from the AR protein) to produce neurodegeneration in SBMA. 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 et al 1994]. 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 [Buchanan et al 2004, Beitel et al 2005]. Recent research advances suggest 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). 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]. NIIs have been found in spinal cord sections from deceased individuals with SBMA [Li et al 1998].