Enzyme replacement therapy in Anderson-Fabry cardiomyopathy

Christoph Kampmann1, Catharina Whybra2, Frank A. Baehner2, Michael Beck2
1Department of Cardiology, 2Department of Lysosomal Storage Diseases,
University Children’s Hospital, Mainz, Germany
Correspondence: Dr med Christoph Kampmann, Universitätskinderklinik Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany. Tel: +49 6131 177328, fax: +49 6131 17477328, e-mail: christoph.kampmann@uni-mainz.de

Abstract

Anderson-Fabry disease is a rare X-linked disorder of glycosphingolipid metabolism, resulting in an accumulation of different lipids, mainly globotriaosylceramide, within vulnerable cell structures, including the myocardium and, to a lesser degree, the epithelial cells of the coronary arteries. The main manifestations in the heart are different forms of hypertrophic cardiomyopathies with valvular thickening. Both genders are affected to the same extent but at different ages. The deficient enzyme a-galactosidase A can now be substituted by enzyme replacement therapy. We report on the effects of 18 months of enzyme replacement therapy with agalsidase alfa on one hemizygous male and three heterozygous females with hypertrophic cardiomyopathy. Cardiac examinations were performed at baseline and at 6-month intervals. n Heart Metab. 2002;18:39–41.


Keywords: Anderson-Fabry disease, hypertrophic cardiomyopathy, enzyme replacement therapy

Introduction
Anderson-Fabry disease (AFD) is a rare X-linked hereditary disorder of glycosphingolipid metabolism. It is caused by a deficiency of the lysosomal enzyme a-galactosidase A (AGALA), resulting in progressive intracellular accumulation of different lipids, mainly globotriaosylceramide (Gb3). The principal cell types affected include renal cells, cardiac myocytes, and dorsal root ganglia cells of the autonomic nervous system. Capillary endothelial cells and smooth muscle cells of the vascular system are also affected but to a lesser degree [1, 2]. Cardiac involvement is a frequent occurrence in both genders, resulting in structural and functional changes to the myocardium, the conduction system, and the valves [3–6]. The most common cardiac finding is concentric left ventricular hypertrophy. Besides the classical form of AFD with multiorgan manifestations, several reports have suggested that there may be a “cardiac variant” of AFD, in which clinical manifestations appear to be limited to the heart. The incidence of this cardiac variant is suggested to be between 3% and 6% of all males with left ventricular hypertrophy of unknown etiology [7, 8]. However, all the patients studied had residual enzyme activity, a history of neuropathic pain, and a family history either of members with known AFD or of unknown cardiac- or kidney-related deaths.
Enzyme replacement therapy is now available in Europe with two different recombinant AGALA preparations: agalsidase alfa (Replagal®), which is produced in a genetically engineered human cell line; and agalsidase beta (Fabrazyme®), which is produced in a Chinese hamster ovary cell line. Both have been shown to be safe in male patients [9–11]. Six months of enzyme replacement therapy with agalsidase alfa have been shown to result in significant reductions in neuropathic pain, improvements in both renal function and pathology, reduction in QRS duration, reversal of bundle branch blocks, and reduction in left ventricular mass [11–13]. Agalsidase beta has been shown to reduce capillary endothelial Gb3 levels [9, 10].
The recommended dosage of the enzyme preparations are 1 mg/kg body weight for agalsidase beta and 0.2 mg/kg body weight for agalsidase alfa. The major differences between the preparations are believed to be related to the human or nonhuman glycosylation with mannose-6-phosphate and the correctly attached sialic acid, which seems to be responsible for liver uptake, inactivation of the enzyme, biodistribution, and the development of specific antibodies.

Figure 1. Left ventricular mass (mean ± 1 SE), indexed to body surface area, in four patients receiving enzyme replacement therapy for 18 months.

