Narrative Review

PHYSIOLOGY IN MEDICINE: A SERIES OF ARTICLES LINKING MEDICINE WITH SCIENCEPhysiology in Medicine: Dennis A. Ausiello, MD, Editor; Dale J. Benos, PhD, Deputy Editor; Francois Abboud, MD,Associate Editor; William J. Koopman, MD, Associate Editor

Annals of Internal Medicine: Paul Epstein, MD, Series Editor

Narrative Review: Fabry DiseaseJoe T.R. Clarke, MD, PhD

Fabry disease is an X-linked, hereditary, lysosomal storage diseasecaused by deficiency of the enzyme �-galactosidase A, which re-sults in the accumulation of the neutral glycosphingolipid globotri-aosylceramide (Gb3) in the walls of small blood vessels, nerves,dorsal root ganglia, renal glomerular and tubular epithelial cells, andcardiomyocytes. It is a complex, multisystem disorder that is char-acterized clinically by chronic pain and acroparesthesia, gastrointes-tinal disturbances, characteristic skin lesions (angiokeratomata), pro-gressive renal impairment, cardiomyopathy, and stroke. Enzymereplacement therapy (ERT) with intravenous infusions of recombi-nant human �-galactosidase A consistently decreases Gb3 levels in

plasma and clears lysosomal inclusions from vascular endothelialcells. The effects of ERT on other tissues are not as obvious,suggesting that treatment must be initiated early in the course ofthe disease to be optimally effective or that some complications ofthe disease are not responsive to enzymes delivered intravenously.

Ann Intern Med. 2007;146:425-433. www.annals.orgFor author affiliation, see end of text.

The patient was a thin, unhealthy-looking 29-year-oldman with a 15-month history of increasing general

malaise and fatigability, polyuria, and swelling of the an-kles. He reported frequent episodes of tingling in his fin-gers and toes associated with severe, lancinating pain in thelegs (especially during febrile illnesses) dating back to mid-dle childhood. The pain was generally unresponsive totreatment with acetaminophen or ibuprofen. The patientalso reported almost daily attacks of diffuse central andupper abdominal pain, which were aggravated by eatingfatty or spicy foods and were accompanied by frequent,loose, small-volume stools, often associated with urgencyand tenesmus. He also reported marked heat intoleranceand almost complete lack of sweating. The patient did nothave a history of drug or alcohol abuse.

The patient’s mother reported that her maternalgrandfather and her only brother had died of end-stagerenal disease, the former at age 55 years and the latter atage 49 years. Her other son, the patient’s brother, wasapparently healthy at age 14 years, and a sister, age 17years, was also apparently well.

On physical examination, the patient appeared chron-ically ill and had mild, diffuse, upper abdominal tendernesson palpation. Examination of the external genitalia re-vealed numerous discrete skin lesions on the scrotum andpenis. The lesions were 1 to 2 mm in diameter, slightlyraised, dark red to black, and lacked inflammation. Theydid not blanch with pressure. Results on neurologic exam-ination were normal aside from patchy impairment of tem-perature sensation in the lower legs and feet.

Urinalysis revealed a specific gravity of 1.010 andmoderate proteinuria (2.4 g/d). The hemoglobin level was110 g/L (11.0 g/dL). The leukocyte count and differentialwere normal, but the erythrocyte sedimentation rate wasincreased at 16 mm/h. Electrocardiography showed sinusbradycardia, first-degree heart block, and voltage evidenceof left ventricular hypertrophy (Figure 1). The plasma cre-atinine concentration was elevated (267 �mol/L [3.02 mg/dL]).

Measurement of �-galactosidase A in the plasma re-vealed less than 2% normal enzyme activity, which wasconsistent with Fabry disease. Mutation analysis subse-quently showed that the patient was hemizygous for a sin-gle base sequence change causing substitution of a prolinefor an alanine residue in codon 143 (A143P).

Renal biopsy was done. Microscopic examinationshowed an irregular pattern of glomerular sclerosis and vac-uolation of glomerular and tubular epithelial cells (Figure2, A). Electron microscopic examination revealed masses ofmembrane-bound, concentric lamellar, membranous inclu-sions within glomerular epithelial cells (Figure 2, B). Enzymereplacement therapy (ERT) was started with biweekly intra-venous infusions of agalsidase-�, a recombinant form of

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Review

© 2007 American College of Physicians 425

�-galactosidase A, which is produced in cultured cells. Oneweek before the first treatment, the patient experienced asudden onset of double vision, associated with the appear-ance on magnetic resonance imaging of a small discretelesion posteromedial to the right red nucleus in the uppermidbrain (Figure 3).

CLINICOPATHOLOGIC CORRELATIONS

Fabry disease is an X-linked lysosomal storage diseasecaused by deficiency of the enzyme �-galactosidase A. Thisdeficiency results in accumulation of 2 neutral glycosphin-golipids (GSLs), globotriaosylceramide (Gb3) and digalac-tosylceramide, in various tissues throughout the body. Al-though the enzyme is also required for degradation ofblood group substances B and P1, these GSLs do not seemto play a substantial role in the pathogenesis of the disease.The incidence of the disease has been estimated to be ap-proximately 1 in 55 000 male births (1), although thisalmost certainly is a substantial underestimate of the truefrequency, particularly of milder variants of the disease (2).Our understanding of the natural history of this rare dis-ease is incomplete. Although death from Fabry disease–related complications before adulthood is probably veryrare, most affected males die by the end of the sixth decadeof life (3, 4). As many as 70% of carrier women experiencesymptoms of the disease, although the clinical manifesta-tions of the disease are generally later in onset and milderin female carriers than in affected males (5–7). Somewomen eventually develop the same severe complicationsas affected males. The decreased overall severity and vari-ability of the disease in women is almost certainly the re-sult, in part, of the effects of X-chromosome inactivation(8, 9).

PainAlthough the patient had had burning pain and acro-

paresthesias in his hands and feet for 20 years, the diagno-sis of Fabry disease was not made until he developed clin-ical and pathologic evidence of advancing renal disease.The first clinical manifestation of Fabry disease is generallyepisodes of burning pain or acroparesthesia, usually involv-ing the hands and feet (3, 10–15). Acroparesthesia may betransient or may persist for several hours and is often pre-cipitated by febrile illness, exercise, emotional stress, orexposure to heat or sometimes to cold. Other forms of painare also common, sometimes involving the large joints.However, the bizarre, intermittent and transient nature ofthe acroparesthesia; the absence of substantial physicalfindings; and a general lack of awareness of Fabry diseasecan cause diagnosis to be delayed for decades (16). In fact,in the absence of a known family history, very few affectedmales are diagnosed before adulthood. Table 1 shows some

Figure 1. Electrocardiogram showing sinus bradycardia andevidence of left ventricular hypertrophy.

