Pharmacology & Therapeutics 122 (2009) 65–77

Contents lists available at ScienceDirect

Pharmacology & Therapeutics

j ourna l homepage: www.e lsev ie r.com/ locate /pharmthera

Associate editor: M.M. Mouradian

Fabry disease

Raphael Schiffmann ⁎Institute of Metabolic Disease, Baylor Research Institute, 3812 Elm Street, Dallas, TX 75226, USA

Abbreviations: Gb3, globotriaosylceramide; ERT, enzythe α-galactosidase A gene; ROS, reactive oxygen specie⁎ Tel.: 214 820 4533; fax: 214 820 4853.

E-mail address: Raphael.Schiffmann@Baylorhealth.e

0163-7258/$ – see front matter © 2009 Elsevier Inc. Aldoi:10.1016/j.pharmthera.2009.01.003

a b s t r a c t

a r t i c l e i n f o

Keywords:

Lysosomal diseaseStrokeRenal insufficiencyCardiac diseaseEnzyme replacement therapyGlycosphingolipidBiomarker

Fabry disease, an X-linked disorder of glycosphingolipids that is caused by the deficiency of α-galactosidaseA, is associated with dysfunction of many cell types and includes a systemic vasculopathy. As a result,patients have a markedly increased risk of developing small-fiber peripheral neuropathy, stroke, myriadcardiac manifestations and chronic renal disease. Virtually all complications of Fabry disease are non-specificin nature and clinically indistinguishable from similar abnormalities that occur in the context of morecommon disorders in the general population. Although Fabry disease was originally thought to be very rare,recent studies have found a much higher incidence of mutations of the GLA gene, suggesting that thisdisorder is under-diagnosed. Although the etiology of Fabry disease has been known for many years, themechanism by which the accumulating α-D-galactosyl moieties cause this multi-organ disorder has onlyrecently been studied and is yet to be completely elucidated. Specific therapy for Fabry disease has beendeveloped in the last few years but its role in the management of the disorder is still being investigated.Fortunately, standard ‘non-specific’ medical and surgical therapy is effective in slowing deterioration orcompensating for organ failure in patients with Fabry disease. All these aspects are discussed in detail in thepresent review.

© 2009 Elsevier Inc. All rights reserved.

Contents

1. Introduction: history and etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 652. Incidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 663. Clinical manifestations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 664. Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 685. Differential diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 696. Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 697. Disease mechanism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 698. Therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74

1. Introduction: history and etiology

The dermatologists Johannes Fabry and William Anderson firstdescribed ‘angiokeratoma corporis diffusum’ in 1898 (Anderson,1898;Fabry,1898). It was recognized early as a systemic vascular disease andlater as a storage disorder (Pompen, Ruiter, & Wyers, 1947) of lipids(Hornbostel & Scriba, 1953). The accumulation of the glycolipidsceramidetrihexoside (now called globotriaosylceramide (Gb3)) and

me replacement therapy; GLA,s.

du.

l rights reserved.

galabiosylceramide in a variety of different cell types was identified in1963 (Sweeley & Klionsky, 1963). In addition, blood group antigens B,B1, and P1 also increase in certain individuals. Several years later,the defect was established as insufficient activity of the enzymeceramidetrihexosidase which catalyses the hydrolytic cleavage of theterminal molecule of galactose from Gb3 (Brady et al., 1967). Theanomeric specificity of ceramidetrihexosidase (α-galactosidase A)was determined in 1970 (Kint, 1970). The X-linked nature of thedisease was first recognized in 1965 (Opitz et al., 1965).

The α-galactosidase A gene (GLA- (MIM No. 300644) is located onXq22.1 (Bishop et al., 1988). It is 12-kb long with seven exons. GLAencodes for a 429 amino acid precursor protein that is processed to370 amino acid glycoprotein functioning as a homodimer (Garman &

Fig. 1. The association of cold perception threshold as expressed by JND units (justnoticeable difference) and the number of hearing frequency regions with hearing lossbased on age and gender-specific percentiles (HL95) in males with Fabry disease. N=58;p=0.002 (ANOVA). The severity of the neuropathy, as determined by cold perception inthe feet was associated with an increased number of affected hearing frequency regions,i.e., none or any or a combination of low-, middle-or high-frequency regions (Ries et al.,2007).

66 R. Schiffmann / Pharmacology & Therapeutics 122 (2009) 65–77

Garboczi, 2004). Based on The Human Gene Mutation Database at theInstitute of Medical Genetics in Cardiff (http://www.hgmd.cf.ac.uk/ac/index.php), there are currently 431 mutations described. Of those,295 are missense/nonsense type mutations, 66 small deletions, 12large deletions, 21 splice defects, 3 complex rearrangements, and onelarge insertion. The cause of this large number of different mutationsin the GLA gene is not known. One might speculate that having theFabry trait presents a selective advantage such as resistance to certaintypes of bacterial infections, in particular those that express theEscherichia coli shiga-like toxin verotoxin (Cilmi et al., 2006). Patientswith the classic, most severe, form of Fabry disease almost alwayshave a mutation that causes a total absence of α-galactosidase Aactivity, while patients with missense mutations often have someresidual enzyme activity ranging from 2% to 25% (Desnick et al, 2001).

2. Incidence

The disease incidence is about 1 in 117,000 live births for males(Meikle et al., 1999), although recent newborn screening surveyssuggest that the incidence may be much higher, up to 1:3100 (Spadaet al., 2006). Because of the higher than expected frequency, the non-specific nature of the complications of Fabry disease and the commonoccurrence of single complications, it is likely that many undiagnosedpatients exist. Furthermore, the presence of equal numbers of femalesand males in large series suggests that up to 50% of the females withFabry disease may be asymptomatic or are not identified (Eng et al.,2007; Mehta et al., 2004).

3. Clinical manifestations

3.1. Classic abnormalities

Patients with the classic form of the disease (with no residualα-galactosidase A activity) have typical dysmorphic abnormalities,particularly in the face. These dysmorphisms have been describedquantitatively and in detail (Ries, Moore et al., 2006) and includeperiorbital fullness, prominent lobules of the ears, bushy eyebrows,recessed forehead, pronounced nasal angle, generous nose/bulbousnasal tip, prominent supraorbital ridges, shallow midface, full lips,prominent nasal bridge, broad alar base, coarse features, posteriorlyrotated ears, and prognathism. Other abnormalities including those ofthe extremities have been identified (Ries, Moore et al., 2006). Thedisease manifestations often start in childhood with episodes ofextremity pain, fever of unknown origin and hypohidrosis thatfrequently lead to decreased exercise tolerance (Cable, Kolodny, &Adams, 1982; Ries et al., 2005). Episodic diarrhea and abdominal painare common, often associated with fatty foods (Hoffmann & Keshav,2007; Rowe et al., 1974). These symptoms often reduce quality of lifeand school attendance in children but because of their relatively non-specific nature usually do not lead to correct diagnosis in the absenceof family history (Mehta et al., 2004; Ries et al., 2005). More specificdisease manifestations that are usually present in late adolescence aretypical vascular skin lesions termed angiokeratoma and asymptomaticcorneal opacities— cornea verticillata (Hashimoto et al., 1965; Macraeet al, 1985; van Mullem & Ruiter, 1970; Weicksel, 1925; Yokota et al.,1995). Thesemay lead to diagnosis by alert dermatologists or ophthal-mologists. However, the importance of Fabry disease lies in the pro-gressive renal and cardiac deterioration, as well as a high propensity todevelop ischemic stroke. These complications may initially presentthemselves in the second decade of life, but more commonly in the3rd–5th decade resulting in decreased life expectancy(Branton et al.,2002; Hopkin et al., 2008; Kampmann, Linhart et al., 2008; Mehtaet al., 2004; Rolfs et al., 2005).

The neuropathic pain (commonly referred to as acroparesthesia) isthought to be due to a small fiber neuropathy (Attal & Bouhassira,1999; Zimmermann, 2001). It often begins in childhood and is present

in the vast majority of patients (MacDermot & MacDermot, 2001). Itreaches its highest severity in the 3rd and 4th decades of life and tendsto diminish thereafter as the sensory function deteriorates. The painmay be continuous aswell as episodic and often brought about by verylow or very high environmental temperature, strenuous exercise orstress. It usually begins in the feet, followed by the hands and canbecome more generalized (Zarate & Hopkin, 2008). Joint pain is notuncommon in Fabry patients. The small-fiber neuropathy of Fabrydisease is associated with an increased threshold of perception of coldand warm stimuli as well as heat pain (Dutsch et al., 2002; Lucianoet al., 2002). Large fiber functions, such as vibration and positionsensation, are usually intact and therefore peripheral nerve conduc-tion velocity is typically normal unless compression neuropathy de-velops, particularly carpal tunnel syndrome (Luciano et al., 2002).Abnormalities suggesting a peripheral nerve dysfunction were alsofound in the Fabry mouse model (Rodrigues et al., 2009). Progressivesensorineural hearing loss of early onset is very common in male andfemale patients with Fabry disease, and its severity is correlated withboth the cerebrovascular and the peripheral nerve manifestationsof the disease (Fig. 1) (Ries et al., 2007). This abnormality is oftenassociated with disturbing tinnitus or episodes of vertigo that canbegin in childhood (Conti & Sergi, 2003; Keilmann, 2003; Ramaswamiet al., 2006; Vibert et al., 2006).

The kidney disease that complicates Fabry disease is usually as-sociated with progressive proteinuria following a decline in glomer-ular filtration rate, leading over a number of years to end-stage renaldisease requiring dialysis and kidney transplantation (Branton et al.,2002; Donati et al., 1987; Ortiz et al., 2008). There is evidence thathyperfiltration often precedes the decline in renal function, particu-larly in childhood (Ries et al., 2005; Vedder et al., 2007). Tubulardysfunction consists of hyposthenuria and polyuria that are never-theless benign (Bichet, 2008).

A patient with Fabry disease may have virtually any cardiac com-plications (Linhart et al., 2000; Senechal & Germain, 2003). Theseinclude progressive hypertrophic cardiomyopathy (Fig. 2) with diastolicdysfunction, a variety of conduction defects and arrhythmia such asshort P–R interval supraventricular and ventricular tachycardia, Othercomplications are atrial fibrillation as well as valvular disease (insuffi-ciency or stenosis) and coronary artery stenosis of large or, morecommonly, of small vessels (Kampmann,Wiethoff et al., 2008; Takenakaet al., 2008; Weidemann et al., 2005). Electrocardiogram is abnormalin most adults with Fabry disease and echography combined with aDoppler heart study is very helpful in characterizing the cardiac ab-normalities of Fabry disease. Progressive bradycardia and decreased

Fig. 2. Hypertrophic cardiomyopathy of the left ventricle in a 47-years-old male withFabry disease who died after 2.5 years of enzyme replacement (Schiffmann et al., 2005).Old scars from previous myocardial infarctions can be seen as well (arrow). The rightventricular wall is of normal thickness.

67R. Schiffmann / Pharmacology & Therapeutics 122 (2009) 65–77

exercise capacity are very common, requiring the placement of a pace-maker in many patients (Lobo et al., 2008; Nakayama et al., 1999).Ejection fraction and cardiac output are often preserved but deterioratein advanced cases (Kawano et al., 2007).

Based on published numbers, one can estimate that patientswith Fabry disease have a 20-fold increased risk of ischemic strokeand transient ischemic attacks compared to the general population(Grysiewicz et al., 2008; Mehta & Ginsberg, 2005). Both small andlarge vessel strokes occur, with brain regions perfused by the posteriorcirculation being affected more commonly than anterior circulation(Moore, Herscovitch, & Schiffmann, 2001; Moore, Scott et al., 2001;Moore, Ye, Schiffmann, & Butman, 2003). The neurological deficits inpatients reflect the localization and extent of ischemic strokes andhave no distinctive element (Fig. 3). Transient ischemic attacks arerelatively common (Mehta & Ginsberg, 2005; Mitsias & Levine, 1996;Moore, Kaneski, Askari, & Schiffmann, 2007; Whybra et al., 2001).Asymptomatic lesions on brain MRI are often present, usually in thewhite matter and are a risk factor for vasculopathic complications inFabry disease patients (Kaneski et al., 2006; Moore, Altarescu et al.,2003). Large vessel embolic strokes of possible cardiac origin mayoccur (Mitsias & Levine, 1996).

Fig. 3. MRI of the brain of a 20-year-old man with a history of repeated strokes since age 14image. C. Fluid-attenuated inversion recovery image (FLAIR). Old lacunar infarcts are seen, inproximal right optic radiations (arrowhead). On the FLAIR image, a small amount of gliosis

3.2. Other abnormalities

A number of endocrine abnormalities have been described. Themost common is antibody-negative hypothyroidism (Faggiano et al.,2006; Hauser et al., 2005). Asthenozoospermia, oligozoospermia andabnormal response to ACTH have also been described (Faggiano et al.,2006).