Patients and results
Four patients (three females and one male), proven to be hetero- or hemizygous, respectively, for AFD, received biweekly intravenous enzyme replacement therapy with 0.2 mg/kg agalsidase alfa for at least 18 months. At baseline and at 6-monthly intervals, all patients underwent a cardiac examination including clinical status, blood pressure measurements, electrocardiograms, and 2-D, M-mode, and Doppler echocardiography as described elsewhere [14]. Mean age at baseline was 45.2 ± 13.3 years and mean body surface area was 1.82 ± 0.18 m2. All patients had left ventricular hypertrophy, ether concentric (three) or eccentric (one). Mean left ventricular mass, indexed to body surface area, was 200 ± 60 g/m2 at baseline (range, 148–288 g/m2). Mean ventricular wall thickness at baseline ranged from 11.3 mm to 19.2 mm, with a mean of 15.4 ± 3.4 mm.

Figure 2. Ventricular wall thickness ((interventricular septal thickness + posterior wall thickness)/2) (mean ± 1 SE) in four patients receiving enzyme replacement therapy for 18 months.


Enzyme replacement therapy over 18 months led to a significant continuous reduction in left ventricular mass (F = 13.67; P = 0.002) (Figure 1) and mean ventricular wall thickness (F = 8.81; P < 0.01) (Figure 2). Left ventricular mass normalized in two of four patients after 1 year of treatment. At baseline two patients were in a state of compensated low cardiac output with a cardiac index below 2 l/min per m2. Over 18 months of enzyme replacement therapy, cardiac index increased in all patients from a mean of 2.1 ± 1.1 l/min per m2 to 3.3 ± 1.3 l/min per m2 and no patient continued with low cardiac output. The increase in cardiac index was related to an increase in heart rate and, mainly, stroke volume, which increased from 38.5 ± 16 ml/m2 to 50 ± 7.1 ml/m2. At baseline two of the four patients were in NYHA heart failure functional class III, but after 18 months of enzyme replacement therapy all patients were in NYHA class II. No patient deteriorated during treatment.

Conclusion
Besides the known benefits of enzyme replacement therapy with agalsidase alfa in relation to cerebral perfusion, pain, quality of life, and kidney involvement in severely affected patients, agalsidase alfa stops the progression of AFD and furthermore is able to reverse organ involvement. In relation to the heart, there was a decrease in QRS duration and a decrease in left ventricular mass accompanied by an increase in cardiac function, resulting in an improvement in patients’ NYHA functional heart failure class. Treatment with agalsidase alfa therefore contributes to a prolonged life expectancy.

REFERENCES
 1. Desnick RJ, Ioannou YA, Eng CM. a-Galactosidase A deficiency: Fabry disease. In: Scriver CH, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. New York, NY: McGraw Hill; 2001:3733–3774.

2: Am J Cardiol. 1969 Jul;24(1):95-110. Related Articles, Links

The heart in Fabry's disease. A histochemical and electron microscopic study.

Ferrans VJ, Hibbs RG, Burda CD.

Publication Types:
  • Review


PMID: 4898362 [PubMed - indexed for MEDLINE]

 
3: J Am Coll Cardiol. 2002 Nov 6;40(9):1668-74. Related Articles, Links
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Cardiac manifestations of Anderson-Fabry disease in heterozygous females.

Kampmann C, Baehner F, Whybra C, Martin C, Wiethoff CM, Ries M, Gal A, Beck M.

Division of Cardiology, University Children's Hospital, Johannes Gutenberg University, Langenbeckstrasse 1, D-55131 Mainz, Germany. christoph.kampmann@uni-mainz.de

OBJECTIVES: We sought to define the prevalence of cardiac involvement in female patients with Anderson-Fabry disease (AFD). BACKGROUND: Anderson-Fabry disease is a rare inborn X-linked lysosomal storage disorder. Globotriaosylceramide (Gb(3)), the major substrate of the deficient alpha-galactosidase A enzyme, accumulates progressively in vulnerable cells, including the cardiovascular system. It has been believed that heterozygous females have less cardiac involvement than hemizygous males with AFD. METHODS: We performed two-dimensional echocardiographic examinations of female patients heterozygous for AFD. RESULTS: Since 1997, a total of 55 female patients (mean age, 39.6 years; range, 6.1 to 70.8 years) with proven AFD have been investigated prospectively at our hospital. Of these, 13 (23.6%) had normal left ventricular (LV) geometry and LV mass (LVM). Seven patients (12.7%) had concentric remodeling, 29 patients (52.7%) concentric LV hypertrophy (LVH), and 6 patients (10.9%) eccentric LVH (2 with subaortic pressure gradients). There was a strong correlation between age and the severity of LVH (r(2) = 0.905; p < 0.0001), and all patients older than 45 years had LVH. With increasing LVM, there was a significant age-independent decrease in systolic and diastolic LV function. Mild thickening of the aortic valve leaflets was present in 25.5% of patients, with the same percentage demonstrating mild thickening of the mitral valve leaflets. Mild mitral valve prolapse was documented in 10.9% of patients. CONCLUSIONS: Cardiac involvement, with LVH and structural valve abnormalities, is very common and worsens with age in females who are heterozygous for AFD, and they should therefore be considered candidates for enzyme replacement therapy.

