Department of Neurology, Universidade Metropolitana de Santos, Rua da Constituicao 374, CEP 11015-470, Santos SP, Brazil.
This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License (http://creativecommons.org/licenses/by-nc-sa/3.0/), which allows others to remix, tweak and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.
Fabry disease (FD) is a rare, progressive, multisystem and highly debilitating disease. FD is an X-linked lysosome storage disorder that results in α-galactosidase A deficiency. The subsequent accumulation of glycosphingolipids is more evident in vascular endothelium and smooth-muscle cells. The resulting effect of the deposition is generalized inflammation and vasculopathy, which can also affect the central and peripheral nervous system. FD progresses with kidney dysfunction, angiokeratoma of the skin, cardiomyopathy, cerebrovascular events and neurological disorders. In the present review, the neurological manifestations of FD are summarized with emphasis on cerebral vasculopathy, cochlear nerve dysfunction, psychiatric and cognitive symptoms, autonomic dysfunction and peripheral neuropathy. Enzyme replacement therapy is also discussed in the light of its more prominent effects when administered early in life, which make it essential to diagnose FD as soon as possible.
Fabry disease, glycosphingolipids, α-galactosidase A, enzyme replacement therapy, neurology
Fabry disease (FD; Online mendelian inheritance in man #301500) is a rare, progressive, multisystem and highly debilitating lysosome storage disorder, resulting in α-galactosidase A (α-Gal A) (*300644) deficiency. FD birth prevalence is approximately 1:40,000 and more than 600 mutations in the α-Gal have been described. The disease is X-linked inherited,[1,2] and X-inactivation in women may render them vulnerable to severe manifestations of FD.[3,4] Even with the same gene mutation there is an intrafamilial variability of phenotypical presentation of FD, leading to variable signs, symptoms and severity of the disease.
α-Gal A deficiency leads to progressive accumulation of glycosphingolipids such as globotriaosylceramide (GL-3) in various tissues and organs. The accumulation is predominantly in vascular endothelial and smooth-muscle cells. In the 19th century, William Anderson and Johannes Fabry described angiokeratoma of the skin as the first clinical sign of the disease. Subsequently, identification of kidney dysfunction, cardiomyopathy, gastrointestinal disorders, cerebrovascular events and other neurological disabilities was reported. These conditions are the most severe clinical manifestation of FD and may lead to increased morbidity and mortality, with concomitant reduction in life expectancy. While the literature on the skin, kidney and cardiovascular manifestations of FD has been consistent, there have been very few reports on the neurological aspects of the disease.
The aim of this article was to describe the neurological manifestations in FD. They may occur at any stage of the disease, including its onset. Therefore, although relatively rare, FD is a differential diagnosis for young individuals with unexplained neurological manifestations.
The prevalence of cerebrovascular diseases such as stroke events in FD patients is 4-6%. These events may be the first clinical manifestation of the disease and are more often observed between the ages of 18 and 55 years, affecting both genders equally.
Cerebral endothelial vasculopathy in FD is not fully understood, but it is accepted that GL-3 accumulation and polymorphisms of pro-thrombotic genes can modify Virchow’s triad and create a pro-thrombotic state.[12,13] These alterations include changes to interleukin-6-G-174C, G894T of endothelial nitric oxide synthase, factor V G1691A mutation and protein Z A-13G or G79A. Few studies have concentraded on intravenous thrombolytic therapy for acute ischemic stroke in FD patients and the outcomes are not fully understood.
Although ischemic stroke and transient ischemic attacks are the main types of cerebrovascular events in FD, cerebral hemorrhage, microbleeding, cerebral venous thrombosis and cervical carotid dissection have also been reported. The main etiology of stroke comes from the effect of the disease on the small arteries. The posterior circulation (vertebrobasilar system) is often more involved than the carotid system.[15-18]
White matter lesions are a reflection of secondary microangiopathy involvement of the central nervous system. As many as 80% of these patients present these abnormalities on magnetic resonance imaging (MRI), even without clinical symptoms of focal neurological involvement. Increased cerebral blood flow, vascular hyper-reactivity and GL-3 deposition ultimately induce cell dysfunction and increase interstitial pressure, thus generating vulnerability of elongated perforating arteries and leading to reduction of cerebral blood flow.