Other abnormalities in the circulation can often be found inFabry disease. These include anemia, elevated sedimentation rate,C-reactive protein, serum myeloperxidase (see also below), anddecreased alpha2-antiplasmin and plaminogen (Moore et al., 2007;Kleinert et al., 2005; Lacomis et al., 2005). These findings defineFabry disease also as an inflammatory disorder. Any of theseaberrations may serve as a biomarker in verifying the effect of ther-apy, alone or in combination.

Lower extremity edema commonly occurs in hemizygous maleswith Fabry disease. Abnormal lymphatic vessels have been describedin one patient but it is likely that other vascular insufficiencies andcardiac disease contribute to this abnormality (Chabas et al., 1994;Kampmann et al., 2005; Lozano et al., 1988). Cardiac insufficiency israrely associated with pedal edema but renal insufficiency is likely acontributing factor in many cases.

3.3. Effect of sex on clinical disease

Fabry disease can be considered an X-linked disorder with a highdegree of intermediate penetrance in females. That term refers tothe fact that only about 70% of females with GLA mutations havemanifestations of Fabry disease while close to 100% of males havecomplications of the disease (Dobyns, 2006; Maat-Kievit et al., 2001;Sen-Chowdhry et al., 2005). Females are affected because there is nocross-correction between cells with normal α-galactosidase A activity(mutated X chromosome is inactivated) and enzyme deficient cells(non-mutated X chromosome is inactivated) (Romeo & Migeon,1970). The expression of the disease in female patients depends on theparticular GLA mutation and especially on the pattern of X chromo-some inactivation in each organ (Dobrovolny et al., 2005; Wang et al.,2007). Therefore, females can develop any of the complications thatare seen in males, including strokes, cardiac disease and progressiverenal insufficiency (Eng et al., 2007; Laaksonen et al., 2008; Martinet al., 2007; Ortiz et al., 2008; Wang et al., 2007; Whybra et al., 2001;Wilcox et al., 2008). However, in general, the clinical abnormalities aremore variable, less severe and of later onset compared to the maleswith similar GLA mutations. Since large series of patients with Fabry

years, despite 3 years of enzyme replacement. A. T1-weighted image. B. T2-weightedcluding internal capsule (arrow), right thalamus and a more recent lacunar infarct in thesurrounds most of these lesions.

Fig. 4. A. Angiokeratoma in fingers. B. Cornea verticillata in a heterozygote female withFabry disease. Courtesy Drs. Lorena Baccaglini and Janine Smith.

68 R. Schiffmann / Pharmacology & Therapeutics 122 (2009) 65–77

disease usually have a roughly equal number of males and femalepatients, it is likely that a substantial number of female patients arenot diagnosed or identified, but also that many females remain largelyasymptomatic.

3.4. Overall view of clinical manifestations and disease modifiers

The clinical signs and symptoms described above can occur in anysequence and combination in any given patient with Fabry disease.A patient may have a number of complications in different organsystems, or just a few or even a single abnormality limited to oneorgan system. The clinical expression of Fabry disease is primarilymodified by the residual α-galactosidase A activity (Branton et al.,2002; Desnick et al., 2001). For example, patients with some residualenzyme activity are often described as having amilder variant of Fabrydisease with predominantly cardiac abnormalities, while having littleor no kidney dysfunction and no painful acroparesthesia (Desnicket al., 2001). The onset of chronic renal insufficiency is significantlydelayed in patients with more than 1% residual enzyme activity whichresults from having a GLA mutation consisting of a single amino acidchange that is chemically conservative (Branton et al., 2002).

In addition to α-galactosidase A residual enzyme activity, it is verylikely that there are many other genetic and non-genetic modifiers.Genotypes of polymorphisms G-174C of interleukin-6, G894T of en-dothelial nitric oxide synthase, factor V G1691A mutation (factor VLeiden), and the A-13G and G79A of protein Z were all significantlyassociated with the presence of presumably ischemic cerebral lesionson brain MRI (Altarescu et al., 2005). Using themousemodel for Fabrydisease, it was shown that the absence of α-galactosidase A activitycombined with the factor V Leiden mutation significantly increasesthe number of vascular thrombi compared to either mouse modelalone (Y. Shen et al., 2006). Similarly, α-galactosidase A deficiencyaccelerates atherosclerosis in mice with apolipoprotein E deficiency(Bodary et al., 2005).

3.5. Fabry trait as a general risk factor

The clinical abnormalities described above are non-specific in thatthey are clinically indistinguishable from similar complications ofother etiologies that occur in the general population. For example,strokes in patients with Fabry disease may be of the small vessel orlarge vessel type and have similar neurological and neuroimagingcharacteristics to hypertensive or embolic strokes (Fig. 3) (Moore,Kaneski et al., 2007). Similarly, Fabry disease cannot be easily diag-nosed in patients with routine electrocardiographic, echographic orMRI techniques. Up to 4% of patients with cryptogenic stroke aged 16–55 years and up to 6% of patients with idiopathic cardiomyopathywere found to have GLA mutations (Morita et al., 2008; Rolfs et al.,2005; Sachdev et al., 2002; Veinot, 2002). Similarly, up to 0.7% ofpatients on renal dialysis were found to have Fabry disease (Andradeet al., 2008; Tanaka et al., 2005; Terryn et al., 2008; Thadhani et al.,2002). The diagnosis of Fabry disease can be accomplished by per-forming kidney or cardiac biopsies but such procedures are rarelydone, especially early in the diagnostic process.

It is therefore likely that that screening has been by far toorestricted and that Fabry genetic trait is an additive risk factor inpatients with other cardiovascular risk factors such as diabetes,atherosclerotic or embolic stroke, arrhythmia and valvular diseasein the general population. This hypothesis is supported by twoother observations: a much higher than expected incidence of GLAmutations found by newborn screening, suggesting the existenceof many undiagnosed patients (Spada et al., 2006), and by thepresence of equal numbers of females and males in large series,suggesting that up to 50% of the females with Fabry disease, many ofwhom may be symptomatic, are not identified (Eng et al., 2007;Mehta et al., 2004). In fact, I hypothesize that low α-galactosidase

A is a risk factor for cardiac disease in the general population evenwhen no deleterious mutation of the GLA gene exists and no overtFabry disease is present. We are currently performing a study to testthis hypothesis.

4. Diagnosis

Fabry disease should be suspected in patients with specific diag-nostic signs such as angiokeratoma in the skin (Fig. 4A) or vascularectasia in the buccal or conjunctival mucosa (Baccaglini et al., 2001).Eye examination will typically reveal cornea verticillata (Fig. 4B),and increased tortuosity of retinal blood vessels will be seen on fun-duscopic examination (Sodi et al., 2007). Non-specific but importantabnormalities indicative of the disease are pain neuropathy, hypohi-drosis, renal insufficiency, particularly if associated with proteinuria;various cardiac abnormalities or stroke should also lead to suspicion ofFabry disease (Brady & Schiffmann, 2000).

A presumed diagnosis of Fabry disease must be confirmed by thefinding of low α-galactosidase A activity on peripheral blood whitecells or cultured skin fibroblasts (Desnick et al., 2001). The latterusually have higher enzyme activity than peripheral white blood cells(Romeo et al., 1975). Generally, levels below 20% of the normal shouldbe considered diagnostic, and activity below 35% should lead tosuspicion of Fabry disease (Desnick et al., 2001; Kitagawa et al., 2008).The enzyme assay is useful in males, but females often have mildlyreduced or normal enzyme activity because of randomX-chromosomeinactivation. Therefore, the finding of a mutated GLA is critical forconfirmation of the diagnosis of Fabry disease in females (Wilcox

69R. Schiffmann / Pharmacology & Therapeutics 122 (2009) 65–77

et al., 2008). Increased urinary sediment Gb3 measured in 24 hcollection is very useful in diagnosing Fabry disease, particularly infemales who almost always have elevated levels (Cable, McCluer et al.,1982; Gupta et al., 2005). However, when whole urine is used, up to40% of affected subjects may bemissed (Auray-Blais et al., 2008; Fulleret al., 2005; Kitagawa et al., 2008).

4.1. Diagnostic imaging

Patients with the classic form of the disease often have presum-ably ischemic white matter lesions on brain MRI that can be focal,multifocal and even confluent (Moore, Altarescu et al., 2003). Ratherspecific are symmetric lesions in the posterior thalamus and pul-vinar that have increased signal intensity on T1-weighted MRI image(Burlina et al., 2008; Moore, Ye et al., 2003; Takanashi et al., 2003).These likely represent subtle dystrophic calcifications and end-organdamage associated with regional hyperperfusion (Moore, Ye et al.,2003). Dystrophic calcifications can be observed in gray-white matterjunction, basal ganglia and cerebellum using MRI or CT scan (Moore,Ye et al., 2003). Fabry patients with strokes have findings on brainMRIthat are no different from those found in ischemic strokes in patientswho do not have Fabry disease (Mitsias & Levine, 1996).

Renal parapelvic cysts are rather typical in Fabry patients and canbe diagnosed using ultrasound, CTorMRI (Glass et al., 2004; Ries et al.,2004). They do not seem to be associated with renal dysfunctionand the mechanism of their development is not known. Cardiachypertrophy with later contrast enhancement seen on MRI is typicalfor Fabry disease, although it is not a diagnostic feature (Weidemannet al., 2005).

5. Differential diagnosis

The use of chloroquine or amiodarone can cause a corneal abnor-mality identical to the cornea verticillata of Fabry disease (D'Amico &Kenyon, 1981; Inagaki et al., 1993; Whitley et al., 1983). Exposure tosilicon dust leads to a clinical and pathological nephropathy that isvery similar to the one seen in Fabry disease (Banks et al., 1983).

Cutaneous lesions identical to angiokeratomas occur in mannosi-dosis, fucosidosis, sialidosis, beta-galactosidase deficiency, Schindlerdisease and other disorders (Beratis et al.,1989; Calzavara-Pinton et al.,1995; Gasparini et al., 1992; George & Graham-Brown, 1994; Kawachiet al., 1998; Kodama et al., 2001; Suzuki et al., 2004). Isolated an-giokeratomas without storage material have been described as well(Fimiani et al., 1997).

6. Pathology

The pathological abnormalities can be divided into disease-specificand secondary changes that are not disease-specific but reflect organabnormalities and dysfunction. The most visually striking and his-torically important are lysosomal inclusions or lipid deposits that areseen in almost all cell types. They are prominent in vascular cells, bothendothelial and smooth muscle cells, cardiac cells including endo-cardial cells, cardiomyocytes and cardiac valves, kidney epithelial cells(tubular and glomerular cells and podocytes) and nerve cells includ-ing dorsal root ganglia and some central nervous system neurons(Duncan, 1970; Elleder, 2003; Gadoth & Sandbank, 1983; Nistal et al.,1983).

The secondary pathological changes are organ-specific but notnecessarily disease-specific. Blood vessels may be thickened with arather characteristic arteriosclerotic change that is different fromtypical atherosclerosis plaque (“Case 2-1984: Fabry's disease”, 1984).True cardiac hypertrophy is often present with secondary fibrosis,and valves are often thickened (Schiffmann et al., 2005). The renalglomeruli undergo progressive change that starts with mesangialwidening, followed by focal fibrosis ending with a completely fibrotic

and obsolescent glomerulus (Alroy et al., 2002; Chatterjee, Guptaet al., 1984). Tubular and interstitial fibrosis occurs as well. The brainmay have rarefied and gliotic lesions secondary to ischemia, butspontaneous neuronal death and cerebral cortical atrophy have notbeen described (Kaye et al., 1988; Okeda & Nisihara, 2008; Schiffmannet al., 2005; Tagliavini et al., 1982).

7. Disease mechanism

The mechanism by which α-galactosidase A deficiency and gly-colipid accumulation cause such a wide variety of complications is notwell understood. Based on the pathology of Fabry disease, the chronicaccumulation of α-D-galactosyl moieties, particularly of Gb3, appearsto be a chronic toxicity state. There is no evidence of massive cell deathalthough it is likely that there is increased turnover of some cell typessuch as vascular endothelial cells (Alroy et al., 2002). A clue to themechanism of the disease may be found in the sub-cellular local-ization of Gb3 (Askari et al., 2007). Using two forms of immunogoldelectron microscopy and light microscopy in patient tissue and cul-tured cells we found that Gb3 is present throughout the cell, includingin lysosomes, endoplasmic reticulum (ER), cell membrane and thenucleus (Askari et al., 2007). This is not surprising since Gb3 reachesthe circulation in the normal and diseased state and therefore passesthrough the secretory pathway at least in the liver (Chatterjee &Kwiterovich, 1984; Clarke et al, 1976; Meuwissen et al., 1982). Gb3 isnormally present in the plasma membrane as the CD77 receptor ofcertain lymphocytes and plays a role in the immune system (Jarviset al., 2007; Schweppe et al., 2008; Thomaidis et al., 2009). Becauseof a theoretical possibility that the in situ labeling we used led to adisplacement of Gb3 to areas in the cell where it is not normallypresent, confirmation of our localization findings by other methodswill be most welcome (Elleder, 2008).