PMID: 12427421 [PubMed - indexed for MEDLINE]
 
4: J Am Soc Nephrol. 2002 Jun;13 Suppl 2:S147-9. Related Articles, Links
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Cardiac involvement in Anderson-Fabry disease.

Kampmann C, Baehner F, Ries M, Beck M.

Division of Cardiology, University Children's Hospital, Johannes Guterberg Universitat, Langenbeckstrasse 1, D-55131 Mainz, Germany. christoph.kampmann@uni-mainz.de

Publication Types:
  • Review
  • Review, Tutorial


PMID: 12068028 [PubMed - indexed for MEDLINE]

 
5: Am Heart J. 2000 Jun;139(6):1101-8. Related Articles, Links
Click here to read 
New insights in cardiac structural changes in patients with Fabry's disease.

Linhart A, Palecek T, Bultas J, Ferguson JJ, Hrudova J, Karetova D, Zeman J, Ledvinova J, Poupetova H, Elleder M, Aschermann M.

Second Department of Internal Medicine, Charles University, Prague, Czech Republic. alinh@lf1.cuni.cz

BACKGROUND: Fabry's disease is an X-linked recessive genetic deficiency of the enzyme alpha-galactosidase leading to the pathologic intracellular deposition of neutral glycosphingolipids. Although cardiac involvement is frequent, there is controversy regarding the character of the associated left ventricular (LV) changes and the severity of valvular involvement. METHODS: Clinical evaluation (disease severity scaling, laboratory tests, and echocardiography) was performed in 13 hemizygous men (mean age 39 +/- 10 years) and 17 heterozygous women (mean age 35 +/- 19 years). RESULTS: LV hypertrophy (LVH) was frequent in subjects older than 30 years, more often in men (61%) than in women (18%, P <.001). The degree of LVH was independently associated with age and the logarithm of alpha-galactosidase activity (r(2) = 0.70, P <.001). The predominant LV geometric patterns were concentric LVH and remodeling, both present in 11 subjects (36%). Three patients had an asymmetric septal hypertrophy mimicking hypertrophic cardiomyopathy. In most subjects with LVH, the systolic function was normal and severe diastolic dysfunction (restrictive pattern) was not noted. Minor structural abnormalities of the mitral valve were found in 17 subjects (57%). The aortic valve was affected in 14 patients (47%). Valvular abnormalities were frequently accompanied by regurgitation of minor to mild degree. The presence of LVH or valvular changes was associated with increased disease severity. CONCLUSIONS: Echocardiographically detectable cardiac involvement is frequent with Fabry's disease, particularly in older subjects, and more pronounced in affected hemizygous men than in heterozygous women. LVH is frequently observed but usually not associated with significant systolic or restrictive diastolic dysfunction. Concentric LVH and remodeling appear to be the major manifestations of LV structural alteration. The frequently noted valvular abnormalities were not associated with a significant degree of regurgitation. Valvular and especially LV structural changes may serve as a useful marker of disease severity.

PMID: 10827394 [PubMed - indexed for MEDLINE]
 
6: J Inherit Metab Dis. 2001;24 Suppl 2:75-83; discussion 65. Related Articles, Links

Cardiac manifestations in Fabry disease.

Linhart A, Lubanda JC, Palecek T, Bultas J, Karetova D, Ledvinova J, Elleder M, Aschermann M.

