Handbook of Clinical Neurology, Vol. 115 (3rd series)Peripheral Nerve DisordersG. Said and C. Krarup, Editors© 2013 Elsevier B.V. All rights reserved

Chapter 37

Fabry disease

KEIKO TOYOOKA*

Department of Neurology, National Hospital Organization Toneyama National Hospital, Toyonaka, Osaka, Japan

INTRODUCTION

Fabry disease is an X-linked lysosomal storage disordercaused by the deficient activity of the lysosomal glyco-hydrolase a-galactosidase A. The enzyme defect leadsto the progressive accumulation of globotriaosylce-ramide (GL-3) and related glycosphingolipids, withinvascular endothelial cells, a range of renal cell types,myocardial cells, and dorsal root ganglia neuronal cells.First manifestations involve small nerve fibers of theperipheral and autonomic nervous system. This neurop-athy is associated with decreased thermal sensation, par-ticularly to cold, with relative preservation of large fiberfunction, such as vibration detection. Neuropathic painand hypohidrosis are the main sources of lower qualityof life. With age, the incidence of life-threatening com-plications involving the kidney, heart, and brain pro-gresses. Both life expectancy and quality of life areseverely compromised.

Recently it has been reported that carrier womendevelop symptoms of Fabry disease including peripheralneuropathy at a higher rate than previously shownand they are at a higher risk of multiple organ failureand premature death. Apart from classic Fabry disease,atypical variants have been introduced, which are stillunderestimated.

With the development of enzyme replacement ther-apy (ERT) using recombinant human a-galactosidaseA, early initiation of ERT before the appearance of irre-versible organ failure is emphasized and its long-termoutcome is currently being investigated.

HISTORICAL ASPECTS

The original clinical descriptions of patients who are nowknown as having Fabry disease were given separately bytwo dermatologists, Johannes Fabry in Germany andWilliam Anderson in England in 1898 (Anderson, 1898;

*Correspondence to: Dr. Keiko Toyooka, Department of Neurology

5-1-1 Toneyama, Toyonaka, Osaka, 560-8552, Japan. Tel:þ81 6 685

Fabry, 1898). They used the term “angiokeratoma cor-poris” and “purpura papulosa haemorrhagica” for thisunusual skin condition. The accumulated substrates inthe kidney of patients with Fabry disease were identifiedas ceramidetrihexoside, now generally referred to asglobotriaosylceramide (GL-3) and galabiosylceramide(Sweeley and Klionsky, 1963). The enzymatic defect inFabry disease was established as insufficient activity ofthe enzyme ceramidetrihexosidase (a-galactosidase A)that catalyzes the hydrolytic cleavage of the terminalmolecule of galactose from accumulating GL-3 (Bradyet al., 1967). A simple and reliable diagnostic methodwas established and it was found that the leukocytesof male patients with Fabry disease were deficient ina-galactosidase and the level of its activity in leukocytesfrom female carriers was 15 to 40% of that in normalleukocytes (Kint, 1970).

EPIDEMIOLOGY

The incidence of Fabry disease has been estimated as onein 40 000 to one in 117 000 live births (Meikle et al., 1999;Desnick et al., 2001). Presenting symptoms are notalways specific, so Fabry disease is probably underes-timated. Screening of newborns in Italy revealed thatthe incidence of a-galactosidase A deficiency was 1 in3100 male babies with an 11:1 ratio of patients with thelater-onset:classic phenotypes, raising the possibility thatlater-onset variants are more frequent than has been pre-viously reported (Spada et al., 2006).

CLINICALMANIFESTATIONS

Classic Fabry disease

Symptoms of the disease typically occur during child-hood or adolescence with recurrent episodes of severeburning pain in the extremities, angiokeratomas,

, National Hospital Organization Toneyama National Hospital,

32001, Fax:þ81 6 68533127, E-mail: ktoyooka@toneyama.go.jp

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hypohidrosis, and cornea verticillata (Brady andSchiffmann, 2000; Zarate and Hopkin, 2008).

Early symptoms

Pain is one of the most disabling complications. Twotypes of pain have been reported: severe episodes of limbpain, called Fabry crises, typically start with hands andfeet and radiate proximally and are frequently triggeredby environmental factors including change of tempera-ture, stress, and exercise; the other is chronic burningand tingling pain. The presence of neuropathic painwas reported in 62–82% of males and in 41–70% offemales (MacDermot et al., 2001a, b; Eng et al., 2007;Hoffmann et al., 2007a). Fabry crises can be associatedwith fever, arthralgia, and increased erythrocyte sedi-mentation rate and may be misdiagnosed as rheumaticfever, rheumatoid arthritis, erythromelalgia, or othercollagen diseases.

Angiokeratomas, reddish-purple skin lesions, areseen in the umbilical, scrotal, inguinal, and gluteallesions. They increase in number and size with age.Angiokeratomas were reported in 66–71% of malesand in 35–36% of females (MacDermot et al., 2001a,b; Orteu et al., 2007). Angiokeratomas are a clue fordiagnosis. The presence of cutaneous vascular lesionswas correlated with the severity of the systemic manifes-tations of the disease (pain, renal failure, cardiacdisease, and premature cerebrovascular disease) asassessed by a severity scoring system (Orteu et al.,2007). Telangiectasia and lymphoedema have also beenreported (Orteu et al., 2007).

