Stroke in Fabry Disease Frequently Occurs Before Diagnosis
and in the Absence of Other Clinical Events
Natural History Data From the Fabry Registry
Katherine Sims, MD; Juan Politei, MD; Maryam Banikazemi, MD; Philip Lee, FRCP
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Background and Purpose—Stroke is a common and serious clinical manifestation of Fabry disease, an X-linked lysosomal
storage disorder caused by deficiency of ␣-galactosidase A activity. This study was undertaken to better understand the
natural history of cerebrovascular manifestations of Fabry disease.
Methods—Data from 2446 patients in the Fabry Registry were analyzed to identify clinical characteristics of patients
experiencing stroke during the natural history period (ie, before enzyme replacement therapy).
Results—A total of 138 patients (86 of 1243 males [6.9%] and 52 of 1203 females [4.3%]) experienced strokes. Median age
at first stroke was 39.0 years in males and 45.7 years in females. Most patients (70.9% of males and 76.9% of females) had
not experienced renal or cardiac events before their first stroke. Fifty percent of males and 38.3% of females experienced
their first stroke before being diagnosed with Fabry disease. Thirty patients (21 males and 9 females) had strokes at age
⬍30 years. Most patients (86.8%) had ischemic strokes, but 16.9% of males and 6.9% of females had hemorrhagic
strokes, among those for whom stroke type was reported. At the most recently available follow-up examination after
their first stroke, 60% of males and 25.5% of females exhibited stage 3 to 5 chronic kidney disease and 66.1% of males
and 59.5% of females had left ventricular hypertrophy.
Conclusions—All patients with Fabry disease, regardless of age or gender, should be monitored for possible cerebrovascular
complications, as stroke can occur in the absence of other key signs of the disease. (Stroke. 2009;40:788-794.)
Key Words: Fabry disease 䡲 cerebrovascular accident 䡲 stroke 䡲 registries
F
quently exhibit white matter lesions, which can be detected
by conventional neuroimaging methods (reviewed in10). Recently, magnetic resonance diffusion tensor imaging has been
used to quantify these abnormalities.11 However, the risk of
clinical cerebrovascular manifestations, such as stroke and
TIAs, is difficult to predict.
Several studies have estimated the incidence of stroke in
various small cohorts of patients with Fabry disease. Vedder
et al12 reported that 12 of 25 males (48%) and 13 of 41
females (32%) had experienced a cerebrovascular accident or
lacunar stroke, at a median age of 46 and 52 years, respectively. Gupta et al13 reported that 4 of 54 female Fabry
patients (7%) had experienced strokes, at a median age of 51
years. Mehta et al14 reported that 24 of 216 males (11%) and
27 of 172 females (16%) had experienced either a TIA or a
stroke. Grewal reviewed various types of imaging data and
reported that 8 of 33 Fabry patients (24%) had experienced
strokes at a median age of 26.5 years.15 Because of the
various ways these and other studies defined cerebrovascular
complications, the stroke incidence and median age at first
stroke cannot be readily compared across studies.
abry disease is an X-linked lysosomal storage disorder,
characterized by decreased or absent activity of lysosomal ␣-galactosidase A.1 As a result, globotriaosylceramide
(GL-3) and other glycosphingolipids progressively accumulate within many cell types, including the vascular endothelium.1 Early symptoms of Fabry disease (typically beginning
during childhood) include neuropathic pain, gastrointestinal
dysfunction, and hypohidrosis.2,3 Later, vital organ function
progressively declines, putting older patients at risk of developing renal failure, cardiovascular dysfunction, and stroke.2,3
Enzyme replacement therapy (ERT) with recombinant
human ␣-galactosidase A effectively reduces plasma and
tissue GL-3accumulation4 – 6 and attenuates many signs and
symptoms of Fabry disease.4 –9 With close monitoring, the
renal and cardiac manifestations of Fabry disease can be
detected and appropriate treatment initiated before the onset
of end organ failure.8,9
Although patients with Fabry disease are known to experience transient ischemic attacks (TIAs) and strokes at an
early age,2,3 there are few quantitative markers of disease
burden in the central nervous system. Fabry patients fre-
Received May 30, 2008; final revision received July 23, 2008; accepted August 21, 2008.
From the Center for Human Genetic Research and Neurology Department (K.S.), Massachusetts General Hospital and Harvard Medical School, Boston, Mass;
Neurology Service (J.P.), Juan Fernandez Hospital, Quilmes, Buenos Aires, Argentina; Departments of Neurology and Pediatrics (M.B.), Columbia University
College of Physicians and Surgeons, New York; Charles Dent Metabolic Unit (P.L.), National Hospital for Neurology & Neurosurgery, Queen Square, London UK.
