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Natural course of Fabry disease: changing pattern of
causes of death in FOS – the Fabry Outcome Survey
Atul Mehta, Joe T R Clarke, Roberto Giugliani, Perry Elliott, Ales Linhart,
Michael Beck, Gere Sunder-Plassman
To cite this version:
Atul Mehta, Joe T R Clarke, Roberto Giugliani, Perry Elliott, Ales Linhart, et al.. Natural course
of Fabry disease: changing pattern of causes of death in FOS – the Fabry Outcome Survey. Journal
of Medical Genetics, BMJ Publishing Group, 2009, 46 (8), pp.548. �10.1136/jmg.2008.065904�. �hal-
00552689�
1
Natural course of Fabry disease: changing pattern of causes of death in
FOS – the Fabry Outcome Survey
Atul Mehta
1
, Joe T. R. Clarke
2
, Roberto Giugliani
3
, Perry Elliott
1
, Aleš Linhart
4
,
Michael Beck
5
and Gere Sunder-Plassmann
6
on behalf of the FOS Investigators
1
University College London, London, UK;
2
Hospital for Sick Children, Toronto,
Canada
and Centre Hospitalier Universitaire, Sherbrooke, Canada;
3
Medical Genetics
Service/HCPA and Department of Genetics/UFRGS, Porto Alegre, RS, Brazil;
4
Charles University, Prague, Czech Republic;
5
University of Mainz, Mainz, Germany;
6
Division of Nephrology and Dialysis, Department of Medicine III, Medical
University Vienna, Vienna, Austria.
Running title: Natural course of Fabry disease
Key words: Agalsidase alfa, enzyme replacement therapy, Fabry disease, outcomes
database, pharmacoepidemiological survey.
Abstract word count: 239 words (max 250)
Main text word count: 2896 words (max 3000)
Tables/illustrations: 5 (max 6)
References: 30 (max 30)
Address for correspondence: Dr Atul Mehta,
Department of Haematology,
Royal Free Hospital,
Pond Street,
London
NW3 2QG,
UK.
Tel.: +44 (0) 207 830 2814
Fax: +44 (0) 207 830 2313
E-mail: atul.mehta@royalfree.nhs.uk
2
ABSTRACT
Background
Fabry disease is a rare X-linked lysosomal storage disorder characterized by severe
multisystemic involvement that leads to major organ failure and premature death in
affected men and women. Over the past 7 years, the Fabry Outcome Survey (FOS)
has collected data on the natural history of Fabry disease and the long-term efficacy
and safety of enzyme replacement therapy. This paper provides an update since the
first analysis of FOS data.
Design
Baseline data on clinical manifestations and causes of death in a cohort of 1453
patients (699 males) from 19 countries worldwide were analysed. Causes of death of
affected relatives were analysed separately.
Results
The most frequently reported signs and symptoms of Fabry disease were neurological.
Cardiac, ocular, gastrointestinal, dermatological, auditory and renal manifestations
were also common. The principal causes of death among 181 affected relatives of
patients in FOS (the majority of whom had died before 2001) were renal failure in
males (42%) and cerebrovascular disease in females (25%). In contrast, among the 42
patients enrolled in FOS whose deaths were reported between 2001 and 2007, cardiac
disease was the main cause of death in both males (34%) and females (57%).
Conclusion
3
These data suggest that the importance of renal disease as a cause of death in patients
with Fabry disease is decreasing, while the importance of cardiac disease is
increasing. This pattern likely reflects improvements in the management of renal
disease in patients with Fabry disease.
4
INTRODUCTION
Fabry disease is a rare X-linked lysosomal storage disorder due to deficient activity of
the enzyme
α
-galactosidase A. It is characterized by severe multisystemic
involvement that ultimately leads to major organ failure and premature death in
affected men and women [1]. The condition has conventionally been considered to be
rare, affecting only 1 in 40,000–117,000 live male births [1, 2]. However, a recent
screening study suggested a much higher incidence of 1 in 3100–4600 individuals [3].
α
-Galactosidase A deficiency is caused by a number of mutations affecting the GLA
gene, many of which are private (i.e. occurring in only single or small numbers of
families) [4]. As a result of
α
-galactosidase A deficiency, there is progressive
accumulation of undegraded glycosphingolipids, predominantly
globotriaosylceramide (Gb
3
), within cell lysosomes throughout the body. Common
clinical features of Fabry disease include acroparaesthesia and pain crises,
gastrointestinal symptoms, angiokeratomas and corneal dystrophy.
Despite the fact that Fabry disease follows an X-linked pattern of inheritance, it is
now widely accepted that female heterozygotes can be severely affected, although
progression of the disease to organ failure generally occurs later in life and symptom
severity tends to be milder and more variable than in males [5–7]. Renal failure has
been found to be a frequent cause of death in several studies, particularly in males [5,
8, 9]. In females, data on small patient groups suggest that cardiac disease and
cerebrovascular disease are the most frequent causes of death [5, 9, 10, 11]. Death
occurs on average 15 years earlier in females and 20 years earlier in males compared
with the general population [6, 10, 12].
