- Email: [email protected]
Fabry disease: Diagnosis and treatment
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, JO¨RN SANDSTEDE, JO¨RG STROTMANN, and CHRISTOPH WANNER Department of Medicine, Divisions of Nephrology and Cardiology, Departments of Radiology and Dermatology, University of Wu¨rzburg, Wu¨rzburg, Germany
Fabry disease: Diagnosis and treatment. Fabry disease is an X-linked lysosomal storage disorder that results from a deficiency of the enzyme ␣-galactosidase A (␣-Gal A). The lack of ␣-Gal A causes an intracellular accumulation of glycosphingolipids, mainly globotriaosyceramide (GL3). Affected organs include, among others, the vascular endothelium, heart, brain, and kidneys, leading to end-stage renal disease (ESRD). Since Fabry disease cannot be cured at present, clinical management is symptomatic. Enzyme replacement therapy (ERT) with recombinant ␣-Gal A has been introduced as a new therapeutic option for the treatment of Fabry patients. Short-term (one year) clinical studies have positively correlated ERT with improvement of clinical symptoms and microvascular endothelial cell clearance. Treatment outcome concerning severe organ manifestations such as proteinuria and renal function impairment, left ventricular hypertrophy, and heart failure in the long run has yet to be shown. In our studies we used sensitive and noninvasive techniques such as ultrasoundbased strain rate imaging and magnetic resonance imaging (MRI), combined with MR-spectroscopy (MR-S), for the quantification of functional abnormalities at an early stage of the disease and during long-term follow-up. Future issues should determine the appropriate timing to start therapy and how children and heterozygous females should be managed. Given the diagnostic and therapeutic potential today, it is of importance to identify patients at an early stage and to start therapeutic intervention before progression of organ damage is inevitable.
Fabry disease was first described more than 100 years ago because of its characteristic skin lesions, known as angiokeratoma corporis diffusum universale [1, 2]. It is an inborn error of glycosphingolipid metabolism, which is due to a wide variety of mutations in the gene that encodes the lysosomal enzyme ␣-Gal A. The deficiency of ␣-Gal A causes an incomplete metabolism and progressive lysosomal accumulation of neutral glycosphingolipids, mainly globotriaosylceramide (GL3), in affected males and to a lesser extent in female carriers. This process leads to damage to various cell types, such Key words: Fabry disease, genetic disorders, lysosomal storage disease, clinical trial.
2003 by the International Society of Nephrology
as renal glomerular and tubular cells, cardiac myocytes and valvular fibrocytes, epithelial cells of the cornea, ganglion cells of the dorsal root and the autonomic nervous system, as well as cortical and brain stem structures. Lipid depositions are also seen in endothelial, perithelial, and smooth muscle cells of the vascular system [3]. SYMPTOMS AND CLINICAL COURSE The presenting symptoms of affected individuals and the clinical course of Fabry disease are highly variable. Acroparesthesia, with an onset in early childhood, constitutes one of the earliest and most debilitating symptoms and is often accompanied by fever, hypohidrosis, and heat intolerance. Other characteristic features are lenticular and corneal opacities, angiokeratoma, edema, and abdominal pain. During the third and fourth decade of life, Fabry disease is characterized by a progressive course and severe morbidity due to cardiac, renal, and cerebrovascular involvement [4]. Renal disease is one of the major causes of morbidity and mortality in Fabry patients [5]. In classically affected males, the first renal manifestations can be observed as proteinuria, microhematuria, and lipiduria. With advancing age, most of these patients show progressive renal failure. ESRD typically occurs in the third to fifth decade of life [5]. Myocardial involvement in patients with Fabry disease is well documented with concentric or asymmetrical left ventricular hypertrophy (LVH) [6, 7]. Clinical signs of cardiac involvement typically occur late in the course of the disease and many patients die from heart failure [8, 9]. Further complications include conduction abnormalities with reduced PR-interval [10] and cardiac arrhythmias [11]. Typical cerebrovascular symptoms in classic male patients are vertigo, headache, diplopia, dysarthria, and hemiataxia. There is an elevated risk for transient ischemic attacks, premature stroke, and dementia [12, 13]. DIAGNOSIS Classic features of Fabry disease are painful attacks of burning pain predominantly in the upper and lower