However, these findings do not describe the molecular cascadesthat lead to widespread cellular dysfunction in Fabry disease.

Fabry disease is to a large extent a systemic vascular disorder caus-ing cardiovascular complications and stroke. We therefore focused ourresearch on the vascular mechanism of the disease. We hypothesizedthat Fabry vasculopathy is associated with abnormalities of blood com-ponents, blood flow and the vessel wall (Virchow's Triad) leading to avascular dysfunction (Fig. 5). The finding of increased soluble sICAM-1,sVCAM-1, P-selectin, PAI, and decreased thrombomodulin combinedwith increased monocyte CD11b expression confirmed a prothromboticstate in Fabry disease (Fig. 5) (DeGraba et al., 2000). Dysfunction ofcerebrovascular circulation has been shown in a number of studies usingimaging end-points such as cerebral perfusion by positron emissiontomographyandarterial spin taggingusingMRI (CBF [ml/100gof tissue/min]). In addition, cerebral blood flow velocity (CBFV [cm/s]) and cere-brovascular reactivity were studied (Hilz, Kolodny et al., 2004; Moore,Altarescu, Herscovitch, & Schiffmann, 2002; Moore, Altarescu, Ling et al.,2002; Moore, Scott et al., 2001; Moore et al., 2004).These studies foundsignificant cerebral hyper-perfusion in Fabry disease compared to con-trols, predominantly in the posterior cerebral circulation (Fig. 5) (Moore,Herscovitch et al., 2001). Hyperperfusion does not exist systemically, asindicated by normal cardiac output found in patients with Fabry diseasecompared to controls (Moore, Scott et al., 2001). Using post-ischemicperfusion measurement, another group showed a decreased hyperemiain the forearm but exaggerated hyperperfusion in the skin (Stemper &Hilz, 2003). This finding suggests heterogeneity in the response toglycolipid storage of different vascular beds. We subsequently demon-strated that cerebral hyperperfusion is a vascular phenomenon notcaused by neuronal overactivity (Moore, Altarescu et al., 2003).Calcifications indicating end-organ damage can be observed in hyper-perfused brain regions such as the white matter and the pulvinar orposterior thalamic regions (Moore, Ye et al., 2003). One can concludefrom the above findings that Fabry disease has all the features of a classicvasculopathy in that there are abnormalities related to blood

Fig. 5. A schematic view of what is known about the mechanism of the vasculopathy in Fabry disease. The abnormalities described include increased Gb3 in various cellularcompartments including the cell membrane (caveolae), endosomes and possibly the mitochondria. This accumulation leads to increased release of ROS. There is activation ofmononuclear cells and endothelial cells associated with increased levels of adhesion molecules as well as priming and activation of polymorphonuclear cells with release of MPO.Endothelial cell activation leads to increased release of microparticles (MP). Activation of plasminogen, possibly by increased release or activity of tPA or uPA leads to consumption ofalpha2-antiplasmin and, in some patients, elevation of D-dimer-products of fibrinogen breakdown. This prothrombotic state in association with cerebral hyperperfusion contributestowards increased stroke risk. See also text.

70 R. Schiffmann / Pharmacology & Therapeutics 122 (2009) 65–77

components, abnormalities related to blood flow and abnormalitiesrelated to vessel wall as shown by the disturbances in vasoreactivity andautoregulation (Fig. 5) (Moore, Kaneski et al., 2007).

We also studied the effect of intra-arterial injection of acetylcho-line on the forearm vascular bed's blood flow (Altarescu et al., 2001).We hypothesized that we shall find a decreased response similar tothat in arterial hypertension and hypercholesterolemia. Surprisingly,we found an increased endothelium-dependent vascular reactivityinstead; it was still present after infusion of a competitive inhibitor ofarginine indicating altered function of the non-nitric oxide pathways(Altarescu et al., 2001). Others have found normal or decreased re-activity to post-ischemic hyperemia in patients (Kalliokoski et al.,2005; Puccio et al., 2005). Similar experiments with acetylcholinein the knockout mouse model for Fabry disease showed reducedreactivity to acetylcholine, which points to the limitations of thismodel (Park et al., 2008).

These findings and the presence of dolichoectasia led us to testthe hypothesis that the vascular dysfunction in Fabry disease is dueto increased release of reactive oxygen species leading to increased

oxidative stress and peroxynitrite formation, potentially resulting inpersistent vasodilation (Wei et al., 1996). We found increasedstaining for 3-nitrotyrosine in dermal and cerebral blood vesselsand increased nitrotyrosine and myeloperoxidase levels in the bloodof patients with Fabry disease compared to controls (Moore, Scott etal., 2001)(Fig. 5). Using arterial spin tagging and MRI we found analtered reactivity of the cerebral vasculature to ascorbate infusion,coupled with low blood levels of ascorbate in Fabry patients (Mooreet al., 2004). The decreased response to ascorbate may be caused byexcess release of ROS.

We recently confirmed that excess Gb3 directly releases ROS, ina dose-dependent manner, from a long-lived cultured vascular en-dothelial cell line (IMFE1, Fig. 6) (J. S. Shen et al., 2008). Increased Gb3also induced expression of intercellular adhesion molecule-1, vascularcell adhesion molecule-1, and E-selectin. Reduction of endogenousGb3 by treatment of the cells with an inhibitor of glycosphingolipidsynthase orα-galactosidase A led to decreased expression of adhesionmolecules. Incubation of Fabry plasma led to significantly increasedROS production in IMFE1 cells when compared to the effect of non-

Fig. 6. Effects of Gb3 on the generation of ROS in IMFE1 cells (Shen et al., 2008). IMFE1cells were incubated with a medium containing Gb3/albumin c omplex for 3 days.Increase of intracellular Gb3 was verified by TLC (A) and immunostaining against Gb3(B). Intracellular Gb3 was significantly increased after incubation with Gb3 (10 lmol/L)without significant changes in other glycosphingolipids. (C) Intracellular ROS generationwas significantly increased in the cells loaded with exogenous Gb3 (5 and 10 μmol/L).The effect on ROS productionwas dependent on the concentrations of Gb3 in the media.Addition of 100 μmol/L vitamin C into the loading media significantly lowered ROSgeneration in the cells and abrogated the effect of Gb3 on ROS generation. The data arepresented asmean±SE (N=6).Mann–WhitneyU testwas used to compare the statisticalsignificance. Results shown are representative of three independent experiments (Shenet al., 2008).

71R. Schiffmann / Pharmacology & Therapeutics 122 (2009) 65–77

Fabry plasma (Shen et al., 2008). However, ROS were elevated evenafter depletion of Gb3, suggesting that it is not the only metaboliteresponsible for the excessive release of ROS.

The reason for excessive ROS production in Fabry disease is un-clear, but may be related to glycolipid accumulation altering en-dothelial caveolar function and mechano-transduction of arterial wallshear stress (Fig. 5). Interestingly, a recent study showed increasedGb3 and related GSL in the caveolar fractions of endothelial cells froma mouse model of Fabry disease (Shu & Shayman, 2007). It is possiblethat lipid rafts (a form of caveolae) altered by Gb3 accumulationcause eNOS uncoupling leading to increased ROS generation suchas superoxide. Alternatively, it is possible that excess Gb3 activatesoxidative enzymes such as mitochondrial nicotinamide adenine dinu-cleotide (phosphate) (NADPH) oxidases— the major source of ROSgeneration in vascular endothelial cells (Forstermann, 2008). ExcessO2•˜ could react with NO to formperoxynitrite (ONOO−), or dismutateto form H2O2, the putative endothelial-dependent hyperpolarizingfactor (EDHF) (Saliez et al., 2008; Sokoya et al., 2006; Takaki et al.,2008). BothO2•˜ andONOO−cause dilation of the cerebral vasculature,suggesting that excess reactive oxygen species could not only lead to

continued vasodilation but also increase vulnerability to other vasculardysfunction such as superimposed atherosclerosis.

Elevated myeloperoxidase in blood may also be related to therecent observation that the Fabry disease process may accelerateatherosclerosis in susceptible individuals (Kaneski et al., 2006).Indeed, we increasingly observe premature fixed coronary arteryand cerebral artery disease in Fabry patients (Kaneski et al., 2006;Schiffmann et al., 2005). Our findings in patients were later sup-ported by another group who found that α-galactosidase A deficien-cy accelerates atherosclerosis in mice deficient in apolipoprotein E(Bodary et al., 2005). These authors also found increased staining for3-nitrotyrosine in aortic lesions and increased iNOS expression invessel wall macrophages.

In addition to Gb3, the deacylated form of this glycosphingolipid orlyso-Gb3 (globotriaosylsphingosine), was recently found to be elevatedin patients with Fabry disease, particularly in blood circulation, where itis over 50-fold higher than normal (Aerts et al., 2008). The plasmaconcentration of lyso-Gb3was in the nMrangewhile itwas in the μMforGb3. Lyso-Gb3 was found to be a potent inhibitor of α-galactosidase Aand α-galactosidase B (N-acetylgalactosaminidase) and promotedsmooth muscle cell proliferation in vitro at concentrations similar tothe ones present in the plasma of Fabry patients (Aerts et al., 2008). Thissuggests a potential role of lyso-Gb3 in the increased intima-mediathickness seen in patients with Fabry disease. However, no correlationwas noted between plasma lyso-Gb3 with regard to age, the clinicalseverity score, or the cardiac mass in hemizygous male patients.Curiously, there was a correlation between plasma lyso-Gb3 levels andcardiac mass in female heterozygotes. Lyso-Gb3 levels were normal inpatients with mutations leading to some residual activity and mainlycardiac manifestations, and they were also markedly elevated in theFabry knockout mouse model. This animal model develops no Fabry-related phenotype. Therefore, it remains to be seen whether lyso-Gb3plays an important role in the pathogenesis of Fabry disease.

Since not all patients with Fabry disease develop cerebral lesions,we were interested in identifying potential genetic modifiers of thisprocess. In a prospective observational study we evaluated 57 con-secutive Fabry hemizygous male patients for brain FLAIR MRI lesions(Altarescu et al., 2005). We found that the-174 G/C of IL6 polymorph-ism of interleukin 6 (IL-6), the G894T polymorphism of endothelialnitric oxide synthase (eNOS), the factor V G1691A mutation as wellas the G79A and the A-13G polymorphisms of protein Z were sig-nificantly associated with cerebral lesions, but not the prothrombinG20210A variant and the methylenetetrahydrofolate reductase(MTHFR) C677T. We therefore found a clear relationship between anumber of pro-thrombotic gene polymorphisms and the presumptiveischemic small-vessel cerebral lesions in Fabry disease (Altarescuet al., 2005). Subsequently, an interaction was found between thefactor VG1691A mutation and α-galactosidase A deficiency in mousemodels (Y. Shen et al., 2006). α-Galactosidase A deficiency markedlyincreased tissue fibrin deposition inmice carrying the factor V G1691Amutation compared with factor V G1691A mutation alone. Recently,patients with polymorphisms of eNOS described above were found tohave higher left ventricular posterior wall thickness — linking geneticmodifiers to a cardiac biomarker in Fabry disease (Rohard et al., 2008).These findings suggest that endogenous proteins may modulate Fa-bry cerebral vasculopathy and will potentially allow the prospectiveidentification of patients who are most at risk for developing thesecomplications. Such complications are likely to be associated witha concomitant increase in oxidative stress and accelerated athero-sclerosis, especially in genotypically susceptible individuals.

The pathogenesis of the disease in the heart and in the kidneyis not known. However, studying the downstream effects of Gb3accumulation is important since it is likely to generate novel andpotentially less expensive approaches to therapy. Fabry hypertrophiccardiomyopathy is associated with increasedmedia-intima thickess asseen in patients with common cardiovascular disease (Barbey et al.,

Fig. 7. Elevated counts of CD144+CD105+endothelial microparticles (EMP) in 11children with Fabry disease and age-matched controls. Prior to the initiation of ERT,children had significant elevation of EMP compared to controls (p=0.03). After6 months therewas a significant decrease in EMP (p=0.02) and after 12 months of ERTEMP was significantly lower than controls (p=0.002). Based on data from Geldermanet al. (2007).

72 R. Schiffmann / Pharmacology & Therapeutics 122 (2009) 65–77

2006). Plasma of patients with Fabry disease caused a greater proli-ferative response on vascular smoothmuscle cells in culture comparedto control plasma, suggesting that a circulating factor is responsible inpart for the cardiac hypertrophy in this disease (Barbey et al., 2006)—a similar phenomenon to the one obtained in vascular endothelialcells (Shen et al., 2008).

Even less is known about the mechanism of renal insufficiency.Besides the storage material, the pathological changes and the pre-sence of progressive glomerulosclerosis and proteinuria resembleother proteinuric nephropathies such as occur in diabetes mellitus(Dronavalli et al., 2008). Fabry proteinuria is not responsive to enzymereplacement infusions, but if the analogy to diabetes is correct one canhypothesize that it is associated with over-expression of cathepsin-Las well as abnormal processing of dynamin, and therefore might bereversible with appropriate treatment (Faul et al., 2008; Sever et al.,2007).

