Cerebrovascular Involvement in Fabry Disease
2014; Lippincott Williams & Wilkins; Volume: 46; Issue: 1 Linguagem: Inglês
10.1161/strokeaha.114.006283
ISSN1524-4628
AutoresEdwin H. Kolodny, Andreas Fellgiebel, Max J. Hilz, Katherine B. Sims, Paul A. Caruso, Thanh G. Phan, Juan Politei, Renzo Manara, Alessandro P. Burlina,
Tópico(s)Cerebrovascular and genetic disorders
ResumoHomeStrokeVol. 46, No. 1Cerebrovascular Involvement in Fabry Disease Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBCerebrovascular Involvement in Fabry DiseaseCurrent Status of Knowledge Edwin Kolodny, MD, Andreas Fellgiebel, MD, Max J. Hilz, MD, Katherine Sims, MD, Paul Caruso, MD, Thanh G. Phan, FRACP, PhD, Juan Politei, MD, Renzo Manara, MD and Alessandro Burlina, MD, PhD Edwin KolodnyEdwin Kolodny From the Department of Neurology, New York University School of Medicine (E.K.); Department of Psychiatry and Psychotherapy, University Medical Center Mainz, Mainz, Germany (A.F.); Department of Neurology, University of Erlangen-Nuremberg, Erlangen, Germany (M.J.H.); Center for Human Genetic Research and Neurology Department (K.S.), Division of Neuroradiology, Department of Radiology (P.C.), Harvard Medical School, Massachusetts General Hospital, Boston; Stroke Unit, Department of Neurosciences, Monash Health and Stroke and Aging Research Group, Department of Medicine, Monash University, Australia (T.G.P.); Department of Neurology, Fundacion Para el Estudio de Enfermedades Neurometabolicas (FESEN), Buenos Aires, Argentina (J.P.); Department of Neuroradiology, University of Salerno, Salerno, Italy (R.M.); and Neurological Unit, Department of Internal Medicine, St Bassiano Hospital, Bassano del Grappa, Italy (A.B.). , Andreas FellgiebelAndreas Fellgiebel From the Department of Neurology, New York University School of Medicine (E.K.); Department of Psychiatry and Psychotherapy, University Medical Center Mainz, Mainz, Germany (A.F.); Department of Neurology, University of Erlangen-Nuremberg, Erlangen, Germany (M.J.H.); Center for Human Genetic Research and Neurology Department (K.S.), Division of Neuroradiology, Department of Radiology (P.C.), Harvard Medical School, Massachusetts General Hospital, Boston; Stroke Unit, Department of Neurosciences, Monash Health and Stroke and Aging Research Group, Department of Medicine, Monash University, Australia (T.G.P.); Department of Neurology, Fundacion Para el Estudio de Enfermedades Neurometabolicas (FESEN), Buenos Aires, Argentina (J.P.); Department of Neuroradiology, University of Salerno, Salerno, Italy (R.M.); and Neurological Unit, Department of Internal Medicine, St Bassiano Hospital, Bassano del Grappa, Italy (A.B.). , Max J. HilzMax J. Hilz From the Department of Neurology, New York University School of Medicine (E.K.); Department of Psychiatry and Psychotherapy, University Medical Center Mainz, Mainz, Germany (A.F.); Department of Neurology, University of Erlangen-Nuremberg, Erlangen, Germany (M.J.H.); Center for Human Genetic Research and Neurology Department (K.S.), Division of Neuroradiology, Department of Radiology (P.C.), Harvard Medical School, Massachusetts General Hospital, Boston; Stroke Unit, Department of Neurosciences, Monash Health and Stroke and Aging Research Group, Department of Medicine, Monash University, Australia (T.G.P.); Department of Neurology, Fundacion Para el Estudio de Enfermedades Neurometabolicas (FESEN), Buenos Aires, Argentina (J.P.); Department of Neuroradiology, University of Salerno, Salerno, Italy (R.M.); and Neurological Unit, Department of Internal Medicine, St Bassiano Hospital, Bassano del Grappa, Italy (A.B.). , Katherine SimsKatherine Sims From the Department of Neurology, New York University School of Medicine (E.K.); Department of Psychiatry and Psychotherapy, University Medical Center Mainz, Mainz, Germany (A.F.); Department of Neurology, University of Erlangen-Nuremberg, Erlangen, Germany (M.J.H.); Center for Human Genetic Research and Neurology Department (K.S.), Division of Neuroradiology, Department of Radiology (P.C.), Harvard Medical School, Massachusetts General Hospital, Boston; Stroke Unit, Department of Neurosciences, Monash Health and Stroke and Aging Research Group, Department of Medicine, Monash University, Australia (T.G.P.); Department of Neurology, Fundacion Para el Estudio de Enfermedades Neurometabolicas (FESEN), Buenos Aires, Argentina (J.P.); Department of Neuroradiology, University of Salerno, Salerno, Italy (R.M.); and Neurological Unit, Department of Internal Medicine, St Bassiano Hospital, Bassano del Grappa, Italy (A.B.). , Paul CarusoPaul Caruso From the Department of Neurology, New York University School of Medicine (E.K.); Department of Psychiatry and Psychotherapy, University