Females with Fabry disease frequently have major organ involvement: Lessons from the Fabry Registry
Introduction
Fabry disease (FD, OMIM #301500) is an X-linked inborn error of metabolism characterized by decreased or absent activity of the lysosomal hydrolase α-galactosidase A (αGAL, E.C. 3.2.1.22), due to mutations in the gene that encodes the αGAL protein (GLA) [1], [2]. Patients with this disorder are unable to effectively degrade membrane glycosphingolipids containing a terminal α-glycosidic galactose, especially globotriaosylceramide (GL-3), which consequently accumulates in various tissues. Deposition of GL-3 increases the risk for characteristic acroparesthesias of the hands and feet, angiokeratoma, strokes, hearing loss, myocardial microvascular ischemia and infarctions, arrhythmias, hypertrophic cardiomyopathy, valvular insufficiency, gastrointestinal symptoms, hypohidrosis, temperature and exercise intolerance, dysregulation of vascular tone and autonomic functions, obstructive lung disease, and chronic kidney disease leading to kidney failure [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14].
FD causes significant morbidity and mortality in affected males. Acroparesthesias, fatigue, and gastrointestinal symptoms reduce emotional well being and productivity. Among males, proteinuria and progressive kidney disease are evident in the second to fifth decades of life [7]. Death occurs typically in the late fifth to early sixth decade from kidney failure, strokes and cardiac events [15].
As recently as 2001, most FD females were thought to be asymptomatic throughout a normal life span or to develop only minor manifestations of the disease [2]. However, several studies have since reported that heterozygous females do develop substantial symptoms of FD and are at risk of premature death [16], [17], [18], [19], [20].
Enzyme replacement therapy (ERT) with recombinant human α-galactosidase A (r-hαGAL) has been developed to treat FD [21], [22]. Multiple studies have demonstrated that biweekly intravenous infusions of r-hαGAL effectively reduce plasma and tissue GL-3 accumulation [22], [23], improve anhidrosis [24], peripheral nerve function [25], pulmonary gas exchange [26], gastrointestinal symptoms [27], acroparesthesias [21], and can stabilize kidney function [28], [29], [30]. Although relatively few women were included in these trials, ERT also appears to benefit females [31].
With an estimated incidence of 1:40,000 in males [2], [32], FD is considered to be an “ultra-orphan” disease. However, screening studies have shown an incidence of 0.1–1% among male dialysis patients [33], [34], [35], [36], 3–5% of “idiopathic” hypertrophic cardiomyopathy cases [37], [38], [39], and 4.9% of male (2.4% of female) patients with cryptogenic strokes [40]. Late onset forms with significant residual enzyme activity may be particularly common, up to 1:4600 in one study [41].
Like other rare diseases, it has been difficult to develop a clear understanding of the natural progression of FD due to the paucity of longitudinal clinical information, particularly on heterozygous females. The Fabry Outcomes Survey (FOS), a European registry of Fabry patients, reported symptoms and manifestations in more than 300 females [19]. The Fabry Registry (http://www.fabryregistry.com), created in 2001, has now collected detailed data on 1077 female patients with FD. We analyzed the data in the Fabry Registry to compare the age at symptom onset and at diagnosis, and the incidence of clinical events among male and female patients (i.e. prior to treatment with ERT).
Section snippets
Data analysis and statistics
The Fabry Registry is an ongoing, observational database that tracks the natural history and outcomes of patients with FD. All FD patients are eligible to enroll in the Fabry Registry, regardless of symptoms or whether or not they are receiving ERT. Patient and physician participation is voluntary. All patients provided informed consent and may decline to participate or withdraw consent at any time. Treating physicians determine the actual frequency of assessments according to a patient’s
Patients demographics and onset of signs and symptoms
As of January 5, 2007, a total of 2236 patients were enrolled in the Fabry Registry, predominantly from North America and Europe. Among these, 1077 patients (48.2%) were female; most patients were white and had a positive family history of FD. Demographic data for male and female patients enrolled in the Fabry Registry are summarized in Table 1. Since it is more likely that symptomatic females would be preferentially enrolled in the Registry, participating physicians were specifically asked to
Discussion
The Fabry Registry provides information on a large, international cohort of patients with FD. In this study, we found that female ‘carriers’ frequently suffer from pain, gastrointestinal symptoms, and major organ system involvement as well as a substantially reduced QoL. Although the size and ascertainment of previously reported studies are different, the results of this natural history study are remarkably similar to other studies [16], [17], [18], [19], [20].
Disclosure
The authors (WRW, JPO, RJH, AO, MB, UF-R, KS, SW, GMP, PL, CME, LM, FB, CW, DGW, DPG) are members of the Board of Advisors of the Fabry Registry, and are compensated for these services by Genzyme Corporation. They are also paid consultants for Genzyme on matters relating to Fabry disease and have received speaking fees and research grants from Genzyme related to Fabry disease. RML is an employee of the Genzyme Corporation.
Acknowledgments
The authors gratefully acknowledge the participation of 191 physicians in 37 countries around the world who contribute data to the Registry, their clinic staff, and especially the patients. We thank Dana Beitner-Johnson for assistance with the technical writing. WRW is supported by a Winnick Family Clinical Development Scholar Award, AO by Programa de Intensificación de la Actividad Investigadora (ISCIII/Agencia “Laín Entralgo” Comunidad de Madrid).
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