Kidney International, Vol. 63, Supplement 84 (2003), pp. S181–S185

Fabry disease: Diagnosis and treatment

FRANK BREUNIG, FRANK WEIDEMANN, MEINRAD BEER, ANDREAS EGGERT, VERA KRANE,MATTHIAS SPINDLER, JORN SANDSTEDE, JORG STROTMANN, and CHRISTOPH WANNER

Department of Medicine, Divisions of Nephrology and Cardiology, Departments of Radiology and Dermatology, University ofWurzburg, Wurzburg, Germany

Fabry disease: Diagnosis and treatment. Fabry disease is an as renal glomerular and tubular cells, cardiac myocytesX-linked lysosomal storage disorder that results from a defi- and valvular fibrocytes, epithelial cells of the cornea,ciency of the enzyme �-galactosidase A (�-Gal A). The lack ganglion cells of the dorsal root and the autonomic ner-of �-Gal A causes an intracellular accumulation of glycosphin-

vous system, as well as cortical and brain stem structures.golipids, mainly globotriaosyceramide (GL3). Affected organsLipid depositions are also seen in endothelial, perithelial,include, among others, the vascular endothelium, heart, brain,

and kidneys, leading to end-stage renal disease (ESRD). Since and smooth muscle cells of the vascular system [3].Fabry disease cannot be cured at present, clinical managementis symptomatic. Enzyme replacement therapy (ERT) with re-combinant �-Gal A has been introduced as a new therapeutic SYMPTOMS AND CLINICAL COURSEoption for the treatment of Fabry patients.

The presenting symptoms of affected individuals andShort-term (one year) clinical studies have positively corre-the clinical course of Fabry disease are highly variable.lated ERT with improvement of clinical symptoms and micro-Acroparesthesia, with an onset in early childhood, con-vascular endothelial cell clearance. Treatment outcome con-

cerning severe organ manifestations such as proteinuria and stitutes one of the earliest and most debilitating symp-renal function impairment, left ventricular hypertrophy, and toms and is often accompanied by fever, hypohidrosis,heart failure in the long run has yet to be shown. In our studies and heat intolerance. Other characteristic features arewe used sensitive and noninvasive techniques such as ultrasound-

lenticular and corneal opacities, angiokeratoma, edema,based strain rate imaging and magnetic resonance imagingand abdominal pain. During the third and fourth decade(MRI), combined with MR-spectroscopy (MR-S), for the quan-

tification of functional abnormalities at an early stage of the of life, Fabry disease is characterized by a progressivedisease and during long-term follow-up. Future issues should course and severe morbidity due to cardiac, renal, anddetermine the appropriate timing to start therapy and how cerebrovascular involvement [4]. Renal disease is one ofchildren and heterozygous females should be managed. Given

the major causes of morbidity and mortality in Fabrythe diagnostic and therapeutic potential today, it is of impor-patients [5]. In classically affected males, the first renaltance to identify patients at an early stage and to start thera-

peutic intervention before progression of organ damage is in- manifestations can be observed as proteinuria, micro-evitable. hematuria, and lipiduria. With advancing age, most of

these patients show progressive renal failure. ESRD typi-cally occurs in the third to fifth decade of life [5]. Myocar-

Fabry disease was first described more than 100 years dial involvement in patients with Fabry disease is wellago because of its characteristic skin lesions, known as documented with concentric or asymmetrical left ventric-angiokeratoma corporis diffusum universale [1, 2]. It is ular hypertrophy (LVH) [6, 7]. Clinical signs of cardiacan inborn error of glycosphingolipid metabolism, which involvement typically occur late in the course of theis due to a wide variety of mutations in the gene that disease and many patients die from heart failure [8, 9].encodes the lysosomal enzyme �-Gal A. The deficiency Further complications include conduction abnormalitiesof �-Gal A causes an incomplete metabolism and pro- with reduced PR-interval [10] and cardiac arrhythmias

[11]. Typical cerebrovascular symptoms in classic malegressive lysosomal accumulation of neutral glycosphin-patients are vertigo, headache, diplopia, dysarthria, andgolipids, mainly globotriaosylceramide (GL3), in af-hemiataxia. There is an elevated risk for transient isch-fected males and to a lesser extent in female carriers.emic attacks, premature stroke, and dementia [12, 13].This process leads to damage to various cell types, such

