Fabry Disease, an Under-Recognized Multisystemic Disorder: Expert Recommendations for Diagnosis, Management, and Enzyme Replacement Therapy

Fabry disease is an X-linked recessive lysosomal storage disorder that is caused by the deficient activity of -galactosidase A (-Gal A, also termed ceramide trihexosidase) (1, 2) and the resultant accumulation of globotriaosylceramide (also termed ceramide trihexoside) and related glycosphingolipids (3-5). In patients with the classic phenotype, levels of -Gal A activity are very low or undetectable. Patients with detectable -Gal A activity have a milder, variant phenotype (6-8). In classically affected males, the progressive glycosphingolipid accumulation, particularly in the vascular endothelium (Figure 1), leads to renal, cardiac, and cerebrovascular manifestations and early death. The disease is panethnic, and estimates of incidence range from about 1 in 40 000 to 60 000 males (5, 9). Fabry disease predominantly affects males, although carrier (heterozygous) females also can be affected to a mild or severe degree because of random X-chromosomal inactivation (5). Figure 1. Distinctive laboratory findings in Fabry disease. A B In the absence of a family member who has already received a diagnosis of the disorder, many cases are not diagnosed until adulthood (average age, 29 years) (9, 10), when the pathology of the disorder may already be advanced. Although clinical onset occurs in childhood, disease presentation may be subtle, and its signs and symptoms are often discounted as malingering or are mistakenly attributed to other disorders, such as rheumatic fever, erythromelalgia, neurosis, the Raynaud syndrome, multiple sclerosis, chronic intermittent demyelinating polyneuropathy, lupus, acute appendicitis, growing pains, or petechiae (5, 11). Fabry disease was first identified a century ago, but until now, no disease-specific treatment has been available. Patients have been managed with supportive, nonspecific treatment for pain management, cardiac and cerebrovascular complications, and end-stage renal disease. These interventions may prolong life, but their utility is limited because they do not address the underlying cause of the disease, that is, the lack of -Gal A and the progressive accumulation of globotriaosylceramide. Recently, enzyme replacement with human -Gal A has been shown to safely reverse the pathogenesis of the major clinical manifestations, to decrease pain, and to stabilize renal function in patients with Fabry disease (12, 13). The European Agency for the Evaluation of Medicinal Products has approved the treatment, and the U.S. Food and Drug Administration is currently reviewing it. Thus, recommendations for the diagnosis and treatment of Fabry disease are timely. Formation of Expert Panel and Basis of Recommendations In June and July of 2001, two groups of investigators published randomized, placebo-controlled trials that demonstrated that enzyme replacement therapy in Fabry disease can reverse the major pathologic consequences and improve outcomes (12, 13). With a disease-specific therapy finally available, the need for prompt and accurate diagnosis of this devastating, progressive disease became paramount so that patients could be identified and treated before incurring irreversible organ damage. Recognizing the need for initial guidelines for diagnosis, management, and the use of enzyme replacement therapy, Dr. Robert Desnick and Dr. Roscoe Brady (senior authors of the enzyme replacement trials) assembled an international panel of experts with extensive clinical experience and diverse subspecialty expertise in Fabry disease and lysosomal storage disorders. Panelists met face-to-face to identify and discuss salient issues. An independent coordinator conducted numerous global and specific searches of the MEDLINE database (19912001), including a global search of the recent literature on Fabry disease. The coordinator then interviewed each panelist in detail and, with the first author, prepared a draft statement. In a second face-to-face session, the draft was reviewed, revised, and finalized by the panel. A teleconference was convened to revise the manuscript after journal review. Support for the expert panel process was obtained from the Genzyme Corporation (Cambridge, Massachusetts), which had no formative role in the literature review, the formulation of recommendations, or the drafting and revising of the manuscript. As would be expected for a rare, under-recognized disease, the literature on Fabry disease mostly consists of single or small case studies and reviews in addition to book chapters written by Fabry experts. The few larger studies focus on disease manifestations and mechanisms of disease rather than the effectiveness of interventions or disease management. The literature on enzyme replacement therapy is limited to the clinical trials published in the last 2 years. Thus, clinical experience and expertise played an important role in the formulation of these recommendations. Disease Pathophysiology and