Brain microangiopathy in FD can be misdiagnosed as multiple sclerosis due to intermittent disseminated sensory deficits and white matter lesions fulfilling the McDonald criteria.[20-22] However, T2-FLAIR MRI of the white matter usually produces asymmetric and confluent images, with little involvement of the corpus callosum and no enhancement of the lesion through gadolinium. There are no lesions in the spinal cord. These characteristics help differentiating FD images from multiple sclerosis. Vertebrobasilar system ectasia, proteinuria, cardiac hypertrophy and histories of death among young relatives (renal, cardiac or cerebrovascular causes) are other frequently found elements in these patients’ medical history.[24,25]
Calcification of cerebrovascular dolichoectasia in cerebral white matter and thalamus (pulvinar region) is due to dysfunction of the cerebrovascular circulation and to GL-3 accumulation. Cerebrovascular hyperperfusion reflects the increased vascular reactivity and the effect on the nitric oxide pathway, while increased oxidative stress and formation of peroxynitrite can create persistent vasodilation and increased risk of atherosclerosis.
The data in the literature on the pathogenesis of cochlear dysfunction in FD are limited. It has been hypothesized that GL-3 accumulation in the cochlear nerve can progress to hearing loss, especially at 2-3 kHz.
High prevalence of neuropsychiatric symptoms, such as depression and neuropsychological deficits, reduces quality of life among FD patients. Although the pathophysiological mechanisms have not been fully elucidated, cerebral vasculopathy is involved. Furthermore, FD patients may be chronically distressed by pain and psychosocial impairment.[28-30]
Hypohidrosis, reduced saliva flow and impaired tear production may be present and have mechanisms that are not fully understood. GL-3 accumulation in autonomic ganglia and dysfunction of eccrine glands are found in patients with FD. Gastrointestinal symptoms (which may be associated with autonomic dysfunction) are the second most common clinical manifestation among children and young adults with FD. During unexplained attacks of abdominal pain, the patients may also suffer from postprandial flatulence and bouts of diarrhea.[31,32]
Peripheral neuropathy has an important negative impact on quality of life among FD patients. It has been described as being present since the beginning of GL-3 deposition, i.e. from these patients’ first years of life. It affects both genders equally, and is often associated with fever and pain during exercise. The pain may last for periods ranging from minutes up to several days, and may be incapacitating.[31-35]
As mentioned above regarding other neurological manifestations of FD, the pathophysiological mechanisms of neuropathy are not fully understood either. It has been proposed that inhibition of central nociceptors would occur as a result of constant activation of nociceptive afferents, in association with neuronal dysfunction, Wallerian degeneration, activation of the inflammatory cascade, vasa nervorum ischemia and molecular changes in the peripheral nociceptor, similar to dying-back neuropathies.[36-40] In addition, disproportion and dysfunction of axonal sodium channels would increase the frequency of nociceptive discharge. This last topic has practical importance, since pain treatment in these patients must be carried out using sodium channel-blocking drugs such as carbamazepine. Involvement of distal, small Aδ- myelinated fibers and C-unmyelinated fibers is prevalent among patients with symptoms relating to temperature. It is important to establish a uniform quantitative assessment battery for sensitive symptoms.[41-45]
Enzyme replacement therapy with humanized recombinant α-Gal A (agalsidade beta, or more recently, agalsidase alpha) reduces the secondary clinical events relating to FD by 60% to 80%. The effect of this enzyme replacement is seen in prevention of cerebral, renal and cardiological life-threatening events, which, in untreated patients, are responsible for more than 90% of deaths.[46,47] There is evidence that early treatment with enzyme replacement therapy can stabilize vascular disease progression and decrease the risk of stroke. Patients may have different response to treatment with agalsidade alpha or beta.[49-51]
Neurological manifestations of FD are often related to significant morbidity and mortality. Early detection and specific treatment of neurological involvement in cases of α-Gal A deficiency may result in improved quality of life for patients with FD.
There are no conflicts of interest.
No patient involved.
This article does not contain any studies with human participants or animals.