DIAGNOSISKey words: Fabry disease, genetic disorders, lysosomal storage disease,clinical trial. Classic features of Fabry disease are painful attacks

of burning pain predominantly in the upper and lower 2003 by the International Society of Nephrology

S-181

Breunig et al: Fabry disease: Diagnosis and treatmentS-182

Table 1. Evaluation tests conducted on all patients recruited to theextremities, which occur in 80% to 90% of patients.Wurzburg outpatient center before start of enzyme replacement

In combination with hypohidrosis, heat intolerance, and therapy for Fabry diseasecharacteristic angiokeratomas, these patients are highly

Tests performedsusceptible for classic Fabry disease. Pathognomonic Medical history/physical examinationsymptoms are corneal opacities (cornea verticillata) and Completion of brief pain inventory

Blood teststypical conjunctival involvement. The presumptive diag-Total blood chemistry, full blood count, coagulation tests, CRPnosis based on the symptoms above is supported by a Blood group; Hepatitis B and C testing

positive family history. The clinical diagnosis must be �-Gal A activity, genotypingCardiac testingconfirmed by assay of �-GAL A activity in leukocytes

ECG, 24-hour ECG, exercise testingor plasma, and/or detection of GL3 deposition in tissue Echocardiography/strain rate imagingbiopsies, and should be followed by a molecular genetic Cardiac MRI, MRS

Kidney function testsanalysis. Taking pedigrees of newly diagnosed patientsUrine sedimentation testis worthwhile and may reveal more affected individuals. 24-hour proteinuria, creatinine clearanceGFR, by 99mTc-DTPAKidney biopsy (in selected patients)

Dermatologic testsESTABLISHING A DIAGNOSTIC ANDPhotographic documentationTREATMENT CENTER FOR FABRY DISEASESkin biopsySweat testIn March 2001, our institution launched an outpatient

Other testscenter for the diagnosis and treatment of Fabry disease.Renal ultrasound

The objectives of the center are to raise awareness of Pulmonary function (spirometry)Cranial MRIFabry disease, to identify patients with no previous diag-Audio-visual testingnosis, and to make ERT accessible to all Fabry patientsAbbreviations are: CRP, C reactive protein; �-Gal A, �-galactosidase; ECG,with an indication for treatment. We seek to enroll suffi-

electrocardiography; MRI, magnetic resonance imaging; MRS, magnetic reso-cient numbers of patients in this evaluation program to nance spectroscopy; GFR, glomerular filtration rate.

reveal efficacy and safety of ERT in clinical practice.Subsequently, all patient data are anonymously enteredinto the Internet-based international Fabry registry. The

clinical benefit. In addition to conventional echocardiog-majority of patients who have attended our center wereraphy, we have introduced ultrasound-based strain ratereferred by adult nephrologists or internists. All patientsimaging in the surveillance of regional LV function be-are provided with a confirmed diagnosis through deter-fore and during ERT. This new technique has beenmination of �-GAL A activity and/or genotyping. Indica-shown to quantify regional changes in myocardial defor-tion for therapy is established and this may depend onmation properties [14]. Myocardial strain measurementsage, sex, and severity of symptoms. Affected males arehave been validated both in correlative experimentalall considered to have an indication for therapy, butsonomicrometry [15] and in clinical studies [16].females and children undergo further evaluation to de-

termine their suitability for treatment.Magnetic resonance imaging (MRI) andspectroscopy (MRS)

