Jan Bultas

Fabry disease: Guidelines for the evaluation and management of multi-organ system involvement

Fabry disease is an X-linked metabolic storage disorder due to the deficiency of lysosomal α-galactosidase A, and the subsequent accumulation of glycosphingolipids, primarily globotriaosylceramide, throughout the body. Males with classical Fabry disease develop early symptoms including pain and hypohidrosis by the second decade of life reflecting disease progression in the peripheral and autonomic nervous systems. An insidious cascade of disease processes ultimately results in severe renal, cardiac, and central nervous system complications in adulthood. The late complications are the main cause of late morbidity, as well as premature mortality. Disease presentation in female heterozygotes may be as severe as in males although women may also remain asymptomatic. The recent introduction of enzyme replacement therapy to address the underlying pathophysiology of Fabry disease has focused attention on the need for comprehensive, multidisciplinary evaluation and management of the multi-organ system involvement. In anticipation of evidence-based recommendations, an international panel of physicians with expertise in Fabry disease has proposed guidelines for the recognition, evaluation, and surveillance of disease-associated morbidities, as well as therapeutic strategies, including enzyme replacement and other adjunctive therapies, to optimize patient outcomes.

Cardiac manifestations in Fabry disease.

Fabry disease is an X-linked recessive genetic disorder of glycosphingolipid metabolism, due to deficiency of the lysosomal enzymeα-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 at rioventricular (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 inpatients 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.

Relationship between X-inactivation and clinical involvement in Fabry heterozygotes. Eleven novel mutations in the α-galactosidase A gene in the Czech and Slovak population

We have identified 21 different α-galactosidase A gene (GLA) mutations in 22 unrelated Czech and Slovak families with Fabry disease. Eleven of these mutations were novel (point mutations D93N, A135V, D155H, G171R, Q280K, G360S, Q330X, splicing errors c.194ins14, c.801ins36 and deletions c.674_732del59, g.3405_6021del2617). Genotyping of family members for family-specific mutations revealed 55 heterozygotes that manifested clinical symptoms of different severity. To examine the contribution of X-inactivation skewing to disease manifestation in Fabry heterozygotes, we have adopted the Mainz severity scoring scheme and compared the score values with the X-inactivation status in 39 carriers in an age-dependent manner. The age-score trendline of Fabry females who had a predominantly inactivated X-chromosome bearing a wild-type GLA allele (10 of 38 females) was markedly steeper than in the rest of the cohort. One female carrier with an inactivated mutated allele had a low score value when compared to the other heterozygotes of the same age. These data suggest that X-inactivation is indeed a major factor determining the severity of clinical involvement in Fabry heterozygotes. There was a statistically significant difference between the severity score values of heterozygotes with random and non-random X-chromosome inactivation at the 5% level of significance. Further studies will show if the degree of the wildtype allele inactivation will be useful as a predictive marker of severity of phenotype in Fabry heterozygotes. Although the correlation between X-inactivation skewing and presentation of the disease in Fabry heterozygotes has previously been suggested in the literature, this report is among the first attempts to examine this relationship systematically.

Onset and progression of the Anderson–Fabry disease related cardiomyopathy

BACKGROUND Cardiac involvement is responsible for substantial morbidity and mortality in Anderson-Fabry disease (AFD). We sought to document its onset and progression in a population of male and female AFD patients. METHODS We performed a cross sectional echocardiographic study of a cohort of 177 male and female AFD patients with subsequent longitudinal follow-up of 76 patients (38 males and 38 females; mean follow-up 4.5 years) who did not receive enzyme replacement therapy. RESULTS In this population, aged 3.3 to 70.8 years, a strong correlation between age and left ventricular mass indexed (LVMi, g/m(2.7)) was found in both males and females (P<0.0001 for both). At the initial examination 48.6% of the male patients and 36.4% of the female patients were classified as having left ventricular hypertrophy (LVH). The cumulative prevalence of LVH peaked at age 40 years in males and 60 years in females. In patients with longitudinal follow-up, LVMi increased by 4.07+/-1.03 g/m(2.7) per year in males and by 2.31+/-0.81 g/m(2.7) in females (P<0.01, Wilcoxon rank sum). In patients with LVH at baseline, the median progression rate was 5.52 g/m(2.7) per year in males and by 1.80 g/m(2.7) in females (P=0.12). CONCLUSION AFD is associated with high prevalence of LVH in both genders. However, the age of onset is delayed in females and progression rate slower.

