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Kennedy’s disease (spinal and bulbar muscular atrophy): a clinically oriented review of a rare disease

  • Marianthi Breza
  • Georgios Koutsis
Review

Abstract

Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy’s disease, is a rare, X-linked hereditary lower motor neuron disease, characterized by progressive muscular weakness. An expanded trinucleotide repeat (CAG > 37) in the androgen receptor gene (AR), encoding glutamine, is the mutation responsible for Kennedy’s disease. Toxicity of this mutant protein affects both motor neurons and muscles. In this review, we provide a comprehensive, clinically oriented overview of the current literature regarding Kennedy’s disease, highlighting gaps in our knowledge that remain to be addressed in further research. Kennedy’s disease mimics are also discussed, as are ongoing and recently completed therapeutic endeavours.

Keywords

Kennedy’s disease Spinal and bulbar muscular atrophy Spinobulbar muscular atrophy Androgen receptor X-linked 

Notes

Funding

None.

Compliance with ethical standards

Ethical approval

Institutional Review Board approval was not required for this paper, because it is a review of previously published articles.

Conflicts of interest

None of the authors have any financial disclosure to make or have any conflict of interest relevant to the manuscript. G. Koutsis has received research grants from Genesis Pharma and Teva, consultation fees, advisory boards and honoraria from Genzyme, Genesis Pharma, Teva, and Novartis.

Supplementary material

Video legend: Fasciculations of tongue in a 61-year-old SBMA patient with wasting of the tongue, scalloping of the borders, and midline furrowing. (MOV 15253 KB)