Correspondence to Katherine Sims, MD, Center for Human Genetic Research, Massachusetts General Hospital, Richard B. Simches Research Center,
CPZN-5300, 185 Cambridge Street, Boston, MA 02114. E-mail [email protected]
© 2009 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org
DOI: 10.1161/STROKEAHA.108.526293
788
Sims et al
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A screening study of 721 young patients (age 18 to 55) who
had strokes of unknown etiology reported that 4.9% of males
and 2.4% of females had Fabry disease.16 Based on these
findings, it was estimated that 1% to 2% of all stroke patients
within this age range could have Fabry disease.16 Others have
suggested that this percentage may be higher17 or lower.18
The mechanisms underlying stroke pathogenesis in Fabry
disease have not been clearly delineated. Progressive accumulation of GL-3 within the endothelium of intracranial
blood vessels is thought to play a primary role in the
vasculopathy and risk of ischemic stroke.19 However, secondary factors, including abnormalities in cerebral blood flow
velocity, a prothrombotic state, and increased production of
reactive oxygen species have also been identified as contributing to the development of stroke in Fabry disease.20 –23
A better understanding of the natural history of cerebrovascular manifestations of Fabry disease may provide valuable information about which patients may be at greatest risk
for stroke. Such information can also raise awareness of
Fabry disease among the broader medical community and
highlight the importance of improved monitoring and management options.
Materials and Methods
Data Analysis and Statistics
The Fabry Registry is an ongoing, observational database that
compiles clinical and laboratory data on patients with Fabry disease.
The Fabry Registry began enrolling patients and collecting data in
April 2001. As of October 5, 2007, the Fabry Registry included 2446
patients with known ERT status. All patients with Fabry disease are
eligible for enrollment, regardless of age, gender, symptoms, or
whether they are receiving ERT. Patient and physician participation
is voluntary. All patients provide informed consent through local
Institutional Review Boards/Ethics Committees and may decline to
participate or withdraw consent at any time. Treating physicians
determine the actual frequency of assessments according to patients’
individualized needs. A schedule of recommended clinical assessments is available at http://www.fabryregistry.com. Given the voluntary nature of reporting data, patients’ ages at clinical assessments
and time intervals between assessments are variable.
Data were analyzed using SAS statistical software version 8 (SAS
Institute Inc) and summarized using descriptive statistics. A Wilcoxon signed rank test was used to compare median age at symptom
onset and median age at diagnosis among patients who had strokes
versus patients who did not.
Data from untreated Fabry Registry patients as well as data
obtained before initiation of treatment from ERT-treated patients
were included in these analyses. The period of data extended from
date of birth until last available follow-up record for each patient.
Patients for whom ERT status was unknown (1.8% of all patients
enrolled) were excluded from these analyses, to ensure all stroke
events occurred before initiation of ERT.
Definition of Stroke and Cardiovascular and
Renal Events
Strokes were defined as either ischemic or hemorrhagic cerebrovascular accidents. At the time of patient enrollment, participating
physicians were asked to indicate whether patients had a previous
medical history of stroke and to report any subsequent strokes to the
Fabry Registry. If patients experienced a stroke while participating in
the Fabry Registry, physicians were asked to provide clinical details,
including the type of stroke, the location of the stroke, what type of
brain imaging was performed and any findings from brain imaging.
Cardiovascular events were defined as myocardial infarction, significant cardiac procedures (eg, pacemaker placement, bypass, stent
Stroke in Fabry Disease
789
placement, valve replacement, transplantation), arrhythmia, angina
pectoris, or congestive heart failure. Renal events were defined as
renal dialysis or renal transplantation.
Analysis of Risk Factors
Medical history data in the Fabry Registry were analyzed to
determine how many patients ever reported experiencing a TIA,
cardiac arrhythmia, hypertension, diabetes, migraine, headache/
migraine, abnormal cholesterol levels, or a history of smoking. These
risk factors may have occurred either before or after a patient’s first
stroke, up until October 5, 2007.
Results
As of October 5, 2007, 138 of 2446 Fabry Registry patients
had experienced stroke during the natural history period,
including 86 of 1243 males (6.9%) and 52 of 1203 females
(4.3%). Most patients (115 of 138, 83.3%) had been enrolled
in the Fabry Registry for ⱖ2 years. The mean follow-up
period among this cohort (from birth to last follow-up visit)
was 40⫾11.9 years among males (n⫽86) and 46⫾14.8 years
among females (n⫽52). Demographic data are summarized in
Table 1.
The median age at first stroke was 39.0 years in males and
45.7 years in females (Table 1). Interestingly, patients who
had strokes reported the onset of Fabry symptoms at a later
age than those who did not, among both genders. Males who
had a stroke experienced their first symptoms at a median age
of 11.1 years, versus 9.6 years among males who did not have
strokes (P⬍0.02). Females who had strokes experienced first
symptoms at a median age of 24.0 years, versus 14.6 years for
females who did not have strokes (P⬍0.06). Similarly, Fabry
Registry patients with strokes were diagnosed later than
patients who did not (Table 1).
As shown in Figure 1, most patients experienced their first
stroke between 20 and 50 years. Males generally experienced
their first stroke at an earlier age than females. The small
percentage of males experiencing their first stroke at ⱖ60
years (2 of 86 patients, or 2.3%) reflects the small number of
surviving males in this age category. Only 32 of 1243 males
in the Fabry Registry (2.6%) were ⱖ60 years old, compared
to 133 of 1203 females (11.1%). Thirty of 138 stroke patients
(21.7%) had strokes at ⬍30 years, including 2 patients who
had strokes during their teen years (a 13.8 year-old male and
a 19.8 year-old female). Among those who had strokes at
⬍30 years, the median age was 25.8 years in males (n⫽21)
and 24.1 years in females (n⫽9).
