Autonomic nervous system activity in patients with Fabry disease


Background: Fabry disease is an inherited, multisystemic and progressive lysosomal storage disorder. The first symptoms of Fabry neuropathy reflect progressive loss of function of both peripheral somatic and autonomic nerve cells. We aimed to evaluate autonomic nervous system (ANS) activity in a cohort of patients with Fabry disease. Methods: ANS activity was evaluated by determining heart rate variability, spontaneous baroreflex sensitivity and ambulatory blood pressure in 9 patients with Fabry disease. Possible correlations between ANS activity and clinical phenotype were investigated. Results: Indices of global activity were frequently high, while ANS balance was disturbed only in a few patients. Sympathetic nervous system parameters were within normal ranges, but indices of parasympathetic parameters were highly variable. Baroreflex sensitivity was significantly correlated with glomerular filtration rate. Conclusion: Distribution of ASN activity indices is wide in patients with Fabry disease. Autonomic imbalance has been associated with non-Fabry chronic kidney disease and cardiovascular risk. In Fabry disease, monitoring of ANS activity may contribute to comprehensive disease staging, and may be of value in identifying patients at high risk of developing renal and cardiac events.

Share and Cite:

Alamartine, E. , Sury, A. , Roche, F. , Pichot, V. and Barthelemy, J. (2012) Autonomic nervous system activity in patients with Fabry disease. Open Journal of Internal Medicine, 2, 116-122. doi: 10.4236/ojim.2012.22021.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Zarate, Y. and Hopkin, R. (2008) Fabry’s disease. The Lancet, 372, 1427-1435. doi:10.1016/S0140-6736(08)61589-5
[2] Najafian, B., Svarstad, E., Bostad, L., Gubler, M.C., Tondel, C., et al. (2011) Progressive podocyte injury and globotriaosylceramide (GL-3) accumulation in young patients with Fabry disease. Kidney International, 79, 663-670. doi:10.1038/ki.2010.484
[3] Ramaswami, U., Najafian, B., Schieppati, A., Mauer, M. and Bichet, D.G. (2010) Assessment of renal pathology and dysfunction in children with Fabry disease. Clinical Journal of the American Society of Nephrology, 5, 365-370. doi:10.2215/CJN.08091109
[4] Tondel, C., Bostad, L., Hirth, A. and Svarstad, E. (2008) Renal biopsy findings in children and adolescents with Fabry disease and minimal albuminuria. American Journal of Kidney Diseases, 51, 767-776. doi:10.1053/j.ajkd.2007.12.032
[5] Schiffmann, R., Hauer, P., Freeman, B., Ries, M., Scott, L.J., et al. (2006) Enzyme replacement therapy and intraepidermal innervation density in Fabry disease. Muscle & Nerve, 34, 53-56. doi:10.1002/mus.20550
[6] Wanner, C., Oliveira, J.P., Ortiz, A., Mauer, M., Germain, D.P., et al. (2010) Prognostic indicators of renal disease progression in adults with Fabry disease: Natural history data from the Fabry registry. Clinical Journal of the American Society of Nephrology, 5, 2220-2228. doi:10.2215/CJN.04340510
[7] Kampmann, C., Wiethoff, C.M., Whybra, C., Baehner, F.A., Mengel, E., et al. (2008) Cardiac manifestations of Anderson-Fabry disease in children and adolescents. Acta Paediatrica, 97, 463-469. doi:10.1111/j.1651-2227.2008.00700.x
[8] Breunig, F., Weidemann, F., Strotmann, J., Knoll, A. and Wanner, C. (2006) Clinical benefit of enzyme replacement therapy in Fabry disease. Kidney International, 69, 1216-1221. doi:10.1038/