PATIENT EVALUATION PROGRAM MRI allows quantitative assessment of cardiac mor-phology and function with high accuracy and objectivity,Due to the variety and variability of possible manifes-as well as detection of inflammatory alterations in thetations, every patient with confirmed diagnosis of Fabrymyocardium, using contrast enhancement techniquesdisease undergoes a comprehensive clinical evaluation[17, 18]. MRS offers the additional possibility to detectprogram before treatment is started (Table 1). This base-fundamental metabolic derangements in cardiomyo-line set of data serves to determine advanced organ dam-cytes, which allow detection of subclinical cardiac com-age and allows the benefits of ERT to be quantitatedmitment in different kinds of heart disease [19]. Forduring follow-up. To date, all patients who have under-MRS, absolute concentrations of energy metabolites,gone the initial evaluation have agreed to participate.such as adenosine triphosphate (ATP) and phosphocre-Parts of the program have been approved by the localatine (PCr), are measured and an energetic index canethical committee and patients have given written con-be determined [20].sent according to the principles of the declaration of

Helsinki.Kidney function and biopsy

Echocardiography Kidney function in patients enrolled so far in clinicaltrials has been well preserved [21, 22]. However, pre-To detect cardiac involvement at an early stage of the

disease, sensitive noninvasive imaging techniques are of treatment biopsies revealed that these patients had ex-

Breunig et al: Fabry disease: Diagnosis and treatment S-183

Fig. 2. Electron micrograph showing the electron dense lipid deposi-tions in the vascular endothelium (arrows) of a skin capillary from a29-year-old male Fabry patient (magnification x 3000).

tensive drugs may delay progressive loss of renal func-tion. Therapy of heart disease includes antiarrhythmicdrugs, artificial pacemakers, and coronary bypass graft-ing in case of coronary heart disease. For patients withchronic pain, the use of gabapentin, carbamazepin, orphenytoin is recommended. New therapeutic approachesfor causal or specific treatment of Fabry disease, suchas substrate deprivation or gene therapy, are promisingbut will not be available in the near future [23, 24].

A new specific treatment option that has reached thestage of clinical use is ERT. After cloning the �-GAL gene[25] and making advances in molecular genetic techniques,recombinant �-GAL is now synthesized by geneticallyFig. 1. Typical angiokeratomas in Fabry disease. Characteristic dark-

red to blue-dark angiectases, typically found between the umbilicus and engineered cell lines and available in two enzyme for-thigh. The lesions range in size from pinpoint to several millimeters.

mulations. Safety and efficacy of the two enzyme prepa-rations have been tested in preclinical studies [26, 27].Subsequently, the enzymes were evaluated in two ran-tensive renal deposition of GL3 at study entry. Thisdomized, double blind, and placebo-controlled trials withexperience suggests that serum creatinine may not be26 patients (agalsidase alpha) and 52 patients (agalsidasean adequate parameter to investigate the benefit of ERTbeta), respectively. Agalsidase alpha was given intrave-in moderate to severe renal disease. Renal function isnously every 14 days at a dose of 0.2 mg/kg/body weightestimated by measurement of the glomerular filtrationfor 24 weeks [21], and a significant reduction of neuro-rate (GFR), as well as by 24-hour creatinine clearance,pathic pain (primary end point) was demonstrated. Ini-or even more accurately by techniques using nucleartial kidney function was well preserved and remainedtrace material (99mTc-DTPA). Additional informationstable in the treatment group, whereas a deteriorationcan be obtained by measuring 24-hour albuminuria/pro-

teinuria. Kidney biopsy should be performed whenever of GFR was found in the placebo group. The second studypatients are enrolled in a controlled clinical program. In used agalsidase beta at a dose of 1 mg/kg/body weightthe absence of significant urinary protein excretion, and [22]. Primary end point was the clearance of interstitialwhen the extent of kidney damage is difficult to deter- microvascular GL3 deposits in renal biopsy specimens.mine, the performance of a renal biopsy may provide After 20 weeks of ERT, there was a significant reductionhelpful information. of depositions in the treatment compared with the pla-

cebo group. This was also noted in heart and skin speci-TREATMENT OPTIONS mens. Initial renal function (GFR and serum creatinine)

was normal and remained stable throughout the studyAt present, treatment of Fabry disease is limited tosymptom management. ACE inhibitors and antihyper- in both groups.