Figure 2. Histopathologic changes in the kidney.

A. Two glomeruli, 1 with marked vacuolation of glomerular epithelialcells (left) and 1 with moderately advanced sclerosis (right) (periodicacid–Schiff stain). B. Electron photomicrograph of glomerular epithelialcells showing intralysosomal concentric lamellar membranous inclusionstypical of Fabry disease.

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of the features that should alert the clinician to the possi-bility of Fabry disease.

The pain and acroparesthesia in Fabry disease are be-lieved to be caused by lysosomal accumulation of GSL inperipheral nerves, dorsal root ganglia, and the spinal cordand atrophy of the small, unmyelinated nerves involved in

pain and temperature sensation (17–27). The acropares-thesia is typically resistant to treatment with conventionalanalgesics, such as acetaminophen or ibuprofen. Acutepainful crises may require treatment with narcotic analge-sics, such as codeine, meperidine, or morphine. Carbamaz-epine is also effective (28). Chronic or frequently recurrentpain often responds, at least partially, to treatment withphenytoin, amitriptyline, or gabapentin (28, 29) or com-binations of these drugs. By the fourth decade of life, thepain and acroparesthesia often become less severe, at aboutthe same age that temperature sensation becomes notice-ably blunted. Acroparesthesia in women is also an earlysymptom, but it is rarely as severe as that experienced bymen (5–7).

Gastrointestinal SymptomsChronic abdominal pain is also common in Fabry dis-

ease. The pain often mimics the discomfort of gastroesoph-ageal reflux, hiatal hernia, or spastic colitis and frequentlyis associated with nausea and vomiting (30, 31). The gas-trointestinal symptoms do not respond well to treatmentwith conventional antispasmodic agents, antacids, or anti-diarrheal drugs. However, many patients report that diar-rhea improves with treatment with loperamide or bismuthsubsalicylate.

AngiokeratomataThe patient had angiokeratomata of the skin of his

scrotum and penis. The lesions are caused by accumulationof GSL in the walls of the small blood vessels, with sec-ondary ectasia and hyperkeratosis. Biopsy specimens of thelesions typically show vacuolation of the capillary endothe-lial cells and smooth-muscle cells of the media (Figure 4).

Figure 3. Axial fluid-attenuated inversion recovery magneticresonance image (TR9002. 0/TE170.5) of the brain showinga lesion in the right posteromedial midbrain (arrow).

Table 1. Clinical Problems That Should Raise Suspicion ofFabry Disease*

Bizarre acroparesthesia or neuritic pain in hands or feet, beginning in laterchildhood, precipitated by illness, fever, exercise, emotional stress, orexposure to heat

Persistent proteinuria of unknown causeHypertrophic cardiomyopathy, especially with prominent diastolic

dysfunction†Progressive renal impairment of obscure cause†Cryptogenic stroke or transient ischemic attacks†Family history of end-stage renal disease, stroke, or hypertrophic

cardiomyopathy showing an X-linked pattern of transmission thatprimarily—but not solely—affects males

Vague, persistent or recurrent abdominal pain associated with nausea,diarrhea, and tenesmus

*Any combination of 2 or more of these problems is highly suggestive of Fabrydisease in either sex.† This may be the only clinical manifestation of Fabry disease in patients of eithersex with variants of classical Fabry disease.

Figure 4. Histopathologic changes in a small cutaneousblood vessel showing vacuolation of endothelial andsmooth-muscle cells (periodic acid–Schiff stain).

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Impaired Renal FunctionImpairment of renal function is particularly common

in males with Fabry disease (3, 32–35). The first indicationis often isosthenuria, which generally occurs in the third orfourth decade of life. Proteinuria generally follows and maybe severe. In a review of the natural history of renal in-volvement in 105 males with the disease, Branton and co-workers (4) reported that 50% of patients had proteinuriaby age 35 years and had end-stage renal disease by age 47years.

Increased awareness and improvements in diagnosishave led to the identification of some important subgroupsof patients with organ-specific variants of Fabry disease.A subgroup of patients with serious renal impairment hasbeen described, but with relatively few nonrenal manifes-tations of the disease (36–41). Surveys of males receivingdialysis to treat end-stage renal disease of obscure causehave revealed that as many as 2% in some series have Fabrydisease (40, 42, 43).

Cardiac Arrhythmias and Left Ventricular HypertrophyCardiac arrhythmias and conduction defects are com-

mon and early manifestations of Fabry disease and oftenproduce symptoms as early as the second decade of life(44–49). The disease is also associated with progressive leftventricular hypertrophy, which may be aggravated by arte-rial hypertension (44, 45, 50–52). As the condition ad-vances, progressive impairment of diastolic filling causesdecreased cardiac output and early death (53–55). In asubgroup of patients with severe cardiomyopathy, non-

cardiac manifestations of the disease may be trivial (56,57).

The pathophysiology of cardiomyopathy in Fabry dis-ease is poorly understood. Although GSL has been shownto accumulate in cardiomyocytes (58), the amount is toosmall to account for the massive increase in left ventricularsize. Failure of left ventricular hypertrophy to respond wellto ERT in some patients, despite apparent clearance ofGb3, suggests that some other process is contributing tothe cardiomyopathy in the disease (59–61), perhaps in-creased levels of a circulating growth-promoting factor(61).

Transient Ischemic Attacks and StrokeOne of the most distressing complications of Fabry

disease is cerebrovascular disease (62–69). Transient isch-emic attacks and stroke are common in male and femalepatients and may occur at an early age, even in femalecarriers (70). A high frequency of Fabry disease has beenreported in patients with cryptogenic stroke, which affectspredominantly the vertebrobasilar circulation (71).

�-GALACTOSIDASE ALysosomal �-galactosidase A is a relatively heat-labile,

homodimeric glycoprotein consisting of 2 identical 49-kDasubunits (72). The enzyme exists in several forms, whichdiffer in the amount of sialic acid in the carbohydratechains. Activity is easily measured with the use of such

Figure 5. Sequence of events in the biosynthesis and trafficking of �-galactosidase A.