Clinical Manifestations The major debilitating manifestations of Fabry disease result from the progressive accumulation of globotriaosylceramide in the vascular endothelium (Figure 1), leading to ischemia and infarction, especially in the kidney, heart, and brain. The ischemia and infarction of small vessels are primarily due to vascular occlusion (5); however, evidence for a prothrombotic state has recently been published (14). In addition, early and substantial deposition of globotriaosylceramide occurs in podocytes, leading to proteinuria and, with age, in cardiomyocytes, causing cardiac hypertrophy and conduction abnormalities (Figure 1). Patients are generally divided into two major groups on the basis of the absence or presence of residual -Gal A activity: classic disease and milder, later-onset, atypical variants (5). Presentation and clinical course can vary within these phenotypes, and an intermediate phenotype has also been described (15-17). The Classic Phenotype Males with classic disease have no or very low -Gal A activity, resulting in severe renal, cardiac, and cerebrovascular disease manifestations. Before treatment of uremia became available, the average lifespan of affected males was about 40 years (18). With the advent of renal dialysis or transplantation, the median survival was about 50 years (19). Clinical manifestations (Figures 1 and 2), which usually begin in childhood or adolescence, include intermittent pain in the extremities (acroparesthesias); episodic Fabry crises of acute pain lasting hours to days; characteristic skin lesions (angiokeratomas); a corneal opacity that does not affect vision; hypohidrosis; heat, cold, and exercise intolerance; mild proteinuria; and gastrointestinal problems. By adulthood, the renal involvement inevitably results in end-stage renal disease, which requires dialysis or transplantation (20, 21). Cardiac manifestations include left ventricular hypertrophy, valvular disease (especially mitral insufficiency), ascending aortic dilatation, coronary artery disease, and conduction abnormalities (Figure 1), leading to congestive heart failure, arrhythmias, and myocardial infarction (5, 22-24). Cerebrovascular manifestations include early stroke, transient ischemic attacks, white matter lesions, hemiparesis, vertigo or dizziness, and complications of vascular disease (such as diplopia, dysarthria, nystagmus, tinnitus, hemiataxia, memory loss, and hearing loss) (5, 25). Figure 2. Distinctive clinical features of Fabry disease. A B C Clinical manifestations in carrier females range from asymptomatic to full-blown disease as severe as that in affected males (5, 26-28). Although many carriers will be relatively asymptomatic and have a normal lifespan, carriers may experience symptoms in childhood and adolescence (such as pain and proteinuria) and adulthood (such as cardiac or, more rarely, renal manifestations). In late adulthood, some carriers develop left ventricular hypertrophy and substantial cardiomyopathy. Data on carriers are limited. A recent study of obligate carrier females found significant disease manifestations in 20 of 60 women, including 17 of whom who had experienced transient ischemic attacks or cerebrovascular accidents (28). Atypical Variants Atypical male variants have a milder, later-onset phenotype (5-7, 17, 29). Because of low residual -Gal A levels, these patients do not have the early major clinical manifestations of classic Fabry disease. For example, cardiac variants present with cardiomegaly and mild proteinuria usually after 40 years of age, when patients with classic Fabry disease would be severely affected or would have died (6, 7, 29). Two recent studies have suggested that the cardiac variant of Fabry disease may be an important cause of idiopathic left ventricular hypertrophy (7) or late-onset hypertrophic cardiomyopathy (30). Tissue biopsies or autopsy studies of cardiac variants reveal globotriaosylceramide accumulation in the myocardium and not in the vascular endothelium throughout the body (5, 6, 29). These findings suggest that even low levels of -Gal A can prevent globotriaosylceramide accumulation in the microvasculature and that this lack of accumulation is associated with the absence or attenuation of disease manifestations. Thus, reversal of the underlying vascular endothelial pathology by enzyme replacement therapy will probably be clinically therapeutic in patients with classic Fabry disease. Enzymatic and Molecular Diagnosis In affected males with the classic or variant phenotype, the disease is readily diagnosed by determining the -Gal A activity in plasma or peripheral leukocytes. In contrast, female carriers can have normal to very low -Gal A activity; therefore, their specific family mutation in the -Gal A gene must be demonstrated. Most kindreds have family-specific or private mutations; to date, more than 300 mutations have been identified, of which most are missense (amino acid substitutions) or nonsense (causing premature truncation of the amino acid sequence) mutations. Spli