2nd Department of Internal Medicine, 1st School of Medicine, Charles University, Prague, Czech Republic. alinh@lf1.cuni.cz

Fabry disease is an X-linked recessive genetic disorder of glycosphingolipid metabolism, due to deficiency of the lysosomal enzyme alpha-galactosidase A. The disease is characterized by the progressive intracellular lysosomal accumulation of neutral glycosphingolipids throughout the body, including the cardiovascular system. It has been reported that cardiac involvement could be the sole manifestation of the disease in some patients. Myocardial abnormalities are characterized mainly by left ventricular (LV) wall thickening without significant cavity dilatation, the most frequent abnormal structural pattern being concentric LV hypertrophy (LVH). In some patients the disease mimics a typical hypertrophic obstructive cardiomyopathy. According to our experience, systolic function is largely preserved in a large majority of affected individuals. In contrast, mild to moderate impairment of diastolic filling is a relatively common finding, representing probably the most important cause of dyspnoea in patients with Fabry disease. However, in a relatively large population of affected patients, severe diastolic dysfunction, typical of restrictive cardiomyopathy, was not found. Valvular structural abnormalities are frequent due to valvular infiltration. In several patients, hypertrophy of papillary muscles and/or systolic anterior motion of the mitral leaflets associated with LV outflow obstruction may aggravate the mitral valve dysfunction. We did not confirm the previously reported high prevalence of mitral valve prolapse. Valvular regurgitation seems to be relatively frequent but mostly non-significant. Electrocardiographic changes in Fabry disease are multiple and include atrioventricular (AV) conduction abnormalities (abbreviation of the P-R interval or AV blocks), signs of LVH and repolarization abnormalities. Our observations suggest that conduction defects and repolarization changes are present predominantly in subjects with LV structural abnormalities. Cardiac symptoms in patients with Fabry disease include shortness of breath on effort (related to LV diastolic dysfunction), vasospastic and/or exertional angina pectoris (due to LVH, endothelial dysfunction and/or fixed coronary artery stenosis) and syncope (related to AV blocks or LV outflow obstruction). The extent of cardiac involvement, in particular LV mass assessment, could represent an ideal surrogate endpoint for evaluating the efficacy of specific therapies.

Publication Types:
  • Review
  • Review, Tutorial


PMID: 11758683 [PubMed - indexed for MEDLINE]

 
7: N Engl J Med. 1995 Aug 3;333(5):288-93. Related Articles, Links
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An atypical variant of Fabry's disease in men with left ventricular hypertrophy.

Nakao S, Takenaka T, Maeda M, Kodama C, Tanaka A, Tahara M, Yoshida A, Kuriyama M, Hayashibe H, Sakuraba H, et al.

First Department of Internal Medicine, Faculty of Medicine, Kagoshima University, Japan.

BACKGROUND. Fabry's disease is considered very rare. Left ventricular hypertrophy is one of the common manifestations in adults with classic hemizygous disease. Recently, several cases of an atypical variant of hemizygous Fabry's disease, with manifestations limited to the heart, have been reported. Therefore, we assessed the incidence of hemizygosity for Fabry's disease among male patients with left ventricular hypertrophy. METHODS. We measured plasma alpha-galactosidase activity in 230 consecutive male patients with left ventricular hypertrophy. Clinical manifestations were assessed, endomyocardial biopsies were performed, and the patients were screened for mutations in the alpha-galactosidase gene. RESULTS. Seven of the 230 patients with left ventricular hypertrophy (3 percent) had low plasma alpha-galactosidase activity (0.4 to 1.2 nmol per hour per milliliter; 4 to 14 percent of the mean value in normal controls). These seven unrelated patients, ranging in age from 55 to 72 years, did not have angiokeratoma, acroparesthesias, hypohidrosis, or corneal opacities, which are typical manifestations of Fabry's disease. Endomyocardial biopsy was performed in five patients and revealed marked sarcoplasmic vacuolization in all five. Samples from four patients were examined by electron microscopy and revealed typical lysosomal inclusions with a concentric lamellar configuration in all four. Two patients had novel missense mutations in exon 1 (Ala20Pro) and exon 6 (Met296lle). The remaining five had no mutations in the coding region of the alpha-galactosidase gene, but the amounts of the alpha-galactosidase messenger RNA were markedly lower than normal. CONCLUSIONS. Seven unrelated patients with atypical variants of hemizygous Fabry's disease were found among 230 men with left ventricular hypertrophy (3 percent). Fabry's disease should be considered as a cause of unexplained left ventricular hypertrophy.