Nascent �-galactosidase A molecules are shown as solid circles. P � phosphorylation of mannose residues; RER � rough endoplasmic reticulum.



synthetic substrates as 4-methylumbelliferyl-�-D-galacto-pyranoside; optimum pH is 4.6.

The GLA gene is located at Xq22 on the long arm ofthe X chromosome. It is approximately 12 kb and contains7 exons that are associated with extensive 5� regulatory and3� flanking sequences. The processed message is 1.45 kband encodes a 50-kDa precursor polypeptide of 429 aminoacids (73–75). The primary polypeptide gene productundergoes cotranslational glycosylation in the endoplasmicreticulum, with downstream trimming of the polypeptideand modification of the oligosaccharide (including 6-O-phosphorylation of mannose residues) required for localiza-tion in lysosomes (76). A proportion of the phosphorylatedenzyme is secreted from the cell and is taken up byreceptor-mediated endocytosis through mannose-6-phos-phate receptors in the plasma membrane (77) (Figure 5).The secretion and reuptake of �-galactosidase A providesthe rationale for ERT (78).

More than half of over 300 mutations in the GLAgene that cause Fabry disease are simple missense muta-tions that result in single amino acid substitutions, al-though insertions and duplications and complex rearrange-ments account for close to 10% of the mutations reportedto date (79). Although some generalizations are possible,attempts to identify specific genotype-phenotype correla-tions have not been very successful.

Mutations that cause clinical disease are invariably as-sociated with marked deficiency of �-galactosidase A activ-ity. As little as 5% to 10% residual enzyme activity seemsto be sufficient to prevent clinically significant Gb3 accu-mulation, a fact that is particularly important when effortsare undertaken to treat the disease with ERT or enzymeenhancement therapy.

GENETICS

Because Fabry disease is an X-linked disorder and mostcases result from inherited mutations rather than new mu-tations, most patients have blood relatives who are eitheraffected males or carrier females. Identification of affectedmales is relatively easy, by using a combination of pedigreeanalysis and measurement of �-galactosidase A activity inplasma or leukocytes. The identification of carrier femalesis more difficult because many have normal levels of �-galactosidase A. The presence of the characteristic cornealverticillata or the demonstration of increased concentra-tions of Gb3 in urine sediment is highly suggestive of thediagnosis. However, the only way to make a definitive di-agnosis is to show that the female carries the same GLAgene mutation as her affected male relative. In symptom-atic women who do not have an affected male relative witha GLA gene mutation, identification of a disease-causingmutation is often difficult and time consuming.

ROUTINE MANAGEMENT OF FABRY DISEASE

Fabry disease is a multisystem disease that requires acomprehensive approach to management. Of particularimportance are aggressive management of pain, attentionto reducing complications caused by comorbid conditions,and careful monitoring for indications that the patientmight need treatment for emerging complications and co-morbid conditions. Table 2 (80) summarizes routine mea-sures to monitor the patient for early complications. Amore comprehensive presentation of guidelines for theevaluation and management of Fabry disease was recentlypublished (81).

ENZYME REPLACEMENT THERAPY

The most important advance in the treatment forFabry disease has been the introduction of ERT. Twoproducts have been developed: agalsidase alfa and agalsi-dase beta. Both are versions of human �-galactosidase Athat are produced in genetically engineered cell lines bydifferent techniques. The primary amino acid sequences ofthe gene products are the same; however, the structures ofthe oligosaccharide side chains are different (82, 83). Com-pared with agalsidase alfa, agalsidase beta contains a higherproportion of the mannose-6-phosphate residues that arerequired for cellular uptake of exogenously administeredenzyme and is taken up more readily by cultured skin fi-broblasts. The recommended doses of agalsidase alfa and

Table 2. Routine Monitoring of Patients with FabryDisease*

Variable Frequency ofMonitoring†

Patients with renal impairmentPlasma creatinine Annually24-hour urinary protein and albumin excretion

with calculation of protein-to-creatinine ratioAnnually

Endogenous creatinine clearance AnnuallyPlasma electrolytes AnnuallyUrinary specific gravity Annually

Patients with cardiomyopathy and arrhythmiaElectrocardiography Annually24-hour Holter monitoring As indicatedEchocardiography BiannuallyCardiac MRI BiannuallyCardiovascular risk factor analysis‡ Annually

Patients with cerebrovascular diseaseNeurologic consultation As indicatedBrain MRI As indicated

Patients with hearing impairmentAudiography Biannually

* Adapted from reference 80. MRI � magnetic resonance imaging.† More frequent monitoring may be indicated in the presence of abnormalities.‡ Measure blood pressure, urinary and fasting plasma glucose, lipids, and homo-cysteine and ask about smoking.

ReviewFabry Disease


agalsidase beta are 0.2 mg/kg and 1.0 mg/kg biweekly,respectively. Only agalsidase beta is approved for treatmentfor Fabry disease in the United States, although bothagents are approved for clinical use in other countries. En-zyme replacement therapy with either drug is very expen-sive, costing approximately $250 000 per year for the av-erage adult with the disease.

Randomized, placebo-controlled, clinical trials andlonger-term, open-label extension studies of both productshave shown that biweekly intravenous infusion of the en-zymes is associated with unambiguous decreases in plasmaand urine sediment Gb3 levels and accumulation of GSLin capillary endothelial cells, renal glomerular cells, andtubular epithelial cells (84–88). These effects of ERT areconsistently reproducible. However, the clinical signifi-cance of the changes in Gb3 levels and capillary endothelialcells, in particular, is unclear. The results of a large obser-vational study of symptomatic women with Fabry diseasefailed to demonstrate a relationship between plasma Gb3levels or inclusions in cutaneous vascular endothelial cellsand severity of symptoms (89). Globotriaosylceramide istransported as an integral component of plasma lipoproteincomplexes (90), and clearance of the inclusions from cap-illary endothelial cells may have as much to do with therate at which the GSL is delivered to the cells as they turnover as it does with uptake of circulating enzyme by thecells.

Enzyme replacement therapy was associated with asubstantial decrease in neuropathic pain in affected men(85, 91, 92) and a statistically significant improvement inperipheral nerve function (93, 94). Relief of gastrointesti-nal symptoms is one of the earliest and most consistentlybeneficial effects of ERT (31, 95). However, cerebrovascu-lar attacks have occurred in some patients despite treat-ment (88).