Medical Center Mainz, Mainz, Germany (A.F.); Department of Neurology, University of Erlangen-Nuremberg, Erlangen, Germany (M.J.H.); Center for Human Genetic Research and Neurology Department (K.S.), Division of Neuroradiology, Department of Radiology (P.C.), Harvard Medical School, Massachusetts General Hospital, Boston; Stroke Unit, Department of Neurosciences, Monash Health and Stroke and Aging Research Group, Department of Medicine, Monash University, Australia (T.G.P.); Department of Neurology, Fundacion Para el Estudio de Enfermedades Neurometabolicas (FESEN), Buenos Aires, Argentina (J.P.); Department of Neuroradiology, University of Salerno, Salerno, Italy (R.M.); and Neurological Unit, Department of Internal Medicine, St Bassiano Hospital, Bassano del Grappa, Italy (A.B.). , Thanh G. PhanThanh G. Phan From the Department of Neurology, New York University School of Medicine (E.K.); Department of Psychiatry and Psychotherapy, University Medical Center Mainz, Mainz, Germany (A.F.); Department of Neurology, University of Erlangen-Nuremberg, Erlangen, Germany (M.J.H.); Center for Human Genetic Research and Neurology Department (K.S.), Division of Neuroradiology, Department of Radiology (P.C.), Harvard Medical School, Massachusetts General Hospital, Boston; Stroke Unit, Department of Neurosciences, Monash Health and Stroke and Aging Research Group, Department of Medicine, Monash University, Australia (T.G.P.); Department of Neurology, Fundacion Para el Estudio de Enfermedades Neurometabolicas (FESEN), Buenos Aires, Argentina (J.P.); Department of Neuroradiology, University of Salerno, Salerno, Italy (R.M.); and Neurological Unit, Department of Internal Medicine, St Bassiano Hospital, Bassano del Grappa, Italy (A.B.). , Juan PoliteiJuan Politei From the Department of Neurology, New York University School of Medicine (E.K.); Department of Psychiatry and Psychotherapy, University Medical Center Mainz, Mainz, Germany (A.F.); Department of Neurology, University of Erlangen-Nuremberg, Erlangen, Germany (M.J.H.); Center for Human Genetic Research and Neurology Department (K.S.), Division of Neuroradiology, Department of Radiology (P.C.), Harvard Medical School, Massachusetts General Hospital, Boston; Stroke Unit, Department of Neurosciences, Monash Health and Stroke and Aging Research Group, Department of Medicine, Monash University, Australia (T.G.P.); Department of Neurology, Fundacion Para el Estudio de Enfermedades Neurometabolicas (FESEN), Buenos Aires, Argentina (J.P.); Department of Neuroradiology, University of Salerno, Salerno, Italy (R.M.); and Neurological Unit, Department of Internal Medicine, St Bassiano Hospital, Bassano del Grappa, Italy (A.B.). , Renzo ManaraRenzo Manara From the Department of Neurology, New York University School of Medicine (E.K.); Department of Psychiatry and Psychotherapy, University Medical Center Mainz, Mainz, Germany (A.F.); Department of Neurology, University of Erlangen-Nuremberg, Erlangen, Germany (M.J.H.); Center for Human Genetic Research and Neurology Department (K.S.), Division of Neuroradiology, Department of Radiology (P.C.), Harvard Medical School, Massachusetts General Hospital, Boston; Stroke Unit, Department of Neurosciences, Monash Health and Stroke and Aging Research Group, Department of Medicine, Monash University, Australia (T.G.P.); Department of Neurology, Fundacion Para el Estudio de Enfermedades Neurometabolicas (FESEN), Buenos Aires, Argentina (J.P.); Department of Neuroradiology, University of Salerno, Salerno, Italy (R.M.); and Neurological Unit, Department of Internal Medicine, St Bassiano Hospital, Bassano del Grappa, Italy (A.B.). and Alessandro BurlinaAlessandro Burlina From the Department of Neurology, New York University School of Medicine (E.K.); Department of Psychiatry and Psychotherapy, University Medical Center Mainz, Mainz, Germany (A.F.); Department of Neurology, University of Erlangen-Nuremberg, Erlangen, Germany (M.J.H.); Center for Human Genetic Research and Neurology Department (K.S.), Division of Neuroradiology, Department of Radiology (P.C.), Harvard Medical School, Massachusetts General Hospital, Boston; Stroke Unit, Department of Neurosciences, Monash Health and Stroke and Aging Research Group, Department of Medicine, Monash University, Australia (T.G.P.); Department of Neurology, Fundacion Para el Estudio de Enfermedades Neurometabolicas (FESEN), Buenos Aires, Argentina (J.P.); Department of Neuroradiology, University of Salerno, Salerno, Italy (R.M.); and Neurological Unit, Department of Internal Medicine, St Bassiano Hospital, Bassano del Grappa, Italy (A.B.). Originally published9 Dec 2014https://doi.org/10.1161/STROKEAHA.114.006283Stroke. 