Hypohidrosis is a classic feature of Fabry disease.Decreased sweating leads to heat and exercise intolerance.The prevalence of hypohidrosis was reported in 53–56%of males and in 28–33% of females (MacDermot et al.,2001a, b; Orteu et al., 2007). On the contrary, hyperhidro-sis also occurs, with female predominance (6.4% in malesvs. 11.9% in females) (Lidove et al., 2006).

Gastrointestinal disturbances, such as nausea, vomit-ing, diarrhea, and abdominal pain, are associated withmeals and cause difficulties with gaining weight. Thereported prevalence was variable (19–69% in males vs.13–58% in females) (MacDermot et al., 2001a, b; Enget al., 2007; Hoffmann et al., 2007b). In one report,female patients were more frequently affected thanmale patients, and there was a high prevalence in chil-dren (Hoffmann et al., 2007b).

In Fabry disease, ophthalmological abnormalitiesoccur mostly at the level of the conjunctival and retinalvessels, the cornea, and the lens. Cornea verticillatawas reported in 73.5% of males and 76.9% of females;vessel tortuosity was observed in 48.7% of males and21.9% of females (Sodi et al., 2007). As these signs

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can be detected by a basic slit-lamp examination, oph-thalmological examination is useful and essential forearly diagnosis.

Hearing difficulty and paroxysmal vertigo are alsoobserved. Self-reported hearing loss was seen in 41%of males, but more frequent sensorimotor deafnesswas confirmed in 78% by audiogram (MacDermotet al., 2001a). Hearing ability of Fabry disease is signif-icantly worse than in an age-matched general population,but leads to clinically relevant hearing impairment inonly 16% of cases (Hegemann et al., 2006). A correlationof neuropathic and vascular damage with hearing losswas suggested in males and residual a-galactosidase Aactivity appears to have a protective effect against hear-ing loss (Ries et al., 2007).

Renal involvement

The first clinical signs of nephropathy include micro-albuminuria, proteinuria, and subsequently progressivedecline in glomerular filtration rate occurring if a criticalnumber of nephrons have been damaged as a result ofinterstitial scarring, glomerulosclerosis, and tubularatrophy. Progress to end-stage renal disease requiringdialysis or transplantation occurs by the fifth decadeof life (Thadhani et al., 2002). Baseline proteinuria,reduced glomerular filtration rate, hypertension, andmale gender were associated with more rapid progres-sion of Fabry nephropathy (Schiffmann et al., 2009).

Cardiac involvement

Cardiac involvement is present early in life but is notdetected clinically until the third or fourth decade(Mehta et al., 2004). Cardiovascular manifestationsinclude arrhythmia, left ventricular hypertrophy, valvu-lar dysfunction, angina pectoris, myocardial infarction,and heart failure (Linhart and Elliot, 2007; Zarate andHopkin, 2008). Although classic cardiac abnormality ishypertrophic cardiomyopathy, arrhythmias may becaused without left ventricular hypertrophy. Diseaseevolution in the heart is characterized initially by myo-cardial hypertrophy. As the disease progresses intersti-tial abnormalities and replacement myocardial fibrosisare seen. Cardiac disease in Fabry disease is associatedwith GL-3 accumulation in all cellular components ofthe heart, including cardiomyocytes, conduction systemcells, valvular fibroblasts, endothelial cells, and vascularsmooth muscle cells. While GL-3 accumulation is histo-logically the most important feature, it represents only1–2% of the total cardiac mass. So it seems that diseasein the heart results from activation of other signalingpathways that lead to hypertrophy, apoptosis, necrosis,and fibrosis (Linhart and Elliot, 2007).

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Cerebrovascular involvement

Strokes and transient ischemic attacks have been fre-quently seen in patients with Fabry disease. The mostfrequent symptoms and signs were as follows: hemipar-esis, vertigo/dizziness, diplopia, dysarthria, nystagmus,nausea/vomiting, head pain, hemiataxia and ataxia ofgait in the hemizygote group; memory loss, dizziness,ataxia, hemiparesis, loss of consciousness, and hemisen-sory symptoms in the heterozygote group (Mitsias andLevine, 1996). Psychiatric behavior and dementia havealso been attributed to the cerebral vasculopathy(Okeda and Nisihara, 2008). The cerebral vasculopathyconsists of ischemic strokes including large and smallvessels. The neuronal accumulation of glycosphingoli-pids appears to have no clinical effect on the natural his-tory of Fabry disease with the possible exception of somereported mild cognitive abnormalities (Moore et al.,2007). The most prominent MRI finding was severeprogressive white matter lesions. Hyperintensity in thepulvinar on T1-weighted images is a common findingin Fabry disease, likely reflecting the presence of calcifi-cation (Moore et al., 2003; Takahashi et al., 2003). Thepulvinar sign is highly specific to Fabry disease and isfound in male patients with cardiac signs and severerenal involvement (Burlina et al., 2008). Although pro-gressive white matter lesions at early age, increased sig-nal intensity in the pulvinar, and tortuosity and dilatationof the large vessels are well known on cranial MRI,increased basilar artery diameter has been shown to besuperior for separating patients with Fabry disease fromcontrols with an accuracy of 87% (Fellgiebel et al., 2009).