[9] Schiffmann, R., Waldek, S., Benigni, A. and Auray-Blais, C. (2010) Biomarkers of Fabry disease nephropathy. Clinical Journal of the American Society of Nephrology, 5, 360-364. doi:10.2215/CJN.06090809
[10] Wilcox, W.R., Oliveira, J.P., Hopkin, R.J., Ortiz, A., Banikazemi, M., et al. (2008) Females with Fabry disease frequently have major organ involvement: Lessons from the Fabry registry. Molecular Genetics and Metabolism, 93, 112-128. doi:10.1016/j.ymgme.2007.09.013
[11] Cable, W.J., Kolodny, E.H. and Adams, R.D. (1982) Fabry disease: Impaired autonomic function. Neurology, 32, 498-502. doi:10.1212/WNL.32.5.498
[12] Dutsch, M., Marthol, H., Stemper, B., Brys, M., Haendl, T., et al. (2002) Small fiber dysfunction predominates in Fabry neuropathy. Journal of Clinical Neurophysiology, 19, 575-586. doi:10.1097/00004691-200212000-00011
[13] Hilz, M.J., Marthol, H., Schwab, S., Kolodny, E.H., Brys, M., et al. (2010) Enzyme replacement therapy improves cardiovascular responses to orthostatic challenge in Fabry patients. Journal of Hypertension, 28, 1438-1448. doi:10.1097/HJH.0b013e328336a077
[14] Pintos-Morell, G. and Beck, M. (2009) Fabry disease in children and the effects of enzyme replacement treatment. European Journal of Pediatrics, 168, 1355-1363. doi:10.1007/s00431-009-0937-9
[15] Lidove, O., West, M.L., Pintos-Morell, G., Reisin, R., Nicholls, K., et al. (2010) Effects of enzyme replacement therapy in Fabry disease—A comprehensive review of the medical literature. Genetics in Medicine, 12, 668-679. doi:10.1097/GIM.0b013e3181f13b75
[16] Schaefer, R.M., Tylki-Szymanska, A. and Hilz, M.J. (2009) Enzyme replacement therapy for Fabry disease: A systematic review of available evidence. Drugs, 69, 2179-2205. doi:10.2165/11318300-000000000-00000
[17] Ortiz, A., Oliveira, J.P., Wanner, C., Brenner, B.M., Waldek, S., et al. (2008) Recommendations and guidelines for the diagnosis and treatment of Fabry nephropathy in adults. Nature Reviews Nephrology, 4, 327-336. doi:10.1038/ncpneph0806
[18] Weidemann, F., Linhart, A., Monserrat, L. and Strotmann, J. (2010) Cardiac challenges in patients with Fabry disease. International Journal of Cardiology, 141, 3-10. doi:10.1016/j.ijcard.2009.08.002
[19] Malik, M. (1996) Heart rate variability: Standards of measurement, physiological interpretation and clinical use. Task force of the European society of cardiology and the North American society of pacing and electrophysiology. Circulation, 93, 1043-1065.
[20] Pichot, V., Gaspoz, J.M., Molliex, S., Antoniadis, A., Busso, T., et al. (1999) Wavelet transform to quantify heart rate variability and to assess its instantaneous changes. Journal of Applied Physiology, 86, 1081-1091.
[21] Cerutti, C., Barres, C. and Paultre, C. (1994) Baroreflex modulation of blood pressure and heart rate variabilities in rats: Assessment by spectral analysis. American Journal of Physiology, 266, H1993-H2000.
[22] Akselrod, S., Gordon, D., Ubel, F.A., Shannon, D.C., Berger, A.C., et al. (1981) Power spectrum analysis of heart rate fluctuation: A quantitative probe of beat-to-beat cardiovascular control. Science, 213, 220-222. doi:10.1126/science.6166045
[23] Pagani, M., Lombardi, F., Guzzetti, S., Rimoldi, O., Furlan, R., et al. (1986) Power spectral analysis of heart rate and arterial pressure variabilities as a marker of sympatho-vagal interaction in man and conscious dog. Circulation Research, 59, 178-193.
[24] Parlow, J., Viale, J.P., Annat, G., Hughson, R. and Quintin, L. (1995) Spontaneous cardiac baroreflex in humans. Comparison with drug-induced responses. Hypertension, 25, 1058-1068.