References

  1. 1.
    La Spada AR, Wilson EM, Lubahn DB et al (1991) Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature 352:77–79.  https://doi.org/10.1038/352077a0 CrossRefPubMedGoogle Scholar
  2. 2.
    Pennuto M, Rinaldi C (2017) From gene to therapy in spinal and bulbar muscular atrophy: are we there yet? Mol Cell Endocrinol.  https://doi.org/10.1016/j.mce.2017.07.005 PubMedGoogle Scholar
  3. 3.
    Kennedy WR, Alter M, Sung JH (1968) Progressive proximal spinal and bulbar muscular atrophy of late onset. Neurology 18Google Scholar
  4. 4.
    Harding AE, Thomas PK, Baraitser M et al (1982) X-linked recessive bulbospinal neuronopathy: a report of ten cases. J Neurol Neurosurg Psychiatry 45:1012–1019.  https://doi.org/10.1136/jnnp.45.11.1012 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Koutsis G, Kladi A, Breza M et al (2015) Spinobulbar muscular atrophy (Kennedy’s disease): a rare diagnosis in the Greek population. J Neurol Sci 359:450–451.  https://doi.org/10.1016/j.jns.2015.10.021 CrossRefPubMedGoogle Scholar
  6. 6.
    Fratta P, Nirmalananthan N, Masset L et al (2014) Correlation of clinical and molecular features in spinal bulbar muscular atrophy. Neurology 82:2077–2084.  https://doi.org/10.1212/WNL.0000000000000507 CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Mariotti C, Castellotti B, Pareyson D et al (2000) Phenotypic manifestations associated with CAG-repeat expansion in the androgen receptor gene in male patients and heterozygous females: a clinical and molecular study of 30 families. Neuromuscul Disord 10:391–397.  https://doi.org/10.1016/S0960-8966(99)00132-7 CrossRefPubMedGoogle Scholar
  8. 8.
    Fischbeck KH (1997) Kennedy disease. J Inherit Metab Dis 20:152–158.  https://doi.org/10.1023/A:1005344403603 CrossRefPubMedGoogle Scholar
  9. 9.
    Guidetti D, Sabadini R, Ferlini A, Torrente I (2001) Epidemiological survey of X-linked bulbar and spinal muscular atrophy, or Kennedy disease, in the province of Reggio Emilia, Italy. Eur J Epidemiol 17:587–591.  https://doi.org/10.1023/A:1014580219761 CrossRefPubMedGoogle Scholar
  10. 10.
    Udd B, Juvonen V, Hakamies L et al (1998) High prevalence of Kennedy’s disease in Western Finland—is the syndrome underdiagnosed? Acta Neurol Scand 98:128–133CrossRefPubMedGoogle Scholar
  11. 11.
    Tanaka F, Doyu M, Ito Y et al (1996) Founder effect in spinal and bulbar muscular atrophy (SBMA). Hum Mol Genet 5:1253–1257.  https://doi.org/10.1093/hmg/5.9.1253 CrossRefPubMedGoogle Scholar
  12. 12.
    Li M, Miwa S, Kobayashi Y et al (1998) Nuclear inclusions of the androgen receptor protein in spinal and bulbar muscular atrophy. Ann Neurol 44:249–254.  https://doi.org/10.1002/ana.410440216 CrossRefPubMedGoogle Scholar
  13. 13.
    Grunseich C, Fischbeck KH (2015) Spinal and bulbar muscular atrophy. Neurol Clin 33:847–854.  https://doi.org/10.1016/j.ncl.2015.07.002 CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Amato A, Prior TW, Barohn RJ et al (1993) Kennedy’s disease: a clinicopathologic correlation with mutations in the androgen receptor gene. Neurology 43:791–794CrossRefPubMedGoogle Scholar
  15. 15.
    Cortes CJ, Ling SC, Guo LT et al (2014) Muscle expression of mutant androgen receptor accounts for systemic and motor neuron disease phenotypes in spinal and bulbar muscular atrophy. Neuron 82:295–307.  https://doi.org/10.1016/j.neuron.2014.03.001 CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Adachi H, Katsuno M, Minamiyama M et al (2005) Widespread nuclear and cytoplasmic accumulation of mutant androgen receptor in SBMA patients. Brain 128:659–670.  https://doi.org/10.1093/brain/awh381 CrossRefPubMedGoogle Scholar
  17. 17.
    Rinaldi C, Bott LC, Fischbeck KH (2014) Muscle matters in Kennedy’s disease. Neuron 82:251–253.  https://doi.org/10.1016/j.neuron.2014.04.005 CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Rocchi A, Milioto C, Parodi S et al (2016) Glycolytic to oxidative fiber type switch and mTOR signaling activation are early-onset features of SBMA muscle modified by high fat diet. Acta Neuropathol 132:127–144.  https://doi.org/10.1007/s00401-016-1550-4 CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Ishihara H, Kanda F, Nishio H et al (2001) Clinical features and skewed X-chromosome inactivation in female carriers of X-linked recessive spinal and bulbar muscular atrophy. J Neurol 248:856–860.  https://doi.org/10.1007/s004150170069 CrossRefPubMedGoogle Scholar