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extremities, which occur in 80% to 90% of patients. In combination with hypohidrosis, heat intolerance, and characteristic angiokeratomas, these patients are highly susceptible for classic Fabry disease. Pathognomonic symptoms are corneal opacities (cornea verticillata) and typical conjunctival involvement. The presumptive diagnosis based on the symptoms above is supported by a positive family history. The clinical diagnosis must be confirmed by assay of ␣-GAL A activity in leukocytes or plasma, and/or detection of GL3 deposition in tissue biopsies, and should be followed by a molecular genetic analysis. Taking pedigrees of newly diagnosed patients is worthwhile and may reveal more affected individuals. ESTABLISHING A DIAGNOSTIC AND TREATMENT CENTER FOR FABRY DISEASE In March 2001, our institution launched an outpatient center for the diagnosis and treatment of Fabry disease. The objectives of the center are to raise awareness of Fabry disease, to identify patients with no previous diagnosis, and to make ERT accessible to all Fabry patients with an indication for treatment. We seek to enroll sufficient numbers of patients in this evaluation program to reveal efficacy and safety of ERT in clinical practice. Subsequently, all patient data are anonymously entered into the Internet-based international Fabry registry. The majority of patients who have attended our center were referred by adult nephrologists or internists. All patients are provided with a confirmed diagnosis through determination of ␣-GAL A activity and/or genotyping. Indication for therapy is established and this may depend on age, sex, and severity of symptoms. Affected males are all considered to have an indication for therapy, but females and children undergo further evaluation to determine their suitability for treatment. PATIENT EVALUATION PROGRAM Due to the variety and variability of possible manifestations, every patient with confirmed diagnosis of Fabry disease undergoes a comprehensive clinical evaluation program before treatment is started (Table 1). This baseline set of data serves to determine advanced organ damage and allows the benefits of ERT to be quantitated during follow-up. To date, all patients who have undergone the initial evaluation have agreed to participate. Parts of the program have been approved by the local ethical committee and patients have given written consent according to the principles of the declaration of Helsinki. Echocardiography To detect cardiac involvement at an early stage of the disease, sensitive noninvasive imaging techniques are of
Table 1. Evaluation tests conducted on all patients recruited to the Wu¨rzburg outpatient center before start of enzyme replacement therapy for Fabry disease Tests performed Medical history/physical examination Completion of brief pain inventory Blood tests Total blood chemistry, full blood count, coagulation tests, CRP Blood group; Hepatitis B and C testing ␣-Gal A activity, genotyping Cardiac testing ECG, 24-hour ECG, exercise testing Echocardiography/strain rate imaging Cardiac MRI, MRS Kidney function tests Urine sedimentation test 24-hour proteinuria, creatinine clearance GFR, by 99mTc-DTPA Kidney biopsy (in selected patients) Dermatologic tests Photographic documentation Skin biopsy Sweat test Other tests Renal ultrasound Pulmonary function (spirometry) Cranial MRI Audio-visual testing Abbreviations are: CRP, C reactive protein; ␣-Gal A, ␣-galactosidase; ECG, electrocardiography; MRI, magnetic resonance imaging; MRS, magnetic resonance spectroscopy; GFR, glomerular filtration rate.
clinical benefit. In addition to conventional echocardiography, we have introduced ultrasound-based strain rate imaging in the surveillance of regional LV function before and during ERT. This new technique has been shown to quantify regional changes in myocardial deformation properties [14]. Myocardial strain measurements have been validated both in correlative experimental sonomicrometry [15] and in clinical studies [16]. Magnetic resonance imaging (MRI) and spectroscopy (MRS) MRI allows quantitative assessment of cardiac morphology and function with high accuracy and objectivity, as well as detection of inflammatory alterations in the myocardium, using contrast enhancement techniques [17, 18]. MRS offers the additional possibility to detect fundamental metabolic derangements in cardiomyocytes, which allow detection of subclinical cardiac commitment in different kinds of heart disease [19]. For MRS, absolute concentrations of energy metabolites, such as adenosine triphosphate (ATP) and phosphocreatine (PCr), are measured and an energetic index can be determined [20]. Kidney function and biopsy Kidney function in patients enrolled so far in clinical trials has been well preserved [21, 22]. However, pretreatment biopsies revealed that these patients had ex-
Breunig et al: Fabry disease: Diagnosis and treatment
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Fig. 2. Electron micrograph showing the electron dense lipid depositions in the vascular endothelium (arrows) of a skin capillary from a 29-year-old male Fabry patient (magnification x 3000).