1. Desnick RJ, Brady R, Barranger J, Collins AJ, Germain DP, Goldman M, Grabowski G, Packman S, Wilcox WR. Fabry disease, an under-recognized multisystemic disorder: expert recommendations for diagnosis, management, and enzyme replacement therapy. Ann Intern Med 2003;138:338-46.DOIPubMed
2. Van der Tol L, Smid BE, Poorthuis BJ, Biegstraaten M, Deprez RH, Linthorst GE, Hollak CE. A systematic review on screening for Fabry disease: prevalence of individuals with genetic variants of unknown significance. J Med Genet 2014;51:1-9.DOIPubMed
3. Bowman MG, Rombach SM, Linthorst GE, Poorthuis BJ, Deprez RH, Aerts JM, Wijburg FA. Early cerebral manifestations in a young female with Fabry disease with skewed X-inactivation. Clin Genet 2011;80:500-2.DOIPubMed
4. Echevarria L, Benistan K, Toussaint A, Dubourg O, Hagege AA, Eladari D, Jabbour F, Beldjord C, De Mazancourt P, Germain DP. X-chromosome inactivation in female patients with Fabry disease. Clin Genet 2016;89:44-54.DOIPubMed
5. Rigoldi M, Concolino D, Morrone A, Pieruzzi F, Ravaglia R, Furlan F, Santus F, Strisciuglio P, Torti G, Parini R. Intrafamilial phenotypic variability in four families with Anderson-Fabry disease. Clin Genet 2014;86:258-63.DOIPubMed
6. Najafian B, Fogo AB, Lusco MA, Alpers CE. AJKD Atlas of Renal Pathology: fabry nephropathy. Am J Kidney Dis 2015;66:e35-6.
7. Frustaci A, Morgante E, Russo MA, Scopelliti F, Grande C, Verardo R, Franciosa P, Chimenti C. Pathology and function of conduction tissue in Fabry disease cardiomyopathy. Circ Arrhythm Electrophysiol 2015;8:799-805.DOIPubMed
8. Politei J, Thurberg BL, Wallace E, Warnock D, Serebrinsky G, Durand C, Schenone AB. Gastrointestinal involvement in Fabry disease. So important, yet often neglected. Clin Genet 2016;89:5-9.DOIPubMed
9. Moore DF, Kaneski CR, Askari H, Schiffmann R. The cerebral vasculopathy of Fabry disease. J Neurol Sci 2007;257:258-63.DOIPubMed
10. Zarate YA, Hopkin RJ. Fabry's disease. Lancet 2008;372:1427-35.DOI
11. Mitsias P, Levine SR. Cerebrovascular complications of Fabry's disease. Ann Neurol 1996;40:8-17.DOIPubMed
12. Utsumi K, Ueda K, Watanabe M, Sakamaki M, Arii K, Yamazaki M, Komaba Y, Katsura K, Iino Y, Katayama Y. Thrombosis in Japanese patients with Fabry disease. J Neurol Sci 2009;283:83-5.DOIPubMed
13. Altarescu G, Moore DF, Schiffmann R. Effect of genetic modifiers on cerebral lesions in Fabry disease. Neurology 2005;64:2148-50.DOIPubMed
14. Saarinen JT, Sillanpää N, Kantola I. A male Fabry disease patient treated with intravenous thrombolysis for acute ischemic stroke. J Clin Neurosci 2015;2:423-5.DOIPubMed
15. Moore DF, Herscovitch P, Schiffmann R. Selective arterial distribution of cerebral hyperperfusion in Fabry disease. J Neuroimaging 2001;11:303-7.DOIPubMed
16. Crutchfield KE, Patronas NJ, Dambrosia JM, Frei KP, Banerjee TK, Barton NW, Schiffmann R. Quantitative analysis of cerebral vascular disease in patients with Fabry disease. Neurology 1998;50:1746-9.DOIPubMed
17. Moore DF, Ye F, Schiffmann R, Butman JA. Increased signal intensity in the pulvinar on T1-weighted images: a pathognomonic sign of MR imaging Fabry disease. AJNR Am J Neuroradiol 2003;24:1096-101.
