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Spinal muscular atrophy

Spinal Muscular Atrophy (SMA) is a term applied to a number of different disorders, all having in common a genetic cause and the manifestation of weakness due to loss of the motor neurons of the spinal cord and brainstem. more...

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Caused by mutation of the SMN gene

The most common form of SMA is caused by mutation of the SMN gene, and manifests over a wide range of severity affecting infants through adults. This spectrum has been divided arbitrarily into three groups by the level of weakness.

  • Infantile SMA - Type 1 or Werdnig-Hoffmann disease (generally 0-6 months). SMA type 1, also known as severe infantile SMA or Werdnig Hoffmann disease, is the most severe, and manifests in the first year of life with the inability to ever maintain an independent sitting position.
  • Intermediate SMA - Type 2 (generally 7-18 months). Type 2 SMA, or intermediate SMA, describes those children who are never able to stand and walk, but who are able to maintain a sitting position at least some time in their life. The onset of weakness is usually recognized some time between 6 and 18 months.
  • Juvenile SMA - Type 3 Kugelberg-Welander disease (generally >18 months). SMA type 3 describes those who are able to walk at some time. It is also known as Kugelberg Welander disease.

Other forms of SMA

Other forms of spinal muscular atrophy are caused by mutation of other genes, some known and others not yet defined. All forms of SMA have in common weakness caused by denervation, i.e. the muscle atrophies because it has lost the signal to contract due to loss of the innervating nerve. Spinal muscular atrophy only affects motor nerves. Heritable disorders that cause both weakness due to motor denervation along with sensory impairment due to sensory denervation are known by the inclusive label Charcot-Marie-Tooth or Hereditary Motor Sensory Neuropathy. The term spinal muscular atrophy thus refers to atrophy of muscles due to loss of motor neurons within the spinal cord.

  • Hereditary Bulbo-Spinal SMA Kennedy's disease (X linked, Androgen receptor)
  • Spinal Muscular Atrophy with Respiratory Distress (SMARD 1) (chromsome 11, IGHMBP2 gene)
  • Distal SMA with upper limb predominance (chromosome 7, glycyl tRNA synthase)


The course of SMA is directly related to the severity of weakness. Infants with the severe form of SMA frequently succumb to respiratory disease due to weakness of the muscles that support breathing. Children with milder forms of SMA naturally live much longer although they may need extensive medical support, especially those at the more severe end of the spectrum.

Although gene replacement strategies are being tested in animals, current treatment for SMA consists of prevention and management of the secondary effect of chronic motor unit loss. It is likely that gene replacement for SMA will require many more years of investigation before it can be applied to humans. Due to molecular biology, there is a better understanding of SMA. The disease is caused by deficiency of SMN (survival motor neuron) protein, and therefore approaches to developing treatment include searching for drugs that increase SMN levels, enhance residual SMN function, or compensate for its loss. The first effective specific treatment for SMA may be only a few years away, as of 2005.


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Age-dependent differences in androgen binding affinity in a family with spinal and bulbar muscular atrophy
From Neurological Research, 7/1/05 by MacLean, Helen E

Objectives: To investigate androgen receptor (AR) function in spinal and bulbar muscular atrophy (SBMA).

Methods: A kindred was identified with five individuals carrying the AR gene CAG repeat expansion that causes SBMA. Androgen binding was measured in cultured genital skin fibroblasts from three affected individuals. One newborn, pre-symptomatic, individual showed normal androgen binding, but two older, symptomatic individuals showed a decrease in androgen binding affinity. This difference was not related to AR CAC repeat size, as all affected individuals in this kindred had 49 repeats (normal range 6-35). Post-mortem analysis in one subject confirmed the signs of androgen insufficiency in the testis, with marked seminiferous tubule atrophy, and the absence of germinal cells. The characteristic neuronal depletion in the anterior horn gray matter was also observed.