Fig. 1. Typical angiokeratomas in Fabry disease. Characteristic darkred to blue-dark angiectases, typically found between the umbilicus and thigh. The lesions range in size from pinpoint to several millimeters.
tensive renal deposition of GL3 at study entry. This experience suggests that serum creatinine may not be an adequate parameter to investigate the benefit of ERT in moderate to severe renal disease. Renal function is estimated by measurement of the glomerular filtration rate (GFR), as well as by 24-hour creatinine clearance, or even more accurately by techniques using nuclear trace material (99mTc-DTPA). Additional information can be obtained by measuring 24-hour albuminuria/proteinuria. Kidney biopsy should be performed whenever patients are enrolled in a controlled clinical program. In the absence of significant urinary protein excretion, and when the extent of kidney damage is difficult to determine, the performance of a renal biopsy may provide helpful information. TREATMENT OPTIONS At present, treatment of Fabry disease is limited to symptom management. ACE inhibitors and antihyper-
tensive drugs may delay progressive loss of renal function. Therapy of heart disease includes antiarrhythmic drugs, artificial pacemakers, and coronary bypass grafting in case of coronary heart disease. For patients with chronic pain, the use of gabapentin, carbamazepin, or phenytoin is recommended. New therapeutic approaches for causal or specific treatment of Fabry disease, such as substrate deprivation or gene therapy, are promising but will not be available in the near future [23, 24]. A new specific treatment option that has reached the stage of clinical use is ERT. After cloning the ␣-GAL gene [25] and making advances in molecular genetic techniques, recombinant ␣-GAL is now synthesized by genetically engineered cell lines and available in two enzyme formulations. Safety and efficacy of the two enzyme preparations have been tested in preclinical studies [26, 27]. Subsequently, the enzymes were evaluated in two randomized, double blind, and placebo-controlled trials with 26 patients (agalsidase alpha) and 52 patients (agalsidase beta), respectively. Agalsidase alpha was given intravenously every 14 days at a dose of 0.2 mg/kg/body weight for 24 weeks [21], and a significant reduction of neuropathic pain (primary end point) was demonstrated. Initial kidney function was well preserved and remained stable in the treatment group, whereas a deterioration of GFR was found in the placebo group. The second study used agalsidase beta at a dose of 1 mg/kg/body weight [22]. Primary end point was the clearance of interstitial microvascular GL3 deposits in renal biopsy specimens. After 20 weeks of ERT, there was a significant reduction of depositions in the treatment compared with the placebo group. This was also noted in heart and skin specimens. Initial renal function (GFR and serum creatinine) was normal and remained stable throughout the study in both groups.
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Breunig et al: Fabry disease: Diagnosis and treatment
PERSPECTIVES The response to ERT, obtained during the treatment period of one year, demonstrates a powerful clearance of microvascular lipid depositions, and a clear potential to improve the clinical symptoms of the disease. Treatment outcome in the long run concerning severe organ manifestations, such as proteinuria, renal function impairment, LVH, and heart failure remains to be shown. Observation over longer treatment periods are needed to assess the value of ERT in patients with advanced organ damage if a definite improvement, or at least stabilization, can be demonstrated. Thus, in a rare disorder like Fabry disease, it is important to collect sufficient and comparable baseline and long-term clinical data on patients under treatment in specialized centers. ERT should be initiated by these centers to obtain a baseline data set and a thorough documentation of the clinical course. At present, it appears that an early intervention, without waiting for organ manifestations such as proteinuria or LVH, should be the goal. A study among 20 heterozygote females showed that severe manifestations, such as reduced