[25] Bavanandan, S., Ajayi, S., Fentum, B., Paul, S.K., Carr, S.J., et al. (2005) Cardiac baroreceptor sensitivity: A prognostic marker in predialysis chronic kidney disease patients? Kidney International, 67, 1019-1027. doi:10.1111/j.1523-1755.2005.00165.x
[26] Blankestijn, P.J. (2004) Sympathetic hyperactivity in chronic kidney disease. Nephrology Dialysis Transplantation, 19, 1354-1357. doi:10.1093/ndt/gfh242
[27] Foley, R.N., Parfrey, P.S. and Sarnak, M.J. (1998) Clinical epidemiology of cardiovascular disease in chronic renal disease. American Journal of Kidney Diseases, 32, S112-S119. doi:10.1053/ajkd.1998.v32.pm9820470
[28] Furuland, H., Linde, T., Englund, A. and Wikstrom, B. (2008) Heart rate variability is decreased in chronic kidney disease but may improve with hemoglobin normalization. Journal of Nephrology, 21, 45-52.
[29] Koomans, H.A., Blankestijn, P.J. and Joles, J.A. (2004) Sympathetic hyperactivity in chronic renal failure: A wakeup call. Journal of the American Society of Nephrology, 15, 524-537. doi:10.1097/01.ASN.0000113320.57127.B9
[30] Masuo, K., Lambert, G.W., Esler, M.D., Rakugi, H., Ogihara, T., et al. (2010) The role of sympathetic nervous activity in renal injury and end-stage renal disease. Hpertension Research, 33, 521-528. doi:10.1038/hr.2010.35
[31] Bigger, J.T., Jr., Fleiss, J.L., Steinman, R.C., Rolnitzky, L.M., Kleiger, R.E., et al. (1992) Frequency domain measures of heart period variability and mortality after myocardial infarction. Circulation, 85, 164-171.
[32] Tsuji, H., Larson, M.G., Venditti, F.J., Jr., Manders, E.S., Evans, J.C., et al. (1996) Impact of reduced heart rate variability on risk for cardiac events. The Framingham Heart Study. Circulation, 94, 2850-2855.
[33] Kleiger, R.E., Miller, J.P., Bigger, J.T., Jr. and Moss, A.J. (1987) Decreased heart rate variability and its association with increased mortality after acute myocardial infarction. American Journal of Cardiology, 59, 256-262. doi:10.1016/0002-9149(87)90795-8
[34] Rombach, S.M., Twickler, T.B., Aerts, J.M., Linthorst, G.E., Wijburg, F.A., et al. (2010) Vasculopathy in patients with Fabry disease: Current controversies and research directions. Molecular Genetics and Metabolism, 99, 99-108. doi:10.1016/j.ymgme.2009.10.004
[35] Biegstraaten, M., van Schaik, I.N., Wieling, W., Wijburg, F.A. and Hollak, C.E. (2010) Autonomic neuropathy in Fabry disease: A prospective study using the Autonomic Symptom Profile and cardiovascular autonomic function tests. BMC Neurology, 10, 38. doi:10.1186/1471-2377-10-38
[36] Auray-Blais, C., Cyr, D., Ntwari, A., West, M.L., Cox-Brinkman, J., et al. (2008) Urinary globotriaosylceramide excretion correlates with the genotype in children and adults with Fabry disease. Molecular Genetics and Metabolism, 93, 331-340. doi:10.1016/j.ymgme.2007.10.001
[37] Beck, M. (2006) The Mainz Severity Score Index (MSSI): Development and validation of a system for scoring the signs and symptoms of Fabry disease. Acta Paediatrica, 95, 43-46. doi: 10.1111/j.1651-2227.2006.tb02388.x
[38] Giannini, E.H., Mehta, A.B., Hilz, M.J., Beck, M., Bichet, D.G., et al. (2010) A validated disease severity scoring system for Fabry disease. Molecular Genetics and Metabolism, 99, 283-290. doi:10.1016/j.ymgme.2009.10.178
[39] Hughes, D.A., Ramaswami, U., Barba Romero, M.A. and Deegan, P. (2010) Age adjusting severity scores for Anderson-Fabry disease. Molecular Genetics and Metabolism, 101, 219-227. doi:10.1016/j.ymgme.2010.06.002

Copyright © 2023 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.