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Current Pain and Headache Reports
Published in: Current Pain and Headache Reports 10/2013

01-10-2013 | Neuropathic Pain (E Eisenberg, Section Editor)

Fabry Disease: A Rare Cause of Neuropathic Pain

Authors: Marieke Biegstraaten, Gabor E. Linthorst, Ivo N. van Schaik, Carla E. M. Hollak

Published in: Current Pain and Headache Reports | Issue 10/2013

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Abstract

Fabry disease is characterized by burning or shooting pains in hands and feet, which have a severe impact on the quality of life of patients. It is therefore of importance that Fabry patients receive adequate diagnosis, counseling, treatment and follow up. This review describes neuropathic pain in classical Fabry disease with the aim to help clinicians to recognize Fabry patients among patients presenting with chronic extremity pain. The diagnostic dilemmas in patients with neuropathic pain and a non-classical disease course are discussed, together with the available diagnostic modalities, pain medication options and the effect of enzyme replacement therapy on small fiber neuropathy.
Literature
1.
Desnick RJ, Ioannou YA, Eng ME. A-galactosidase A deficiency: Fabry disease. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The metabolic and molecular bases of inherited disease. New York: McGraw-Hill; 2001. p. 3733–74.
2.
3.
Nakao S, Takenaka T, Maeda M, Kodama C, Tanaka A, Tahara M, et al. An atypical variant of Fabry's disease in men with left ventricular hypertrophy. N Engl J Med. 1995;333:288–93.PubMedCrossRef
4.
Lee BH, Heo SH, Kim GH, Park JY, Kim WS, Kang DH, et al. Mutations of the GLA gene in Korean patients with Fabry disease and frequency of the E66Q allele as a functional variant in Korean newborns. J Hum Genet. 2010;55:512–7.PubMedCrossRef
5.
Maier EM, Osterrieder S, Whybra C, Ries M, Gal A, Beck M, et al. Disease manifestations and X inactivation in heterozygous females with Fabry disease. Acta Paediatr Suppl. 2006;95:30–8.PubMedCrossRef
6.
MacDermot KD, Holmes A, Miners AH. Anderson-Fabry disease: clinical manifestations and impact of disease in a cohort of 60 obligate carrier females. J Med Genet. 2001;38:769–75.PubMedCrossRef
7.
Vedder AC, Linthorst GE, van Breemen MJ, Groener JE, Bemelman FJ, Strijland A, et al. The Dutch Fabry cohort: diversity of clinical manifestations and Gb3 levels. J Inherit Metab Dis. 2007;30:68–78.PubMedCrossRef
8.
Schiffmann R, Kopp JB, Austin HAI, Sabnis S, Moore DF, Weibel T, et al. Enzyme replacement therapy in Fabry disease: a randomized controlled trial. JAMA. 2001;285:2743–9.PubMedCrossRef
9.
Eng CM, Guffon N, Wilcox WR, Germain DP, Lee P, Waldek S, et al. Safety and efficacy of recombinant human alpha-galactosidase A–replacement therapy in Fabry's disease. N Engl J Med. 2001;345:9–16.PubMedCrossRef
10.
Schiffmann R, Askari H, Timmons M, Robinson C, Benko W, Brady RO, et al. Weekly enzyme replacement therapy may slow decline of renal function in patients with Fabry disease who are on long-term biweekly dosing. J Am Soc Nephrol. 2007;18:1576–83.PubMedCrossRef
11.