  20. 20.
    La Spada A (1996) Spinal and bulbar muscular atrophy. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A (eds) GeneReviews®. University of Washington, Seattle. http://www.ncbi.nlm.nih.gov/books/NBK1333/. Accessed 10 mar 2018Google Scholar
  21. 21.
    Biancalana V, Serville F, Pommier J et al (1992) Moderate instability of the trinucleotide repeat in spinobulbar muscular atrophy. Hum Mol Genet 1:255–258CrossRefPubMedGoogle Scholar
  22. 22.
    Atsuta N, Watanabe H, Ito M et al (2006) Natural history of spinal and bulbar muscular atrophy (SBMA): a study of 223 Japanese patients. Brain 129:1446–1455.  https://doi.org/10.1093/brain/awl096 CrossRefPubMedGoogle Scholar
  23. 23.
    Grunseich C, Kats IR, Bott LC et al (2014) Early onset and novel features in a spinal and bulbar muscular atrophy patient with a 68 CAG repeat. Neuromuscul Disord 24:978–981.  https://doi.org/10.1016/j.nmd.2014.06.441 CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Kooy RF, Reyniers E, Storm K et al (1999) CAG Repeat contraction in the androgen receptor gene in three brothers with mental retardation. Am J Med Genet 213:209–213CrossRefGoogle Scholar
  25. 25.
    Kuhlenbäumer G, Kress W, Ringelstein EB, Stögbauer F (2001) Thirty-seven CAG repeats in the androgen receptor gene in two healthy individuals. J Neurol 248:23–26.  https://doi.org/10.1007/s004150170265 CrossRefPubMedGoogle Scholar
  26. 26.
    Koutsis G, Karadima G, Kladi A, Panas M (2014) Late-onset Huntington’s disease: diagnostic and prognostic considerations. Parkinsonism Relat Disord 20:726–730.  https://doi.org/10.1016/j.parkreldis.2014.03.017 CrossRefPubMedGoogle Scholar
  27. 27.
    Chahin N, Sorenson EJ (2009) Serum creatine kinase levels in spinobulbar muscular atrophy and amyotrophic lateral sclerosis. Muscle Nerve 40:126–129.  https://doi.org/10.1002/mus.21310 CrossRefPubMedGoogle Scholar
  28. 28.
    Rhodes LE, Freeman BK, Auh S et al (2009) Clinical features of spinal and bulbar muscular atrophy. Brain 132:3242–3251.  https://doi.org/10.1093/brain/awp258 CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Querin G, Bertolin C, Da Re E et al (2015) Non-neural phenotype of spinal and bulbar muscular atrophy: results from a large cohort of Italian patients. J Neurol Neurosurg Psychiatry.  https://doi.org/10.1136/jnnp-2015-311305 PubMedCentralGoogle Scholar
  30. 30.
    Manzano R, Sorarú G, Grunseich C et al (2018) Beyond motor neurons: expanding the clinical spectrum in Kennedy’ s disease. J Neurol Neurosurg Psychiatry.  https://doi.org/10.1136/jnnp-2017-316961 PubMedGoogle Scholar
  31. 31.
    Hijikata Y, Hashizume A, Yamada S et al (2018) Biomarker-based analysis of preclinical progression in spinal and bulbar muscular atrophy. Neurology.  https://doi.org/10.1212/WNL.0000000000005360.PubMedGoogle Scholar
  32. 32.
    Rhodes LE, Freeman BK, Auh S et al (2009) Clinical features of spinal and bulbar muscular atrophy. Brain 25:285–287.  https://doi.org/10.1093/brain/awp258 Google Scholar
  33. 33.
    Parboosingh JS, Figlewicz D, Krizus A et al (1997) Spinobulbar muscular atrophy can mimic ALS: the importance of genetic testing in male patients with atypical ALS. Neurology 49:568–572.  https://doi.org/10.1212/WNL.49.2.568 CrossRefPubMedGoogle Scholar
  34. 34.
    Ferrante M, Wilbourn AJ (1997) The characteristic electrodiagnostic features of Kennedy’s disease. Muscle Nerve 20:323–329CrossRefPubMedGoogle Scholar
  35. 35.
    Garg N, Park SB, Vucic S et al (2016) Differentiating lower motor neuron syndromes. J Neurol Neurosurg Psychiatry.  https://doi.org/10.1136/jnnp-2016-313526 PubMedPubMedCentralGoogle Scholar
  36. 36.
    Fischbeck KH (2016) Spinal and Bulbar Muscular Atrophy. J Mol Neurosci 58:317.  https://doi.org/10.1007/s12031-015-0674-7 CrossRefPubMedGoogle Scholar
  37. 37.
    Sumner CJ, Fischbeck KH (2002) Jaw drop in Kennedy’s disease. Neurology 59:1471–1472.  https://doi.org/10.1212/01.WNL.0000033325.01878.13 CrossRefPubMedGoogle Scholar
  38. 38.
    Praline J, Guennoc AM, Malinge MC et al (2008) Pure bulbar motor neuron involvement linked to an abnormal CAG repeat expansion in the androgen receptor gene. Amyotroph Lateral Scler 9:40–42.  https://doi.org/10.1080/17482960701553915 CrossRefPubMedGoogle Scholar
  39. 39.