Many reports have described stabilization of renalfunction and cardiomyopathy. In the same study in whichthey examined the effect of ERT on pain, Schiffmann andcolleagues (85) showed that the creatinine clearance stabi-lized in patients who were receiving ERT, whereas patientswho received placebo had a substantial decrease over thesame period. A summary of the renal data from a large,longitudinal, observational study of patients receiving ERT(96) concluded that treatment with agalsidase alfa “cansignificantly improve renal function in patients with Fabrydisease, at least in those with a mild decrease in glomerularfiltration rate, and may be able to slow down the naturaldecline in renal function in patients with moderate reduc-tion in glomerular filtration rate.” Although patients withnormal or only mildly abnormal renal function seem toremain stable while receiving ERT, renal function deterio-rates in those with glomerular filtration rates less than 60mL/min, although perhaps at a slower rate (97). The re-cently published results of a randomized, controlled trial oftreatment with agalsidase beta showed that the rate of pro-gression to a composite clinical outcome of renal, cardiac,

and cerebrovascular complications and death in patientswith moderately severe renal impairment was slowed (98).Although the study sample was relatively small, the resultssuggest that early intervention with ERT may prevent ir-reversible end-organ damage in patients with the disease.

In open-label studies, Weidemann and colleagues (99)and Mignani and colleagues (100) showed decreased leftventricular mass and improved myocardial function after12 to 18 months of treatment with agalsidase beta. Baeh-ner and coworkers (101) reported a significant decrease inleft ventricular mass and improvement in quality of life insymptomatic female patients receiving ERT with agalsidasealfa. However, the coronary microvascular dysfunction thatoccurs is apparently not reversed by ERT (60, 102). Post-mortem studies in a man with Fabry disease who died ofcoronary artery disease after more than 2 years of ERTrevealed cardiomyopathy and glomerular nephropathy typ-ical of the disease, despite clearance of GSL inclusions fromvascular endothelial cells (103).

In several studies (104–107), positron emission to-mography and transcranial Doppler studies showed a par-adoxical increase in regional cerebral blood flow and dys-regulation of the nitric oxide pathway in patients withFabry disease. These effects were reversed by ERT. Theclinical significance of these findings is not clear.

ENZYME ENHANCEMENT (CHAPERONE) THERAPY

Many investigators have shown that some mutationsin GLA genes result in destabilization, aggregation, andpremature degradation of a mutant enzyme polypeptidethat is catalytically active. Strategies directed at preventingpremature degradation by pharmacologic stabilizing of themutant protein have been shown to substantially increaseresidual �-galactosidase A activity (108, 109). Because thelevel of enzyme activity necessary to prevent disease is rel-atively low (�10%), even a modest increase in chaperone-induced enzyme activity might be expected to arrest theprogression of Fabry disease. Chaperone therapy is still be-ing investigated and is not available for clinical use.

CONCLUSIONS

Enzyme replacement therapy by intravenous infusionsof recombinant human �-galactosidase A produced markedimprovements in pain, acroparesthesia, and gastrointestinalsymptoms in the case patient, and his heart size and func-tion have remained stable during more than 4 years ofERT. However, his renal function continued to deterio-rate, and the patient had 2 more small strokes, causingheadache and diplopia. His overall quality of life is mar-ginally improved, but he continues to experience fatigabil-ity. It is not known whether the patient would have donebetter if ERT had been started earlier, preventing the de-velopment of irreversible secondary cellular and tissuedamage.

The normal function of Gb3 is still a mystery, and thepotential contribution of secondary metabolic phenomena



to the evolution of Fabry disease is unknown. Globotriao-sylceramide has been shown to function as a receptor forverotoxin (110), which is responsible for the hemolyticuremic syndrome associated with pathogenic Escherichiacoli infections (111). It seems to play a role in verotoxin-mediated apoptosis (112). However, the significance ofthese and related findings for patients with Fabry disease isunclear.

From the Hospital for Sick Children and University of Toronto, To-ronto, Ontario, Canada; and Centre Hospitalier Universitaire de Sher-brooke, Hopital Fleurimont, Sherbrooke, Quebec, Canada.

Potential Financial Conflicts of Interest: Honoraria: Genzyme Corp.,Genzyme Canada, Transkaryotic Therapies Inc., Shire HGT; Grantsreceived: Genzyme Corp., Genzyme Canada, Transkaryotic TherapiesInc., Shire HGT.

Requests for Single Reprints: Joe T.R. Clarke, MD, PhD, Division ofClinical & Metabolic Genetics, Hospital for Sick Children, 555 Univer-sity Avenue, Toronto, Ontario M5G 1X8, Canada; e-mail, [email protected].