Breunig et al: Fabry disease: Diagnosis and treatmentS-184

5. Thadhani R, Wolf M, West ML, et al: Patients with Fabry diseasePERSPECTIVESon dialysis in the United States. Kidney Int 61:249–255, 2002

The response to ERT, obtained during the treatment 6. Linhart A, Palecek T, Bultas J, et al: New insights in cardiacstructural changes in patients with Fabry disease. Am Heart Jperiod of one year, demonstrates a powerful clearance139:1101–1108, 2000of microvascular lipid depositions, and a clear potential

7. Frustraci A, Chiment C, Ricci R, et al: Improvement in cardiacto improve the clinical symptoms of the disease. Treat- function in the cardiac variant of Fabry’s disease with galactose

infusion therapy. N Engl J Med 345:9–16, 2001ment outcome in the long run concerning severe organ8. Cantor WJ, Butany J, Cusimao RJ, Iwanochko M: Restrictivemanifestations, such as proteinuria, renal function im-

cardiomyopathy secondary to Fabry’s disease. Circulation 98:1457–pairment, LVH, and heart failure remains to be shown. 1459, 1998Observation over longer treatment periods are needed 9. von Scheidt W, Eng CM, Fitzmaurice TF, et al: An atypical

variant of Fabry’s disease with manifestations confined to the myo-to assess the value of ERT in patients with advancedcardium. N Engl J Med 324:395–399, 1991organ damage if a definite improvement, or at least stabi-

10. Pochis WT, Litzow JT, King BG, Kenny D: Electrophysiologiclization, can be demonstrated. Thus, in a rare disorder findings in Fabry’s disease with a short PR interval. Am J Cardiol

74:203–204, 1994like Fabry disease, it is important to collect sufficient11. Eckart RE, Kinney KG, Belnap CM, Le TD: Ventricular fibrilla-and comparable baseline and long-term clinical data on

tion refractory to automatic internal cardiac defibrillator in Fabry’spatients under treatment in specialized centers. ERT disease. Cardiology 94:208–212, 2000should be initiated by these centers to obtain a baseline 12. Mitsias P, Levine SR: Cerebrovascular complications of Fabry’s

disease. Ann Neurol 40:8–17, 1996data set and a thorough documentation of the clinical13. Mendez MF, Stanley TM, Medel NM, et al: The vascular demen-course. At present, it appears that an early intervention,

tia of Fabry’s disease. Dement Geriatr Cogn Disord 8:252–257,without waiting for organ manifestations such as protein- 1997

14. Heimdal A, Støylen A, Torp H, et al: Real-time strain rate imaginguria or LVH, should be the goal. A study among 20of the left ventricle by ultrasound. J Am Soc Echocardiogr 11:1013–heterozygote females showed that severe manifestations,1019, 1998such as reduced GFR, lymphedema, and cardiomyopa- 15. Urheim S, Edvardsen T, Torp T, et al: Myocardial strain by Dopp-

thy, were present in more than 50% of the patients; ler echocardiography. Validation of a new method to quantifyregional myocardial function. Circulation 102:1158–1164, 2000symptoms like acroparesthesia and vertigo were seen in

16. Weidemann F, Eyskens B, Mertens L, et al: Quantification of90% of the patients [28]. Similar results were reportedregional right and left ventricular function by ultrasonic strain rate

in a British survey among female carriers [29], indicating and strain indices after surgical repair of tetralogy of fallot. Am Jthe need for evaluation and therapy not only for affected Cardiol 90:133–138, 2002

17. Shimada T, Shimada K, Sakane T, et al: Diagnosis of cardiacmales but also for symptomatic women. Screening stud-sarcoidosis and evaluation of the effects of steroid therapy byies among high-risk populations, such as patients suffer- gadolinium-DTPA-enhanced magnetic resonance imaging. Am J

ing from unexplained myocardial hypertrophy or ESRD, Med 110:520–527, 200118. Wassmuth R, Lentzsch S, Erdbruegger U, et al: Subclinicalhave revealed a surprisingly high prevalence of unrecog-

cardio toxic effects of anthracyclines as assessed by magnetic reso-nized Fabry disease as the underlying cause [30, 31].nance imaging – a pilot study. Am Heart J 141:1007–1013, 2001

There are similar reports about renal variants that de- 19. Neubauer S: High-energy phosphate metabolism in normal, hyper-velop renal failure and about the significant prevalence trophied and failing human myocardium. Heart Fail Rev 4:269–280,