8. Therapy

8.1. Specific therapy

Enzyme replacement therapy (ERT) is the first specific therapy forFabry disease. It has been available since 2001, so it is a little early toreach any definitive conclusions as to whether this therapy can modifythe natural history of Fabry disease. Two forms of α-galactosidase Afor ERT exist. These are agalsidase alfa (Replagal, Shire Human GeneticTherapies, Cambridge, MA, 0.2 mg/kg per infusion) and agalsidasebeta (Fabrazyme, Genzyme Corporation, Cambridge, MA, 1 mg/kg perinfusion). Both are approved in Europe and many other countries (Eng,Guffon et al., 2001; Schiffmann et al., 2001), but in the US the FDAapproved only agalsidase beta (Eng, Guffon et al., 2001). Both formsof the enzyme are usually administered every two weeks. No cleardifference in clinical effect was demonstrated between the two enzymepreparations in a randomized controlled prospective study using eitherthe same or the approved dose (Vedder et al., 2008). The latter studywas not randomized and has a number of flaws (Mehta et al., 2008).

One can describe the effect of ERT by looking at specific organsystems. Accumulating evidence suggests that ERT slows the declineof renal glomerular function (Banikazemi et al., 2007; Germain et al.,2007; Schiffmann et al., 2007; Schiffmann, Ries et al., 2006; Tahir et al.,2007). It may be particularly effective if initiated before kidney re-serve is exhausted and glomerular filtration rate becomes significantlydecreased (Banikazemi et al., 2007). In patients who have significantdecline in kidney function despite ERT, weekly enzyme infusions mayfurther slow the decline in the glomerular filtration rate (Schiffmannet al., 2007). The extent of proteinuria is an important factor in pre-dicting the rate of decline of renal function and the response to ERT(Banikazemi et al., 2007). However, ERT does not reduce proteinuriaor normalize tubular function. ERT reduces lysosomal inclusions inkidney vascular endothelial cells and urinary excretion of Gb3 (Eng,Banikazemi et al., 2001; Eng, Guffon et al., 2001; Schiffmann et al.,2001), but Gb3 has not been confirmed as a useful surrogate biomarkerin clinical trials. For example, the stabilization of renal function thatwas achieved by changing the frequency of administration of ERT fromevery two weeks to every week was not associated with furtherreduction in urinary Gb3 (Schiffmann et al., 2007).

ERT reduced left ventricular mass in one small randomized con-trolled trial and in some non-controlled studies, but there is so farno evidence that it can fundamentally change Fabry cardiac disease(Spinelli et al., 2004; Weidemann et al., 2003) (Hughes et al., 2008). Itis possible that once irreversible changes such as fibrosis occur, ERTis no longer effective. The clinical impression is that the cardiac ab-normalities, including progressive bradycardia and conduction ab-normalities as well as valvular and coronary artery disease, continueto progress inmany patients (Beer et al., 2006; Kalliokoski et al., 2006;Mougenot et al., 2008).

Along with other researchers we have attempted to assess theeffect of ERT on the neurological manifestations of Fabry disease. Idescribe below the effect of ERTon vascular dysfunction, the incidenceof stroke, small-fiber neuropathy (pain and thermal threshold) andhypohidrosis in patients with Fabry disease.

Since it may take years and many patients to demonstrate a pos-sible reduction in stroke risk, we evaluated the effect of ERT on cere-bral vascular perfusion and function in two 6-month randomizedcontrolled trials of agalsidase alfa. In our initial study, using H2

15O andpositron emission tomography (PET) we found a significant decreasein resting cerebral blood flow in patients on ERT compared with theplacebo group (Moore, Scott et al., 2001). This indicates at least apartial reversal of the cerebral hyperperfusion seen in this disorder(Moore, Scott et al., 2001). The decrease in resting hyperperfusionwasconfirmed using two other methods; one consisted of a quantitativemeasurement of cerebral blood perfusion and the other of measuringcerebral blood flow velocity (transcranial Doppler) (Moore, Altarescu,Ling et al., 2002; Moore et al., 2004). In the initial study we alsoexamined the response of the cerebral vasculature to acetazolamide, adrug that maximally dilates the cerebral blood vessels by decreasingthe pH of the extracellular vessel wall (Settakis et al., 2003). Cerebralblood vessels of patients with Fabry disease remained maximallydilated significantly longer than controls (Moore, Altarescu, Herscov-itch et al., 2002). We found that agalsidase alfa reverses the excessivereactivity to acetazolamide compared with placebo after 6 months oftreatment. As evidence of cellular access of intravenously infusedα-galactosidase A beyond the vascular endothelial cells is lacking, theimproved acetazolamide response suggested a role for vascular en-dothelial cells in the CNS aspects of Fabry disease.

In another randomized placebo-controlled trial, we tested thehypothesis that reactive oxygen species (ROS) contribute to the cere-bral hyperperfusion in Fabry disease by assessing the response ofcerebral blood flow to the intravenous infusion of 1 g ascorbate over4 min, a known ‘quencher’ of ROS (Moore et al., 2004). This study,using quantitative arterial spin tagging and magnetic resonanceimaging, confirmed the cerebral hyperperfusion seen with PET, andalso demonstrated that healthy controls and patients on ERT re-sponded similarly to ascorbate infusion by a decrease in cerebral bloodflow. The patients on placebo had a significant delay in the reductionof cerebral blood flow, again suggesting a defect in vessel reactivitypossibly due to an excess of ROS in Fabry disease (Moore et al., 2004).In the initial NIH randomized controlled trial, we found a significantreduction in dermal 3-nitrotyrosine staining, suggesting reductionin the potentially toxic effect of ROS secondary to peroxynitrite for-mation (Moore, Scott et al., 2001). In pediatric patients we found

Fig. 9. The effect of changing the dosing frequency of agalsidase alfa from every otherweek (EOW) to weekly in patients whose estimated GFR (eGFR) declines at N5 ml/minper 1.73 m2/year during long-term EOW therapy. Each symbol represents an individualpatient, and the squares represent the mean±SEM during EOW and weekly dosing(Schiffmann et al., 2007).

73R. Schiffmann / Pharmacology & Therapeutics 122 (2009) 65–77

increased circulating vascular endothelial microparticles that de-creased to the normal range after 6 weeks of ERT but at the 12 monthstime point the level of endothelial microparticles was below normal(Fig. 7) (Gelderman et al., 2007). The significance of this finding isunclear at present (see also below).

Despite the significant improvement in the function of the cerebralvasculature, four of 25 patients in our original study, followed for4.5 years on ERT, developed non-debilitating strokes and one patienthad a transient ischemic attack (Schiffmann, Ries et al., 2006). Onestroke involved a large vessel (vertebral artery occlusion) and the otherswere small-vessel strokes. Based on our experience and that of others,strokes also continue to occur in patients on agalsidase beta (Buechneret al., 2008; Wilcox et al., 2004), and there is no indication of a markedreduction in stroke risk in the first few years following initiation of ERTin adulthood. A pediatric patient of ours continued to have strokes onERT for a number of years (Fig. 3) (Ries, Clarke et al., 2006).

The lack of an observed clinical effect of ERT, particularly on stroke,can be explained in a number of ways: A. There may be a smalltherapeutic effect that cannot be detected in the relatively small numberof patients studied. B. It is also possible that the infusedα-galactosidaseA does not have access to the entire thickness of cerebral vessels andtherefore leaves untreated a significant component of the vessel wall(Fig. 8) (Murray et al., 2007). C. The intermittent nature of ERT may beinsufficient to prevent the chronic toxic process that is described in thisreview. In support of this hypothesis is the fact that low levels of enzymeactivity in patients withmild mutations are sufficient to delay the onsetof chronic renal insufficiency by at least one decade (Branton et al.,2002). The additional effect of weekly enzyme infusions furthersupports the need for continuous activity of α-galctosidase A in the

Fig. 8. The heart of a Fabry knockoutmouse injectedwith agalsidase alfa shows granularstaining in myocardial capillaries (arrow) but not in myocytes. B. Vehicle control has noagalsidase alfa immunoreactivity (40×) (Murray et al., 2007).

cell (Fig. 9) (Schiffmann et al., 2007). D. The possibility of pre-existingirreversible structural changes in the vasculature may limit the effect ofERT when initiated in adulthood. It is unfortunate that we do not knowwhether earlier treatment will be more efficacious than later. Arandomized controlled trial of early ERT versus delayed ERT in childrenwith Fabry disease is probably the only way to reliably answer thatquestion.

There is evidence that the effect of ERTon Fabry diseasemay be evenmore complicated. Using the Fabry mouse model we characterized thegenomic response to ERT in the cardiovascular system (Moore, Gelder-man et al., 2007). We found that partial normalization of genomicexpression was associated with abnormal expression of other sets ofgenes, including anabnormality of gene splicing thatwaspresentonly inthe enzyme-treated Fabry mouse. This suggests that at least in themouse model ERT is associated with a unique biological state (the 3rdstate) rather than a simple progression from the diseased statetoward the healthy state. In a cell culture model, α-galactosidase Aappears to enhance oxidative stress and the reactivity of the vascularendothelial cells to inflammatory cytokines, suggesting that thebiological effects of ERT may lead to more than depletionof accumulated Gb3 (Shen et al., 2008). Endothelial microparticleswere elevated in childrenwith Fabry disease (Gelderman et al., 2007).After 6 months of ERT the microparticles level normalized but at the12 months time point the endothelial microparticles level was signi-ficantly belowcontrol level (Fig. 7). If reflecting a true abnormality, thisfinding suggests that ERT is associated with a change in the quality ofthe membrane of vascular endothelial cells.

We attempted to evaluate the effect of ERT on neuropathic pain.In the initial NIH 6-month randomized controlled study we found asignificant reduction in pain scores, using the Brief Pain Inventory, inpatients on ERT compared with placebo (Schiffmann et al., 2001).When the patients on placebo crossed over to receive agalsidase alfa,they exhibited a similar benefit (Schiffmann et al., 2003a,b). Whenfollowed over a longer period of time, however, there was no furtherreduction in pain scores. For these studies, patients were selected forsevere neuropathic pain, and neuropathic pain medication was stop-ped 1 week prior to pain scoring (12). The clinical impression sincethen confirms these initial findings in adults (Eto et al., 2005; Guffon &Fouilhoux, 2004; Hoffmann et al., 2005) and children (Ries, Clarkeet al., 2006). However, neuropathic pain is often not completely eli-minated and patients commonly need to continue with their painmedication, albeit at a lower dose.

74 R. Schiffmann / Pharmacology & Therapeutics 122 (2009) 65–77

ERT with agalsidase alfa had no significant effect on warm and coldsensation over the 6-month randomized controlled trial (Schiffmannet al., 2001). Over the 3 years of open-label treatment, however, therewas a significantbutmodest reduction in the cold andwarmthdetectionthresholds in the foot in both groups, and for warmth perception in thethigh (Schiffmann et al., 2003a,b). There was also a trend toward re-duction of cold detection thresholds in the hand. This effect took about18 months to develop, and sensory function seemed to stabilize there-after. Similar results, looking particularly at heat pain thresholds, wereobtained by a group treating patients with agalsidase beta (Hilz, Bryset al., 2004). These authors also described an improvement in vibrationdetection thresholds. The functional improvement in cold perception ofabout 10%was not associatedwith an increase in epidermal innervationdensity (Schiffmann, Hauer et al., 2006).

Overall, although these findings are encouraging, they do not sug-gest complete normalization of peripheral nerve function. It is possiblethat early treatment before irreversible axonal damage, or higher andmore frequent dosing, may be more effective. Alternatively, asmentioned above for the Fabry vascular diathesis, perhaps the infusedenzyme has insufficient access to affected sensory nerves and ganglia(Murray et al., 2007).

Sweat function in Fabry disease is of particular interest, as it ispossible to measure sweat gland function directly. Moreover, as thecapillaries around the sweat glands are fenestrated, itmight be expectedthat ERT would improve sweat-gland function relatively early in thecourse of therapy. We studied sweat function using the quantitativesudomotor sweat test (QSART) (Low&Opfer-Gehrking,1999). Aswedidnot have this technique at our disposal at the start of our initialrandomized controlled study, the study of sweat functionwas started atthe 3-year time point for this patient cohort. Sweat function was foundto improve 24–72 h after enzyme infusion compared with pre-infusionvalues,while theQSARTresponse normalized in four anhidrotic patients(Schiffmann et al., 2003a,b). To date, however, some patients haveremained anhidrotic despite years of ERT.

There is little information on the effect of ERTon auditory function.Although we did not systematically examine hearing in our patientsbeyond this, hearing loss appeared to progress in our patient pop-ulation, with instances of sudden hearing loss and the need for hearingaids in a number of patients on ERT (Ries et al., 2007). Another groupreported small but statistically significant improvement in hearing(Hajioff et al., 2003; Lemkens et al., 2002). The mean improvement of4.9 dB is less than the value considered clinically significant, and iswithin the accepted range of test–retest variability and learning effects(Lemkens et al., 2002).