    Araki K, Nakanishi H, Nakamura T et al (2015) Myotonia-like symptoms in a patient with spinal and bulbar muscular atrophy. Neuromuscul Disord 25:913–915.  https://doi.org/10.1016/j.nmd.2015.08.006 CrossRefPubMedGoogle Scholar
  40. 40.
    Finsterer J, Soraru G (2015) Onset manifestations of spinal and bulbar muscular atrophy (Kennedy’s disease). J Mol Neurosci.  https://doi.org/10.1007/s12031-015-0663-x PubMedGoogle Scholar
  41. 41.
    Finsterer J (2009) Bulbar and spinal muscular atrophy (Kennedy’s disease): a review. Eur J Neurol 16:556–561.  https://doi.org/10.1111/j.1468-1331.2009.02591.x CrossRefPubMedGoogle Scholar
  42. 42.
    Nishiyama A, Sugeno N, Tateyama M et al (2014) Postural leg tremor in X-linked spinal and bulbar muscular atrophy. J Clin Neurosci 21:799–802.  https://doi.org/10.1016/j.jocn.2013.07.026 CrossRefPubMedGoogle Scholar
  43. 43.
    Warnecke T, Oelenberg S, Teismann I et al (2009) Dysphagia in X-linked bulbospinal muscular atrophy (Kennedy disease). Neuromuscul Disord 19:704–708.  https://doi.org/10.1016/j.nmd.2009.06.371 CrossRefPubMedGoogle Scholar
  44. 44.
    Hashizume A, Banno H, Katsuno M et al (2017) Quantitative assessment of swallowing dysfunction in patients with spinal and bulbar muscular atrophy. Intern Med 56:3159–3165.  https://doi.org/10.2169/internalmedicine.8799-16 CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Sperfeld AD, Hanemann CO, Ludolph AC, Kassubek J (2005) Laryngospasm: an underdiagnosed symptom of X-linked spinobulbar muscular atrophy. Neurology 64:753–754.  https://doi.org/10.1212/01.WNL.0000151978.74467.E7 CrossRefPubMedGoogle Scholar
  46. 46.
    Finsterer J (2010) Perspectives of Kennedy’s disease. J Neurol Sci 298:1–10.  https://doi.org/10.1016/j.jns.2010.08.025 CrossRefPubMedGoogle Scholar
  47. 47.
    Pedroso JL, Vale TC, Barsottini OG et al (2018) Perioral and tongue fasciculations in Kennedy’s disease. Neurol Sci 39:777–779.  https://doi.org/10.1007/s10072-017-3170-8 CrossRefPubMedGoogle Scholar
  48. 48.
    Jokela ME, Udd B (2015) Diagnostic clinical, electrodiagnostic and muscle pathology features of spinal and bulbar muscular atrophy. J Mol Neurosci.  https://doi.org/10.1007/s12031-015-0684-5 PubMedGoogle Scholar
  49. 49.
    Rocchi C, Greco V, Urbani A, Giorgio A (2011) Subclinical autonomic dysfunction in spinobulbar muscular atrophy. Muscle Nerve 44:737–740.  https://doi.org/10.1002/mus.22159 CrossRefPubMedGoogle Scholar
  50. 50.
    Romigi A, Liguori C, Placidi F et al (2014) Sleep disorders in spinal and bulbar muscular atrophy (Kennedy’s disease): a controlled polysomnographic and self-reported questionnaires study. J Neurol 261:889–893.  https://doi.org/10.1007/s00415-014-7293-z CrossRefPubMedGoogle Scholar
  51. 51.
    Araki A, Katsuno M, Suzuki K et al (2014) Brugada syndrome in spinal and bulbar muscular atrophy. Neurology 82:1813–1821.  https://doi.org/10.1212/WNL.0000000000000434 CrossRefPubMedGoogle Scholar
  52. 52.
    Rosenbohm A, Hirsch S, Volk AE et al (2018) The metabolic and endocrine characteristics in spinal and bulbar muscular atrophy. J Neurol 265:1–11.  https://doi.org/10.1007/s00415-018-8790-2 CrossRefGoogle Scholar
  53. 53.
    Guber RD, Takyar V, Kokkinis A et al (2017) Nonalcoholic fatty liver disease in spinal and bulbar muscular atrophy. Neurology 89:2481–2490.  https://doi.org/10.1212/WNL.0000000000004748 CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Kassubek J, Juengling FD, Sperfeld A (2007) Widespread white matter changes in Kennedy disease: a voxel based morphometry study. J Neurol Neurosurg Psychiatry 78:1209–1213.  https://doi.org/10.1136/jnnp.2006.112532 CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Soukup GR, Sperfeld AD, Uttner I et al (2009) Frontotemporal cognitive function in X-linked spinal and bulbar muscular atrophy (SBMA): a controlled neuropsychological study of 20 patients. J Neurol 256:1869–1875.  https://doi.org/10.1007/s00415-009-5212-5 CrossRefPubMedGoogle Scholar
  56. 56.
    Di Rosa E, Sorarù G, Kleinbub JR et al (2014) Theory of mind, empathy and neuropsychological functioning in X-linked Spinal and Bulbar Muscular Atrophy: a controlled study of 20 patients. J Neurol 262:394–401.  https://doi.org/10.1007/s00415-014-7567-5 CrossRefPubMedGoogle Scholar
  57. 57.
    Lai TH, Liu RS, Yang BH et al (2013) Cerebral involvement in spinal and bulbar muscular atrophy (Kennedy’s disease): a pilot study of PET. J Neurol Sci 335:139–144.  https://doi.org/10.1016/j.jns.2013.09.016 CrossRefPubMedGoogle Scholar