PMID: 7596372 [PubMed - indexed for MEDLINE]
 
8: Circulation. 2002 Mar 26;105(12):1407-11. Related Articles, Links

Comment in:

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Prevalence of Anderson-Fabry disease in male patients with late onset hypertrophic cardiomyopathy.

Sachdev B, Takenaka T, Teraguchi H, Tei C, Lee P, McKenna WJ, Elliott PM.

Department of Cardiological Sciences, St Georges Hospital Medical School, London, UK.

BACKGROUND: Although studies have suggested that "late-onset" hypertrophic cardiomyopathy (HCM) may be caused by sarcomeric protein gene mutations, the cause of HCM in the majority of patients is unknown. This study determined the prevalence of a potentially treatable cause of hypertrophy, Anderson-Fabry disease, in a HCM referral population. METHODS AND RESULTS: Plasma alpha-galactosidase A (alpha-Gal) was measured in 79 men with HCM who were diagnosed at > or =40 years of age (52.9+/-7.7 years; range, 40-71 years) and in 74 men who were diagnosed at <40 years (25.9+/-9.2 years; range, 8-39 years). Five patients (6.3%) with late-onset disease and 1 patient (1.4%) diagnosed at <40 years had low alpha-Gal activity. Of these 6 patients, 3 had angina, 4 were in New York Heart Association class 2, 5 had palpitations, and 2 had a history of syncope. Hypertrophy was concentric in 5 patients and asymmetric in 1 patient. One patient had left ventricular outflow tract obstruction. All patients with low alpha-Gal activity had alpha-Gal gene mutations. CONCLUSION: Anderson-Fabry disease should be considered in all cases of unexplained hypertrophy. Its recognition is important given the advent of specific replacement enzyme therapy.

PMID: 11914245 [PubMed - indexed for MEDLINE]

 
9: N Engl J Med. 2001 Jul 5;345(1):9-16. Related Articles, Links

Comment in:

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Safety and efficacy of recombinant human alpha-galactosidase A--replacement therapy in Fabry's disease.

Eng CM, Guffon N, Wilcox WR, Germain DP, Lee P, Waldek S, Caplan L, Linthorst GE, Desnick RJ; International Collaborative Fabry Disease Study Group.

Mount Sinai School of Medicine, New York, NY 10029, USA.

BACKGROUND: Fabry's disease, lysosomal alpha-galactosidase A deficiency, results from the progressive accumulation of globotriaosylceramide and related glycosphingolipids. Affected patients have microvascular disease of the kidneys, heart, and brain. METHODS: We evaluated the safety and effectiveness of recombinant alpha-galactosidase A in a multicenter, randomized, placebo-controlled, double-blind study of 58 patients who were treated every 2 weeks for 20 weeks. Thereafter, all patients received recombinant alpha-galactosidase A in an open-label extension study. The primary efficacy end point was the percentage of patients in whom renal microvascular endothelial deposits of globotriaosylceramide were cleared (reduced to normal or near-normal levels). We also evaluated the histologic clearance of microvascular endothelial deposits of globotriaosylceramide in the endomyocardium and skin, as well as changes in the level of pain and the quality of life. RESULTS: In the double-blind study, 20 of the 29 patients in the recombinant alpha-galactosidase A group (69 percent) had no microvascular endothelial deposits of globotriaosylceramide after 20 weeks, as compared with none of the 29 patients in the placebo group (P<0.001). Patients in the recombinant alpha-galactosidase A group also had decreased microvascular endothelial deposits of globotriaosylceramide in the skin (P<0.001) and heart (P<0.001). Plasma levels of globotriaosylceramide were directly correlated with clearance of the microvascular deposits. After six months of open-label therapy, all patients in the former placebo group and 98 percent of patients in the former recombinant alpha-galactosidase A group who had biopsies had clearance of microvascular endothelial deposits of globotriaosylceramide. The incidence of most treatment-related adverse events was similar in the two groups, with the exception of mild-to-moderate infusion reactions (i.e., rigors and fever), which were more common in the recombinant alpha-galactosidase A group. IgG seroconversion occurred in 88 percent of patients who received recombinant alpha-galactosidase A. CONCLUSIONS: Recombinant alpha-galactosidase A replacement therapy cleared microvascular endothelial deposits of globotriaosylceramide from the kidneys, heart, and skin in patients with Fabry's disease, reversing the pathogenesis of the chief clinical manifestations of this disease.