ERT has been studied in children, but exclusively thus far in open-label clinical trials. It has been determined as safe and associated withreduction skin and urinary Gb3, less neuropathic pain, fewer gas-trointestinal symptoms, increased heart rate variability, stable renalfunction and cardiac structure and function (Ramaswami, 2008; Ries,Clarke et al., 2006; Wraith et al., 2008). However, one patient in ourstudy continued to have strokes for a number of years on ERT (Ries,Clarke et al., 2006). As stated above, these studies cannot tell us whento initiate ERT in children in order to obtainmaximal preventive effect.

Other specific therapeutic approaches are being developed. Ofparticular interest are pharmacological chaperones (Fan & Ishii,2007). These are small molecules that are active-site inhibitors thatat low doses can promote the normal folding and trafficking ofmisfolded wild type and mutated proteins. Preliminary results of aphase 2 multicenter study showed that the drug AT1001 (migalastathydrochloride) is safe and well tolerated (Schiffmann, Germain et al.,2008). Significant increase in enzyme levels in peripheral whiteblood cells and kidney tissue was found that paralleled a decrease inurinary Gb3. Additional studies to assess the clinical usefulness ofpharmacological chaperones are planned. Substrate reduction andgene therapy have been proposed for Fabry disease but no usefuldata currently exist.

8.2. Non-specific therapy

Since Fabry disease causes medical complications that are non-specific in nature and indistinguishable from similar complicationsthat occur in the general population, it is expected that they will beresponsive to standard medical and surgical care. This is indeed thecase. Effective anti-platelet agents such as clopidogrel and aspirin/long acting dipyridamole should be used to prevent strokes in allpatients with Fabry disease, and in particular those with a familyhistory of stroke. This is important since, as noted above, ERT on itsown does not seem to appreciably reduce the incidence of stroke.

The kidney dysfunction in Fabry disease responds well to angio-tensin converting enzyme inhibitors (ACEI) and angiotensin receptorblockers (ARB). They seem especially useful when used in conjunctionwith ERT with a goal to reduce proteinuria to less than 500 mg/24 h(Tahir et al., 2007). Normalization of blood pressure is very importantto preserve kidney function and prevent other vascular events. Renaltransplantation is as effective in Fabry disease patients who reachedend-stage renal disease as in any other disorder (Ojo et al., 2000).Patients are increasingly transplanted early with kidneys from bothlive donors and cadavers (Ojo et al., 2000).

The neuropathic pain is often treated with relatively low dosesof anti-epileptic medication such as carbamazepine, neurontin andlamotrigine (Horowitz, 2007; Ries et al., 2003; Tremont-Lukats et al.,2000). Non-steroidal anti-inflammatory drugs are less effective andnarcotics are effective but usually avoided (Gordon et al., 1995).Pancreatic enzymes are useful to prevent post-prandial diarrhea inpatients (personal observations).

References

Aerts, J. M., Groener, J. E., Kuiper, S., Donker-Koopman, W. E., Strijland, A., Ottenhoff, R.,et al. (2008). Elevated globotriaosylsphingosine is a hallmark of Fabry disease. ProcNatl Acad Sci U S A 105(8), 2812−2817.

Alroy, J., Sabnis, S., & Kopp, J. B. (2002). Renal pathology in Fabry disease. J Am SocNephrol 13(Suppl 2), S134−S138.

Altarescu, G., Moore, D. F., Pursley, R., Campia, U., Goldstein, S., Bryant, M., et al. (2001).Enhanced endothelium-dependent vasodilation in Fabry disease. Stroke 32(7),1559−1562.

Altarescu, G., Moore, D. F., & Schiffmann, R. (2005). Effect of genetic modifiers oncerebral lesions in Fabry disease. Neurology 64(12), 2148−2150.

Anderson, W. A. (1898). A case of angiokeratoma. Br J Dermatol 18, 113−117.Andrade, J.,Waters, P. J., Singh, R. S., Levin, A., Toh, B. C.,Vallance,H.D., et al. (2008). Screening

for Fabry disease in patients with chronic kidney disease: Limitations of plasma alpha-galactosidase assay as a screening test. Clin J Am Soc Nephrol 3(1), 139−145.

Askari, H., Kaneski, C. R., Semino-Mora, C., Desai, P., Ang, A., Kleiner, D. E., et al. (2007).Cellular and tissue localization of globotriaosylceramide in Fabry disease. VirchowsArch 451(4), 823−834.

Attal, N., & Bouhassira, D. (1999). Mechanisms of pain in peripheral neuropathy. ActaNeurol Scand Suppl 173, 12−24.

Auray-Blais, C., Cyr, D., Ntwari, A., West, M. L., Cox-Brinkman, J., Bichet, D. G., et al.(2008). Urinary globotriaosylceramide excretion correlates with the genotype inchildren and adults with Fabry disease. Mol Genet Metab 93(3), 331−340.

Baccaglini, L., Schiffmann, R., Brennan,M. T., Lancaster, H. E., Jr., Kulkarni, A. B., & Brahim,J. S. (2001). Oral and craniofacial findings in Fabry's disease: a report of 13 patients.Oral Surg Oral Med Oral Pathol Oral Radiol Endo 92(4), 415−419.

Banikazemi, M., Bultas, J., Waldek, S., Wilcox, W. R., Whitley, C. B., McDonald, M., et al.(2007). Agalsidase-beta therapy for advanced Fabry disease: a randomized trial.Ann Intern Med 146(2), 77−86.

Banks, D. E., Milutinovic, J., Desnick, R. J., Grabowski, G. A., Lapp, N. L., & Boehlecke, B. A.(1983). Silicon nephropathy mimicking Fabry's disease. Am J Nephrol 3(5), 279−284.

Barbey, F., Brakch, N., Linhart, A., Rosenblatt-Velin, N., Jeanrenaud, X., Qanadli, S., et al.(2006). Cardiac and vascular hypertrophy in Fabry disease: evidence for a newmechanism independent of blood pressure and glycosphingolipid deposition. Ar-terioscler Thromb Vasc Biol 26(4), 839−844.

Beer, M., Weidemann, F., Breunig, F., Knoll, A., Koeppe, S., Machann, W., et al. (2006).Impact of enzyme replacement therapy on cardiac morphology and function andlate enhancement in Fabry's cardiomyopathy. Am J Cardiol 97(10), 1515−1518.

Beratis, N. G., Varvarigou-Frimas, A., Beratis, S., & Sklower, S. L. (1989). Angiokeratomacorporis diffusum in GM1 gangliosidosis, type 1. Clin Genet 36(1), 59−64.

Bichet, D. G. (2008). Vasopressin receptor mutations in nephrogenic diabetes insipidus.Semin Nephrol 28(3), 245−251.

Bishop, D. F., Kornreich, R., & Desnick, R. J. (1988). Structural organization of the humanalpha-galactosidase A gene: further evidence for the absence of a 3' untranslatedregion. Proc Natl Acad Sci U S A 85(11), 3903−3907.

Bodary, P. F., Shen, Y., Vargas, F. B., Bi, X., Ostenso, K. A., Gu, S., et al. (2005). Alpha-galactosidase A deficiency accelerates atherosclerosis in mice with apolipoprotein Edeficiency. Circulation 111(5), 629−632.

75R. Schiffmann / Pharmacology & Therapeutics 122 (2009) 65–77

Brady, R., Gal, A.E., Bradley, R.M.,Martensson, E.,Warshaw,A. L., & Laster, L. (1967). Enzymaticdefect in Fabry disease: ceramide trihexosidase deficiency.N Engl J Med 276, 1163−1167.

Brady, R. O., & Schiffmann, R. (2000). Clinical features of and recent advances in therapyfor Fabry disease. JAMA 284(21), 2771−2775.

Branton, M. H., Schiffmann, R., Sabnis, S. G., Murray, G. J., Quirk, J. M., Altarescu, G., et al.(2002). Natural history of Fabry renal disease: influence of alpha-galactosidase Aactivity andgeneticmutations on clinical course.Medicine (Baltimore)81(2),122−138.

Buechner, S., Moretti, M., Burlina, A. P., Cei, G., Manara, R., Ricci, R., et al. (2008). Centralnervous system involvement in Anderson–Fabry disease: a clinical and MRIretrospective study. J Neurol Neurosurg Psychiatry 79(11), 1249−1254.

Burlina,A. P.,Manara,R., Caillaud,C., Laissy, J. P., Severino,M.,Klein, I., et al. (2008). Thepulvinarsign: frequency and clinical correlations in Fabry disease. J Neurol 255(5), 738−744.

Cable, W. J., Kolodny, E. H., & Adams, R. D. (1982). Fabry disease: impaired autonomicfunction. Neurology 32(5), 498−502.

Cable, W. J., McCluer, R. H., Kolodny, E. H., & Ullman, M. D. (1982). Fabry disease:detection of heterozygotes by examination of glycolipids in urinary sediment.Neurology 32(10), 1139−1145.

Calzavara-Pinton, P. G., Colombi, M., Carlino, A., Zane, C., Gardella, R., Clemente, M., et al.(1995). Angiokeratoma corporis diffusum and arteriovenous fistulas with dominanttransmission in the absence of metabolic disorders. Arch Dermatol 131(1), 57−62.

Case 2-1984: Fabry's disease (1984). N Engl J Med 310(24), 1607.Chabas, A., Coll, M. J., Aparicio, M., & Rodriguez Diaz, E. (1994). Mild phenotypic

expression of alpha-N-acetylgalactosaminidase deficiency in two adult siblings.J Inherit Metab Dis 17(6), 724−731.

Chatterjee, S., Gupta, P., Pyeritz, R. E., & Kwiterovich, P. O., Jr. (1984). Immunohisto-chemical localization of glycosphingolipid in urinary renal tubular cells in Fabry'sdisease. Am J Clin Pathol 82(1), 24−28.

Chatterjee, S., & Kwiterovich, P. O., Jr. (1984). Glycosphingolipids and plasmalipoproteins: a review. Can J Biochem Cell Biol 62(6), 385−397.

Cilmi, S. A., Karalius, B. J., Choy,W., Smith, R. N., & Butterton, J. R. (2006). Fabry disease inmice protects against lethal disease caused by Shiga toxin-expressing enterohe-morrhagic Escherichia coli. J Infect Dis 194(8), 1135−1140.

Clarke, J. T., Stoltz, J. M., & Mulcahey, M. R. (1976). Neutral glycosphingolipids of serumlipoproteins in Fabry's disease. Biochim Biophys Acta 431(2), 317−325.

Conti, G., & Sergi, B. (2003). Auditory and vestibular findings in Fabry disease: a study ofhemizygous males and heterozygous females.Acta Paediatr Suppl 92(443), 33−37discussion 27.

D'Amico, D. J., & Kenyon, K. R. (1981). Drug-induced lipidoses of the cornea andconjunctiva. Int Ophthalmol 4(1–2), 67−76.

DeGraba, T., Azhar, S., Dignat-George, F., Brown, E., Boutiere, B., Altarescu, G., et al.(2000). Profile of endothelial and leukocyte activation in Fabry patients. Ann Neurol47(2), 229−233.

Desnick, R. J., Ioannou, Y. A., & Eng, C. M. (2001). a-galactosidase A deficiency: Fabrydisease. In C. R. Scriver, A. L. Beaudet, W. S. Sly, & D. Valle (Eds.), The metabolic andmolecular bases of inherited disease (pp. 3733−3774)., 8 ed. NewYork:McGraw-Hill.

Dobrovolny, R., Dvorakova, L., Ledvinova, J., Magage, S., Bultas, J., Lubanda, J. C., et al.(2005). Relationship between X-inactivation and clinical involvement in Fabryheterozygotes. Eleven novel mutations in the alpha-galactosidase A gene in theCzech and Slovak population. J Mol Med 83, 647−654.

Dobyns, W. B. (2006). The pattern of inheritance of X-linked traits is not dominant orrecessive, just X-linked. Acta Paediatr Suppl 95(451), 11−15.

Donati, D., Novario, R., & Gastaldi, L. (1987). Natural history and treatment of uremiasecondary to Fabry's disease: an European experience. Nephron 46(4), 353−359.

Dronavalli, S., Duka, I., & Bakris, G. L. (2008). The pathogenesis of diabetic nephropathy.Nat Clin Pract Endocrinol Metab 4(8), 444−452.

Duncan, C. (1970). The renal lesion of angiokeratoma corporis diffusum (Fabry'sdisease): report of three cases including some electron microscopic findings.Pathology 2(1), 9−14.

Dutsch, M., Marthol, H., Stemper, B., Brys, M., Haendl, T., & Hilz, M. J. (2002). Small fiberdysfunction predominates in Fabry neuropathy. J Clin Neurophysiol 19(6), 575−586.

Elleder, M. (2003). Sequelae of storage in Fabry disease—pathology and comparison withother lysosomal storage diseases.Acta Paediatr Suppl 92(443), 46−53 discussion 45.

Elleder, M. (2008). Cellular and tissue localization of globotriaosylceramide in Fabrydisease.Virchows Arch 452(6), 705 author reply 707–708.