Conclusion: mis report raises the possibility that age- or puberty-related changes in androgen binding could occur, which could potentially contribute to the progressive development of androgen resistance in affected men. [Neurol Res 2005; 27: 548-551]

Keywords: Androgen receptor; CAG; polyglutamine; spinal and bulbar muscular atrophy; trinucleotide repeat


Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy's disease, is an X-linked form of motor neuron disease caused by the expansion of the trinucleotide CAG repeat in exon 1 of the androgen receptor (AR) gene1. This results in the generation of AR carrying an expanded polyglutamine (polyGln) repeat in the N-terminal transactivation domain. The disease is characterized by its X-linked recessive mode of inheritance, and symptoms include cramps, fasciculations, distal and proximal muscle weakness, dysphagia and dysarthria2. SBMA is one of a group of neurological disorders caused by expansions of polyGin tracts in different proteins3.

The AR, which mediates androgen action, has widespread expression in the reproductive system, but is also expressed in the brain, spinal cord and other tissues4. In SBMA, neuronal degeneration is limited to only a sub-set of the cells that express the AR: the spinal and bulbar motor neurons, and some sensory neurons. The presence of AR containing an expanded polyGln tract is toxic to motor neurons. However, it is not known why degeneration is limited to these cells, and the pathogenic mechanism of SBMA is still unclear. Nuclear inclusions containing aggregates of the AR have been observed in motor neurons from patients with SBMA5, and are a hallmark of poiyGln diseases, but their role in disease pathogenesis remains to be elucidated6. In a mouse model of SBMA, nuclear localization of the AR caused by the presence of ligand or anti-androgen was required for disease pathogenesis7.

Studying SBMA may be useful in understanding polyGln diseases, because AR function has been well characterized in reproductive tissues. The loss of AR function results in androgen insensitivity, causing disorders of masculinization8. Patients with SBMA also show features of androgen resistance9, suggesting this component of the disease is caused by AR dysfunction. We have shown previously abnormal AR binding in cultured supra-pubic fibroblasts from subjects with SBMA10. In the current study, we present our investigations of one family with SBMA, to determine if abnormal AR function shows any correlation with the onset of symptoms.


Amplification and sizing of the CAG repeat

DNA was isolated from cultured genital skin fibroblasts and whole blood10, and paraffin blocks11 as described. A PCR to amplify the AR CAG repeat was performed as described previously12. The reverse primer was labeled with fluorescein, and PCR products were sized by electrophoresis on a 4% denaturing polyacrylamide gel, using an ABI Prism 377 Sequencer (Perkin Elmer). Size analysis was performed using Cenescan software (version 2.1, Perkin Elmer) with comparison to ET-ROX-550 Standard size markers (Amersham) and control samples validated by sequencing.

AR binding assay

Fibroblasts were cultured and assayed for AR binding in monolayer, and the maximum binding capacity (B^sub max^) and the apparent binding affinity (K^sub d^) were calculated as described previously10.



All studies were carried out under the guidelines of the Royal Children's Hospital and Royal Melbourne Hospital Ethics in Human Research committees, and informed consent was obtained from all individuals. Genetic counseling was provided prior to all testing. As required by the ethics committees, and with agreement from the parents, the results from the tests performed on individuals under the age of 16 years were used only in this research study and not made available to the individuals or their family.

Members of an extended family with SBMA were investigated (see anonymized pedigree, Figure 1A). In all subjects described except F2, the diagnosis or carrier status was confirmed by PCR amplification of the AR CAG repeat.

The index case, F1, was 70 years of age when first investigated, and had been wheelchair-bound since the age of 65. He first developed cramps around the age of 30 years, with the onset of weakness at ~40 years. An EMG performed when he was 50 showed the preservation of action potentials, no slowing of motor conduction velocity and severe chronic partial denervation. He had severe dysphagia, and a tracheotomy was performed when he was 65 years old, and a laryngectomy at 66 years old. Serum hormonal analysis performed at age 70 years showed slightly low levels of testosterone (9.5 nM, normal range 10.0-35.0 nM), and at the same age he was noted to have moderate gynecomastia and testicular atrophy (testicular volume 12 ml bilaterally, normal range 15-25 ml). F1 reported that his mother had no pubic or axillary hair, and suffered from cramps and tics all her life. Subject F1 died at the age of 72 years, after a recurrent bout of aspiration pneumonia.