Cardiac and Vascular Hypertrophy in Fabry Disease: Evidence for a New Mechanism Independent of Blood Pressure and Glycosphingolipid Deposition

Objectives—Fabry disease is an X-linked disorder resulting from α-galactosidase A deficiency. The cardiovascular findings include left ventricular hypertrophy (LVH) and increased intima-media thickness of the common carotid artery (CCA IMT). The current study examined the possible correlation between these parameters. To corroborate these clinical findings in vitro, plasma from Fabry patients was tested for possible proliferative effect on rat vascular smooth muscle cells (vascular smooth muscle cell [VSMC]) and mouse neonatal cardiomyocytes. Methods and Results—Thirty male and 38 female patients were enrolled. LVH was found in 60% of men and 39% of women. Increased CCA IMT was equally present in males and females. There was a strong positive correlation between LV mass and CCA IMT (r2=0.27; P<0.0001). VSMC and neonatal cardiomyocyte proliferative response in vitro correlated with CCA IMT (r2=0.39; P<0.0004) and LV mass index (r2=0.19; P=0.028), respectively. Conclusions—LVH and CCA IMT occur concomitantly in Fabry suggesting common pathogenesis. The underlying cause may be a circulating growth-promoting factor whose presence has been confirmed in vitro.

Placebo-controlled evaluation of three doses of a controlled-onset, extended-release formulation of verapamil in the treatment of stable angina pectoris

This double-blind, placebo-controlled, parallel-group, multicenter study was designed to evaluate the safety and efficacy of a new controlled-onset, extended-release formulation of verapamil hydrochloride called physiologic pattern release (PPR) verapamil. The study was conducted at 24 sites (13 United States, 5 Canada, 6 overseas; see Appendix). Following a 1- to 3-week single-blind placebo lead-in period, 278 patients with chronic stable angina pectoris (247 males, 31 females, mean age 60.8 years, range 32 to 78) were randomly assigned to 1 of 4 once-daily, fixed-dose treatment groups: verapamil 180, 360, or 540 mg, or placebo. PPR verapamil at all doses significantly increased (p < 0.05) time to moderate angina and symptom-limited exercise duration, and verapamil 360 mg significantly increased (p < 0.05) time to > or = 1 mm ST-segment depression, after 4 weeks of treatment when assessed 24 hour after the previous dose. Larger doses of verapamil were associated with proportionately greater improvements in exercise tolerance. Frequency of anginal attacks was also reduced by verapamil. The most frequently observed adverse events were dizziness, headache, constipation, and nausea. The incidence of constipation was high (20.9%) within the 540 mg treatment group. This verapamil formulation can be clinically titrated within a 180 to 540 mg dosing range, permitting effective once-daily administration for the treatment of chronic stable angina.

The pharmacology of multiple regimens of agalsidase alfa enzyme replacement therapy for Fabry disease

Purpose: This 10-week study was conducted to determine the pharmacokinetics of varying doses of agalsidase alfa and evaluate the effect of dose and dosing frequency on plasma Gb3 levels.Methods: Eighteen adult male Fabry patients, naive to enzyme replacement therapy, were randomized to one of five regimens: 0.1, 0.2, or 0.4 mg/kg weekly; 0.2 mg/kg every other week (the approved dose); or 0.4 mg/kg every other week. Intravenous infusion rate was 0.1 mg/kg per 20 minutes. Plasma Gb3 levels were assessed at baseline and periodically during the study.Results: The mean half-life was 56–76 minutes, and the mean volume of distribution at steady state was 17%–18% of body weight, with no significant association between dose and half-life, clearance, or volume of distribution at steady state. The area under the curve was linearly proportional to the dose from 0.1 to 0.4 mg/kg. Baseline average plasma Gb3 was 9.12 ± 2.61 nmol/mL and after 10 weeks of treatment was significantly reduced by about 50% in each group with no statistically significant differences between groups.Conclusions: Reduction of plasma Gb3 levels was independent of dose or dose frequency in the range tested. These observations, coupled with the clinical trial experience of both agalsidase alfa and agalsidase beta, indicate that the standard dose of agalsidase alfa is sufficient to maximally reduce plasma Gb3. However, because plasma Gb3 is not a validated surrogate of disease severity in Fabry disease, further clinical study will be required to determine the optimal dosing regimen for providing maximal clinical benefit.