Eng, C. M., Banikazemi, M., Gordon, R. E., Goldman, M., Phelps, R., Kim, L., et al. (2001). Aphase 1/2 clinical trial of enzyme replacement in fabry disease: pharmacokinetic,substrate clearance, and safety studies. Am J Hum Genet 68(3), 711−722.

Eng, C. M., Fletcher, J., Wilcox, W. R., Waldek, S., Scott, C. R., Sillence, D. O., et al. (2007).Fabry disease: baseline medical characteristics of a cohort of 1765 males andfemales in the Fabry Registry. J Inherit Metab Dis 30(2), 184−192.

Eng, C. M., Guffon, N., Wilcox, W. R., Germain, D. P., Lee, P., Waldek, S., et al. (2001).Safety and efficacy of recombinant human alpha-galactosidase A— replacementtherapy in Fabry's disease. N Engl J Med 345(1), 9−16.

Eto, Y., Ohashi, T., Utsunomiya, Y., Fujiwara, M., Mizuno, A., Inui, K., et al. (2005). Enzymereplacement therapy in Japanese Fabry disease patients: The results of a phase 2bridging study. J Inherit Metab Dis 28(4), 575−583.

Fabry, J. (1898). Ein Betrag zur Kenntnis der Ppurpura hammarrhagica nodularis. ArchDermatol Syphilol 43, 187−200.

Faggiano, A., Pisani, A., Milone, F., Gaccione, M., Filippella, M., Santoro, A., et al. (2006).Endocrine dysfunction in patients with Fabry disease. J Clin Endocrinol Metab 91(11),4319−4325.

Fan, J. Q., & Ishii, S. (2007). Active-site-specific chaperone therapy for Fabry disease. Yinand Yang of enzyme inhibitors. Febs J 274(19), 4962−4971.

Faul, C., Donnelly, M., Merscher-Gomez, S., Chang, Y. H., Franz, S., Delfgaauw, J., et al.(2008). The actin cytoskeleton of kidney podocytes is a direct target of theantiproteinuric effect of cyclosporine A. Nat Med 14(9), 931−938.

Fimiani, M., Mazzatenta, C., Rubegni, P., & Andreassi, L. (1997). Idiopathic angioker-atoma corporis diffusum. Clin Exp Dermatol 22(4), 205−206.

Forstermann, U. (2008). Oxidative stress in vascular disease: causes, defensemechanisms and potential therapies. Nat Clin Pract Cardiovasc Med 5(6), 338−349.

Fuller, M., Sharp, P. C., Rozaklis, T., Whitfield, P. D., Blacklock, D., Hopwood, J. J., et al.(2005). Urinary lipid profiling for the identification of fabry hemizygotes andheterozygotes. Clin Chem 51(4), 688−694.

Gadoth, N., & Sandbank, U. (1983). Involvement of dorsal root ganglia in Fabry's disease.J Med Genet 20(4), 309−312.

Garman, S. C., & Garboczi, D. N. (2004). The molecular defect leading to Fabry disease:structure of human alpha-galactosidase. J Mol Biol 337(2), 319−335.

Gasparini, G., Sarchi, G., Cavicchini, S., & Bertagnolio, B. (1992). Angiokeratoma corporisdiffusum in a patient with normal enzyme activities and Turner's syndrome. ClinExp Dermatol 17(1), 56−59.

Gelderman, M. P., Schiffmann, R., & Simak, J. (2007). Elevated endothelial microparticlesin Fabry children decreased after enzyme replacement therapy. Arterioscler ThrombVasc Biol 27(7), e138−e139.

George, S., &Graham-Brown, R. A. (1994). Angiokeratoma corporis diffusum in fucosidosis.J R Soc Med 87(11), 707.

Germain, D. P., Waldek, S., Banikazemi, M., Bushinsky, D. A., Charrow, J., Desnick, R. J., et al.(2007). Sustained, long-term renal stabilization after 54 months of agalsidase betatherapy in patients with Fabry disease. J Am Soc Nephrol 18(5), 1547−1557.

Glass, R. B., Astrin, K. H., Norton, K. I., Parsons, R., Eng, C. M., Banikazemi, M., et al.(2004). Fabry disease: renal sonographic andmagnetic resonance imaging findingsin affectedmales and carrier females with the classic and cardiac variant phenotypes.J Comput Assist Tomogr 28(2), 158−168.

Gordon, K. E., Ludman, M. D., & Finley, G. A. (1995). Successful treatment of painfulcrises of Fabry disease with low dose morphine. Pediatr Neurol 12(3), 250−251.

Grysiewicz, R. A., Thomas, K., & Pandey, D. K. (2008). Epidemiology of ischemic andhemorrhagic stroke: incidence, prevalence, mortality, and risk factors. Neurol Clin26(4), 871−895.

Guffon, N., & Fouilhoux, A. (2004). Clinical benefit in Fabry patients given enzymereplacement therapy—a case series. J Inherit Metab Dis 27(2), 221−227.

Gupta, S., Ries, M., Kotsopoulos, S., & Schiffmann, R. (2005). The relationship of vascularglycolipid storage to clinical manifestations of Fabry disease: a cross-sectional studyof a large cohort of clinically affected heterozygous women. Medicine (Baltimore)84(5), 261−268.

Hajioff, D., Enever, Y., Quiney, R., Zuckerman, J., Mackermot, K., & Mehta, A. (2003).Hearing loss in Fabry disease: the effect of agalsidase alfa replacement therapy.J Inherit Metab Dis 26(8), 787−794.

Hashimoto, K., Gross, B. G., & Lever, W. F. (1965). Angiokeratoma corporis diffusum(Fabry). Histochemical and electron microscopic studies of the skin. J InvestDermatol 44, 119.

Hauser, A. C., Gessl, A., Lorenz, M., Voigtlander, T., Fodinger, M., & Sunder-Plassmann, G.(2005). High prevalence of subclinical hypothyroidism in patients with Anderson–Fabry disease. J Inherit Metab Dis 28(5), 715−722.

Hilz, M. J., Brys, M., Marthol, H., Stemper, B., & Dutsch, M. (2004). Enzyme replacementtherapy improves function of C-, Adelta-, and Abeta-nerve fibers in Fabry neuropathy.Neurology 62(7), 1066−1072.

Hilz, M. J., Kolodny, E. H., Brys, M., Stemper, B., Haendl, T., & Marthol, H. (2004). Reducedcerebral blood flow velocity and impaired cerebral autoregulation in patients withFabry disease. J Neurol 251(5), 564−570.

Hoffmann, B., Garcia de Lorenzo, A., Mehta, A., Beck, M., Widmer, U., & Ricci, R. (2005).Effects of enzyme replacement therapy on pain and health related quality of life inpatients with Fabry disease: data from FOS (Fabry Outcome Survey). J Med Genet 42(3), 247−252.

Hoffmann, B., & Keshav, S. (2007). Gastrointestinal symptoms in Fabry disease:everything is possible, including treatment. Acta Paediatr Suppl 96(455), 84−86.

Hopkin, R. J., Bissler, J., Banikazemi, M., Clarke, L., Eng, C. M., Germain, D. P., et al. (2008).Characterization of Fabry disease in 352 pediatric patients in the Fabry Registry.Pediatr Res 64(5), 550−555.

Hornbostel, H., & Scriba, K. (1953). [Excision of skin in diagnosis of Fabry'sangiokeratoma with cardio-vasorenal syndrome as phosphatide storage disease.].Klin Wochenschr 31(3–4), 68−69.

Horowitz, S. H. (2007). The diagnostic workup of patients with neuropathic pain. MedClin North Am 91(1), 21−30.

Hughes, D. A., Elliott, P. M., Shah, J., Zuckerman, J., Coghlan, G., Brookes, J., et al. (2008).Effects of enzyme replacement therapy on the cardiomyopathy of Anderson–Fabrydisease: a randomised, double-blind, placebo-controlled clinical trial of agalsidasealfa. Heart 94(2), 153−158.

Inagaki, M., Katsumoto, T., Nanba, E., Ohno, K., Suehiro, S., & Takeshita, K. (1993).Lysosomal glycosphingolipid storage in chloroquine-induced alpha-galactosidase-deficient human endothelial cells with transformation by simian virus 40: in vitromodel of Fabry disease. Acta Neuropathol 85(3), 272−279.

Jarvis, R. M., Chamba, A., Holder, M. J., Challa, A., Smith, D. C., Hodgkin, M. N., et al.(2007). Dynamic interplay between the neutral glycosphingolipid CD77/Gb3 andthe therapeutic antibody target CD20 within the lipid bilayer of model B lymphomacells. Biochem Biophys Res Commun 355(4), 944−949.

Kalliokoski, R. J., Kalliokoski, K. K., Sundell, J., Engblom, E., Penttinen, M., Kantola, I., et al.(2005). Impaired myocardial perfusion reserve but preserved peripheral endothe-lial function in patients with Fabry disease. J Inherit Metab Dis 28(4), 563−573.

Kalliokoski, R. J., Kantola, I., Kalliokoski, K. K., Engblom, E., Sundell, J., Hannukainen, J. C.,et al. (2006). The effect of 12-month enzyme replacement therapy on myocardialperfusion in patients with Fabry disease. J Inherit Metab Dis 29(1), 112−118.

Kampmann, C., Baehner, F. A., Whybra, C., Bajbouj, M., Baron, K., Knuf, M., et al. (2005). Theright ventricle in Fabry disease.Acta Paediatr Suppl 94(447), 15−18 discussion 19–10.

76 R. Schiffmann / Pharmacology & Therapeutics 122 (2009) 65–77

Kampmann, C., Linhart, A., Baehner, F., Palecek, T.,Wiethoff, C.M.,Miebach, E., et al. (2008).Onset and progression of the Anderson–Fabry disease related cardiomyopathy. Int JCardiol 130(3), 367−373.

Kampmann, C., Wiethoff, C. M., Whybra, C., Baehner, F. A., Mengel, E., & Beck, M. (2008).Cardiac manifestations of Anderson–Fabry disease in children and adolescents.Acta Paediatr 97(4), 463−469.

Kaneski, C. R., Moore, D. F., Ries, M., Zirzow, R., Schiffmann, R. (2006). Myeloperoxidasepredicts risk for vasculopathic events in Fabry disease. Neurology 67, 2045–2047.

Kawachi, Y., Matsu-ura, K., Sakuraba, H., & Otsuka, F. (1998). Angiokeratoma corporisdiffusum associated with galactosialidosis. Dermatology 197(1), 52−54.

Kawano, M., Takenaka, T., Otsuji, Y., Teraguchi, H., Yoshifuku, S., Yuasa, T., et al. (2007).Significance of asymmetric basal posterior wall thinning in patients with cardiacFabry's disease. Am J Cardiol 99(2), 261−263.

Kaye, E. M., Kolodny, E. H., Logigian, E. L., & Ullman, M. D. (1988). Nervous systeminvolvement in Fabry's disease: clinicopathological and biochemical correlation.Ann Neurol 23(5), 505−509.

Keilmann, A. (2003). Inner ear function in children with Fabry disease.Acta PaediatrSuppl 92(443), 31−32 discussion 27.

Kint, J. A. (1970). Fabry's disease: alpha-galactosidase deficiency. Science 167(922),1268−1269.

Kitagawa, T., Suzuki, K., Ishige, N., Ohashi, T., Kobayashi, M., Eto, Y., et al. (2008). Non-invasive high-risk screening for Fabry disease hemizygotes and heterozygotes. Pe-diatr Nephrol 23(9), 1461−1471.

Kleinert, J., Dehout, F., Schwarting, A., de Lorenzo, A. G., Ricci, R., Kampmann, C., et al.(2005). Anemia is a new complication in Fabry disease: data from the FabryOutcome Survey. Kidney Int 67(5), 1955−1960.

Kodama, K., Kobayashi, H., Abe, R., Ohkawara, A., Yoshii, N., Yotsumoto, S., et al. (2001). Anew case of alpha-N-acetylgalactosaminidase deficiency with angiokeratomacorporis diffusum, with Meniere's syndrome and without mental retardation. Br JDermatol 144(2), 363−368.

Laaksonen, S. M., Roytta, M., Jaaskelainen, S. K., Kantola, I., Penttinen, M., & Falck, B.(2008). Neuropathic symptoms and findings in women with Fabry disease. ClinNeurophysiol 119(6), 1365−1372.

Lacomis, D., Roeske-Anderson, L., & Mathie, L. (2005). Neuropathy and Fabry's disease.Muscle Nerve 31(1), 102−107.

Lemkens, N., Vermeire, K., Brokx, J. P., Fransen, E., Van Camp, G., & Van De Heyning, P. H.(2002). Interpretation of pure-tone thresholds in sensorineural hearing loss(SNHL): a review of measurement variability and age-specific references. ActaOtorhinolaryngol Belg 56(4), 341−352.

Linhart, A., Palecek, T., Bultas, J., Ferguson, J. J., Hrudova, J., Karetova, D., et al. (2000).New insights in cardiac structural changes in patients with Fabry's disease. AmHeart J 139(6), 1101−1108.

