The metabolic and endocrine characteristics in spinal and bulbar muscular atrophy

Abstract

Objective

Spinal and bulbar muscular atrophy (SBMA) is caused by an abnormal expansion of the CAG repeat in the androgen receptor gene. This study aimed to systematically phenotype a German SBMA cohort (n = 80) based on laboratory markers for neuromuscular, metabolic, and endocrine status, and thus provide a basis for the selection of biomarkers for future therapeutic trials.

Methods

We assessed a panel of 28 laboratory parameters. The clinical course and blood biomarkers were correlated with disease duration and CAG repeat length. A subset of 11 patients was evaluated with body fat MRI.

Results

Almost all patients reported muscle weakness (99%), followed by dysphagia (77%), tremor (76%), and gynecomastia (75%) as major complaints. Creatine kinase was the most consistently elevated (94%) serum marker, which, however, did not relate with either the disease duration or the CAG repeat length. Paresis duration and CAG repeat length correlated with dehydroepiandrosterone sulfate after correction for body mass index and age. The androgen insensitivity index was elevated in nearly half of the participants (48%).

Conclusions

Metabolic alterations in glucose homeostasis (diabetes) and fat metabolism (combined hyperlipidemia), and sex hormone abnormalities (androgen insensitivity) could be observed among SBMA patients without association with the neuromuscular phenotype. Dehydroepiandrosterone sulfate was the only biomarker that correlated strongly with both weakness duration and the CAG repeat length after adjusting for age and BMI, indicating its potential as a biomarker for both disease severity and duration and, therefore, its possible use as a reliable outcome measure in future therapeutic studies.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  1. 1.

    La Spada AR, Wilson EM, Lubahn DB, Harding AE, Fischbeck KH (1991) Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature 352(6330):77–79

    Article  PubMed  Google Scholar 

  2. 2.

    Tanaka F, Reeves MF, Ito Y et al (1999) Tissue-specific somatic mosaicism in spinal and bulbar muscular atrophy is dependent on CAG-repeat length and androgen receptor–gene expression level. Am J Hum Genet 65(4):966–973

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Rhodes LE, Freeman BK, Auh S et al (2009) Clinical features of spinal and bulbar muscular atrophy. Brain 132(Pt 12):3242–3251

    Article  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Nakatsuji H, Araki A, Hashizume A, Hijikata Y, Yamada S, Inagaki T, Suzuki K, Banno H, Suga N, Okada Y, Ohyama M, Nakagawa T, Kishida K, Funahashi T, Shimomura I, Okano H, Katsuno M, Sobue G (2017) Correlation of insulin resistance and motor function in spinal and bulbar muscular atrophy. J Neurol 264(5):839–847

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Katsuno M, Banno H, Suzuki K, Adachi H, Tanaka F, Sobue G (2012) Molecular pathophysiology and disease-modifying therapies for spinal and bulbar muscular atrophy. Arch Neurol 69:436–440

    Article  PubMed  Google Scholar 

  6. 6.

    Rocchi A, Pennuto M (2013) New routes to therapy for spinal and bulbar muscular atrophy. J Mol Neurosci 50:514–523

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Fischbeck KH (2012) Developing treatment for spinal and bulbar muscular atrophy. Prog Neurobiol 99(3):257–261

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    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(2):140–147

    Article  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Katsuno M, Tanaka F, Adachi H et al (2012) Pathogenesis and therapy of spinal and bulbar muscular atrophy (SBMA). Prog Neurobiol 99(3):246–256

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Weydt P, Sagnelli A, Rosenbohm A, Pradat P-F, Ludolph AC, Pareyson D (2015) Clinical trials in spinal and bulbar muscular atrophy-past, present, and future. J Mol Neurosci 58(3):379–387

    Article  PubMed  Google Scholar 

  11. 11.

    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(Pt 6):1446–1455

    Article  PubMed  Google Scholar 

  12. 12.

    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(12):2300–2302

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Lee J-H, Shin J-H, Park K-P et al (2005) Phenotypic variability in Kennedy’s disease: implication of the early diagnostic features. Acta Neurol Scand 112(1):57–63

    Article  PubMed  Google Scholar 

  14. 14.

    Sperfeld AD, Karitzky J, Brummer D et al (2002) X-linked bulbospinal neuronopathy: Kennedy disease. Arch Neurol 59(12):1921–1926

    Article  PubMed  Google Scholar 

  15. 15.

    Dejager S (2002) A comprehensive endocrine description of Kennedy’s disease revealing androgen insensitivity linked to cag repeat length. J Clin Endocrinol Metab 87(8):3893

    CAS  PubMed  Google Scholar 

  16. 16.

    Katsuno M, Adachi H, Kume A et al (2002) Testosterone reduction prevents phenotypic expression in a transgenic mouse model of spinal and bulbar muscular atrophy. Neuron 35(5):843–854

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    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 Psychiatr. 87(8):810–816

    Article  Google Scholar 

  18. 18.

    Pennuto M, Greensmith L, Pradat P-F et al (2015) 210th ENMC International Workshop: research and clinical management of patients with spinal and bulbar muscular atrophy, 27–29 March, 2015, Naarden, The Netherlands. Neuromuscul Disord 25:802–812

    Article  PubMed  Google Scholar 

  19. 19.