The mean age of onset of symptomatic cerebrovascu-lar disease was 38.4 years in themale stroke patients, and40.3 years in the female group (Rolfs et al., 2005).According to the FabryOutcome Survey (FOS) database,heterozygous women are more likely to experiencestroke (27%) than men (12%). The mean age at onsetof stroke was 28.8 years in men and 43.3 years in women(Mehta et al., 2004). Data from the Fabry Registryshowed the prevalence of strokes was estimated as6.9% in males and 4.3% in females. Median age at firststroke was 39.0 years in males and 45.7 years in females.Most patients (70.9% of males and 76.9% of females)experienced their first stroke before renal or cardiacevents. Fifty percent of males and 38.3% of femalesexperienced their first stroke before being diagnosedwith Fabry disease (Sims et al., 2009). The higher fre-quency of infarctions in the vertebrobasilar area(46.4% Fabry vs. 21.4% non-Fabry) correlated with morepronounced changes in the vertebrobasilar vessels likedolichoectatic pathology (42.9% vs. 6.8%) (Rolfs et al.,2005). Fabry disease must be considered in all cases ofunexplained stroke in young patients, especially in cases

with a combination of infarction in the vertebrobasilarartery system and proteinuria (Rolfs et al., 2005).

The pathogenesis of Fabry vasculopathy remainspoorly understood, but is associated with abnormalfunctional control of the vessel secondary to endothelialdysfunction, cerebral hyper-perfusion, and a prothrom-botic state with likely increased production of reactiveoxygen species (Moore et al., 2007). A patient with pro-gressive brainstem features was initially misdiagnosedas having multiple sclerosis (Lehmann et al., 2006).Misdiagnosis of Fabry disease is common. The meandelay from onset of symptoms to correct diagnosiswas 13.7 years in males and 16.3 years in females(Mehta et al., 2004).

Outcome

Death occurs from complications of renal disease, car-diac involvement, and/or cerebrovascular disease. Themedian cumulative survival was reported to be 50 yearsin hemizygous males and 70 years in obligate carrierfemales (MacDermot et al., 2001a, b). Recently accord-ing to the Fabry Registry, the average life expectancy ofmales with Fabry disease was reported to be 58.2 yearsand that of females 75.4 years (Waldek et al., 2009).The most common cause of death among both genderswas cardiovascular disease. Most (57%) of patients whodied of cardiovascular disease had previously receivedrenal replacement therapy (Waldek et al., 2009). Accord-ing to FOS database, the principal cause of death wasshifting away from renal failure to cardiac disease(Mehta et al., 2009a).

Female heterozygotes

Female carriers for the classic phenotype have a range ofclinical presentations due to random X-inactivation,ranging from being asymptomatic or having mild man-ifestations in the majority to rare carriers who are as seri-ously affected as males (Willard, 2001).

In a cross-sectional study of a large cohort, cardiac,renal, or cerebrovascular abnormalities were documen-ted in 52 of the 57 women (91%) with confirmed Fabrygenotypes (Gupta et al., 2005). Heterozygotes sufferedfrom significant multisystemic disease and reducedquality of life. Fatigue, present in 59%, was associatedwith reduced maximum oxygen consumption and exer-cise intolerance, present in 83%, was associated withreduced maximum heart rate during exercise testing(Wang et al., 2007). Of the 1077 enrolled females inthe Fabry Registry, 69.4% had symptoms and signs ofFabry disease. The median age at onset was 13 years.Twenty percent of females experienced major cerebro-vascular, cardiac, or renal events at a median age of46 years (Wilcox et al., 2008). Although it was previously

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thought that serious manifestations are seen only inhemizygous males, female heterozygotes for Fabry dis-ease have a significant risk for major organ involvementand decreased quality of life and must be regularly mon-itored for signs and symptoms.

Atypical variants of Fabry disease

Late-onset Fabry disease with manifestations of cardio-vascular, renal, and cerebrovascular disease may beunderestimated.

CARDIAC VARIANT

Screening of 230 Japanese male patients with left ven-tricular hypertrophy by plasma a-galactosidase A assaysrevealed that 3% of patients were previously unrecog-nized “cardiac variants” (Nakao et al., 1995). Recentlya screening study of 508 patients (328 males and 180females) with hypertrophic cardiomyopathy reportedthat 1% of patients had undiagnosed Fabry disease(Monserrat et al., 2007).

RENAL VARIANT

Following measurement of plasma a-galactosidase Aactivity in a series of 514 consecutive, unrelated Japanesemale patients undergoing hemodialysis previously diag-nosed with “chronic glomerulonephritis”, six (1.2%)patients were revealed as having Fabry disease. Noneof them had angiokeratoma or corneal and lenticulardystrophy (Nakao et al., 2003).

CEREBROVASCULAR VARIANT

A screening study of 721 German adults aged 18 to 55years who had had strokes of unknown etiology reportedthat 4.9% of males and 2.4% of females had Fabry dis-ease. Based on this data, it is estimated that Fabry diseaseis responsible for 1.2% of cryptogenic strokes in patientsyounger than 55 years (Rolfs et al., 2005). Screening ofyoung patients presenting with cerebrovascular diseasein Belgium revealed that a-galactosidase A deficiencymay play a role in up to 1% of cases (Brouns et al., 2010).