Lobo, T., Morgan, J., Bjorksten, A., Nicholls, K., Grigg, L., Centra, E., et al. (2008).Cardiovascular testing in Fabry disease: exercise capacity reduction, chronotropicincompetence and improved anaerobic threshold after enzyme replacement. InternMed J 38(6), 407−414.

Low, P. A., & Opfer-Gehrking, T. L. (1999). The autonomic laboratory. Am JElectroneurodiagn Technol 39(2), 65−76.

Lozano, F., Garcia-Talavera, R., & Gomez-Alonso, A. (1988). An unusual cause oflymphoedema—confirmed by isotopic lymphangiography. Eur J Vasc Surg 2(2),129−131.

Luciano, C. A., Russell, J. W., Banerjee, T., Quirk, J. M., Scott, L. J., Dambrosia, J. M., et al.(2002). Physiologic characterization of neuropathy in Fabry disease. Muscle Nerve26(5), 622−629.

Maat-Kievit, A., Losekoot,M., VanDenBoer-VanDenBerg, H., VanOmmen,G. J., Niermeijer,M., Breuning, M., et al. (2001). New problems in testing for Huntington's disease: theissue of intermediate and reduced penetrance alleles. J Med Genet 38(4), E12.

MacDermot, J., & MacDermot, K. D. (2001). Neuropathic pain in Anderson–Fabrydisease: pathology and therapeutic options. Eur J Pharmacol 429(1–3), 121−125.

Macrae,W.G., Ghosh,M.,&McCulloch, C. (1985). Corneal changes inFabry's disease: a clinico-pathologic case report of a heterozygote.Ophthalmic Paediatr Genet 5(3), 185−190.

Martin, L., Sturgess, A., Sillence, D., & Murrell, D. F. (2007). Fabry disease in a hetero-zygote presenting as hand ischaemia and painful acroparaesthesia. Australas JDermatol 48(1), 40−42.

Mehta, A., Beck, M., Kampmann, C., Frustaci, A., Germain, D. P., Pastores, G. M., et al.(2008). Enzyme replacement therapy in Fabry disease: comparison of agalsidasealfa and agalsidase beta. Mol Genet Metab 95(1–2), 114−115.

Mehta, A., & Ginsberg, L. (2005). Natural history of the cerebrovascular complications ofFabry disease.Acta Paediatr Suppl 94(447), 24−27 discussion 29–10.

Mehta, A., Ricci, R., Widmer, U., Dehout, F., Garcia de Lorenzo, A., Kampmann, C., et al.(2004). Fabry disease defined: baseline clinical manifestations of 366 patients inthe Fabry Outcome Survey. Eur J Clin Invest 34(3), 236−242.

Meikle, P. J., Hopwood, J. J., Clague, A. E., & Carey, W. F. (1999). Prevalence of lysosomalstorage disorders. JAMA 281(3), 249−254.

Meuwissen, S. G., Dingemans, K. P., Strijland, A., Tager, J. M., & Ooms, B. C. (1982). Ultra-structural and biochemical liver analyses in Fabry's disease.Hepatology 2(2), 263−268.

Mitsias, P., & Levine, S. R. (1996). Cerebrovascular complications of Fabry's disease. AnnNeurol 40(1), 8−17.

Moore, D. F., Altarescu, G., Barker, W. C., Patronas, N. J., Herscovitch, P., & Schiffmann, R.(2003). White matter lesions in Fabry disease occur in ‘prior’ selectivelyhypometabolic and hyperperfused brain regions. Brain Res Bull 62(3), 231−240.

Moore, D. F., Altarescu, G., Herscovitch, P., & Schiffmann, R. (2002). Enzyme replacementreverses abnormal cerebrovascular responses in Fabry disease. BMC Neurol 2(1), 4.

Moore, D. F., Altarescu, G., Ling, G. S., Jeffries, N., Frei, K. P., Weibel, T., et al. (2002).Elevated cerebral blood flow velocities in Fabry disease with reversal after enzymereplacement. Stroke 33(2), 525−531.

Moore, D. F., Gelderman, M. P., Ferreira, P. A., Fuhrmann, S. R., Yi, H., Elkahloun, A., et al.(2007). Genomic abnormalities of the murine model of Fabry disease after disease-related perturbation, a systems biology approach. Proc Natl Acad Sci U S A 104(19),8065−8070.

Moore, D. F., Herscovitch, P., & Schiffmann, R. (2001). Selective arterial distribution ofcerebral hyperperfusion in Fabry disease. J Neuroimaging 11(3), 303−307.

Moore, D. F., Kaneski, C. R., Askari, H., & Schiffmann, R. (2007). The cerebralvasculopathy of Fabry disease. J Neurol Sci 257(1–2), 258−263.

Moore, D. F., Krokhin, O. V., Beavis, R. C., Ries, M., Robinson, C., Goldin, E., et al. (2007).Proteomics of disease-related perturbations in Fabry disease: A strategy to identifybiological abnormalities. Proc Natl Acad Sci U S A 104, 2873–2878.

Moore, D. F., Scott, L. T., Gladwin, M. T., Altarescu, G., Kaneski, C., Suzuki, K., et al. (2001).Regional cerebral hyperperfusion and nitric oxide pathway dysregulation in Fabrydisease: reversal by enzyme replacement therapy. Circulation 104(13), 1506−1512.

Moore, D. F., Ye, F., Brennan, M. L., Gupta, S., Barshop, B. A., Steiner, R. D., et al. (2004).Ascorbate decreases Fabry cerebral hyperperfusion suggesting a reactive oxygen speciesabnormality: an arterial spin tagging study. J Magn Reson Imaging 20(4), 674−683.

Moore, D. F., Ye, F., Schiffmann, R., & Butman, J. A. (2003). Increased signal intensity inthe pulvinar on T1-weighted images: a pathognomonic MR imaging sign of Fabrydisease. AJNR Am J Neuroradiol 24(6), 1096−1101.

Morita, H., Rehm, H. L., Menesses, A., McDonough, B., Roberts, A. E., Kucherlapati, R., et al.(2008). Shared genetic causes of cardiac hypertrophy in children and adults.N Engl JMed 358(18), 1899−1908.

Mougenot, P., Lidove,O., Caillaud, C., Arnaud, P., &Papo, T. (2008). Fabrydisease and treatmentwith agalsidase alpha: unsuspected cardiac arrhythmia in two heterozygous women. Inreference to pharmacovigilance. Eur J Clin Pharmacol 64(6), 635−639.

Murray, G. J., Anver, M. R., Kennedy, M. A., Quirk, J. M., & Schiffmann, R. (2007). Cellularand tissue distribution of intravenously administered agalsidase alfa. Mol GenetMetab 90(3), 307−312.

Nakayama, Y., Tsumura, K., Yamashita, N., & Yoshimaru, K. (1999). Dynamic leftventricular arterial pressure gradient and sick sinus syndrome with heterozygousFabry's disease improved following implantation of a dual chamber pacemaker.Pacing Clin Electrophysiol 22(7), 1114−1115.

Nistal, M., Paniagua, R., & Picazo, M. L. (1983). Testicular and epididymal involvement inFabry's disease. J Pathol 141(2), 113−124.

Ojo, A., Meier-Kriesche, H. U., Friedman, G., Hanson, J., Cibrik, D., Leichtman, A., et al.(2000). Excellent outcome of renal transplantation in patients with Fabry's disease.Transplantation 69(11), 2337−2339.

Okeda, R., & Nisihara, M. (2008). An autopsy case of Fabry disease with neuropatho-logical investigation of the pathogenesis of associated dementia. Neuropathology 28(5), 532−540.

Opitz, J. M., Stiles, F. C., Wise, D., von Gemmingen, G., Race, R. R., Sander, R., et al. (1965).The genetics of angiokeratoma corporis diffusum (Fabry's disease), and its linkagewith Xg(a) locus. Am J Hum Genet 17, 325−342.

Ortiz, A., Oliveira, J. P., Waldek, S., Warnock, D. G., Cianciaruso, B., & Wanner, C. (2008).Nephropathy in males and females with Fabry disease: cross-sectional descriptionof patients before treatment with enzyme replacement therapy. Nephrol DialTransplant 23(5), 1600−1607.

Park, J. L., Whitesall, S. E., D'Alecy, L. G., Shu, L., & Shayman, J. A. (2008). Vasculardysfunction in the alpha-galactosidase A-knockout mouse is an endothelial cell-,plasma membrane-based defect. Clin Exp Pharmacol Physiol 35(10), 1156−1163.

Pompen, A. W., Ruiter, M., & Wyers, H. J. (1947). Angiokeratoma corporis diffusum(universale) Fabry, as a sign of an unknown internal disease; two autopsy reports.Acta Med Scand 128(3), 234−255.

Puccio, D., Coppola, G., Corrado, E., Muratori, I., Pistone, G., Buongiorno, M. R., et al.(2005). Non invasive evaluation of endothelial function in patients with Anderson–Fabry disease. Int Angiol 24(3), 295−299.

Ramaswami, U. (2008). Fabry disease during childhood: clinical manifestations andtreatment with agalsidase alfa. Acta Paediatr Suppl 97(457), 38−40.

Ramaswami, U., Whybra, C., Parini, R., Pintos-Morell, G., Mehta, A., Sunder-Plassmann,G., et al. (2006). Clinical manifestations of Fabry disease in children: data from theFabry Outcome Survey. Acta Paediatr 95(1), 86−92.

Ries, M., Bettis, K. E., Choyke, P., Kopp, J. B., Austin, H. A., 3rd, Brady, R. O., et al. (2004).Parapelvic kidney cysts: a distinguishing feature with high prevalence in Fabrydisease. Kidney Int 66(3), 978−982.

Ries, M., Clarke, J. T., Whybra, C., Timmons, M., Robinson, C., Schlaggar, B. L., et al. (2006).Enzyme-replacement therapy with agalsidase alfa in children with Fabry disease.Pediatrics 118(3), 924−932.

Ries, M., Gupta, S., Moore, D. F., Sachdev, V., Quirk, J. M., Murray, G. J., et al. (2005).Pediatric Fabry disease. Pediatrics 115(3), e344−e355.

Ries, M., Kim, H. J., Zalewski, C. K., Mastroianni, M. A., Moore, D. F., Brady, R. O., et al.(2007). Neuropathic and cerebrovascular correlates of hearing loss in Fabry disease.Brain 130(Pt 1), 143−150.

Ries, M., Mengel, E., Kutschke, G., Kim, K. S., Birklein, F., Krummenauer, F., et al. (2003).Use of gabapentin to reduce chronic neuropathic pain in Fabry disease. J InheritMetab Dis 26(4), 413−414.

Ries, M., Moore, D. F., Robinson, C. J., Tifft, C. J., Rosenbaum, K. N., Brady, R. O., et al.(2006). Quantitative dysmorphology assessment in Fabry disease. Genet Med 8(2),96−101.

Rodrigues, L. G., Ferraz, M. J., Rodrigues, D., Pais-Vieira, M., Lima, D., Brady, R. O., et al.(2009). Neurophysiological, behavioral and morphological abnormalities in theFabry knockout mice. Neurobiol Dis 33(1), 48−56.

Rohard, I., Schaefer, E., Kampmann, C., Beck, M., & Gal, A. (2008). Association betweenpolymorphisms of endothelial nitric oxide synthase gene (NOS3) and left posteriorwall thickness (LPWT) of the heart in Fabry disease. J Inherit Metab Dis. doi:10.1007/s10545-008-0920-z.

77R. Schiffmann / Pharmacology & Therapeutics 122 (2009) 65–77

Rolfs, A., Bottcher, T., Zschiesche, M., Morris, P., Winchester, B., Bauer, P., et al. (2005).Prevalence of Fabry disease in patients with cryptogenic stroke: a prospectivestudy. Lancet 366(9499), 1794−1796.

Romeo, G., D'Urso, M., Pisacane, A., Blum, E., De Falco, A., & Ruffilli, A. (1975). Residualactivity of alpha-galactosidase A in Fabry's disease.BiochemGenet 13(9–10), 615−628.

Romeo, G., & Migeon, B. R. (1970). Genetic inactivation of the alpha-galactosidase locusin carriers of Fabry's disease. Science 170(954), 180−181.

Rowe, J. W., Gilliam, J. I., & Warthin, T. A. (1974). Intestinal manifestations of Fabry'sdisease. Ann Intern Med 81(5), 628−631.

Sachdev, B., Takenaka, T., Teraguchi, H., Tei, C., Lee, P., McKenna, W. J., et al. (2002).Prevalence of Anderson–Fabry disease in male patients with late onset hyper-trophic cardiomyopathy. Circulation 105(12), 1407−1411.

Saliez, J., Bouzin, C., Rath, G., Ghisdal, P., Desjardins, F., Rezzani, R., et al. (2008). Role ofcaveolar compartmentation in endothelium-derived hyperpolarizing factor-mediated relaxation: Ca2+ signals and gap junction function are regulated bycaveolin in endothelial cells. Circulation 117(8), 1065−1074.