1999of undiagnosed Fabry patients among patients on hemo-20. Meininger M, Landschutz W, Beer M, et al: Concentrations ofdialysis. Interestingly, these cardiac and renal variants

human cardiac phosphorus metabolites determined by SLOOP 31Pseem to have residual enzyme activity and do not develop NMR spectroscopy. Magn Reson Med 39:679–685, 1999

21. Schiffmann R, Kopp JB, Austin HA III, et al: Enzyme replacementclassical symptoms [9, 32].therapy in Fabry disease: A randomised controlled trial. JAMA285:2743–2749, 2001Reprint requests to Frank Breunig, M.D., Department of Medicine,

Division of Nephrology, University Hospital, Josef-Schneider-Str. 2, 22. Eng CM, Guffon N, Wilcox WR, et al: Safety and efficacy of97080 Wurzburg, Germany. recombinant human �-galactosidase A replacement in Fabry dis-E-mail: f.breunig@medizin.uni-wuerzburg.de ease. N Engl J Med 345:9–16, 2001

23. Jung SC, Han IP, Limaye A, et al: Adeno-associated viral vector-mediated gene transfer results in long-term enzymatic and func-REFERENCES tional correction in multiple organs of fabry mice. Proc Natl AcadSci USA 98:2676–2681, 20011. Fabry J: Ein Beitrag zur Kenntnis der purpura haemorrhagica

24. Abe A, Gregory S, Kulkarny A, et al: Reduction of globotriaosyl-nodularis (Purpura haemorrhagica nodularis hebrae). Arch Dermceramide in Fabry disease mice by substrate deprivation. J ClinSyph 43:187–200, 1898Invest 105:1563–1571, 20002. Anderson W: A case of angiokeratoma. Br J Dermatol 10:113–117,

25. Bishop DF, Calhoun DH, Bernstein, Hanzopoulos P, Quinn1898M, Desnick RJ: Human �-galactosidase A: Nucleotide sequence3. Desnick RJ, Ioannou YA, Eng CM: �-Galactosidase A deficiency:of a c-DNA clone encoding the mature enzyme. Proc Natl AcadFabry disease in The metabolic and molecular bases of inheritedSci 83:4859–4863, 1986disease, (8th ed), edited by Scriver CR, Beaudet AL, Sly WS, et

26. Schiffmann R, Murray GJ, Treco D, et al: Infusion of alfa galac-al, New York, McGraw-Hill; 2001, pp 3733–3774tosidase A reduces tissue globotriaosylceramide storage in patients4. Moore DF, Altaresu G, Geoffrey SF, et al: Elevated cerebralwith Fabry disease. Proc Natl Acad Sci USA 97:365–370, 2000blood flow velocities in Fabry disease with reversal after enzyme

replacement. Stroke 33:525–531, 2002 27. Eng CM, Banikazemi M, Gordon RE, et al: A phase I/II clinical

Breunig et al: Fabry disease: Diagnosis and treatment S-185

trial of enzyme replacement in Fabry disease: Pharmacokinetic, 30. Sachdev B, Takenaka T, Teraguchi H, et al: Prevalence of Ander-son-Fabry disease in male patients with late onset hypertrophicsubstrate clearance, and safety studies. Am J Hum Genet 68:711–

722, 2001 cardiomyopathy. Circulation 105:1407–1411, 200231. Nakao S, Takenaka T, Maeda M, et al: An atypical variant of28. Whybra C, Kampmann C, Beck M, et al: Anderson-Fabry disease:

Clinical manifestations of disease in female heterozygotes. J Inherit Fabry’s disease in men with left ventricular hypertrophy. N EnglJ Med 333:288–293, 1995Metab Dis 24:715–724, 2001

29. McDermot KD, Holmes A, Miners AH: Anderson-Fabry disease: 32. Desnick RJ, Banikazemi M, Wasserstein M: Enzyme replace-ment therapy for Fabry disease, an inherited nephropathy. ClinClinical manifestations and impact of disease in a cohort of 60

obligate carrier females. J Med Genet 38:769–775, 2001 Nephrol 57:1–8, 2002