References1. Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomalstorage disorders. JAMA. 1999;281:249-54. [PMID: 9918480]2. Spada M, Pagliardini S, Yasuda M, Tukel T, Thiagarajan G, Sakuraba H, etal. High incidence of later-onset Fabry disease revealed by newborn screening.Am J Hum Genet. 2006;79:31-40. [PMID: 16773563]3. MacDermot KD, Holmes A, Miners AH. Anderson-Fabry disease: clinicalmanifestations and impact of disease in a cohort of 98 hemizygous males. J MedGenet. 2001;38:750-60. [PMID: 11694547]4. Branton MH, Schiffmann R, Sabnis SG, Murray GJ, Quirk JM, AltarescuG, et al. Natural history of Fabry renal disease: influence of alpha-galactosidase Aactivity and genetic mutations on clinical course. Medicine (Baltimore). 2002;81:122-38. [PMID: 11889412]5. European FOS Investigators. Natural history of Fabry disease in females in theFabry Outcome Survey. J Med Genet. 2006;43:347-52. [PMID: 16227523]6. Whybra C, Kampmann C, Willers I, Davies J, Winchester B, Kriegsmann J,et al. Anderson-Fabry disease: clinical manifestations of disease in femaleheterozygotes. J Inherit Metab Dis. 2001;24:715-24. [PMID: 11804208]7. MacDermot KD, Holmes A, Miners AH. Anderson-Fabry disease: clinicalmanifestations and impact of disease in a cohort of 60 obligate carrier females[Letter]. J Med Genet. 2001;38:769-75. [PMID: 11732485]8. Dobrovolny R, Dvorakova L, Ledvinova J, Magage S, Bultas J, Lubanda JC,et al. 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. 2005;83:647-54. [PMID: 15806320]9. Maier EM, Osterrieder S, Whybra C, Ries M, Gal A, Beck M, et al. Diseasemanifestations and X inactivation in heterozygous females with Fabry disease.Acta Paediatr Suppl. 2006;95:30-8. [PMID: 16720462]10. FOS European Investigators. Clinical manifestations of Fabry disease inchildren: data from the Fabry Outcome Survey. Acta Paediatr. 2006;95:86-92.[PMID: 16498740]11. Ries M, Gupta S, Moore DF, Sachdev V, Quirk JM, Murray GJ, et al.Pediatric Fabry disease. Pediatrics. 2005;115:e344-55. [PMID: 15713906]12. Desnick RJ, Brady RO. Fabry disease in childhood. J Pediatr. 2004;144:S20-6. [PMID: 15126980]13. Gold KF, Pastores GM, Botteman MF, Yeh JM, Sweeney S, Aliski W, et al.Quality of life of patients with Fabry disease. Qual Life Res. 2002;11:317-27.[PMID: 12086117]14. MacDermot J, MacDermot KD. Neuropathic pain in Anderson-Fabry dis-ease: pathology and therapeutic options. Eur J Pharmacol. 2001;429:121-5.[PMID: 11698033]15. Shelley ED, Shelley WB, Kurczynski TW. Painful fingers, heat intolerance,and telangiectases of the ear: easily ignored childhood signs of Fabry disease.Pediatr Dermatol. 1995;12:215-9. [PMID: 7501549]

16. Mehta A, Ricci R, Widmer U, Dehout F, Garcia de Lorenzo A, KampmannC, et al. Fabry disease defined: baseline clinical manifestations of 366 patientsin the Fabry Outcome Survey. Eur J Clin Invest. 2004;34:236-42. [PMID:15025684]17. Gomes I, Nora DB, Becker J, Ehlers JA, Schwartz IV, Giugliani R, et al.Nerve conduction studies, electromyography and sympathetic skin response inFabry’s disease. J Neurol Sci. 2003;214:21-5. [PMID: 12972384]18. Dutsch M, Marthol H, Stemper B, Brys M, Haendl T, Hilz MJ. Small fiberdysfunction predominates in Fabry neuropathy. J Clin Neurophysiol. 2002;19:575-86. [PMID: 12488789]19. Luciano CA, Russell JW, Banerjee TK, Quirk JM, Scott LJ, DambrosiaJM, et al. Physiological characterization of neuropathy in Fabry’s disease. MuscleNerve. 2002;26:622-9. [PMID: 12402283]20. Vital A, Vital C, Maleville J. Fabry’s disease: an ultrastructural study ofmuscle and peripheral nerve. Clin Neuropathol. 1984;3:168-72. [PMID:6434215]21. Gemignani F, Marbini A, Bragaglia MM, Govoni E. Pathological studyof the sural nerve in Fabry’s disease. Eur Neurol. 1984;23:173-81. [PMID:6088246]22. Gadoth N, Sandbank U. Involvement of dorsal root ganglia in Fabry’s dis-ease. J Med Genet. 1983;20:309-12. [PMID: 6413695]23. Cable WJ, Dvorak AM, Osage JE, Kolodny EH. Fabry disease: significanceof ultrastructural localization of lipid inclusions in dermal nerves. Neurology.1982;32:347-53. [PMID: 6278363]24. Pellissier JF, Van Hoof F, Bourdet-Bonerandi D, Monier-Faugere MC,Toga M. Morphological and biochemical changes in muscle and peripheral nervein Fabry’s disease. Muscle Nerve. 1981;4:381-7. [PMID: 6793867]25. Sheth KJ, Swick HM. Peripheral nerve conduction in Fabry disease. AnnNeurol. 1980;7:319-23. [PMID: 6246835]26. Sung JH. Autonomic neurons affected by lipid storage in the spinal cord inFabry’s disease: distribution of autonomic neurons in the sacral cord. J Neuro-pathol Exp Neurol. 1979;38:87-98. [PMID: 122226]27. Sima AA, Robertson DM. Involvement of peripheral nerve and muscle inFabry’s disease. Histologic, ultrastructural, and morphometric studies. Arch Neu-rol. 1978;35:291-301. [PMID: 417704]28. Filling-Katz MR, Merrick HF, Fink JK, Miles RB, Sokol J, Barton NW.Carbamazepine in Fabry’s disease: effective analgesia with dose-dependent exac-erbation of autonomic dysfunction. Neurology. 1989;39:598-600. [PMID:2494569]29. Ries M, Mengel E, Kutschke G, Kim KS, Birklein F, Krummenauer F, etal. Use of gabapentin to reduce chronic neuropathic pain in Fabry disease. JInherit Metab Dis. 2003;26:413-4. [PMID: 12971431]30. Hoffmann B, Reinhardt D, Koletzko B. Effect of enzyme-replacement ther-apy on gastrointestinal symptoms in Fabry disease. Eur J Gastroenterol Hepatol.2004;16:1067-9. [PMID: 15371935]31. Banikazemi M, Ullman T, Desnick RJ. Gastrointestinal manifestations ofFabry disease: clinical response to enzyme replacement therapy. Mol GenetMetab. 2005;85:255-9. [PMID: 15939645]32. Studio Multicentrico Italiano sulla Malattia di Anderson-Fabry. Evolution ofrenal pathology in Fabry disease. Acta Paediatr Suppl. 2003;92:6-8. [PMID:14989458]33. Sessa A, Meroni M, Battini G, Righetti M, Maglio A, Tosoni A, et al. Renalinvolvement in Anderson-Fabry disease. J Nephrol. 2003;16:310-3. [PMID:12774774]34. Grunfeld JP, Lidove O, Joly D, Barbey F. Renal disease in Fabry patients. JInherit Metab Dis. 2001;24 Suppl 2:71-4. [PMID: 11758682]35. Nissenson AR, Port FK. Outcome of end-stage renal disease in patients withrare causes of renal failure. I. Inherited and metabolic disorders. Q J Med. 1989;73:1055-62. [PMID: 2516341]36. Ko YH, Kim HJ, Roh YS, Park CK, Kwon CK, Park MH. Atypical Fabry’sdisease. An oligosymptomatic variant. Arch Pathol Lab Med. 1996;120:86-9.[PMID: 8554452]37. Nakao S, Kodama C, Takenaka T, Tanaka A, Yasumoto Y, Yoshida A, etal. Fabry disease: detection of undiagnosed hemodialysis patients and identifica-tion of a “renal variant” phenotype. Kidney Int. 2003;64:801-7. [PMID:12911529]38. Rosenthal D, Lien YH, Lager D, Lai LW, Shang S, Leung N, et al. A novelalpha-galactosidase a mutant (M42L) identified in a renal variant of Fabry disease.Am J Kidney Dis. 2004;44:e85-9. [PMID: 15492942]39. Hauser AC, Lorenz M, Sunder-Plassmann G. The expanding clinical spec-