Schiffmann, R., Askari, H., Timmons, M., Robinson, C., Benko, W., Brady, R. O., et al. (2007).Weekly enzyme replacement therapy may slow decline of renal function in patientswith Fabry disease who are on long-term biweekly dosing. J Am Soc Nephrol 18(5),1576−1583.

Schiffmann, R., Floeter, M. K., Dambrosia, J. M., Gupta, S., Moore, D. F., Sharabi, Y., et al.(2003). Enzyme replacement therapy improves peripheral nerve and sweatfunction in Fabry disease. Muscle Nerve 28, 703−710.

Schiffmann, R., Floeter, M. K., Dambrosia, J. M., Gupta, S., Moore, D. F., Sharabi, Y., et al.(2003). Enzyme replacement therapy improves peripheral nerve and sweatfunction in Fabry disease. Muscle Nerve 28(6), 703−710.

Schiffmann, R., Germain, D. P., Castelli, J., Shenker, A., & Lockhart, D. J. (2008). Phase 2clinical trials of the pharmacological chaperone AT1001 for the treatment of Fabrydisease.Paper presented at the AnnualMeeting of the America Society ofHumanGenetics.

Schiffmann, R., Hauer, P., Freeman, B., Ries, M., Scott, L. J., Polydefkis, M., et al. (2006).Enzyme replacement therapy and intraepidermal innervation density in Fabrydisease. Muscle Nerve 34(1), 53−56.

Schiffmann, R., Kopp, J. B., Austin, H. A., 3rd, Sabnis, S., Moore, D. F., Weibel, T., et al.(2001). Enzyme replacement therapy in fabry disease: a randomized controlledtrial. JAMA 285(21), 2743−2749.

Schiffmann, R., Rapkiewicz, A., Abu-Asab, M., Ries, M., Askari, H., Tsokos, M., et al.(2005). Pathological findings in a patient with Fabry disease who died after2.5 years of enzyme replacement. Virchows Arch, 1−7.

Schiffmann, R., Ries, M., Timmons, M., Flaherty, J. T., & Brady, R. O. (2006). Long-termtherapy with agalsidase alfa for Fabry disease: safety and effects on renal functionin a home infusion setting. Nephrol Dial Transplant 21(2), 345−354.

Schweppe, C. H., Bielaszewska, M., Pohlentz, G., Friedrich, A. W., Buntemeyer, H.,Alexander Schmidt, M., et al. (2008). Glycosphingolipids in vascular endothelialcells: relationship of heterogeneity in Gb3Cer/CD77 receptor expression withdifferential Shiga toxin 1 cytotoxicity. Glycoconj J 25(4), 291−304.

Sen-Chowdhry, S., Syrris, P., & McKenna, W. J. (2005). Genetics of right ventricularcardiomyopathy. J Cardiovasc Electrophysiol 16(8), 927−935.

Senechal, M., & Germain, D. P. (2003). Fabry disease: a functional and anatomical studyof cardiac manifestations in 20 hemizygous male patients. Clin Genet 63(1), 46−52.

Settakis, G., Molnar, C., Kerenyi, L., Kollar, J., Legemate, D., Csiba, L., et al. (2003).Acetazolamideasavasodilatory stimulus in cerebrovasculardiseasesand inconditionsaffecting the cerebral vasculature. Eur J Neurol 10(6), 609−620.

Sever, S., Altintas, M. M., Nankoe, S. R., Moller, C. C., Ko, D., Wei, C., et al. (2007).Proteolytic processing of dynamin by cytoplasmic cathepsin L is a mechanism forproteinuric kidney disease. J Clin Invest 117(8), 2095−2104.

Shen, Y., Bodary, P. F., Vargas, F. B., Homeister, J. W., Gordon, D., Ostenso, K. A., et al.(2006). Alpha-galactosidase A deficiency leads to increased tissue fibrin depositionand thrombosis in mice homozygous for the factor V Leiden mutation. Stroke 37(4),1106−1108.

Shen, J. S., Meng, X. L., Moore, D. F., Quirk, J. M., Shayman, J. A., Schiffmann, R., et al. (2008).Globotriaosylceramide inducesoxidative stress andup-regulates cell adhesionmoleculeexpression in Fabry disease endothelial cells.Mol Genet Metab 95(3), 163−168.

Shu, L., & Shayman, J. A. (2007). Caveolin-associated accumulation of globotriaosylcer-amide in the vascular endothelium of alpha-galactosidase A null mice. J Biol Chem282(29), 20960−20967.

Sodi, A., Ioannidis, A. S., Mehta, A., Davey, C., Beck, M., & Pitz, S. (2007). Ocular mani-festations of Fabry's disease: data from the Fabry Outcome Survey. Br J Ophthalmol91(2), 210−214.

Sokoya, E. M., Burns, A. R., Setiawan, C. T., Coleman, H. A., Parkington, H. C., & Tare, M.(2006). Evidence for the involvement of myoendothelial gap junctions in EDHF-mediated relaxation in the rat middle cerebral artery. Am J Physiol Heart Circ Physiol291(1), H385−393.

Spada, M., Pagliardini, S., Yasuda, M., Tukel, T., Thiagarajan, G., Sakuraba, H., et al.(2006). High incidence of later-onset Fabry disease revealed by newborn screening.Am J Hum Genet 79(1), 31−40.

Spinelli, L., Pisani, A., Sabbatini, M., Petretta, M., Andreucci, M. V., Procaccini, D., et al.(2004). Enzyme replacement therapy with agalsidase beta improves cardiacinvolvement in Fabry's disease. Clin Genet 66(2), 158−165.

Stemper, B., & Hilz, M. J. (2003). Postischemic cutaneous hyperperfusion in the presenceof forearm hypoperfusion suggests sympathetic vasomotor dysfunction in Fabrydisease. J Neurol 250(8), 970−976.

Suzuki, N., Konohana, I., Fukushige, T., & Kanzaki, T. (2004). Beta-mannosidosis withangiokeratoma corporis diffusum. J Dermatol 31(11), 931−935.

Sweeley, C. C., & Klionsky, B. L. (1963). Fabry's disease: classification as a sphingolipidosisand partial characterization of a novel glycolipid. J Biol Chem 238, PC3148.

Tagliavini, F., Pietrini, V., Gemignani, F., Lechi, A., Pallini, R., & Federico, A. (1982).Anderson–Fabry's disease: neuropathological and neurochemical investigation.Acta Neuropathol 56(2), 93−98.

Tahir, H., Jackson, L. L., & Warnock, D. G. (2007). Antiproteinuric therapy and fabrynephropathy: sustained reduction of proteinuria in patients receiving enzymereplacement therapy with agalsidase-beta. J Am Soc Nephrol 18(9), 2609−2617.

Takaki, A., Morikawa, K., Tsutsui, M., Murayama, Y., Tekes, E., Yamagishi, H., et al. (2008).Crucial role of nitric oxide synthases system in endothelium-dependent hyperpo-larization in mice. J Exp Med 205(9), 2053−2063.

Takanashi, J., Barkovich, A. J., Dillon, W. P., Sherr, E. H., Hart, K. A., & Packman, S. (2003).T1 hyperintensity in the pulvinar: key imaging feature for diagnosis of Fabrydisease. AJNR Am J Neuroradiol 24(5), 916−921.

Takenaka, T., Teraguchi, H., Yoshida, A., Taguchi, S., Ninomiya, K., Umekita, Y., et al.(2008). Terminal stage cardiac findings in patients with cardiac Fabry disease:an electrocardiographic, echocardiographic, and autopsy study. J Cardiol 51(1),50−59.

Tanaka, M., Ohashi, T., Kobayashi, M., Eto, Y., Miyamura, N., Nishida, K., et al. (2005).Identification of Fabry's disease by the screening of alpha-galactosidase A activityin male and female hemodialysis patients. Clin Nephrol 64(4), 281−287.

Terryn, W., Poppe, B., Wuyts, B., Claes, K., Maes, B., Verbeelen, D., et al. (2008). Two-tierapproach for the detection of alpha-galactosidase A deficiency in a predominantlyfemale haemodialysis population. Nephrol Dial Transplant 23(1), 294−300.

Thadhani, R., Wolf, M., West, M. L., Tonelli, M., Ruthazer, R., Pastores, G. M., et al. (2002).Patientswith Fabrydisease on dialysis in theUnited States.Kidney Int 61(1), 249−255.

Thomaidis, T., Relle, M., Golbas, M., Brochhausen, C., Galle, P. R., Beck, M., et al. (2009).Downregulation of alpha-galactosidase A upregulates CD77: Functional impact forFabry nephropathy. Kidney Int 75, 399−407.

Tremont-Lukats, I.W.,Megeff, C., & Backonja,M.M. (2000). Anticonvulsants for neuropathicpain syndromes: mechanisms of action and place in therapy. Drugs 60(5), 1029−1052.

van Mullem, P. J., & Ruiter, M. (1970). Fine structure of the skin in angiokeratomacorporis diffusum (Fabry's disease). J Pathol 101(3), 221−226.

Vedder, A. C., Breunig, F., Donker-Koopman,W. E.,Mills, K., Young, E.,Winchester, B., et al.(2008). Treatment of Fabry disease with different dosing regimens of agalsidase:effects on antibody formation and GL-3. Mol Genet Metab 94(3), 319−325.

Vedder, A. C., Linthorst, G. E., van Breemen, M. J., Groener, J. E., Bemelman, F. J., Strijland,A., et al. (2007). The Dutch Fabry cohort: diversity of clinical manifestations andGb3 levels. J Inherit Metab Dis 30(1), 68−78.

Veinot, J. P. (2002). Prevalence of Anderson–Fabry disease in male patients with lateonset hypertrophic cardiomyopathy.Circulation 106(15), e73 author reply e73.

Vibert, D., Blaser, B., Ozdoba, C., & Hausler, R. (2006). Fabry's disease: otoneurologicfindings in twelve members of one family. Ann Otol Rhinol Laryngol 115(6),412−418.

Wang, R. Y., Lelis, A., Mirocha, J., &Wilcox,W. R. (2007). Heterozygous Fabry women arenot just carriers, but have a significant burden of disease and impaired quality oflife. Genet Med 9(1), 34−45.

Wei, E. P., Kontos, H. A., & Beckman, J. S. (1996). Mechanisms of cerebral vasodilationby superoxide, hydrogen peroxide, and peroxynitrite. Am J Physiol 271(3 Pt 2),H1262−1266.

Weicksel, J. (1925). Angiomatosis, bzw. Angiokeratosis universalis (eine sehr selteneHaut-und Gafasskrankheit). Dtsch Med Wochenschr 51, 898.

Weidemann, F., Breunig, F., Beer, M., Sandstede, J., Stork, S., Voelker, W., et al. (2005).The variation of morphological and functional cardiac manifestation in Fabrydisease: potential implications for the time course of the disease. Eur Heart J 26(12),1221−1227.

Weidemann, F., Breunig, F., Beer, M., Sandstede, J., Turschner, O., Voelker, W., et al. (2003).Improvement of cardiac function during enzyme replacement therapy in patientswith Fabry disease: a prospective strain rate imaging study. Circulation 108(11),1299−1301.

Whitley, C. B., Tsai, M. Y., Heger, J. J., Prystowsky, E. N., & Zipes, D. P. (1983). Amiodaronephenocopy of Fabry's keratopathy. Jama 249(16), 2177−2178.

Whybra, C., Kampmann,C.,Willers, I., Davies, J.,Winchester, B., Kriegsmann, J., et al. (2001).Anderson–Fabry disease: clinical manifestations of disease in female heterozygotes.J Inherit Metab Dis 24(7), 715−724.

Wilcox, W. R., Banikazemi, M., Guffon, N., Waldek, S., Lee, P., Linthorst, G. E., et al.(2004). Long-term safety and efficacy of enzyme replacement therapy for Fabrydisease. Am J Hum Genet 75(1), 65−74.

Wilcox, W. R., Oliveira, J. P., Hopkin, R. J., Ortiz, A., Banikazemi, M., Feldt-Rasmussen, U.,et al. (2008). Females with Fabry disease frequently havemajor organ involvement:Lessons from the Fabry Registry. Mol Genet Metab 93(2), 112−128.

Wraith, J. E., Tylki-Szymanska, A., Guffon, N., Lien, Y. H., Tsimaratos, M., Vellodi, A., et al.(2008). Safety and efficacy of enzyme replacement therapywith agalsidase beta: aninternational, open-label study in pediatric patients with Fabry disease.J Pediatr 152(4), 563−570 570 e561.

Yokota, M., Koji, M., & Yotsumoto, S. (1995). Histopathologic and ultrastructural studiesof angiokeratoma corporis diffusum in Kanzaki disease. J Dermatol 22(1), 10−18.

Zarate, Y. A., & Hopkin, R. J. (2008). Fabry's disease. Lancet 372(9647), 1427−1435.Zimmermann,M. (2001). Pathobiologyof neuropathic pain.Eur J Pharmacol429(1–3), 23−37.