The brother of the index case, F2, died at 63 years from aspiration pneumonia. He had a 15-year history of progressive weakness, with the onset of cramps occurring at 15 years of age. He was reported to have gynecomastia and testicular atrophy, and in addition, it was noted that he had no chest hair, female pubic hair distribution, and only shaved two to three times per week. The affected cousin of the index case, F3, died at 65 years of age from pneumonia. He had a 40-year history of weakness and tremor, dysphagia, and had recurrent aspiration pneumonia.

F1 had two heterozygote daughters, F4 and F5, aged 44 and 39 years, respectively. F4 reported occasional calf cramps and a slight hand tremor, and she had equivocal plantar responses, although her creatine kinase levels were normal. F5 also reported occasional calf cramps, but had normal reflexes.

F4 had two sons, F6 and F7, aged 20 and 19 years, respectively. F6 had cramps in his feet for the last 3 years, and had occasional fasciculations in the tongue. Nerve conduction studies were normal, except for mild slowing of the central motor conduction time to the right abductor digiti minim (data not shown). An EMG showed a few fasciculations and grouped discharges in the right mentalis muscle. Serum creatine kinase, testosterone, LH and FSH levels were all normal (data not shown). F6 had normal testicular volume (15 ml bilaterally), but showed slight gynecomastia. A supra-pubic skin biopsy was taken to culture genital skin fibroblasts.

F7 was apparently pre-symptomatic, although reflexes were absent except with reinforcement. F7 also had normal testicular volume (20 ml bilaterally), and no gynecomastia. F5 had one son, F8. No clinical examination was performed on this boy; however, genital skin fibroblasts were cultured following routine circumcision at birth.

Sizing the CAG repeat allele

PCR products spanning the CAG repeat region in exon 1 of the AR gene were initially fractionated using agarose gel electrophoresis (Figure 1B). Three affected males were identified, F6, F7 and F8. They were all grandsons of the index case, F1, whose daughters were shown to be heterozygotes based on this analysis. The number of CAG repeats from affected individuals F1, F3, F6, F7 and F8 was determined, and each individual had 49 CAG repeats (normal range 6-35)12.

AR binding in affected and pre-symptomatic males

AR binding was investigated in cultured genital skin fibroblasts from three members of this family (Table 7), and compared with our previously reported normal ranges10,13. Scatchard analysis of AR binding performed on fibroblasts from the index case, F1, showed AR with normal maximal binding capacity, but reduced the apparent binding affinity (K^sub d^). Fibroblasts from subject F6, aged 20 years, also showed a normal maximal binding capacity, but reduced the apparent binding affinity (Figure 2B). Fibroblasts from the pre-symptomatic newborn male, F8, showed a normal maximal binding capacity, and also showed normal apparent binding affinity (Figure 2A and B).

Post-mortem analysis

Post-mortem analysis was performed on subject F1, who died at 72 years from aspiration pneumonia. The testes appeared markedly atrophie, with a marked degree of atrophy of the seminiferous tubules, proliferation of interstitial Leydig cells and no germinal cells (Figure 3A), Sections of skeletal muscle showed muscle fibers ranging in diameter from

Gross examination of the spinal cord showed wasting of the anterior nerve rootlets, particularly the C5-T1 and T12-S4 rootlets. This correlated with the severe neuronal depletion from the anterior horn gray matter, particularly in the cervical and lumbosacral region (Figure 3C), compared with the control spinal cord (Figure 3D). The sciatic nerve showed a marked depletion of myelinated axons and extensive fibrosis. Sections of the brain from the medulla oblongata showed severe neuronal depletion from the hypoglossal nucleus, and less severe depletion from the IXth and Xth cranial nerve nuclei (data not shown). Sections of the anterior pituitary showed a normal content and distribution of functional cells. In particular, the content of the AR-responsive gonadotropin-secreting cells14 appeared within normal limits (data not shown).