Hughes DA, Elliot PM, Shah J, Zuckerman J, Coghlan G, Brookes J, et al. Effects of enzyme replacement therapy on the cardiomyopathy of Anderson-Fabry disease: a randomised, double-blind, placebo-controlled clinical trial of agalsidase alfa. Heart. 2008;94:153–8.PubMedCrossRef
12.
Banikazemi M, Bultas J, Waldek S, Wilcox WR, Whitley CB, McDonald M, et al. Agalsidase-beta therapy for advanced Fabry disease: a randomized trial. Ann Intern Med. 2007;146:77–86.PubMedCrossRef
13.
Rombach SM, Smid BE, Bouwman MG, Linthorst GE, Dijkgraaf MG, Hollak CE. Long term enzyme replacement therapy for Fabry disease: effectiveness on kidney, heart and brain. Orphanet J Rare Dis. 2013;8:47.PubMedCrossRef
14.
Weidemann F, Niemann M, Störk S, Breunig F, Beer M, Sommer C, Herrmann S, Ertl G, Wanner C. Long-term outcome of enzyme-replacement therapy in advanced Fabry disease: evidence for disease progression towards serious complications. J Intern Med. 2013. doi:10.​1111/​joim.​12077.
15.
• Marchesoni CL, Roa N, Pardal AM, Neumann P, Cáceres G, Martínez P, et al. Misdiagnosis in Fabry disease. J Pediatr. 2010;156:828–31. This study of 45 Fabry patients revealed that pain is the presenting symptom in most patients, and that rheumatic fever was the most common diagnosis. The correct diagnosis was obtained after about 20 years.PubMedCrossRef
16.
Mehta A, Ricci R, Widmer U, Dehout F, Garcia de Lorenzo A, Kampmann C, et al. Fabry disease defined: baseline clinical manifestations of 366 patients in the Fabry Outcome Survey. Eur J Clin Invest. 2004;34:236–42.PubMedCrossRef
17.
Gold KF, Pastores GM, Botteman MF, Yeh JM, Sweeney S, Aliski W, et al. Quality of life of patients with Fabry disease. Qual Life Res. 2002;11:317–27.PubMedCrossRef
18.
Cole AL, Lee PJ, Hughes DA, Deegan PB, Waldek S, Lachmann RH. Depression in adults with Fabry disease: a common and under-diagnosed problem. J Inherit Metab Dis. 2007;30:943–51.PubMedCrossRef
19.
Biegstraaten M, Binder A, Maag R, Hollak CEM, Baron R, van Schaik IN. The relation between small nerve fibre function, age, disease severity and pain in Fabry disease. Eur J Pain. 2011;15:822–9.PubMedCrossRef
20.
MacDermot KD, Holmes A, Miners AH. Anderson-Fabry disease: clinical manifestations and impact of disease in a cohort of 98 hemizygous males. J Med Genet. 2001;38:750–60.PubMedCrossRef
21.
22.
Baron R, Binder A, Wasner G. Neuropathic pain: diagnosis, pathophysiological mechanisms, and treatment. Lancet Neurol. 2010;9:807–19.PubMedCrossRef
23.
Arning K, Naleschinski D, Maag R, Biegstraaten M, Kropp P, Lorenzen J, et al. FabryScan: a screening tool for early detection of Fabry disease. J Neurol. 2012;259:2393–400.PubMedCrossRef
24.
Tanislav C, Kaps M, Rolfs A, Böttcher T, Lackner K, Paschke E, et al. Frequency of Fabry disease in patients with small-fibre neuropathy of unknown aetiology: a pilot study. Eur J Neurol. 2011;18:631–6.PubMedCrossRef
25.
Aerts JM, Groener JE, Kuiper S, Donker-Koopman WE, Strijland A, Ottenhoff R, et al. Elevated globotriaosylsphingosine is a hallmark of Fabry disease. Proc Natl Acad Sci U S A. 2008;105:2812–7.PubMedCrossRef
26.
Rombach SM, Dekker N, Bouwman MG, Linthorst GE, Zwinderman AH, Wijburg FA, et al. Plasma globotriaosylsphingosine: diagnostic value and relation to clinical manifestations of Fabry disease. Biochim Biophys Acta. 2010;1802:741–8.PubMedCrossRef
27.