2015;46:302–313Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2014: Previous Version 1 Fabry disease (FD) is a rare and highly debilitating lysosomal storage disorder that results from a total lack of, or deficiency in, the enzyme α-galactosidase A (α-Gal A) because of mutations in the GLA gene.1 FD is inherited as an X-linked trait; many of the male patients develop a classic severe phenotype with early onset of symptoms, whereas heterozygous females exhibit phenotypes ranging from asymptomatic to major involvement of vital organs.2 Most families inherit private mutations; to date, >600 mutations have been identified and are listed in the online FD database (Fabry-database.org).3 The deficiency in α-Gal A causes the accumulation of globotriaosylceramide (GL-3; also abbreviated Gb3) in various cellular compartments, particularly lysosomes, causing structural damage and cellular dysfunction, as well as triggering secondary, tissue-level responses, such as inflammation, ischemia, hypertrophy, and the development of fibrosis resulting in progressive organ dysfunction.4 Deacylated globotriaosylceramide (lyso- globotriaosylceramide [lyso-GL-3]) has also been shown to be present in increased concentrations in the plasma of patients with FD. It has been suggested that lyso-GL-3 promotes GL-3 accumulation, induces proliferation of smooth muscle cells in vitro, and may have deleterious effects on the intima and media of small arterioles.5 Many cell types are involved in FD pathology, including vascular cells (endothelial and smooth muscle cells), cardiac cells (cardiomyocytes and valvular cells), a variety of renal cells (tubular and glomerular cells, and podocytes), and nerve cells.2The underlying pathophysiological mechanisms of FD are complex and incompletely understood.6 Early pathophysiological changes are thought to predominantly involve the microvasculature.7 As age increases, arterial remodeling and intima-media thickening in medium-to-large caliber vessels occur.2 The first clinical symptoms of FD occur in childhood (eg, neuropathic pain, hypohidrosis, and gastrointestinal problems)8 and are primarily because of autonomic neuropathy.9 As the disease pathology progresses, organ damage occurs and patients are at risk of developing life-threatening complications mainly because of damage to the kidneys, heart, and the brain. Cerebrovascular complications caused by cerebral vasculopathy are a major cause of morbidity and early mortality in both male and female patients with FD.10This review is based on a roundtable discussion that was held at an International Expert Panel on Cerebrovascular Involvement in FD, in Boston, MA, in January 2013. The panel comprised 9 experts in cerebrovascular complications in FD and clinical neuroimaging from Europe, South America, Australia, and the United States. Relevant literature published during the development of this review was also considered. This review provides a synopsis of the state of knowledge on the clinical and neuroradiological aspects, as well as the neurophysiology of cerebrovascular involvement in Fabry patients. It aims to identify developments that could lead to improved prediction and monitoring of cerebrovascular events in patients with FD. Of note, the expert panel also discussed therapeutic aspects (enzyme replacement therapy: agalsidase β [Fabrazyme; Genzyme, a Sanofi company] and agalsidase α [Replagal; Shire Human Genetic Therapies], conventional treatment) and intends to describe these separately.Cerebral Manifestations of FDAlthough ischemic strokes and transient ischemic attacks are the most prevalent types of overt cerebrovascular events in FD,10 cases of intracerebral hemorrhages,11 subarachnoid hemorrhage,12 microbleeds,13 cerebral venous thrombosis,14 and cervical carotid dissection15 have also been reported. To our knowledge, no cases of vertebral dissection or spinal cord infarction have been documented in the literature to date. Although silent infarcts are common events, also among young patients with stroke,16 there are no reports on the frequency of silent brain infarcts in FD. Aseptic meningitis can occur concomitantly in Fabry patients who have had cerebrovascular complications.17 One case of prolonged transient global amnesia has been reported in a Fabry patient.18 Dementia, cognitive impairment, and depression occur in patients with FD19 although additional studies are needed to establish a direct link to FD.StrokePrevalence, Age at Onset, and Influence of SexRetrospective studies in small cohorts of Fabry patients have reported a wide range of stroke incidence (24%–48%).20 In patients with Fabry-related stroke, the neurological symptoms experienced are normally consistent with the vascular territory affected and the extent of