GFR, lymphedema, and cardiomyopathy, were present in more than 50% of the patients; symptoms like acroparesthesia and vertigo were seen in 90% of the patients [28]. Similar results were reported in a British survey among female carriers [29], indicating the need for evaluation and therapy not only for affected males but also for symptomatic women. Screening studies among high-risk populations, such as patients suffering from unexplained myocardial hypertrophy or ESRD, have revealed a surprisingly high prevalence of unrecognized Fabry disease as the underlying cause [30, 31]. There are similar reports about renal variants that develop renal failure and about the significant prevalence of undiagnosed Fabry patients among patients on hemodialysis. Interestingly, these cardiac and renal variants seem to have residual enzyme activity and do not develop classical symptoms [9, 32]. Reprint requests to Frank Breunig, M.D., Department of Medicine, Division of Nephrology, University Hospital, Josef-Schneider-Str. 2, 97080 Wu¨rzburg, Germany. E-mail: [email protected]
REFERENCES 1. Fabry J: Ein Beitrag zur Kenntnis der purpura haemorrhagica nodularis (Purpura haemorrhagica nodularis hebrae). Arch Derm Syph 43:187–200, 1898 2. Anderson W: A case of angiokeratoma. Br J Dermatol 10:113–117, 1898 3. Desnick RJ, Ioannou YA, Eng CM: ␣-Galactosidase A deficiency: Fabry disease in The metabolic and molecular bases of inherited disease, (8th ed), edited by Scriver CR, Beaudet AL, Sly WS, et al, New York, McGraw-Hill; 2001, pp 3733–3774 4. Moore DF, Altaresu G, Geoffrey SF, et al: Elevated cerebral blood flow velocities in Fabry disease with reversal after enzyme replacement. Stroke 33:525–531, 2002
5. Thadhani R, Wolf M, West ML, et al: Patients with Fabry disease on dialysis in the United States. Kidney Int 61:249–255, 2002 6. Linhart A, Palecek T, Bultas J, et al: New insights in cardiac structural changes in patients with Fabry disease. Am Heart J 139:1101–1108, 2000 7. Frustraci A, Chiment C, Ricci R, et al: Improvement in cardiac function in the cardiac variant of Fabry’s disease with galactose infusion therapy. N Engl J Med 345:9–16, 2001 8. Cantor WJ, Butany J, Cusimao RJ, Iwanochko M: Restrictive cardiomyopathy secondary to Fabry’s disease. Circulation 98:1457– 1459, 1998 9. von Scheidt W, Eng CM, Fitzmaurice TF, et al: An atypical variant of Fabry’s disease with manifestations confined to the myocardium. N Engl J Med 324:395–399, 1991 10. Pochis WT, Litzow JT, King BG, Kenny D: Electrophysiologic findings in Fabry’s disease with a short PR interval. Am J Cardiol 74:203–204, 1994 11. Eckart RE, Kinney KG, Belnap CM, Le TD: Ventricular fibrillation refractory to automatic internal cardiac defibrillator in Fabry’s disease. Cardiology 94:208–212, 2000 12. Mitsias P, Levine SR: Cerebrovascular complications of Fabry’s disease. Ann Neurol 40:8–17, 1996 13. Mendez MF, Stanley TM, Medel NM, et al: The vascular dementia of Fabry’s disease. Dement Geriatr Cogn Disord 8:252–257, 1997 14. Heimdal A, Støylen A, Torp H, et al: Real-time strain rate imaging of the left ventricle by ultrasound. J Am Soc Echocardiogr 11:1013– 1019, 1998 15. Urheim S, Edvardsen T, Torp T, et al: Myocardial strain by Doppler echocardiography. Validation of a new method to quantify regional myocardial function. Circulation 102:1158–1164, 2000 16. Weidemann F, Eyskens B, Mertens L, et al: Quantification of regional right and left ventricular function by ultrasonic strain rate and strain indices after surgical repair of tetralogy of fallot. Am J Cardiol 90:133–138, 2002 17. Shimada T, Shimada K, Sakane T, et al: Diagnosis of cardiac sarcoidosis and evaluation of the effects of steroid therapy by gadolinium-DTPA-enhanced magnetic resonance imaging. Am J Med 110:520–527, 2001 18. Wassmuth R, Lentzsch S, Erdbruegger U, et al: Subclinical cardio toxic effects of anthracyclines as assessed by magnetic resonance imaging – a pilot study. Am Heart J 141:1007–1013, 2001 19. Neubauer S: High-energy phosphate metabolism in normal, hypertrophied and failing human myocardium. Heart Fail Rev 4:269–280, 1999 20. Meininger M, Landschu¨tz W, Beer M, et al: Concentrations of human cardiac phosphorus metabolites determined