  58. 58.
    Sperfeld AD, Karitzky J, Brummer D et al (2002) X-linked bulbospinal neuronopathy. Arch Neurol 59:1921.  https://doi.org/10.1001/archneur.59.12.1921 CrossRefPubMedGoogle Scholar
  59. 59.
    Igarashi S, Tanno Y, Onodera O et al (1992) Strong correlation between the number of CAG repeats in androgen receptor genes and the clinical onset of features of spinal and bulbar muscular atrophy. Neurology 42:2300–2302CrossRefPubMedGoogle Scholar
  60. 60.
    Nakatsuji H, Araki A, Hashizume A et al (2017) Correlation of insulin resistance and motor function in spinal and bulbar muscular atrophy. J Neurol 264:839–847.  https://doi.org/10.1007/s00415-017-8405-3 CrossRefPubMedGoogle Scholar
  61. 61.
    Sobue G, Doyu M, Kachi T et al (1993) Subclinical phenotypic expressions in heterozygous females of X-linked recessive bulbospinal neuronopathy. J Neurol Sci 117:74–78.  https://doi.org/10.1016/0022-510X(93)90157-T CrossRefPubMedGoogle Scholar
  62. 62.
    Manganelli F, Iodice V, Provitera V et al (2007) Small-fiber involvement in spinobulbar muscular atrophy (Kennedy’s disease). Muscle Nerve 36:816–820.  https://doi.org/10.1002/mus.20872 CrossRefPubMedGoogle Scholar
  63. 63.
    Antonini G, Gragnani F, Romaniello A et al (2000) Sensory involvement in spinal-bulbar muscular atrophy (Kennedy’s disease). Muscle Nerve 23:252–258CrossRefPubMedGoogle Scholar
  64. 64.
    Banno H (2012) Molecular pathophysiology and disease-modifying therapies for spinal and bulbar muscular atrophy. Arch Neurol 69:436.  https://doi.org/10.1001/archneurol.2011.2308 CrossRefPubMedGoogle Scholar
  65. 65.
    Meriggioli MN, Rowin J, Sanders DB (1999) Distinguishing clinical and electrodiagnostic features of X-linked bulbospinal neuronopathy. Muscle Nerve 22:1693–1697CrossRefPubMedGoogle Scholar
  66. 66.
    Fernández-Rhodes LE, Kokkinis AD, White MJ et al (2011) Efficacy and safety of dutasteride in patients with spinal and bulbar muscular atrophy: a randomised placebo-controlled trial. Lancet Neurol 10:140–147.  https://doi.org/10.1016/S1474-4422(10)70321-5 CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Dahlqvist JR, Vissing J (2016) Exercise therapy in spinobulbar muscular atrophy and other neuromuscular disorders. J Mol Neurosci 58:388–393.  https://doi.org/10.1007/s12031-015-0686-3 CrossRefPubMedGoogle Scholar
  68. 68.
    Katsuno M, Adachi H, Doyu M et al (2003) Leuprorelin rescues polyglutamine-dependent phenotypes in a transgenic mouse model of spinal and bulbar muscular atrophy. Nat Med 9:768–773.  https://doi.org/10.1038/nm878 CrossRefPubMedGoogle Scholar
  69. 69.
    Banno H, Katsuno M, Suzuki K et al (2009) Phase 2 trial of leuprorelin in patients with spinal and bulbar muscular atrophy. Ann Neurol 65:140–150.  https://doi.org/10.1002/ana.21540 CrossRefPubMedGoogle Scholar
  70. 70.
    Hashizume A, Katsuno M, Suzuki K et al (2017) Long-term treatment with leuprorelin for spinal and bulbar muscular atrophy: Natural history-controlled study. J Neurol Neurosurg Psychiatry 88:1026–1032.  https://doi.org/10.1136/jnnp-2017-316015 CrossRefPubMedGoogle Scholar
  71. 71.
    Querin G, D’Ascenzo C, Peterle E et al (2013) Pilot trial of clenbuterol in spinal and bulbar muscular atrophy. Neurology 80:2095–2098.  https://doi.org/10.1212/WNL.0b013e318295d766 CrossRefPubMedGoogle Scholar
  72. 72.
    Pourshafie N, Lee PR, Chen K et al (2016) MiR-298 counteracts mutant androgen receptor toxicity in spinal and bulbar muscular atrophy. Mol Ther.  https://doi.org/10.1038/mt.2016.13 PubMedPubMedCentralGoogle Scholar
  73. 73.
    Weydt P, Sagnelli A, Rosenbohm A et al (2015) Clinical trials in spinal and bulbar muscular atrophy—past, present, and future. J Mol Neurosci.  https://doi.org/10.1007/s12031-015-0682-7 PubMedGoogle Scholar
  74. 74.
    Pareyson D, Fratta P, Pradat P et al (2016) Towards a european registry and biorepository for patients with spinal and bulbar muscular atrophy. J Mol Neurosci.  https://doi.org/10.1007/s12031-015-0704-5 Google Scholar

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© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Neurogenetics Unit, 1st Department of Neurology, Eginition Hospital, Medical SchoolNational and Kapodistrian University of AthensAthensGreece

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