Publication Types:

  • Clinical Trial
  • Multicenter Study
  • Randomized Controlled Trial


PMID: 11439963 [PubMed - indexed for MEDLINE]

 
10: Am J Hum Genet. 2001 Mar;68(3):711-22. Epub 2001 Feb 01. Related Articles, Links
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A phase 1/2 clinical trial of enzyme replacement in fabry disease: pharmacokinetic, substrate clearance, and safety studies.

Eng CM, Banikazemi M, Gordon RE, Goldman M, Phelps R, Kim L, Gass A, Winston J, Dikman S, Fallon JT, Brodie S, Stacy CB, Mehta D, Parsons R, Norton K, O'Callaghan M, Desnick RJ.

Department of Human Genetics, Mount Sinai School of Medicine, Fifth Avenue and 100th Street, New York, NY, 10029, USA.

Fabry disease results from deficient alpha-galactosidase A (alpha-Gal A) activity and the pathologic accumulation of the globotriaosylceramide (GL-3) and related glycosphingolipids, primarily in vascular endothelial lysosomes. Treatment is currently palliative, and affected patients generally die in their 40s or 50s. Preclinical studies of recombinant human alpha-Gal A (r-halphaGalA) infusions in knockout mice demonstrated reduction of GL-3 in tissues and plasma, providing rationale for a phase 1/2 clinical trial. Here, we report a single-center, open-label, dose-ranging study of r-halphaGalA treatment in 15 patients, each of whom received five infusions at one of five dose regimens. Intravenously administered r-halphaGalA was cleared from the circulation in a dose-dependent manner, via both saturable and non-saturable pathways. Rapid and marked reductions in plasma and tissue GL-3 were observed biochemically, histologically, and/or ultrastructurally. Clearance of plasma GL-3 was dose-dependent. In patients with pre- and posttreatment biopsies, mean GL-3 content decreased 84% in liver (n=13), was markedly reduced in kidney in four of five patients, and after five doses was modestly lowered in the endomyocardium of four of seven patients. GL-3 deposits were cleared to near normal or were markedly reduced in the vascular endothelium of liver, skin, heart, and kidney, on the basis of light- and electron-microscopic evaluation. In addition, patients reported less pain, increased ability to sweat, and improved quality-of-life measures. Infusions were well tolerated; four patients experienced mild-to-moderate reactions, suggestive of hypersensitivity, that were managed conservatively. Of 15 patients, 8 (53%) developed IgG antibodies to r-halphaGalA; however, the antibodies were not neutralizing, as indicated by unchanged pharmacokinetic values for infusions 1 and 5. This study provides the basis for a phase 3 trial of enzyme-replacement therapy for Fabry disease.

Publication Types:
  • Clinical Trial
  • Clinical Trial, Phase I
  • Clinical Trial, Phase II


PMID: 11179018 [PubMed - indexed for MEDLINE]

 
11: JAMA. 2001 Jun 6;285(21):2743-9. Related Articles, Links

Comment in:

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Enzyme replacement therapy in Fabry disease: a randomized controlled trial.

Schiffmann R, Kopp JB, Austin HA 3rd, Sabnis S, Moore DF, Weibel T, Balow JE, Brady RO.

Developmental and Metabolic Neurology Branch, National Institute of Neurological Disorders and Stroke, Bldg 10, Room 3D03, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892-1260, USA. rs4e@nih.gov