by SLOOP 31P NMR spectroscopy. Magn Reson Med 39:679–685, 1999 21. Schiffmann R, Kopp JB, Austin HA III, et al: Enzyme replacement therapy in Fabry disease: A randomised controlled trial. JAMA 285:2743–2749, 2001 22. Eng CM, Guffon N, Wilcox WR, et al: Safety and efficacy of recombinant human ␣-galactosidase A replacement in Fabry disease. N Engl J Med 345:9–16, 2001 23. Jung SC, Han IP, Limaye A, et al: Adeno-associated viral vectormediated gene transfer results in long-term enzymatic and functional correction in multiple organs of fabry mice. Proc Natl Acad Sci USA 98:2676–2681, 2001 24. Abe A, Gregory S, Kulkarny A, et al: Reduction of globotriaosylceramide in Fabry disease mice by substrate deprivation. J Clin Invest 105:1563–1571, 2000 25. Bishop DF, Calhoun DH, Bernstein, Hanzopoulos P, Quinn M, Desnick RJ: Human ␣-galactosidase A: Nucleotide sequence of a c-DNA clone encoding the mature enzyme. Proc Natl Acad Sci 83:4859–4863, 1986 26. Schiffmann R, Murray GJ, Treco D, et al: Infusion of alfa galactosidase A reduces tissue globotriaosylceramide storage in patients with Fabry disease. Proc Natl Acad Sci USA 97:365–370, 2000 27. Eng CM, Banikazemi M, Gordon RE, et al: A phase I/II clinical
Breunig et al: Fabry disease: Diagnosis and treatment trial of enzyme replacement in Fabry disease: Pharmacokinetic, substrate clearance, and safety studies. Am J Hum Genet 68:711– 722, 2001 28. Whybra C, Kampmann C, Beck M, et al: Anderson-Fabry disease: Clinical manifestations of disease in female heterozygotes. J Inherit Metab Dis 24:715–724, 2001 29. McDermot KD, Holmes A, Miners AH: Anderson-Fabry disease: Clinical manifestations and impact of disease in a cohort of 60 obligate carrier females. J Med Genet 38:769–775, 2001
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30. Sachdev B, Takenaka T, Teraguchi H, et al: Prevalence of Anderson-Fabry disease in male patients with late onset hypertrophic cardiomyopathy. Circulation 105:1407–1411, 2002 31. Nakao S, Takenaka T, Maeda M, et al: An atypical variant of Fabry’s disease in men with left ventricular hypertrophy. N Engl J Med 333:288–293, 1995 32. Desnick RJ, Banikazemi M, Wasserstein M: Enzyme replacement therapy for Fabry disease, an inherited nephropathy. Clin Nephrol 57:1–8, 2002
Fabry disease: Diagnosis and treatment FRANK BREUNIG, FRANK WEIDEMANN, MEINRAD BEER, ANDREAS EGGERT, VERA KRANE, MATTHIAS SPINDLER, JO¨RN SANDSTEDE, JO¨RG STROTMANN, and CHRISTOPH WANNER Department of Medicine, Divisions of Nephrology and Cardiology, Departments of Radiology and Dermatology, University of Wu¨rzburg, Wu¨rzburg, Germany
Fabry disease: Diagnosis and treatment. Fabry disease is an X-linked lysosomal storage disorder that results from a deficiency of the enzyme ␣-galactosidase A (␣-Gal A). The lack of ␣-Gal A causes an intracellular accumulation of glycosphingolipids, mainly globotriaosyceramide (GL3). Affected organs include, among others, the vascular endothelium, heart, brain, and kidneys, leading to end-stage renal disease (ESRD). Since Fabry disease cannot be cured at present, clinical management is symptomatic. Enzyme replacement therapy (ERT) with recombinant ␣-Gal A has been introduced as a new therapeutic option for the treatment of Fabry patients. Short-term (one year) clinical studies have positively correlated ERT with improvement of clinical symptoms and microvascular endothelial cell clearance. Treatment outcome concerning severe organ manifestations such as proteinuria and renal function impairment, left ventricular hypertrophy, and heart failure in the long run has yet to be shown. In our studies we used sensitive and noninvasive techniques such as ultrasoundbased strain rate imaging and magnetic resonance imaging (MRI), combined with MR-spectroscopy (MR-S), for the quantification of functional abnormalities at an early stage of the disease and during long-term follow-up. Future issues should determine the appropriate timing to start therapy and how children and heterozygous females should be managed. Given the diagnostic and therapeutic potential today, it is of importance to identify patients at an early stage and to start therapeutic intervention before progression of organ damage is inevitable.