This paper presents the characterization of AR function and post-mortem tissue in a family with SBMA. We determined that AR binding in the genital skin fibroblasts from F6 at 20 years of age and with early signs of SBMA including gynecomastia, and F1, the index case, showed a decrease in affinity for androgen. In contrast, the binding affinity in one newborn presymptomatic male, F8, was normal. The differences in binding affinity for androgen in fibroblasts from the newborn versus the two symptomatic individuals is not related to the size of the AR CAG repeat, because all the affected individuals had 49 CAG repeats. This suggests that factors other than the size of the CAG repeat affect the affinity of the receptor for androgen. One explanation of these differences in affinity is that a decrease in affinity occurs post-puberty, which could potentially be associated with the gradual accumulation of AR aggregates. This could contribute to the age-related development of signs of androgen resistance that occurs in SBMA patients9. Because SBMA is a rare disease, it is highly unlikely that many pre-symptomatic pre-pubertal males will be identified. Thus, it may be difficult to confirm this hypothesis in humans, and animal models of SBMA may be required to definitively investigate this question7.

Two heterozygote females were examined in this family, with both women reporting occasional cramps and tremor. Females may be protected from the full manifestation of the disease by the fact that the low levels of circulating androgens in women limit the degree of AR nuclear localization, which appears to be required for full disease development . Interestingly, the mother of F1 and F2, who is an obligate heterozygote, was reported to have had no pubic or axillary hair. To our knowledge, there have been no other reports of heterozygote carriers of SBMA showing androgen resistance. Signs of androgen resistance were also observed in the post-mortem analysis of subject F1, with seminiferous tubule atrophy observed in the testis, as described previously15,16. These results suggest that androgen resistance in the testis is a common feature of SBMA. This may arise due to the decreased androgen binding affinity, or may also occur through sequestration of the AR in aggregates or altered interactions with co-activator proteins17.

The post-mortem examination of subject F1 confirmed previous neurological findings, showing a marked loss of neurons in the motor nuclei of the Vth nerve as well as facial, ambiguus and hypoglossal nuclei and anterior horn of the entire spinal cord2,16. Many parts of the brain express AR, including expression in neurons of the pituitary14. Histological examination of these sections of the brain showed no neuronal loss, confirming that the characteristic neuronal degeneration in SBMA is limited to motor and some sensory neurons. This specificity of neuronal loss is also found in other trinucleotide repeat diseases18; however, the reasons for this specificity are still unknown.

In summary, we have identified changes in AR binding affinity in genital skin fibroblasts from subjects with SBMA. We have shown the altered binding affinity in an early symptomatic and an older symptomatic man, but normal binding affinity in a pre-symptomatic baby. The affinity for androgen does not relate to AR CAG repeat size, which is identical in the different individuals of this family, but might instead be age-related. Puberty-dependent changes in affinity for ligand could potentially explain why affected men develop progressive signs of androgen insensitivity, but further investigation is required.


We thank Angela Lamantia and Stephen Harrap, Department of Physiology, University of Melbourne, for assistance in CAG repeat sizing. This research was supported by the NHMRC (Australia). H.E.M. was supported by an NHMRC C] Martin Fellowship, #987029, and a University of Melbourne Early Career Researcher Grant.