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PERIPHERALNEUROPATHYANDPATHOPHYSIOLOGY

Early symptoms in Fabry patients include burning pain inthe hands and feet, hypohidrosis, and gastrointestinalsymptoms. Detailed neurophysiological examinationrevealed small fiber dysfunction was more prominentthan large fiber dysfunction (D€utsch et al., 2002;Luciano et al., 2002). It is generally agreed that cold per-ception is conveyed primarily by small myelinated (A-d)fibers andwarm perception is conveyed by unmyelinated

(C) fibers, as well as that conventional nerve conductionstudies and vibratory detection threshold assess thefunction of large myelinated fibers (A-a and A-b).One group showed that nerve conduction studies inpatients with Fabry disease were mostly normal exceptfor an increased frequency of median nerve entrapment(27%) at the wrist and sympathetic skin responses werepreserved (95%) (Luciano et al., 2002). Another groupfound lower compound muscle action potentials, lowersensory action potentials, and lower amplitude of sym-pathetic skin responses in Fabry patients as comparedto controls (D€utsch et al., 2002). Quantitative sensorytesting showed increased or unmeasurable cold andwarmdetection thresholds in patients, whichwere signif-icantly different from controls in the hand and foot.Cold thresholds were more severely impaired than warmthresholds. A consistent pattern of thermo-hypoesthesia,affecting the feet more than hands, was seen (Lucianoet al., 2002). Neurophysiologically, it was shown thatthe peripheral neuropathy in Fabry disease was charac-terized by thermal afferent fiber dysfunction in alength-dependent fashion, with greater impairment ofcold than warm sensation, and relative preservationof large myelinated fiber function. Clinical peripheralneuropathy that predominately affected thermal sensa-tion with variable involvement of pinprick and lighttouch was shown in 20 male and 2 female Australianpatients. Quantitative sensory testing confirmed thesefindings (Low et al., 2007). Decreased sweating wasalso demonstrated by thermoregulatory sweat test andquantitative sudomotor axon reflex test (Schiffmannet al., 2003).

Sural nerve biopsy specimens from hemizygous maleand heterozygous female Fabry patients showed dense,osmiophilic, lamellated bodies in the endothelial cells,pericytes, smooth muscle cells, and fibroblasts, aswell as in the circumferential and fascicle-separatingperineurial cells. In the endoneurial cells the lamellatedbodies were numerous and pleomorphic, but capillarieswere not occluded. On electronmicroscopy, 2.1 nm-thickdense lines were assembled into 5.4 nm periodicity(Figs. 37.1 to 37.4). Histograms of myelinated fibers(MFs) and unmyelinated fibers (UFs) showed that smallMFs and UFs were relatively selectively decreased in ahemizygous male and to a lesser extent, in a symptom-atic heterozygous female (Toyooka and Said, 1997;Figs. 37.5 and 37.6). In addition to this preferentialloss of small MFs and UFs (Ohnishi and Dyck, 1974;Tabira et al., 1974; Tome et al., 1977; Mutoh et al.,1988), preferential loss of small neurons in the dorsalroot ganglia has also been reported (Ohnishi andDyck, 1974). On the other hand, a few authors have dem-onstrated the preferential depletion of large MFs (Vitalet al., 1984).

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Symptoms of peripheral nervous system and auto-nomic dysfunction might be related to the storage ofGL-3 in dorsal root ganglion cells and autonomic gan-glion cells. Neuropathologically, extensive GL-3 accu-mulation has been reported in neurons of sympatheticand dorsal root ganglia in hemizygotes (Tabira et al.,

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Fig. 37.2. Electron micrograph showing lamellated bodies in

perineurial cells in a hemizygote. Scale bar: 0.3 mm. From

Toyooka and Said (1997) with permission of Springer Science

and Business Media.

Fig. 37.3. Electronmicrograph of an endoneurial blood vessel

in a hemizygote. Lamellated bodies in endothelial cells and

pericytes are shown. Scale bar: 2 mm. From Toyooka and

Said (1997) with permission of Springer Science and Business

Media.

Fig. 37.4. Electron micrograph showing osmiophilic inclu-

sions indicated by an arrow in perineurial cells and well pre-

served myelinated and unmyelinated fibers. A few collagen

pockets are seen. Scale bar: 2 mm (by courtesy of Professor

Said).

Fig. 37.1. Transverse epoxy section showing osmiophilic

inclusions indicated by arrows in the endothelial cells, peri-

cytes, and perineurial cells. Thionin staining. Scale bar:

10 mm (by courtesy of Professor Said).

Myelinated fibers

Fiber diameter

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er d

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01-3mm 3-5mm 5-7mm 7-9mm 9-11mm 11-13mm

Hemizygote(2721)

Heterozygote(5410)

Control(7650)

13-15mm 15-17mm

Fig. 37.5. Histogram of myelinated fibers (MFs) of hemizygote, heterozygote, and control. From Toyooka and Said (1997) with

permission of Springer Science and Business Media.

Unmyelinated fibers10000

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Control(37500)

Fig. 37.6. Histogram of unmyelinated fibers (UFs) of hemizygote, heterozygote, and control. From Toyooka and Said (1997) with

permission of Springer Science and Business Media.