Fabry disease was first described more than 100 years ago because of its characteristic skin lesions, known as angiokeratoma corporis diffusum universale [1, 2]. It is an inborn error of glycosphingolipid metabolism, which is due to a wide variety of mutations in the gene that encodes the lysosomal enzyme ␣-Gal A. The deficiency of ␣-Gal A causes an incomplete metabolism and progressive lysosomal accumulation of neutral glycosphingolipids, mainly globotriaosylceramide (GL3), in affected males and to a lesser extent in female carriers. This process leads to damage to various cell types, such Key words: Fabry disease, genetic disorders, lysosomal storage disease, clinical trial.
2003 by the International Society of Nephrology
as renal glomerular and tubular cells, cardiac myocytes and valvular fibrocytes, epithelial cells of the cornea, ganglion cells of the dorsal root and the autonomic nervous system, as well as cortical and brain stem structures. Lipid depositions are also seen in endothelial, perithelial, and smooth muscle cells of the vascular system [3]. SYMPTOMS AND CLINICAL COURSE The presenting symptoms of affected individuals and the clinical course of Fabry disease are highly variable. Acroparesthesia, with an onset in early childhood, constitutes one of the earliest and most debilitating symptoms and is often accompanied by fever, hypohidrosis, and heat intolerance. Other characteristic features are lenticular and corneal opacities, angiokeratoma, edema, and abdominal pain. During the third and fourth decade of life, Fabry disease is characterized by a progressive course and severe morbidity due to cardiac, renal, and cerebrovascular involvement [4]. Renal disease is one of the major causes of morbidity and mortality in Fabry patients [5]. In classically affected males, the first renal manifestations can be observed as proteinuria, microhematuria, and lipiduria. With advancing age, most of these patients show progressive renal failure. ESRD typically occurs in the third to fifth decade of life [5]. Myocardial involvement in patients with Fabry disease is well documented with concentric or asymmetrical left ventricular hypertrophy (LVH) [6, 7]. Clinical signs of cardiac involvement typically occur late in the course of the disease and many patients die from heart failure [8, 9]. Further complications include conduction abnormalities with reduced PR-interval [10] and cardiac arrhythmias [11]. Typical cerebrovascular symptoms in classic male patients are vertigo, headache, diplopia, dysarthria, and hemiataxia. There is an elevated risk for transient ischemic attacks, premature stroke, and dementia [12, 13]. DIAGNOSIS Classic features of Fabry disease are painful attacks of burning pain predominantly in the upper and lower
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extremities, which occur in 80% to 90% of patients. In combination with hypohidrosis, heat intolerance, and characteristic angiokeratomas, these patients are highly susceptible for classic Fabry disease. Pathognomonic symptoms are corneal opacities (cornea verticillata) and typical conjunctival involvement. The presumptive diagnosis based on the symptoms above is supported by a positive family history. The clinical diagnosis must be confirmed by assay of ␣-GAL A activity in leukocytes or plasma, and/or detection of GL3 deposition in tissue biopsies, and should be followed by a molecular genetic analysis. Taking pedigrees of newly diagnosed patients is worthwhile and may reveal more affected individuals. ESTABLISHING A DIAGNOSTIC AND TREATMENT CENTER FOR FABRY DISEASE In March 2001, our institution launched an outpatient center for the diagnosis and treatment of Fabry disease. The objectives of the center are to raise awareness of Fabry disease, to identify patients with no previous diagnosis, and to make ERT accessible to all Fabry patients with an indication for treatment. We seek to enroll sufficient numbers of patients in this evaluation program to reveal efficacy and safety of ERT in clinical practice. Subsequently, all patient data are anonymously