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trum of Anderson-Fabry disease: a challenge to diagnosis in the novel era ofenzyme replacement therapy. J Intern Med. 2004;255:629-36. [PMID:15147526]40. Ichinose M, Nakayama M, Ohashi T, Utsunomiya Y, Kobayashi M, Eto Y.Significance of screening for Fabry disease among male dialysis patients. Clin ExpNephrol. 2005;9:228-32. [PMID: 16189631]41. Cybulla M, Schaefer E, Wendt S, Ling H, Krober SM, Hovelborn U, et al.Chronic renal failure and proteinuria in adulthood: Fabry disease predominantlyaffecting the kidneys. Am J Kidney Dis. 2005;45:e82-9. [PMID: 15861341]42. Tanaka M, Ohashi T, Kobayashi M, Eto Y, Miyamura N, Nishida K, et al.Identification of Fabry’s disease by the screening of alpha-galactosidase A activityin male and female hemodialysis patients. Clin Nephrol. 2005;64:281-7. [PMID:16240899]43. Helin I. Fabry’s disease. A brief review in connection with a Scandinaviansurvey. Scand J Urol Nephrol. 1979;13:335-7. [PMID: 119314]44. Linhart A, Magage S, Palecek T, Bultas J. Cardiac involvement in Fabrydisease. Acta Paediatr Suppl. 2002;91:15-20. [PMID: 12572837]45. Kampmann C, Wiethoff CM, Perrot A, Beck M, Dietz R, Osterziel KJ.The heart in Anderson Fabry disease. Z Kardiol. 2002;91:786-95. [PMID:12395219]46. Efthimiou J, McLelland J, Betteridge DJ. Short PR intervals and tachyar-rhythmias in Fabry’s disease. Postgrad Med J. 1986;62:285-7. [PMID: 3086855]47. Rowe JW, Caralis DG. Accelerated atrioventricular conduction in Fabry’sdisease: a case report. Angiology. 1978;29:562-8. [PMID: 99064]48. Mehta J, Tuna N, Moller JH, Desnick RJ. Electrocardiographic and vector-cardiographic observations in Fabry’s disease. Adv Cardiol. 1978;21:220-2.[PMID: 413336]49. Shah JS, Hughes DA, Sachdev B, Tome M, Ward D, Lee P, et al. Preva-lence and clinical significance of cardiac arrhythmia in Anderson-Fabry disease.Am J Cardiol. 2005;96:842-6. [PMID: 16169374]50. Perrot A, Osterziel KJ, Beck M, Dietz R, Kampmann C. Fabry disease:focus on cardiac manifestations and molecular mechanisms. Herz. 2002;27:699-702. [PMID: 12439642]51. Linhart A, Lubanda JC, Palecek T, Bultas J, Karetova D, Ledvinova J, et al.Cardiac manifestations in Fabry disease. J Inherit Metab Dis. 2001;24 Suppl2:75-83. [PMID: 11758683]52. Colucci WS, Lorell BH, Schoen FJ, Warhol MJ, Grossman W. Hypertro-phic obstructive cardiomyopathy due to Fabry’s disease. N Engl J Med. 1982;307:926-8. [PMID: 6810178]53. Linhart A, Palecek T, Bultas J, Ferguson JJ, Hrudova J, Karetova D, et al.New insights in cardiac structural changes in patients with Fabry’s disease. AmHeart J. 2000;139:1101-8. [PMID: 10827394]54. Goldman ME, Cantor R, Schwartz MF, Baker M, Desnick RJ. Echocar-diographic abnormalities and disease severity in Fabry’s disease. J Am CollCardiol. 1986;7:1157-61. [PMID: 3082958]55. Palecek T, Linhart A, Lubanda JC, Magage S, Karetova D, Bultas J, et al.Early diastolic mitral annular velocity and color M-mode flow propagation veloc-ity in the evaluation of left ventricular diastolic function in patients with Fabrydisease. Heart Vessels. 2006;21:13-9. [PMID: 16440143]56. Germain DP. A new phenotype of Fabry disease with intermediate severitybetween the classical form and the cardiac variant. Contrib Nephrol. 2001:234-40. [PMID: 11688386]57. Chimenti C, Ricci R, Pieroni M, Natale L, Russo MA, Frustaci A. Cardiacvariant of Fabry’s disease mimicking hypertrophic cardiomyopathy. Cardiologia.1999;44:469-73. [PMID: 10389354]58. von Scheidt W, Eng CM, Fitzmaurice TF, Erdmann E, Hubner G, OlsenEG, et al. An atypical variant of Fabry’s disease with manifestations confined tothe myocardium. N Engl J Med. 1991;324:395-9. [PMID: 1846223]59. Owens CL, Russell SD, Halushka MK. Histologic and electron microscopyfindings in myocardium of treated Fabry disease. Hum Pathol. 2006;37:764-8.[PMID: 16733219]60. Kalliokoski RJ, Kantola I, Kalliokoski KK, Engblom E, Sundell J, Hannu-kainen JC, et al. The effect of 12-month enzyme replacement therapy on myo-cardial perfusion in patients with Fabry disease. J Inherit Metab Dis. 2006;29:112-8. [PMID: 16601877]61. Barbey F, Brakch N, Linhart A, Rosenblatt-Velin N, Jeanrenaud X, Qa-nadli S, et al. Cardiac and vascular hypertrophy in Fabry disease: evidence for anew mechanism independent of blood pressure and glycosphingolipid deposition.Arterioscler Thromb Vasc Biol. 2006;26:839-44. [PMID: 16469946]62. Grewal RP, McLatchey SK. Cerebrovascular manifestations in a female car-