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1974; Kaye et al., 1988). The most dramatic GL-3increases occurred in the dorsal root ganglia, choroidplexus, and leptomeninges – a more than 150-foldincrease in somemales (Kaye et al., 1988). The permeableblood–brain barrier and blood–nerve barrier regions ofthe central and peripheral nervous systems containedincreased quantities of GL-3. In the symptomatic hetero-zygous female, the accumulations of GL-3 in spinal andsympathetic ganglia were 34 and 48 times the amount innormal controls, respectively (Hozumi et al., 1989). Thepathophysiology of the painful attacks in Fabry diseasehas not been elucidated. Significant accumulation of gly-colipids in dorsal root ganglia may support the hypothe-sis that painful attacks are caused by involvement of thislesion. Another possible hypothesis is an increase in thenumber of small regenerating UFs as seen in some cases(Ohnishi and Dyck,1974; Tabira et al., 1974; Toyooka and

Said, 1997), but not in the heterozygote without painfulepisodes (Mutoh et al., 1988). Hyperexcitability andspontaneous firing of sprouting (regenerating) unmy-elinated neuritis arising from nociceptive axons havebeen suggested as a pain mechanism of peripheral nerveorigin (Asbury and Fields, 1984). In addition, glycosphin-golipid deposition in the small vessels that supply bloodto the peripheral nerve might contribute to neuropathicpain. The endothelial glycosphingolipid accumulationmight narrow the vascular lumen, and vessel spasmsor frank infarction might cause the excruciating pain(Mehta and Hughes, 2002).

Using skin biopsy specimens, Scott et al. (1999)described severe loss of intraepidermal innervation atthe ankle and less severe loss at the distal thigh wasshown in hemizygotes. They demonstrated a length-dependence on the distribution of nerve damage that

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was consistent with the length-dependent abnormalityof thermal afferents as shown before (Luciano et al.,2002). Although the gold standard for identifying andquantitating small fiber neuropathy is nerve biopsy,the advantage of skin biopsy over nerve biopsy is thepossibility of repeating performances to check the sever-ity of neuropathy and the degree of regenerating processfollowed by ERT.

Recent studies suggested that heterozygous femaleFabry patients develop peripheral neuropathy. In 12women with Fabry disease, 10 had symptoms of smallfiber neuropathy, and five had decreased intraepidermalnerve fiber density (IENFD) or thermal hypoesthesia(Laaksonen et al., 2008). In a study of 19 female patientswith Fabry disease (TorvinMoller et al., 2009), daily painwas present in 63% of patients, with a mean visual ana-log scale (VAS) score of 4.0. Tactile detection thresholdand pressure pain threshold were lower and cold detec-tion thresholds were increased in patients. Sensory nerveaction potential amplitude andmaximal sensory conduc-tion velocity values did not differ from those of controls,whereas there was a highly significant reduction inIENFD. No correlation between pain VAS score, quanti-tative sensory testing, and IENFD was found (TorvinMoller et al., 2009). Following skin biopsy, it was sug-gested that heterozygous Fabry females, althoughasymptomatic, might have somatic and autonomic smallfiber neuropathy in a length-dependent fashion (Liguoriet al., 2010).

Numerous characteristic cytoplasmic inclusions wereobserved in the eccrine sweat glands and the small ves-sels around the eccrine glands may be responsible for thedecreased sweating ability (Lao et al., 1998). Acuteimprovement in sweat function 24–72 h post enzymeinfusion suggests that the hypohidrosis in Fabry diseaseis partly due to a functional defect at the sweat glandlevel rather than to a gross structural abnormality(Schiffmann et al., 2003).

By means of noncontact corneal aesthesiometry toquantify loss of corneal sensation and the novel nonin-vasive techniques of corneal confocal microscopy toquantify small fiber neuropathy, early small nerve fiberdamage and dysfunction were detected (Tavakoli et al.,2009). This was in good accordance with previous obser-vations in sural nerve and skin biopsies.

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GENETICS

The a-galactosidase A gene (GLA) is located on the longarm of the X chromosome, in position Xq22, spansapproximately 12 kb of genomic DNA, and containsseven exons (Kornreich et al., 1989). The complementaryDNA is 1290 bases and encodes a polypeptide of 429amino acids including a 31 amino acid signal peptide.

The structure is a homodimer of approximately101 kDa with each monomer containing a (beta/alpha)8 domain with the active site and an antiparallel betadomain. N-linked carbohydrate appears at six sites inthe glycoprotein dimer, revealing the basis for lysosomaltransport via the mannose-6-phosphate receptor (Bishopet al., 1986; Garman and Garboczi, 2004).

Newly synthesized a-galactosidase A protein tra-verses the rough endoplasmic reticulumwhere it receivesN-linked oligosaccharide side chains. Subsequently itpasses through the Golgi apparatus where the oligosac-charide side chains undergo a series of posttranslationalmodifications. It receives the mannose-6-phosphaterecognition marker. Αlpha-galactosidase A bearingmannose-6-phosphate marker, which binds to themannose-6-phosphate receptor in the trans-Golginetwork,is packed into clathrin-coated vesicles and transported toendosomes (Kornfeld and Mellman, 1989). Due to thelow pH in this cellular compartment the receptor–ligandcomplexes dissociate and a-galactosidase A is deliv-ered to lysosomes. Αlpha-galactosidase A, which doesnot receive the mannose-6-phosphate recognitionmarker in the Golgi apparatus, is secreted. This extra-cellular a-galactosidase A can bind to plasma mem-brane located mannose-6-phosphate receptors, whichmediates its endocytosis and transport to the lyso-somes. This mechanism is an essential prerequisitefor the effectiveness of ERT (Ghosh et al., 2003).