entered into the Internet-based international Fabry registry. The majority of patients who have attended our center were referred by adult nephrologists or internists. All patients are provided with a confirmed diagnosis through determination of ␣-GAL A activity and/or genotyping. Indication for therapy is established and this may depend on age, sex, and severity of symptoms. Affected males are all considered to have an indication for therapy, but females and children undergo further evaluation to determine their suitability for treatment. PATIENT EVALUATION PROGRAM Due to the variety and variability of possible manifestations, every patient with confirmed diagnosis of Fabry disease undergoes a comprehensive clinical evaluation program before treatment is started (Table 1). This baseline set of data serves to determine advanced organ damage and allows the benefits of ERT to be quantitated during follow-up. To date, all patients who have undergone the initial evaluation have agreed to participate. Parts of the program have been approved by the local ethical committee and patients have given written consent according to the principles of the declaration of Helsinki. Echocardiography To detect cardiac involvement at an early stage of the disease, sensitive noninvasive imaging techniques are of
Table 1. Evaluation tests conducted on all patients recruited to the Wu¨rzburg outpatient center before start of enzyme replacement therapy for Fabry disease Tests performed Medical history/physical examination Completion of brief pain inventory Blood tests Total blood chemistry, full blood count, coagulation tests, CRP Blood group; Hepatitis B and C testing ␣-Gal A activity, genotyping Cardiac testing ECG, 24-hour ECG, exercise testing Echocardiography/strain rate imaging Cardiac MRI, MRS Kidney function tests Urine sedimentation test 24-hour proteinuria, creatinine clearance GFR, by 99mTc-DTPA Kidney biopsy (in selected patients) Dermatologic tests Photographic documentation Skin biopsy Sweat test Other tests Renal ultrasound Pulmonary function (spirometry) Cranial MRI Audio-visual testing Abbreviations are: CRP, C reactive protein; ␣-Gal A, ␣-galactosidase; ECG, electrocardiography; MRI, magnetic resonance imaging; MRS, magnetic resonance spectroscopy; GFR, glomerular filtration rate.
clinical benefit. In addition to conventional echocardiography, we have introduced ultrasound-based strain rate imaging in the surveillance of regional LV function before and during ERT. This new technique has been shown to quantify regional changes in myocardial deformation properties [14]. Myocardial strain measurements have been validated both in correlative experimental sonomicrometry [15] and in clinical studies [16]. Magnetic resonance imaging (MRI) and spectroscopy (MRS) MRI allows quantitative assessment of cardiac morphology and function with high accuracy and objectivity, as well as detection of inflammatory alterations in the myocardium, using contrast enhancement techniques [17, 18]. MRS offers the additional possibility to detect fundamental metabolic derangements in cardiomyocytes, which allow detection of subclinical cardiac commitment in different kinds of heart disease [19]. For MRS, absolute concentrations of energy metabolites, such as adenosine triphosphate (ATP) and phosphocreatine (PCr), are measured and an energetic index can be determined [20]. Kidney function and biopsy Kidney function in patients enrolled so far in clinical trials has been well preserved [21, 22]. However, pretreatment biopsies revealed that these patients had ex-
Breunig et al: Fabry disease: Diagnosis and treatment
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Fig. 2. Electron micrograph showing the electron dense lipid depositions in the vascular endothelium (arrows) of a skin capillary from a 29-year-old male Fabry patient (magnification x 3000).
Fig. 1. Typical angiokeratomas in Fabry disease. Characteristic darkred to blue-dark angiectases, typically found between the umbilicus and thigh. The lesions range in size from pinpoint to several millimeters.