18. Hilz MJ, Kolodny EH, Brys M, Stemper B, Haendl T, Marthol H. Reduced cerebral blood flow velocity and impaired cerebral autoregulation in patients with Fabry disease. J Neurol 2004;251:564-70.DOIPubMed
19. Moore DF, Altarescu G, Barker WC, Patronas NJ, Herscovitch P, Schiffmann R. White matter lesions in Fabry disease Occur in 'prior' selectively hypometabolic and hypoperfusion brain regions. Brain Res Bull 2003;62:231-40.DOIPubMed
20. Saip S, Uluduz D, Erkol G. Fabry disease mimicking multiple sclerosis. Clin Neurol Neurosurg 2007;109:361-3.DOIPubMed
21. Invernizzi P, Bonometti MA, Turri E, Benedetti MD, Salviati A. A case of Fabry disease with central nervous system (CNS) demyelinating lesions: a double trouble? Mult Scler 2008;14:1003-6.
22. Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, Fujihara K, Havrdova E, Hutchinson M, Kappos L, Lublin FD, Montalban X, O'Connor P, Sandberg-Wollheim M, Thompson AJ, Waubant E, Weinshenker B, Wolinsky JS. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 2011;69:292-302.DOIPubMedPMC
23. Fazekas F, Enzinger C, Schmidt R, Grittner U, Giese AK, Hennerici MG, Huber R, Jungehulsing GJ, Kaps M, Kessler C, Martus P, Putaala J, Ropele S, Tanislav C, Tatlisumak T, Thijs V, von Sarnowski B, Norrving B, Rolfs A; SIFAP 1 Investigators. Brain magnetic resonance imaging findings fail to suspect Fabry disease in young patients with an acute cerebrovascular event. Stroke 2015;46:1548-53.DOIPubMed
24. Tuttolomondo A, Pecoraro R, Simonetta I, Miceli S, Pinto A, Licata G. Anderson-Fabry disease: a multiorgan disease. Curr Pharm Des 2013;19:5974-96.DOIPubMed
25. Laney DA, Fernhoff PM. Diagnosis of Fabry disease via analysis of family history. J Genet Couns 2008;17:79-83.DOIPubMed
26. Wei EP, Kontos HA, Beckman JS. Mechanisms of cerebral vasodilation by superoxide, hydrogen peroxide, and peroxynitrite. Am J Physiol 1996;271:H1262-6.
27. Sakurai Y, Kojima H, Shiwa M, Ohashi T, Eto Y, Moriyama H. The hearing status in 12 female and 15 male Japanese Fabry patients. Auris Nasus Larynx 2009;36:627-32.DOIPubMed
28. Mendez MF, Stanley TM, Medel NM, Li Z, Tedesco DT. The vascular dementia of Fabry's disease. Dement Geriatr Cogn Disord 1997;8:252-7.DOIPubMed
29. Liston EH, Levine MD, Philippart M. Psychosis in Fabry disease and treatment with phenoxybenzamine. Arch Gen Psychiatry 1973;29:402-3.DOIPubMed
30. Grewal RP. Psychiatric disorders in Patients with Fabry's disease. Int J Psychiatry Med 1993;23:307-12.DOIPubMed
31. Eng CM, Fletcher J, Wilcox WR, Waldek S, Scott CR, Sillence DO, Breunig F, Charrow J, Germain DP, Nicholls K, Banikazemi M. Fabry disease: baseline medical characteristics of a cohort of 1765 males and females in the Fabry Registry. J Inherit Metab Dis 2007;30:184-92.DOIPubMed
32. Mehta A, Ricci R, Widmer U, Dehout F, Garcia de Lorenzo A, Kampmann C, Linhart A, Sunder-Plassmann G, Ries M, Beck M. Fabry disease defined: baseline clinical manifestations of 366 patients in the Fabry Outcome Survey. Eur J Clin Invest 2004;34:236-42.DOIPubMed
33. MacDermot J, MacDermot KD. Neuropathic pain in Anderson-Fabry disease: pathology and therapeutic options. Eur J Pharmacol 2001;429:121-5.DOI
34. Le Bars D, Dickenson AH, Besson JM. Diffuse noxious inhibitory controls (DNIC). I. Effects on dorsal horn convergent neurones in the rat. Pain 1979;6:283-304.DOI
35. Dickenson AH, Mathews EA, Suzuki R. Central nervous system mechanisms of pain in peripheral neuropathy. In: Hansson PT, Fields HL, RG Hill, Marchettini P, editors. Neuropathic pain: pathophysiology and treatment. Seattle: IASP Press; 2001. pp. 85-106.