More than 500 mutations have been identified in thegene for a-galactosidase A (The Human Gene MutationDatabase at the Institute ofMedical Genetics in Cardiff,2011). Point mutations (missense or nonsense mutations)are the most frequent, but small and large deletions,splicing mutations, or insertions are also seen.

Mutations leading to complete loss of function of thegene product are associated with classic forms of the dis-ease, whereas mutations resulting in amino acid substi-tutions might occasionally be associated with a milderphenotype and late variants. Efforts to establish geno-type–phenotype correlation have been limited becauseeach family with Fabry disease has a private mutation.Genotype/phenotype correlations revealed that certainmutations previously found inmild variant patients werealso found in classic patients, suggesting that other mod-ifying factors are involved in disease expression(Ashton-Prolla et al., 2000).

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DIAGNOSIS

Diagnosis is frequently delayed because of the nonspe-cific nature of symptoms and signs. Suspicion of thepossibility of having Fabry disease is important. Delayin diagnosis from onset of neuropathic pain was a meanof 8.18 years and from onset of angiokeratoma was a

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mean of 10.7 years (MacDermot et al., 2001a). Thediagnosis was often made incidentally and recognitionof cornea verticillata or angiokeratoma by ophthal-mologists or dermatologists, respectively, was high(MacDermot et al., 2001a).

In males, screening for greatly deficient or absent a-galactosidase A activity in plasma or peripheral leuko-cytes, or gene sequencing should be done. In females,measurement of a-galactosidase A enzyme activity isunreliable because many carrier females have normalactivity (Linthorst et al., 2005).Molecular genetic testingis the most reliable method for the diagnosis of carrierfemales.

TREATMENT

An international panel of physicians with expertise inFabry disease has proposed guidelines for the recogni-tion, evaluation, and surveillance of disease-associatedmorbidities, as well as therapeutic strategies (Enget al., 2006).

Conventional therapy

NEUROPATHIC PAIN

Based upon self-assessment of pain levels, carbama-zepine showed moderate to complete relief for severepain of Fabry disease. But preexisting autonomic dys-functions such as ileus, urinary retention, and gastro-intestinal disturbance were exacerbated in somepatients (Filling-Katz et al., 1989). Neuropathic painwas decreased comparedwith baseline using the anticon-vulsant gabapentin, as measured using the Brief PainInventory (Ries et al., 2003).

GASTROINTESTINAL DISTURBANCE

For the delayed gastric emptying shown by radionuclidegastric emptying studies, motility agents such as meto-clopramide are reported to produce symptomatic orsometimes functional improvement (Argoff et al., 1998).

RENAL INVOLVEMENT

Angiotensin-converting enzyme (ACE) inhibitors orangiotensin-receptor blockers (ARB) might be usefulto reduce proteinuria. Normalization of blood pressureis important to preserve renal function. For end-stagerenal involvement of Fabry disease, renal dialysis andrenal transplantation are the choices.

CARDIAC INVOLVEMENT

Treatment of symptomatic heart disease in patients withFabry disease is similar to that for those who havethe same cardiac problems but from other causes.

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Conventional treatment with ACE inhibitors anddiuretics should be used in patients with evidence of sys-tolic impairment. In patients with supraventricularrhythm disturbances, anticoagulant treatment shouldbe initiated. A permanent cardiac pacemaker is usedfor patients with higher degrees of A-V block. Patientswith chest pain should receive conventional anti-anginaltreatment together with antiplatelet treatment. Foradvanced congestive heart failure heart transplantationmay be considered, as the intrinsic enzyme productionwithin the graft should prevent reoccurrence of disease(Linhart and Elliot, 2007).

CEREBROVASCULAR INVOLVEMENT

Administration of aspirin and other antiplatelet agentsare recommended for preventing strokes, but thisapproach is not sufficient.

Enzyme replacement therapy

ERTwas the first specific therapy for Fabry disease and ithas been available since 2001. Two forms ofa-galactosidase A are available: agalsidase alfa (Repla-galR: Shire Human Genetic Therapies, Boston, MA,USA) at a dose of 0.2 mg/kg every other week; agalsidasebeta (FabrazymeR: Genzyme Corporation, Cambridge,MA,USA) at a dose of 1.0 mg/kg every other week. Agal-sidase alfa is produced in a human fibroblast cell line andagalsidase beta in a Chinese hamster ovary host cell line.They are functionally indistinguishable, with comparablespecific activities per milligram and glycosylation pat-terns (Lee et al., 2003). Infused a-galactosidase A canbind to plasma membrane located mannose-6-phosphatereceptors, which mediates its endocytosis and transportsto the lysosomes. During the treatment about half ofthe patients experienced mild-to-moderate infusionreactions (i.e., rigors and fever) (Eng et al., 2001;Schiffmann et al., 2001). All were transient and managedconservatively. IgG seroconversion occurred in 88% whoreceived agalsidase beta (Eng et al., 2001). Infusion-associated reactions decreased over time, as did anti-rh- a-galactosidase A IgG antibody titers (Wilcoxet al., 2004). Agalsidase beta therapy could be success-fully reinstated in patients with Fabry disease who havedeveloped IgE antibodies or skin test reactivity to therecombinant enzyme (Wilcox et al., 2004; Bodensteineret al., 2008). The main problems of ERT are repeatedintravenous infusion and high costs.