the stroke.2 Although many patients have clear neuroradiological findings on MRI, the causes of clinically asymptomatic brain lesions and chronic white matter hyperintensities (CWMH) in Fabry patients remain controversial.21An analysis of a large cohort of 2446 patients in the Fabry Registry (Fabryregistry.com) reported that stroke occurs in 6.9% of men and 4.3% of women. Of these, 87% of first strokes were found to be ischemic, with hemorrhagic stroke reported in 13% of cases. Although the incidence of stroke increases with age in patients with FD,10 as in the general population,22 analysis of the Fabry Registry has indicated that the incidence of stroke among patients with FD is markedly higher than that observed in the general US population across all age categories (Figure 1).10 For example, in men aged 35 to 45 years, the relative risk of stroke is 12.2× higher in Fabry patients when compared with healthy subjects. The relative risk of stroke is lower in women when compared with that in men, but still higher in Fabry patients when compared with that in healthy subjects: risk is highest at 4.2 in the 35 to 45 year age category. In the Fabry Registry cohort, a majority of Fabry patients experienced a first stroke between the age of 20 and 50 years, with 22% of patients having a first stroke at 70%), stroke was the first serious FD complication and a high proportion (50% of men and 38% of women) had, therefore, not yet been diagnosed with FD.10 Another large-scale analysis of the Fabry Outcome Survey reported that 13.2% (15.1% men and 11.5% women) of a cohort of 688 Fabry patients had either a stroke or transient ischemic attack. In the Fabry Outcome Survey, the mean age at first stroke was <30 years (men) and <45 years (women).23 Smaller studies reported that the median age at first stroke ranged from 28 to 54 years.20,24–27Download figureDownload PowerPointFigure 1. The incidence of stroke in patients in the Fabry Registry compared with the general US population. *There were no Fabry Registry males in the age group 65 to <75 years. †None of the 11 women in the age group 75 to 1 family and 2 mutations in >2 families. The study also found an occurrence of cerebrovascular disease in a patient with R112H, a mutation that has been found to be associated with myocardial hypertrophy. Therefore, a clear genotype–phenotype correlation in FD has not yet been established, underlining the need for additional studies.Several surveys have revealed a small percentage of young patients with stroke and a D313Y alteration in the GLA gene (Gly937Ala alteration at cDNA level).14,15,48 Although these individuals were presumed to have FD, there was no evidence of other FD manifestations. It has been suggested that the D313Y variant mutation, which results in normal α-Gal A activity in leukocytes and severely reduced α-Gal A activity in plasma, is a pseudodeficiency polymorphism. The identification of D313Y in 0.45% of normal X chromosomes further supports this theory.49 Nevertheless, an association between the D313Y variant and CWMH has been shown in the absence of other FD-specific symptoms, suggesting that D313Y carriers may be more susceptible to neural tissue damage.44 Nevertheless, the pathogenic role of the D313Y GLA variant continues to be debated.50,51 Recently, Rolfs et al38 also hypothesized that the mutations S126G and A143T, previously reported by Brouns et al,15 are associated with a stroke-only phenotype in FD.The question of whether there is a cerebrovascular variant of FD can be approached by classifying mutations by their effect on residual enzyme activity.47 Lukas et al52 divided GLA mutations into 4 classes according to in vitro enzyme activity measurement. In those with severe mutation and classic disease, mutation-specific enzyme activity correlated well with elevation in lyso-GL-3, albeit less so in heterozygous female patients. However, Lukas et al52 did not specifically address stroke risk of the 171 mutations that were studied.Risk Factors of Ischemic Stroke in FDSeveral modifiable, lifestyle-related factors are likely to increase the risk of stroke in Fabry patients, as in the general population. These factors include smoking, obesity, lack of physical exercise, dyslipidemia, and arterial hypertension.53 However, genetic modifiers, such as paraoxonase gene polymorphisms,54 angiotensin promoter, and angiotensin II receptor type I gene polymorphism, interleukin-6, protein Z,55 inflammatory factors (myeloperoxidase, C-reactive protein),56,57 and hyperhomocysteinemia,58,59 could also predispose a young Fabry patient to stroke. It has been suggested that the presence of factor V Leiden may be a link between FD and stroke.60,61 However, caution must be exercised