CONTEXT: Fabry disease is a metabolic disorder without a specific treatment, caused by a deficiency of the lysosomal enzyme alpha-galactosidase A (alpha-gal A). Most patients experience debilitating neuropathic pain and premature mortality because of renal failure, cardiovascular disease, or cerebrovascular disease. OBJECTIVE: To evaluate the safety and efficacy of intravenous alpha-gal A for Fabry disease. DESIGN AND SETTING: Double-blind placebo-controlled trial conducted from December 1998 to August 1999 at the Clinical Research Center of the National Institutes of Health. PATIENTS: Twenty-six hemizygous male patients, aged 18 years or older, with Fabry disease that was confirmed by alpha-gal A assay. INTERVENTION: A dosage of 0.2 mg/kg of alpha-gal A, administered intravenously every other week (12 doses total). MAIN OUTCOME MEASURE: Effect of therapy on neuropathic pain while without neuropathic pain medications measured by question 3 of the Brief Pain Inventory (BPI). RESULTS: Mean (SE) BPI neuropathic pain severity score declined from 6.2 (0.46) to 4.3 (0.73) in patients treated with alpha-gal A vs no significant change in the placebo group (P =.02). Pain-related quality of life declined from 3.2 (0.55) to 2.1 (0.56) for patients receiving alpha-gal A vs 4.8 (0.59) to 4.2 (0.74) for placebo (P =.05). In the kidney, glomeruli with mesangial widening decreased by a mean of 12.5% for patients receiving alpha-gal vs a 16.5% increase for placebo (P =.01). Mean inulin clearance decreased by 6.2 mL/min for patients receiving alpha-gal A vs 19.5 mL/min for placebo (P =.19). Mean creatinine clearance increased by 2.1 mL/min (0.4 mL/s) for patients receiving alpha-gal A vs a decrease of 16.1 mL/min (0.3 mL/s) for placebo (P =.02). In patients treated with alpha-gal A, there was an approximately 50% reduction in plasma glycosphingolipid levels, a significant improvement in cardiac conduction, and a significant increase in body weight. CONCLUSION: Intravenous infusions of alpha-gal A are safe and have widespread therapeutic efficacy in Fabry disease.

Publication Types:

  • Clinical Trial
  • Randomized Controlled Trial


PMID: 11386930 [PubMed - indexed for MEDLINE]

12. Kampmann C, Ries M, Baehner F, Kim KS, Bajbouj M, Beck M. Influence of enzyme replacement therapy (ERT) on Anderson Fabry disease associated hypertrophic infiltrative cardiomyopathy (HIC) [abstract]. Eur J Pediatr. 2002;161:R5.
13. MacDermot KD, Brown A, Lones Y, Zuckerman J. Enzyme replacement therapy reverses the cardiomyopathy of Fabry disease: results of a randomized, double blind, placebo controlled trial. Eur
J Hum Genet. 2001;9:S92.

14: Circulation. 1978 Dec;58(6):1072-83. Related Articles, Links

Recommendations regarding quantitation in M-mode echocardiography: results of a survey of echocardiographic measurements.

Sahn DJ, DeMaria A, Kisslo J, Weyman A.

Four hundred M-mode echocardiographic surveys were distributed to determine interobserver variability in M-mode echocardiographic measurements. This was done with a view toward examining the need and determining the criteria for standardization of measurement. Each survey consisted of five M-mode echocardiograms with a calibration marker, measured by the survey participants anonymously. The echoes were judged of adequate quality for measurement of structures. Seventy-six of the 400 (19%) were returned, allowing comparison of interobserver variability as well as examination of the measurement criteria which were used. Mean measurements and percent uncertainty were derived for each structure for each criterion of measurement. For example, for the aorta, 33% of examiners measured the aorta as an outer/inner or leading edge dimension, and 20% measured it as an outer/outer dimension. The percent uncertainty for the measurement (1.97 SD divided by the mean) showed a mean of 13.8% for the 25 packets of five echoes measured using the former criteria and 24.2% using the latter criteria. For ventricular chamber and cavity measurements, almost one-half of the examiners used the peak of the QRS and one-half of the examiners used the onset of the QRS for determining end-diastole. Estimates of the percent of measurement uncertainty for the septum, posterior wall and left ventricular cavity dimension in this study were 10--25%. They were much higher (40--70%) for the right ventricular cavity and right ventricular anterior wall. The survey shows significant interobserver and interlaboratory variation in measurement when examining the same echoes and indicates a need for ongoing education, quality control and standardization of measurement criteria. Recommendations for new criteria for measurement of M-mode echocardiograms are offered.

PMID: 709763 [PubMed - indexed for MEDLINE]

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