    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(11):978–981

    Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Palazzolo I, Stack C, Kong L et al (2009) Overexpression of IGF-1 in muscle attenuates disease in a mouse model of spinal and bulbar muscular atrophy. Neuron 63(3):316–328

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    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(6):391–397

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Ni W, Chen S, Qiao K, Wang N, Wu Z-Y (2015) Genotype-phenotype correlation in Chinese patients with spinal and bulbar muscular atrophy. PLoS One 10(3):e0122279

    Article  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Ranganathan S, Harmison GG, Meyertholen K, Pennuto M, Burnett BG, Fischbeck KH (2008) Mitochondrial abnormalities in spinal and bulbar muscular atrophy. Hum Mol Genet 18(1):27–42

    Article  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Harding AE, Thomas PK, Baraitser M, Bradbury PG, Morgan-Hughes JA, Ponsford JR (1982) X-linked recessive bulbospinal neuronopathy: a report of ten cases. Brain 45(11):1012–1019

    CAS  Google Scholar 

  25. 25.

    Amato AA, Prior TW, Barohn RJ, Snyder P, Papp A, Mendell JR (1993) Kennedy’s disease: a clinicopathologic correlation with mutations in the androgen receptor gene. Neurology. 43(4):791–794

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Doyu M, Sobue G, Mukai E et al (1992) Severity of X-linked recessive bulbospinal neuronopathy correlates with size of the tandem CAG repeat in androgen receptor gene. Ann Neurol 32:707–710

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Müller H-P, Raudies F, Unrath A, Neumann H, Ludolph AC, Kassubek J (2010) Quantification of human body fat tissue percentage by MRI. NMR Biomed 24(1):17–24

    Article  Google Scholar 

  28. 28.

    Lindauer E, Dupuis L, Müller H-P, Neumann H, Ludolph AC, Kassubek J (2013) Adipose tissue distribution predicts survival in amyotrophic lateral sclerosis. PLoS One 8(6):e67783

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Fischer K, Moewes D, Koch M et al (2015) MRI-determined total volumes of visceral and subcutaneous abdominal and trunk adipose tissue are differentially and sex-dependently associated with patterns of estimated usual nutrient intake in a northern German population. Am J Clin Nutr 101(4):794–807

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    Proschan MA, Waclawiw MA (2001) Practical guidelines for multiplicity adjustment in clinical trials. Control Clin Trials 21(6):527–539

    Article  Google Scholar 

  31. 31.

    Rinaldi C, Bott LC, Fischbeck KH (2014) Muscle matters in Kennedy’s disease. Neuron 82(2):251–253

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Cortes CJ, Ling S-C, 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(2):295–307

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Lieberman AP, Yu Z, Murray S et al (2014) Peripheral androgen receptor gene suppression rescues disease in mouse models of spinal and bulbar muscular atrophy. Cell Rep. 7(3):774–784

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Sorarù G, Hashizume Y, Mukai E, Hirayama M, Mitsuma T, Takahashi A et al (1989) X-linked recessive bulbospinal neuronopathy. A clinicopathological study. Brain 112(1):209–232 (Pt 1)

    Article  Google Scholar 

  35. 35.

    Sorarù G, D’Ascenzo C, Polo A et al (2007) Spinal and bulbar muscular atrophy: skeletal muscle pathology in male patients and heterozygous females. J Neurol Sci 264(1–2):100–105

    PubMed  Google Scholar 

  36. 36.

    Sinclair R, Greenland KJ, van Egmond S, Hoedemaker C, Chapman A, Zajac JD (2007) Men with Kennedy disease have a reduced risk of androgenetic alopecia. Br J Dermatol 157(2):290–294

    CAS  Article  PubMed  Google Scholar 

  37. 37.

    Lindauer E, Dupuis L, Hüller HP, Neumann H, Ludolph AC, Kassubek J (2013) Adipose tissue distribution predicts survival in amyotrophic lateral sclerosis. PLoS One 27(8):e67783. https://doi.org/10.1371/journal.pone.0067783

    Article  Google Scholar 

  38. 38.

    Papanikolaou T, Ellerby LM (2009) IGF-1: elixir for motor neuron diseases. Neuron 63(3):277–278

    CAS  Article  PubMed  Google Scholar 

  39. 39.

    Fischbeck KH (2015) Spinal and bulbar muscular atrophy overview. J Mol Neurosci 58(3):317–320

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Nicola Laemmle for her excellent work as a study nurse and for her assistance with sample collection and Nayana Gaur for the critical reading of the manuscript.

Funding

This study was funded partly by the German Network of ALS (BMBF 01GM1103A).

Author information

Affiliations

Authors

Corresponding author

Correspondence to Albert C. Ludolph.

Ethics declarations

Conflicts of interest

The authors declare that they have no conflict of interest.

Ethical approval

All persons gave their informed consent prior to their inclusion in the study. The study was approved by the local ethics committee of the University of Ulm (73/10 and 92/10).

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Rosenbohm, A., Hirsch, S., Volk, A.E. et al. The metabolic and endocrine characteristics in spinal and bulbar muscular atrophy. J Neurol 265, 1026–1036 (2018). https://doi.org/10.1007/s00415-018-8790-2

Download citation

Keywords

  • Kennedy’s disease
  • Spinobulbar muscular atrophy
  • Motor neuron disease
  • Diabetes
  • Biomarker
  • MRI