1 La Spada AR, Wilson EM, Lubahn DB, et al. Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature 1991; 352: 77-79

2 Kennedy WR, Alter M, Sung JH. Progressive proximal spinal and bulbar muscular atrophy of late onset. A sex-linked recessive trait. Neurology 1968; 18: 671-680

3 Ross CA. Polyglutamine pathogenesis: Emergence of unifying mechanisms for Huntington's disease and related disorders. Neuron 2002; 35: 819-822

4 Sar M, Lubahn DB, French FS, et al, lmmunohistochemical localization of the androgen receptor in rat and human tissues. Endocrinology 1990; 127: 3180-3186

5 Li M, Miwa S, Kobayashi Y, et al. Nuclear inclusions of the androgen receptor protein in spinal and bulbar muscular atrophy. Ann Neurol 1 998; 44: 249-254

6 Walcott JL, Merry DE. Trinucleotide repeat disease. The androgen receptor in spinal and bulbar muscular atrophy. Vitam Horm 2002; 65: 127-147

7 Katsuno M, Adachi H, Doyu M, et at. Leuprorelin rescues polyglutamine-dependent phenotypes in a transgenic mouse model of spinal and bulbar muscular atrophy. Nat Med 2003; 9: 768-773

8 MacLean HE, Warne GL, Zajac JD. Defects of androgen receptor function: From sex reversal to motor neurone disease. Mol Cell Endocrinol 1995; 112: 133-141

9 Dejager S, Bry-Gauillard H, Bruckert E, et al. A comprehensive endocrine description of Kennedy's disease revealing androgen insensitivity linked to CAG repeat length. J CHn Endocrinol Metab 2002; 87: 3893-3901

10 MacLean HE, Choi WT, Rekaris G, et al. Abnormal androgen receptor binding affinity in subjects with Kennedy's disease (spinal and bulbar muscular atrophy). J Clin Endocrinol Metab 1995; 80: 508-516

11 Wright DK, Manos MM. Sample preparation from paraffin-embedded tissues. In: Innis MA, Gelfand DH, Sninsky JJ, White TJ, eds. PCR Protocols. San Diego: Academic Press, 1990: pp. 153-158

12 Beilin J, Harewood L, Frydenberg M, et al. A case-control study of the androgen receptor gene CAG repeat polymorphism in Australian prostate carcinoma subjects. Cancer 2001; 92: 941-949

13 MacLean HE, Chu S, Joske F, et al. Androgen receptor binding studies on heterozygotes in a family with androgen insensitivity syndrome. Biochem Mol Med 1995; 55: 31-37

14 Kimura N, Mizokami A, Oonuma T, et al. Immunocytochemical localization of androgen receptor with polydonal antibody in paraffin-embedded human tissues. I Histochem Cytochem 1993; 41: 671-678

15 Arbizu T, Santamaria J, Gomez JM, et al. A family with adult spinal and bulbar muscular atrophy, X-linked inheritance and associated testicular failure. J Neurol Sci 1983; 59: 371-382

16 Nagashima T, Seko K, Hirose K, et al. Familial bulbo-spinal muscular atrophy associated with testicular atrophy and sensory neuropathy (Kennedy-Alter-Sung syndrome). Autopsy case report of two brothers. J Neurol Sci 1988; 87: 141-152

17 Irvine RA, Ma H, Yu MC, et al. Inhibition of p160-mediated coactivation with increasing androgen receptor polyglutamine length. Hum MoI Genet 2000; 9: 267-274

18 Trottier Y, Devys D, Imbert G, et al. Cellular localization of the Huntington's disease protein and discrimination of the normal and mutated form. Nat Genet 1995; 10: 104-110

Helen E. MacLean*, Michael Gonzales[dagger], Karen J. Greenland[double dagger], Carry L. Warne[double dagger] and Jeffrey D. Zajac*

* Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria 3084, Australia

[dagger] Neuropathology Laboratory, Department of Anatomical Pathology, Royal Melbourne Hospital, Parkville, Victoria 3052, Australia

[double dagger] Centre for Hormone Research, Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria 3052, Australia

Correspondence and reprint requests to: Helen MacLean, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria 3084, Australia, [] Accepted for publication February 2005.

Copyright Maney Publishing Jul 2005
Provided by ProQuest Information and Learning Company. All rights Reserved

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