rier of Fabry’s disease. Acta Neurol Belg. 1992;92:36-40. [PMID: 1546524]63. Grewal RP, Barton NW. Fabry’s disease presenting with stroke. Clin NeurolNeurosurg. 1992;94:177-9. [PMID: 1324819]64. Wendrich K, Whybra C, Ries M, Gal A, Beck M. Neurological manifesta-tion of Fabry disease in females. Contrib Nephrol. 2001:241-4. [PMID:11688387]65. Kolodny EH, Pastores GM. Anderson-Fabry disease: extrarenal, neurologicmanifestations. J Am Soc Nephrol. 2002;13 Suppl 2:S150-3. [PMID:12068029]66. Banerjee TK. Fabry disease with special reference to neurological manifesta-tions. Eur Rev Med Pharmacol Sci. 2004;8:275-81. [PMID: 15745387]67. Jardim L, Vedolin L, Schwartz IV, Burin MG, Cecchin C, Kalakun L, et al.CNS involvement in Fabry disease: clinical and imaging studies before and after12 months of enzyme replacement therapy. J Inherit Metab Dis. 2004;27:229-40. [PMID: 15159654]68. Schiffmann R, Ries M. Fabry’s disease—an important risk factor for stroke.Lancet. 2005;366:1754-6. [PMID: 16298202]69. FOS Investigators. Natural history of the cerebrovascular complications ofFabry disease. Acta Paediatr Suppl. 2005;94:24-7. [PMID: 15895708]70. Giacomini PS, Shannon PT, Clarke JT, Jaigobin C. Fabry’s disease present-ing as stroke in a young female. Can J Neurol Sci. 2004;31:112-4. [PMID:15038481]71. Rolfs A, Bottcher T, Zschiesche M, Morris P, Winchester B, Bauer P, et al.Prevalence of Fabry disease in patients with cryptogenic stroke: a prospectivestudy. Lancet. 2005;366:1794-6. [PMID: 16298216]72. Bishop DF, Desnick RJ. Affinity purification of alpha-galactosidase A fromhuman spleen, placenta, and plasma with elimination of pyrogen contamination.Properties of the purified splenic enzyme compared to other forms. J Biol Chem.1981;256:1307-16. [PMID: 6256390]73. Bishop DF, Calhoun DH, Bernstein HS, Hantzopoulos P, Quinn M,Desnick RJ. Human alpha-galactosidase A: nucleotide sequence of a cDNA cloneencoding the mature enzyme. Proc Natl Acad Sci U S A. 1986;83:4859-63.[PMID: 3014515]74. Bishop DF, Kornreich R, Desnick RJ. Structural organization of the humanalpha-galactosidase A gene: further evidence for the absence of a 3� untranslatedregion. Proc Natl Acad Sci U S A. 1988;85:3903-7. [PMID: 2836863]75. Kornreich R, Bishop DF, Desnick RJ. The gene encoding alpha-galactosi-dase A and gene rearrangements causing Fabry disease. Trans Assoc Am Physi-cians. 1989;102:30-43. [PMID: 2561643]76. Mach L. Biosynthesis of lysosomal proteinases in health and disease. BiolChem. 2002;383:751-6. [PMID: 12108539]77. Ghosh P, Dahms NM, Kornfeld S. Mannose 6-phosphate receptors: newtwists in the tale. Nat Rev Mol Cell Biol. 2003;4:202-12. [PMID: 12612639]78. Brady RO. Enzyme replacement for lysosomal diseases. Annu Rev Med.2006;57:283-96. [PMID: 16409150]79. Schafer E, Baron K, Widmer U, Deegan P, Neumann HP,Sunder-Plassmann G, et al. Thirty-four novel mutations of the GLA gene in 121patients with Fabry disease. Hum Mutat. 2005;25:412. [PMID: 15776423]80. Garrod Association. Accessed at www.garrod.ca on 1 October 2006.81. Eng CM, Germain DP, Banikazemi M, Warnock DG, Wanner C, HopkinRJ, et al. Fabry disease: guidelines for the evaluation and management of multi-organ system involvement. Genet Med. 2006;8:539-48. [PMID: 16980809]82. Lee K, Jin X, Zhang K, Copertino L, Andrews L, Baker-Malcolm J, et al.A biochemical and pharmacological comparison of enzyme replacement therapiesfor the glycolipid storage disorder Fabry disease. Glycobiology. 2003;13:305-13.[PMID: 12626384]83. Sakuraba H, Murata-Ohsawa M, Kawashima I, Tajima Y, Kotani M,Ohshima T, et al. Comparison of the effects of agalsidase alfa and agalsidase betaon cultured human Fabry fibroblasts and Fabry mice. J Hum Genet. 2006;51:180-8. [PMID: 16372133]84. International Collaborative Fabry Disease Study Group. Safety and efficacyof recombinant human alpha-galactosidase A—replacement therapy in Fabry’sdisease. N Engl J Med. 2001;345:9-16. [PMID: 11439963]85. Schiffmann R, Kopp JB, Austin HA 3rd, Sabnis S, Moore DF, Weibel T,et al. Enzyme replacement therapy in Fabry disease: a randomized controlled trial.JAMA. 2001;285:2743-9. [PMID: 11386930]86. Thurberg BL, Randolph Byers H, Granter SR, Phelps RG, Gordon RE,O’Callaghan M. Monitoring the 3-year efficacy of enzyme replacement therapyin fabry disease by repeated skin biopsies. J Invest Dermatol. 2004;122:900-8.[PMID: 15102080]