Cardiac involvement in Fabry disease

Fabry disease is a rare X‐linked defect of the lysosomal enzyme α‐galactosidase A. The disease is characterized by progressive intracellular accumulation of neutral glycosphingolipids. The storage occurs within various tissues and cells, including cardiocytes, the cardiac conduction system, and valvular fibrocytes. Cardiac involvement may be the sole manifestation of the disease, particularly in individuals with residual enzyme activity. In general, hemizygous men are more seriously affected than heterozygous women. The main cardiac manifestations include myocardial hypertrophy, which, in some patients, mimics hypertrophic cardiomyopathy. Conduction system involvement leads to PR shortening or, in later stages, to AV blocks. Arrhythmias presenting with variable severity also appear to be common. Valvular involvement is frequently noted but generally mild and clinically non‐significant. Newly available enzyme replacement therapy has produced promising results in preventing further functional deterioration of affected organs and possibly also in reversing impaired function.

Increased carotid intima-media thickness in the absence of atherosclerotic plaques in an adult population with Fabry disease.

AIM Fabry disease is considered primarily as a progressive small vessel disease, with ischaemic degenerative lesions involving the kidneys, brain and heart. Macrovascular involvement in male patients includes an accelerated wall hypertrophy of the radial artery and a thickening of the intima-media of the common carotid artery. The aim of this study is to evaluate the prevalence and severity of carotid artery atherosclerosis in hemizygous and heterozygous patients with Fabry disease, compared with a matched control population. METHODS The common carotid artery intima-media thickness (IMT) of 53 patients with Fabry disease (24 men, 29 women) was measured by high-definition ultrasonography, and the presence or absence of atherosclerotic plaques reported. Results were compared with those of 120 age-matched healthy individuals (83 men, 37 women). RESULTS The common carotid artery IMT was increased to the same extent in male and female patients with Fabry disease (706+/-211 microm and 749+/-395 microm, respectively) compared with that of the control population (614+/-113 microm). In the Fabry population, IMT did not correlate with either systolic blood pressure or with renal function (plasma creatinine). In the control population, only systolic blood pressure was positively and significantly correlated with IMT. Atherosclerotic plaques in the common carotid artery were not observed in any patient with Fabry disease, whereas 34% of the control population had carotid artery plaques, as evidenced by focal non-homogeneous intima-media thickening greater than 1.2 mm. CONCLUSION This study presents evidence of a major increase in common carotid artery IMT, both in hemizygous and heterozygous patients with Fabry disease, in the absence of focal atherosclerotic plaques. These results suggest that the conduit arteries may be protected from atherosclerosis in Fabry disease.

Natural history of the respiratory involvement in Anderson–Fabry disease

SummaryBackground:Anderson–Fabry disease (AFD) is an X-linked disorder caused by deficient activity of enzyme α-galactosidase A, resulting in the accumulation of glycosphingolipids within lysosomes. Pulmonary involvement in AFD has previously been documented, but until now has been studied only in a few series of patients without any longitudinal follow-up. The aim of this study was to compare spirometric changes in AFD patients with a matched control population and to follow the subsequent progression of the disease.Materials and methods:Fifty individuals (27 women, 23 men, mean age 40±14 years) with AFD from 14 families underwent a static spirometric examination under standard conditions. A set of indices was compared with that of the control population. Out of this cohort, 39 individuals not receiving enzyme replacement therapy were longitudinally evaluated (median follow-up time 24 months).Results:A clinically significant reduction in spirometric parameters, corresponding to mild to severe airway obstruction, was observed in 26% of women and 61% of men. During the serial follow-up, a significant (p<0.05) age-dependent reduction of predicted %FVC and %FEV1 values was observed in male patients, while the influence of age was not seen in female patients. The %FEF25–75 values decreased by similar degrees in men and women and in older and younger patients, indicating that progressive bronchial disease affects the small airways first.Conclusions:We have demonstrated a clinically relevant age- and sex-dependent progressive pulmonary involvement in AFD patients. The effects of enzyme replacement therapy on pulmonary involvement remain to be demonstrated.