NEUROPATHY, PAIN, HYPOHIDROSIS

Schiffmann et al. (2001) demonstrated in a 6-monthdouble-blind placebo-controlled study that ERT (agalsi-dase alfa 0.2 mg/kg every other week) significantly

OKA

DI

reduced neuropathic pain and use of pain medications,and improved pain-related quality of life and renalpathology. There was an approximately 50% reductionin plasma GL-3 levels, a significant improvement in car-diac conduction, and a significant increase in bodyweight. In the same cohort, 3-year open-label extensionof ERT lead to a modest but significant improvementin the clinical manifestations of small fiber neuropathyshowing reduced neuropathic pain, improved sweating,and reduced detection threshold for cold and warm tem-peratures in the hands and feet (Schiffmann et al., 2003).It was investigated whether this kind of functionalimprovement associated with ERT corresponded toincreased IENFD. After 6 months of placebo-controlledstudy followed by an additional 12 months of open-labelERT, there were no significant differences in IENFDbetween the enzyme and the placebo groups. Further-more, after an additional year of ERT, there was asignificant reduction in IENFD in the patient group,attributed to the declining glomerular filtration rate.Thermal thresholds remained unchanged. So it wasconcluded that epidermal nerve fiber regeneration didnot occur after 12–18 months of ERT (Schiffmannet al., 2006a). According to the FOS database, agalsidasealfa improved pain score and quality of life in a cohort of314 patients who were receiving ERT (Beck et al., 2004).

As previously shown, vibratory, cold, and heat–paindetection threshold testing adequately characterizesAb-, Ad-, and C-fiber dysfunction in Fabry patients(Dutsch et al., 2002). Hilz et al. (2004b) showed thatERT with agalsidase beta 1.0 mg/kg every other weeksignificantly improved function of C-, Ad-, and Ab-nerve fibers and intradermal vibration receptors in Fabryneuropathy by performing quantitative sensory testing.Lack of recovery in some patients with severe dysfunc-tion of thermal perception suggested that early ERT,prior to irreversible nerve fiber loss, was necessary.

In the double-blind placebo-controlled study of ERT(agalsidase beta 1 mg/kg every other week), Eng et al.(2001) reported significant improvements in pain scoresafter 20 weeks of treatment in both treatment groups.There was no significant difference between groups inany pain assessment, possibly because of low scores atbase line and placebo effect. In this double-blind study,20 of 29 patients in the agalsidase beta treated group hadno renal microvascular endothelial deposits of GL-3, ascompared with none of 29 patients in the placebo group(p<0.001). Patients treated with agalsidase beta also haddecreased deposits of GL-3 in the skin (p<0.001) andheart (p<0.001) compared with placebo patients.Plasma concentrations of GL-3 were undetectable afterweek 20 in all 20 patients who had no deposits of GL-3 inrenal biopsy. During the open-label extension study of 30months, five of 58 patients stopped all pain medications

FABRY

and six of 58 patients had a reduction on dose and/or fre-quency of their pain medications (Wilcox et al., 2004).The final extension study of 54 months showed signifi-cant improvement in pain scores (Germain et al., 2007).

Although based on a small number of patients, ERTwith agalsidase alfa was reported to reverse the hearingdeterioration gradually (Hajioff et al., 2003).

RENAL INVOLVEMENT

According to the FOS database, treatment with agalsi-dase alfa stabilized renal function in patients with a mildor moderate deterioration in renal function at baseline(Beck et al., 2004). In an open-label extension study aftera 6-month randomized placebo-controlled study, esti-mated glomerular filtration rate (GFR) remained stablein subgroups of patients with Stage I (GFR>90 mL/minute) or Stage II (GFR 60–89 mL/minute) chronic kid-ney disease at baseline. In contrast, in the subgroup ofpatients with Stage III chronic kidney disease (GFR30–59 ml/min), the slope of the decline in GFR wasreduced compared with comparable historical controls,suggesting that ERT was slowing the decline of renalfunction (Schiffmann et al., 2006b). In an open-label,phase III extension study after a 20-week, double-blind,randomized, placebo-controlled phase III study of agal-sidase beta, patients older than 40 years who had signif-icant proteinuria at baseline and evidence of scleroticglomeruli pretreatment showed renal disease progres-sion (Germain et al., 2007).

CARDIAC INVOLVEMENT

According to the FOS database, treatment with agalsi-dase alfa reduced left ventricular size in patients whohad an enlarged heart at baseline (Beck et al., 2004).

In a randomized, double-blind, placebo-controlledstudy, left ventricular mass, as measured by MRI, wassignificantly reduced following 6 months of treatmentwith agalsidase alfa compared with placebo (p¼0.041),and a mean 20% reduction in myocardial GL-3 contentsassessed by serial intravenous endocardial biopsies wasdemonstrated over 6 months of enzyme replacementcompared to a mean 10% increase in patients recei-ving placebo (p¼0.42). ERT resulted in regression ofthe hypertrophic cardiomyopathy with Fabry disease(Hughes et al., 2008).

In another study, it was examined whether ERT waseffective in all stages of Fabry cardiomyopathy duringlong-term follow-up. In patients without fibrosis, ERT(agalsidase beta) resulted in a significant reduction inleft ventricular mass, an improvement in myocardialfunction, and a higher exercise capacity. In contrast,patients with mild or severe fibrosis showed a minorreduction in left ventricular hypertrophy and no

SEASE 637

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improvement in myocardial function or exercise capac-ity (Weidemann et al., 2009). Hence, it seems that onceirreversible fibrosis occurs, ERT is no longer effective.