tensive renal deposition of GL3 at study entry. This experience suggests that serum creatinine may not be an adequate parameter to investigate the benefit of ERT in moderate to severe renal disease. Renal function is estimated by measurement of the glomerular filtration rate (GFR), as well as by 24-hour creatinine clearance, or even more accurately by techniques using nuclear trace material (99mTc-DTPA). Additional information can be obtained by measuring 24-hour albuminuria/proteinuria. Kidney biopsy should be performed whenever patients are enrolled in a controlled clinical program. In the absence of significant urinary protein excretion, and when the extent of kidney damage is difficult to determine, the performance of a renal biopsy may provide helpful information. TREATMENT OPTIONS At present, treatment of Fabry disease is limited to symptom management. ACE inhibitors and antihyper-
tensive drugs may delay progressive loss of renal function. Therapy of heart disease includes antiarrhythmic drugs, artificial pacemakers, and coronary bypass grafting in case of coronary heart disease. For patients with chronic pain, the use of gabapentin, carbamazepin, or phenytoin is recommended. New therapeutic approaches for causal or specific treatment of Fabry disease, such as substrate deprivation or gene therapy, are promising but will not be available in the near future [23, 24]. A new specific treatment option that has reached the stage of clinical use is ERT. After cloning the ␣-GAL gene [25] and making advances in molecular genetic techniques, recombinant ␣-GAL is now synthesized by genetically engineered cell lines and available in two enzyme formulations. Safety and efficacy of the two enzyme preparations have been tested in preclinical studies [26, 27]. Subsequently, the enzymes were evaluated in two randomized, double blind, and placebo-controlled trials with 26 patients (agalsidase alpha) and 52 patients (agalsidase beta), respectively. Agalsidase alpha was given intravenously every 14 days at a dose of 0.2 mg/kg/body weight for 24 weeks [21], and a significant reduction of neuropathic pain (primary end point) was demonstrated. Initial kidney function was well preserved and remained stable in the treatment group, whereas a deterioration of GFR was found in the placebo group. The second study used agalsidase beta at a dose of 1 mg/kg/body weight [22]. Primary end point was the clearance of interstitial microvascular GL3 deposits in renal biopsy specimens. After 20 weeks of ERT, there was a significant reduction of depositions in the treatment compared with the placebo group. This was also noted in heart and skin specimens. Initial renal function (GFR and serum creatinine) was normal and remained stable throughout the study in both groups.
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Breunig et al: Fabry disease: Diagnosis and treatment
PERSPECTIVES The response to ERT, obtained during the treatment period of one year, demonstrates a powerful clearance of microvascular lipid depositions, and a clear potential to improve the clinical symptoms of the disease. Treatment outcome in the long run concerning severe organ manifestations, such as proteinuria, renal function impairment, LVH, and heart failure remains to be shown. Observation over longer treatment periods are needed to assess the value of ERT in patients with advanced organ damage if a definite improvement, or at least stabilization, can be demonstrated. Thus, in a rare disorder like Fabry disease, it is important to collect sufficient and comparable baseline and long-term clinical data on patients under treatment in specialized centers. ERT should be initiated by these centers to obtain a baseline data set and a thorough documentation of the clinical course. At present, it appears that an early intervention, without waiting for organ manifestations such as proteinuria or LVH, should be the goal. A study among 20 heterozygote females showed that severe manifestations, such as reduced GFR, lymphedema, and cardiomyopathy, were present in more than 50% of the patients; symptoms like acroparesthesia and vertigo were seen in 90% of the patients [28]. Similar results were reported in a British survey among female carriers [29], indicating the need for evaluation and therapy not only for affected males but also for symptomatic women. Screening studies among high-risk populations, such as patients suffering from unexplained myocardial hypertrophy or ESRD, have revealed a surprisingly high prevalence of unrecognized Fabry disease as the underlying cause [30, 31]. There are similar reports about renal variants that develop renal failure and about the significant prevalence of undiagnosed Fabry patients among patients on hemodialysis. Interestingly, these cardiac and renal variants seem to have residual enzyme activity and do not develop classical symptoms [9, 32]. Reprint requests to Frank Breunig, M.D., Department of Medicine, Division of Nephrology, University Hospital, Josef-Schneider-Str. 2, 97080 Wu¨rzburg, Germany. E-mail: [email protected]
REFERENCES 1. Fabry J: Ein Beitrag zur Kenntnis der purpura haemorrhagica nodularis (Purpura haemorrhagica nodularis hebrae). Arch Derm Syph 43:187–200, 1898 2. Anderson W: A case of angiokeratoma. Br J Dermatol 10:113–117, 1898 3. Desnick RJ, Ioannou YA, Eng CM: ␣-Galactosidase A deficiency: Fabry disease in The metabolic and molecular bases of inherited disease, (8th ed), edited by Scriver CR, Beaudet AL, Sly WS, et al, New York, McGraw-Hill; 2001, pp 3733–3774 4. Moore DF, Altaresu G, Geoffrey SF, et al: Elevated cerebral blood flow velocities in Fabry disease with reversal after enzyme replacement. Stroke 33:525–531, 2002
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