in drawing strong conclusions from case reports because the factor V Leiden mutation is also common in the general community.62 Further evidence is needed to clarify the role of factor V Leiden, the above-mentioned genetic modifiers, and serum molecules in the genesis of stroke in patients with FD.Fabry-related cardiac and renal disease may also affect the risk of cerebrovascular complications. The vasoregulation of the microvasculature of the brain shares similar hemodynamic properties with the kidney, and the 2 organs have common vascular risk factors, such as hypertension and diabetes mellitus. Accordingly, researchers have looked for associations between cerebrovascular involvement (determined as severity of CWMH load) and kidney function, as well as possible links to stroke risk.63 A recent study reported that Fabry patients with the most stable estimated glomerular filtration rate had fewer strokes than those Fabry patients with rapidly progressing renal disease.64 An analysis of 2500 patients in the Stroke In Young Fabry Patients (SIFAP) study65 demonstrated that lower estimated glomerular filtration rates within the normal range were associated with the presence of a moderate to severe CWMH load. In this study, increasing severity of CWMH was significantly associated with a lower estimated glomerular filtration rate,65 raising the possibility that reduced estimated glomerular filtration rates could indicate an increased risk of CWMH and early stroke in patients with FD. Evidence is also emerging of an age-independent association between CWMH load and cardiomyopathy in patients with FD,66 which may relate to the risk of ischemic stroke.Other possible influences on stroke severity in FD include polymorphisms in interleukin-6, endothelial nitric oxide synthase, and protein Z67; fibrinolysis and angiogenesis factors68,69; elevations in serum myeloperoxidase56 and C-reactive protein57; paraoxonase gene polymorphism54; and angiotensinogen promoter and angiotensinogen receptor type I.55 The risk of stroke in FD seems, therefore, to be related to residual enzyme activity as determined by GLA mutations, as well as other genetic and epigenetic factors not yet characterized fully. Careful follow-up studies for clinical manifestations of FD in young patients with cryptogenic stroke and sequence alterations in the GLA gene are needed to elucidate these factors further.Cerebral Arteries/Territories Involved in FD-Related StrokeCerebral manifestations in patients with FD can be classified as either large- or small-vessel disease. Large-vessel stroke occurs because of occlusion of the large intracranial vessels or because of cardiac embolism (from the heart or large-vessel disease).68 Small-vessel disease is more commonly seen in patients with FD, manifesting as either subcortical stroke or the frequently asymptomatic CWMH and subcortical infarcts seen in neuroimaging studies.68In patients with FD, stroke occurs in both the anterior and the posterior circulatory systems, as well as in cortical and subcortical locations. However, the mechanism and topography of stroke in FD have not been systematically studied because of the fact that the evaluation of FD has been focused on patients with cryptogenic stroke rather than all types of stroke. Because patients with FD can have large artery disease and arrhythmia as a result of cardiomyopathy, the observed pattern of infarcts in descriptive studies may not reflect the true topography of infarcts in FD.10,20A significantly enlarged basilar artery diameter has been reported in patients with FD (compared with the general population),70 the cause of which is postulated to be insufficient autoregulation leading to aberrant vascular remodeling. Importantly, the basilar artery diameter seems to be a promising radiological parameter for separating patients with FD from controls70 and may be a useful predictive tool for Fabry-related stroke. Recently, the basilar artery diameter was confirmed to be significantly increased in male patients with FD when compared with healthy controls.71 Furthermore, a recent study of 70 Fabry patients suggested that vertebrobasilar dolichoectasia could serve as an early marker of neurovascular involvement, as it was present in 56% of men and 35% of women and was apparent at a younger age when compared with signs of ischemia.72 Tortuous, dilated cerebral vessels are also found in FD, and similar anatomic findings are also present in ocular vessels of Fabry patients.73 However, largely overlapping diameter ranges strongly reduce the diagnostic value of this measure in routine clinical practice. Moreover, no difference was found between male patients with FD
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