87. Thurberg BL, Rennke H, Colvin RB, Dikman S, Gordon RE, Collins AB,et al. Globotriaosylceramide accumulation in the Fabry kidney is cleared frommultiple cell types after enzyme replacement therapy. Kidney Int. 2002;62:1933-46. [PMID: 12427118]88. International Fabry Disease Study Group. Long-term safety and efficacy ofenzyme replacement therapy for Fabry disease. Am J Hum Genet. 2004;75:65-74. [PMID: 15154115]89. Gupta S, Ries M, Kotsopoulos S, Schiffmann R. The relationship of vascularglycolipid storage to clinical manifestations of Fabry disease: a cross-sectionalstudy of a large cohort of clinically affected heterozygous women. Medicine(Baltimore). 2005;84:261-8. [PMID: 16148726]90. Clarke JT, Stoltz JM, Mulcahey MR. Neutral glycosphingolipids of serumlipoproteins in Fabry’s disease. Biochim Biophys Acta. 1976;431:317-25.[PMID: 181056]91. Pisani A, Spinelli L, Sabbatini M, Andreucci MV, Procaccini D, Abbater-usso C, et al. Enzyme replacement therapy in Fabry disease patients undergoingdialysis: effects on quality of life and organ involvement. Am J Kidney Dis.2005;46:120-7. [PMID: 15983965]92. FOS European Investigators. Effects of enzyme replacement therapy on painand health related quality of life in patients with Fabry disease: data from FOS(Fabry Outcome Survey). J Med Genet. 2005;42:247-52. [PMID: 15744039]93. Schiffmann R, Floeter MK, Dambrosia JM, Gupta S, Moore DF, SharabiY, et al. Enzyme replacement therapy improves peripheral nerve and sweat func-tion in Fabry disease. Muscle Nerve. 2003;28:703-10. [PMID: 14639584]94. Hilz MJ, Brys M, Marthol H, Stemper B, Dutsch M. Enzyme replacementtherapy improves function of C-, Adelta-, and Abeta-nerve fibers in Fabry neu-ropathy. Neurology. 2004;62:1066-72. [PMID: 15079003]95. Dehout F, Roland D, Treille de Granseigne S, Guillaume B, Van Malder-gem L. Relief of gastrointestinal symptoms under enzyme replacement therapy[corrected] in patients with Fabry disease. J Inherit Metab Dis. 2004;27:499-505.[PMID: 15303007]96. FOS Investigators. Effects of enzyme replacement therapy with agalsidase alfaon glomerular filtration rate in patients with Fabry disease: preliminary data. ActaPaediatr Suppl. 2003;92:14-5. [PMID: 14989460]97. Schiffmann R, Ries M, Timmons M, Flaherty JT, Brady RO. Long-termtherapy with agalsidase alfa for Fabry disease: safety and effects on renal functionin a home infusion setting. Nephrol Dial Transplant. 2006;21:345-54. [PMID:16204287]98. Fabry Disease Clinical Trial Study Group. Agalsidase-beta therapy for ad-vanced Fabry disease: a randomized trial. Ann Intern Med. 2007;146:77-86.[PMID: 17179052]99. Weidemann F, Breunig F, Beer M, Sandstede J, Turschner O, Voelker W,et al. Improvement of cardiac function during enzyme replacement therapy inpatients with Fabry disease: a prospective strain rate imaging study. Circulation.2003;108:1299-301. [PMID: 12952834]100. Mignani R, Panichi V, Giudicissi A, Taccola D, Boscaro F, Feletti C, et al.

Enzyme replacement therapy with agalsidase beta in kidney transplant patientswith Fabry disease: a pilot study. Kidney Int. 2004;65:1381-5. [PMID:15086478]101. Baehner F, Kampmann C, Whybra C, Miebach E, Wiethoff CM, BeckM. Enzyme replacement therapy in heterozygous females with Fabry disease:results of a phase IIIB study. J Inherit Metab Dis. 2003;26:617-27. [PMID:14707510]102. Elliott PM, Kindler H, Shah JS, Sachdev B, Rimoldi OE, Thaman R, etal. Coronary microvascular dysfunction in male patients with Anderson-Fabrydisease and the effect of treatment with alpha galactosidase A. Heart. 2006;92:357-60. [PMID: 16085718]103. Schiffmann R, Rapkiewicz A, Abu-Asab M, Ries M, Askari H, Tsokos M,et al. Pathological findings in a patient with Fabry disease who died after 2.5 yearsof enzyme replacement. Virchows Arch. 2006;448:337-43. [PMID: 16315019]104. Moore DF, Ye F, Brennan ML, Gupta S, Barshop BA, Steiner RD, et al.Ascorbate decreases Fabry cerebral hyperperfusion suggesting a reactive oxygenspecies abnormality: an arterial spin tagging study. J Magn Reson Imaging. 2004;20:674-83. [PMID: 15390234]105. Moore DF, Altarescu G, Ling GS, Jeffries N, Frei KP, Weibel T, et al.Elevated cerebral blood flow velocities in Fabry disease with reversal after enzymereplacement. Stroke. 2002;33:525-31. [PMID: 11823664]106. Moore DF, Herscovitch P, Schiffmann R. Selective arterial distribution ofcerebral hyperperfusion in Fabry disease. J Neuroimaging. 2001;11:303-7.[PMID: 11462299]107. Moore DF, Scott LT, Gladwin MT, Altarescu G, Kaneski C, Suzuki K, etal. Regional cerebral hyperperfusion and nitric oxide pathway dysregulation inFabry disease: reversal by enzyme replacement therapy. Circulation. 2001;104:1506-12. [PMID: 11571244]108. Frustaci A, Chimenti C, Ricci R, Natale L, Russo MA, Pieroni M, et al.Improvement in cardiac function in the cardiac variant of Fabry’s disease withgalactose-infusion therapy. N Engl J Med. 2001;345:25-32. [PMID: 11439944]109. Yam GH, Bosshard N, Zuber C, Steinmann B, Roth J. Pharmacologicalchaperone corrects lysosomal storage in Fabry disease caused by trafficking-incompetent variants. Am J Physiol Cell Physiol. 2006;290:C1076-82. [PMID:16531566]110. Keusch GT, Jacewicz M, Acheson DW, Donohue-Rolfe A, Kane AV,McCluer RH. Globotriaosylceramide, Gb3, is an alternative functional receptorfor Shiga-like toxin 2e. Infect Immun. 1995;63:1138-41. [PMID: 7868240]111. Louise CB, Kaye SA, Boyd B, Lingwood CA, Obrig TG. Shiga toxin-associated hemolytic uremic syndrome: effect of sodium butyrate on sensitivity ofhuman umbilical vein endothelial cells to Shiga toxin. Infect Immun. 1995;63:2766-9. [PMID: 7790096]112. Mori T, Kiyokawa N, Katagiri YU, Taguchi T, Suzuki T, Sekino T, et al.Globotriaosyl ceramide (CD77/Gb3) in the glycolipid-enriched membrane do-main participates in B-cell receptor-mediated apoptosis by regulating lyn kinaseactivity in human B cells. Exp Hematol. 2000;28:1260-8. [PMID: 11063874]

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