Dütsch M, Marthol H, Stemper B, Brys M, Haendl T, Hilz MJ. Small fiber dysfunction predominates in Fabry neuropathy. J Clin Neurophysiol. 2002;19:575–86.PubMedCrossRef
28.
Luciano CA, Russell JW, Banerjee TK, Quirk JM, Scott LJ, Dambrosia JM, et al. Physiological characterization of neuropathy in Fabry's disease. Muscle Nerve. 2002;26:622–9.PubMedCrossRef
29.
Maag R, Binder A, Maier C, Scherens A, Toelle T, Treede RD, et al. Detection of a characteristic painful neuropathy in Fabry disease: a pilot study. Pain Med. 2008;9:1217–23.PubMedCrossRef
30.
31.
Hoeijmakers JG, Faber CG, Lauria G, Merkies IS, Waxman SG. Small-fibre neuropathies–advances in diagnosis, pathophysiology and management. Nat Rev Neurol. 2012;8:369–79.PubMedCrossRef
32.
Devigili G, Tugnoli V, Penza P, Camozzi F, Lombardi R, Melli G, et al. The diagnostic criteria for small fibre neuropathy: from symptoms to neuropathology. Brain. 2008;131:1912–25.PubMedCrossRef
33.
Laaksonen SM, Roytta M, Jaaskelainen SK, Kantola I, Penttinen M, Falck B. Neuropathic symptoms and findings in women with Fabry disease. Clin Neurophysiol. 2008;119:1365–72.PubMedCrossRef
34.
Torvin Møller A, Winther Bach F, Feldt-Rasmussen U, Rasmussen A, Hasholt L, Lan H, et al. Functional and structural nerve fiber findings in heterozygote patients with Fabry disease. Pain. 2009;145:237–45.PubMedCrossRef
35.
Morgan SH, Rudge P, Smith SJM, Bronstein AM, Kendall BE, Holly E, et al. The neurological complications of Anderson-Fabry disease (alpha-galactosidase A deficiency)–investigation of symptomatic and presymptomatic patients. Q J Med. 1990;75:491–507.PubMed
36.
Low M, Nicholls K, Tubridy N, Hand P, Velakoulis D, Kiers L, et al. Neurology of Fabry disease. Intern Med J. 2007;37:436–47.PubMedCrossRef
37.
• Üçeyler N, He L, Schönfeld D, Kahn AK, Reiners K, Hilz MJ, et al. Small fibers in Fabry disease: baseline and follow-up data under enzyme replacement therapy. J Peripher Nerv Syst. 2011;16:304–14. This paper describes small fiber function and morphology at baseline and until 4 years follow-up in a large cohort of 120 Fabry patients. Functional impairment was found to be progressive, while skin biopsies from the back revealed an increase in IENFD in patients on ERT.PubMedCrossRef
38.
Valeriani M, Mariotti P, Le Pera D, Restuccia D, De Armas L, Maiese T, et al. Functional assessment of A delta and C fibers in patients with Fabry's disease. Muscle Nerve. 2004;30:708–13.PubMedCrossRef
39.
Üçeyler N, Kahn AK, Kramer D, Zeller D, Casanova-Molla J, Wanner C, et al. Impaired small fiber conduction in patients with Fabry disease: a neurophysiological case–control study. BMC Neurol. 2013;13:47.PubMedCrossRef
40.
Scott LJC, Griffin JW, Luciano C, Barton NW, Banerjee T, Crawford T, et al. Quantitative analysis of epidermal innervation in Fabry disease. Neurology. 1999;52:1249–54.PubMedCrossRef
41.
Biegstraaten M, Hollak CEM, Bakkers M, Faber CG, Aerts JMFG, van Schaik IN. Small fiber neuropathy in Fabry disease. Mol Genet Metab. 2012;106:135–41.PubMedCrossRef
42.
Shun CT, Wu HP, Hsieh SC, Lin WM, Lin YH, Tai TY, et al. Skin denervation in type 2 diabetes: correlations with diabetic duration and functional impairments. Brain. 2004;127:1593–605.PubMedCrossRef
43.