36. Sato J, Perl ER. Adrenergic excitation of cutaneous pain receptors induced by peripheral nerve injury. Science 1991;251:1608-10.DOIPubMed
37. Birklein F, Schmelz M, Schifter S, Weber M. The important role of neuropeptides in complex regional pain syndrome. Neurology 2001;57:2179-84.DOIPubMed
38. Hilz MJ, Stemper B, Kolodny EH. Lower limb cold exposure induces pain and Prolonged small fiber dysfunction in Fabry Patients. Pain 2000;84:361-5.DOI
39. Amir R, Michaelis M, Devor M. Membrane potential oscillations in dorsal root ganglion neurons: role in normal electrogenesis and neuropathic pain. J Neurosci 1999;19:8589-96.
40. Dib-Hajj SD, Fjell J, Cummins TR, Zheng Z, Fried K, LaMotte R, Black JA, Waxman SG. Plasticity of sodium channel expression in DRG neurons in the chronic constriction injury model of neuropathic pain. Pain 1999;83:591-600.DOI
41. Tal M, Wall PD, Devor M. Myelinated afferent fiber types that become spontaneously active and mechanosensitive following nerve transection in the rat. Brain Res 1999;824:218-23.DOI
42. Luciano CA, Russell JW, Banerjee TK, Quirk JM, Scott LJ, Dambrosia JM, Barton NW, Schiffmann R. Physiological characterization of neuropathy in Fabry's disease. Muscle Nerve 2002;26:622-9.DOIPubMed
43. Deutsch 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.DOI
44. Dyck PJ, O'Brien PC, Kosanke JL, Gillen DA, Karnes JL. The 4, 2, and 1 stepping algorithm for quick and accurate estimation of cutaneous sensation threshold. Neurology 1993;43:1508-12.DOIPubMed
45. Dyck PJ, Zimmerman I, Gillen DA, Johnson D, Karnes JL, O'Brien PC. Cool, warm, and heat-pain detection thresholds: testing methods and inferences about anatomic distribution of receptors. Neurology 1993;43:1500-8.DOIPubMed
46. Maag R, Binder A, Maier C, Scherens A, Toelle T, Treede RD, Baron R. Detection of the characteristic painful neuropathy in Fabry disease: a pilot study. Pain Med 2008;9:1217-23.DOIPubMed
47. Banikazemi M, Bultas J, Waldek S, Wilcox WR, Whitley CB, McDonald M, Finkel R, Packman S, Bichet DG, Warnock DG, Desnick RJ; Fabry Disease Clinical Trial Study Group. Agalsidase-beta therapy for advanced Fabry disease: a randomized trial. Ann Intern Med 2007;146:77-86.DOIPubMed
48. Germain DP, Charrow J, Desnick RJ, Guffon N, Kempf J, Lachmann RH, Lemay R, Linthorst GE, Packman S, Scott CR, Waldek S, Warnock DG, Weinreb NJ, Wilcox WR. Ten-year outcome of enzyme replacement therapy with agalsidase beta in patients with Fabry disease. J Med Genet 2015;52:353-8.DOIPubMedPMC
49. Fellgiebel A, Gartenschläger M, Wildberger K, Scheurich A, Desnick RJ, Sims K. Enzyme replacement therapy stabilized white matter lesion progression in Fabry disease. Cerebrovasc Dis 2014;38:448-56.DOIPubMed
50. Tsuboi K, Yamamoto H, Somura F, Goto H. Successful management of enzyme replacement therapy in related fabry disease patients with severe adverse events by switching from agalsidase Beta (fabrazyme(®)) to agalsidase alfa (replagal (®)). JIMD Rep 2015;15:105-11.
51. Politei J, Schenone AB, Cabrera G, Heguilen R, Szlago M. Fabry disease and enzyme replacement therapy in classic patients with same mutation: different formulations - different outcome? Clin Genet 2016;89:88-92.
Brooks JBB, Fragoso YD. Neurological manifestations in Fabry disease. Neuroimmunol Neuroinflammation 2016;3:228-231. http://dx.doi.org/10.20517/2347-8659.2016.36
Full-Text Views Each Month
PDF Downloads Each Month
Quantities of Citations Each Year
* All the data come from Crossref