Long-term treatment with recombinant humana-galactosidaseA (agalsidase beta)may halt the progres-sion of vascular pathology and prevent the clinicalmanifestations of atherosclerotic disease (Thurberget al., 2009).

638 K. TO

CEREBROVASCULAR INVOLVEMENT

Patients with Fabry disease were reported to have ele-vated cerebral blood flow velocities assessed with trans-cranial Doppler (Moore et al., 2002). In a 6-month,double-blind, placebo-controlled trial of agalsidase alfafollowed by an 18-month open-label trial, these velocitiessignificantly decreased (Moore et al., 2002). On the con-trary, reduced cerebral blood flow velocities andimpaired cerebral autoregulation were shown in patientswith Fabry disease using transcranial Doppler (Hilz et al.,2004a), and these observations are still under discussion.Although functional improvement of cerebral bloodflow could be obtained, four of 25 patients receivinglong-term therapy with agalsidase alfa for 4 to 4.5 yearssuffered a cerebrovascular accident or a transient ische-mic attack (Schiffmann et al., 2006b). Five of 17men andtwo of six women receiving agalsidase beta demon-strated neurological deterioration, especially those whohad preexisting cerebrovascular disease before startingERT (Buechner et al., 2008). Neither agalsidase alfanor agalsidase beta cross the blood–brain barrier. Evi-dence of a favorable impact of ERT on central nervoussystem signs and symptoms has not been established(Salviati et al., 2010). The long-term clinical effects ofERT on cerebral vasculopathy still needs to be fullyassessed.

GASTROINTESTINAL DISTURBANCE

After 6–7 months of agalsidase beta therapy, all fourpatients reported no or only occasional abdominal painor diarrhea, and gained 3–8 kg in weight (Banikazemiet al., 2005).

BASIC RESEARCH

Animal models

Knockout mice and transgenic mice for Fabry diseasehave been generated (Ohshima et al., 1997; Shimmotoet al., 1997). These animal models have been used forexperiments with bone marrow transplantation, ERT,and gene therapy (Ohshima et al., 1999; Jung et al.,2001; Takahashi et al., 2002; Ishii et al., 2004; Tajimaet al., 2009). Positive results have been reported.

Gene replacement therapy

A recombinant adeno-associated viral vector encodinghuman a-galactosidase A (rAAV-AGA) was injectedinto the hepatic portal vein (Jung et al., 2001) or intothe right quadriceps muscles (Takahashi et al., 2002)of Fabry mice. In parallel to the elevated enzymelevels, a significant reduction in GL-3 levels was seen.AAV-mediated gene transfer might be useful forthe treatment of Fabry disease (Jung et al., 2001;Takahashi et al., 2002).

Chemical chaperone therapy

Chemical chaperone therapy has recently emerged as apotential therapeutic alternative for Fabry disease.Chemical chaperones are small molecules that bind tomutant enzyme proteins and assist in their correct fold-ing, maturation, and trafficking to their functional site,such as the lysosomes (Yam et al., 2005; Motabar et al.,2010). Oral administration of 1-deoxygalactonojirimycin(DGJ), a potent competitive inhibitor of a-galactosidaseA, to transgenic mice expressing human R301Q a-galactosidase A yielded higher a-galactosidase A activ-ity in major tissues (Fan and Ishii, 2007). DGJ (marketedas AmigalTM by Amicus Therapeutics, Cranbury, NJ,USA) is currently being studied in a phase 3 clinical trialas a chaperone therapeutic agent for Fabry disease.

Modified a–N-acetylgalactosaminidase

A modified a–N-acetylgalactosaminidase (NAGA) witha-galactosidase A-like substrate specificity wasdesigned and produced in Chinese hamster ovary cells.The enzyme acquired the ability to catalyze the degrada-tion of 4-methylumbelliferyl- a–D-galactopyranoside.The enzyme cleavedGL-3 accumulated in cultured fibro-blasts from a patient with Fabry disease. This modifiedNAGA is hardly expected to cause an allergic reaction,so it is highly promising as a new and safe enzyme forERT for Fabry disease (Tajima et al., 2009).

Induced pluripotent stem cells

Recently iPS (induced pluripotent stem) cells generatedfrom mouse models of Fabry disease demonstrateddefects in disease-specific enzyme activities and signif-icant accumulation of substrates for their enzymes.Functional cardiomyocytes, which were efficiently dif-ferentiated from Fabry-iPS cells, might be useful inmechanistic and therapeutic studies (Meng et al., 2010).

CONCLUSIONS

On the neurophysiological and neuropathologicalinvestigations, Fabry neuropathy is characterized as a

DISEASE 639

length-dependent peripheral neuropathy affectingmainly the small myelinated (Ad) fibers and unmyelin-ated (C) fibers.

ERT has been shown to have a positive effect on renaland cardiac function especially in the early stage, gastro-intestinal disturbance, neuropathic pain, the detectionthreshold for thermal sensation, and sweat function.On the contrary, evidence of a favorable impact ofERT on the central nervous system has not been estab-lished. ERT should be initiated early before the appear-ance of irreversible organ failure and other therapeuticstrategies are necessary.

Female heterozygotes should be carefully and regu-larly monitored for signs and symptoms and consideredfor ERT for the reason that they are not just carriersof Fabry disease but can also develop a range of thesymptoms.

FABRY

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