Vlckova-Moravcova E, Bednarik J, Belobradkova J, Sommer C. Small-fibre involvement in diabetic patients with neuropathic foot pain. Diabet Med. 2008;25:692–9.PubMedCrossRef
44.
Heldestad V, Nordh E. Quantified sensory abnormalities in early genetically verified transthyretin amyloid polyneuropathy. Muscle Nerve. 2007;35:189–95.PubMedCrossRef
45.
Onishi A, Dyck PJ. Loss of small peripheral sensory neurons in Fabry disease. Histologic and morphometric evaluation of cutaneous nerves, spinal ganglia, and posterior columns. Arch Neurol. 1974;31:120–7.PubMedCrossRef
46.
Kaye EM, Kolodny EH, Logigian EL, Ullman MD. Nervous system involvement in Fabry's disease: clinicopathological and biochemical correlation. Ann Neurol. 1988;23:505–9.PubMedCrossRef
47.
Gemignani F, Marbini A, Bragaglia MM, Govoni E. Pathological study of the sural nerve in Fabry's disease. Eur Neurol. 1984;23:173–81.PubMedCrossRef
48.
Schiffmann R, Scott LJC. Pathophysiology and assessment of neuropathic pain in Fabry disease. Acta Paediatr. 2002;439:S48–52.CrossRef
49.
Geevasinga N, Tchan M, Sillence D, Vucic S. Upregulation of inward rectifying currents and Fabry disease neuropathy. J Peripher Nerv Syst. 2012;17:399–406.PubMedCrossRef
50.
Penno A, Reilly MM, Houlden H, Laura M, Rentsch K, Niederkofler V, et al. Hereditary sensory neuropathy type 1 is caused by the accumulation of two neurotoxic sphingolipids. J Biol Chem. 2010;285:11178–87.PubMedCrossRef
51.
Filling-Katz MR, Merrick HF, Fink JK, Miles RB, Sokol J, Barton NW. Carbamazepine in Fabry's disease: effective analgesia with dose-dependent exacerbation of autonomic dysfunction. Neurology. 1989;39:598–600.PubMedCrossRef
52.
Ries M, Mengel E, Kutschke G, Kim KS, Birklein F, Krummenauer F, et al. Use of gabapentin to reduce chronic neuropathic pain in Fabry disease. J Inherit Metab Dis. 2003;26:413–4.PubMedCrossRef
53.
•• Burlina AP, Sims KB, Politei JM, Bennett GJ, Baron R, Sommer C, et al. Early diagnosis of peripheral nervous system involvement in Fabry disease and treatment of neuropathic pain: the report of an expert panel. BMC Neurol. 2011;11:61. This report provides guidance on how to diagnose unrecognized Fabry patients and offers useful recommendations to control neuropathic pain in patients with Fabry disease.PubMedCrossRef
54.
Schiffmann R, Hauer P, Freeman B, Ries M, Scott LJ, Polydefkis M, et al. Enzyme replacement therapy and intraepidermal innervation density in Fabry disease. Muscle Nerve. 2006;34:53–6.PubMedCrossRef
55.
Schiffmann R, Floeter MK, Dambrosia JM, Gupta S, Moore DF, Sharabi Y, et al. Enzyme replacement therapy improves peripheral nerve and sweat function in Fabry disease. Muscle Nerve. 2003;28:703–10.PubMedCrossRef
56.
Hilz MJ, Brys M, Marthol H, Stemper B, Dütsch M. Enzyme replacement therapy improves function of C-, Ad, and Ab-nerve fibers in Fabry neuropathy. Neurology. 2004;62:1066–72.PubMedCrossRef
Metadata
Title
Fabry Disease: A Rare Cause of Neuropathic Pain
Authors
Marieke Biegstraaten
Gabor E. Linthorst
Ivo N. van Schaik
Carla E. M. Hollak
Publication date
01-10-2013
Publisher
Springer US
Published in
Current Pain and Headache Reports / Issue 10/2013
Print ISSN: 1531-3433
Electronic ISSN: 1534-3081
DOI
https://doi.org/10.1007/s11916-013-0365-4

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