The incidence rates of first strokes in all 2446 Fabry
Registry patients in the natural history population and in the
general US population are shown in Figure 2. Within each
age category, Fabry patients exhibited a markedly higher
incidence of stroke than the general US population. Among
Fabry males ⬎45 years, stroke incidence increased dramatically with each passing decade. The mean age at first stroke
among Fabry patients (39.8 years for males and 45.7 years for
females, Table 1) was also considerably younger than the
mean age at first stroke among the general population: 76
years in males and 81 years in females, for strokes occurring
between 1990 and 2004.24
The majority of first strokes experienced by Fabry Registry
patients were described as ischemic. Of the 121 patients for
790
Table 1.
Stroke
March 2009
Summary of Demographics of Fabry Registry Patients by Stroke Category and by Gender
Characteristics
Males With Strokes Males Without Strokes Females With Strokes Females Without Strokes All Patients With Strokes
(n⫽86)
(n⫽1157)
(n⫽52)
(n⫽1151)
(n⫽138)
Ethnicity, n (%)
White
80 (93.0)
867 (74.9)
46 (88.5)
892 (77.5)
126 (91.3)
Black
1 (1.2)
25 (2.2)
2 (3.8)
19 (1.7)
3 (2.2)
Hispanic
2 (2.3)
82 (7.1)
2 (3.8)
76 (6.6)
4 (2.9)
Asian
0
42 (3.6)
0
12 (1.0)
0
Other
2 (2.3)
42 (3.6)
1 (1.9)
28 (2.4)
3 (2.2)
Not Specified
1 (1.2)
99 (8.6)
1 (1.9)
124 (10.8)
2 (1.4)
Age at First Stroke (years)
Mean (SD)
39.8 (11.92)
45.7 (14.75)
42.0 (13.32)
Median (range)
39.0 (13.8, 80.1)
45.7 (19.8, 74.8)
40.6 (13.8, 80.1)
Age at Fabry Symptom Onset (years)
n
70
885
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Mean (SD)
16.3 (13.15)
Median (range)
11.1 (3.8, 63.4)
13.8 (12.14)
9.6 (0.0, 70.6)
86
1139
43
618
113
26.6 (18.99)
20.3 (15.41)
20.2 (16.34)
24.0 (4.6, 69)
14.6 (0.0, 77.7)
12.3 (3.8, 69)
Age at Fabry Diagnosis (years)
n
47
1103
133
Mean (SD)
35.8 (16.01)
26.2 (15.73)
40.4 (18.54)
32.6 (17.62)
37.4 (17.03)
Median (range)
35.5 (4.3, 78.9)
24.0 (0.0, 81)
38.1 (0.0, 78.3)
32.0 (0.0, 80.6)
36.5 (0.0, 78.9)
Stroke patients are those with recorded stroke events during the natural history time period, i.e., before the start of ERT. Note that dates of symptom onset and
diagnosis were not available for all patients. SD indicates standard deviation.
whom stroke type was reported, 105 (86.8%) had ischemic
and 16 had hemorrhagic strokes (13.2%). Hemorrhagic
strokes were more prevalent in males (13 of 77, 16.9%) than
in females (3 of 44, 6.8%). Of the 16 patients with hemorrhagic strokes, the median age at first stroke was 47.8 years
in males (range 25.8 to 57.3) and 57.7 years in females (range
32.6 to 65). For ischemic strokes in which vessel size was
reported, the majority (38 of 54, 70.4%) occurred within
small vessels (lacunar). Where reported, the most common
areas where ischemic strokes occurred were the middle
cerebral artery territory (15 of 38, 39.5%), the anterior
cerebrum (10 of 38, 26.3%), and vertebrobasilar region (7 of
38, 18.4%). For ischemic strokes, the vessel size and location
of strokes were similar in males and females.
Of the 138 patients who had strokes, 93 patients (67.4%)
also reported experiencing a cardiac or renal event at some
time. The majority (70.9% of males and 76.9% of females)
either had a stroke before a renal or cardiac event or
experienced a stroke only (ie, did not have any other clinical
events), as shown in Figure 3. Females were much more
likely than males to experience a stroke as their only clinical
event (26 of 52, 50.0%), compared to males (19 of 86,
22.1%). Furthermore, 18 of 47 (the temporal relationship
between stroke and diagnosis was unknown for 5 of the 52
females) females (38.3%) and 43 of 86 males (50.0%)
experienced their first stroke before they were diagnosed with
Fabry disease. Thus, most patients had either not experienced
other major complications or were not known to have Fabry
disease before their stroke.
We also examined the sequence of clinical events among
the 30 patients who had strokes at a young age and the 16
patients who had hemorrhagic strokes (Figure 3). Patients
Figure 1. Age at first stroke in Fabry Registry
patients. Percentages of patients experiencing
their first stroke during 6 age categories are
shown. Data for males are in dark gray bars and
data for females are in light gray bars, with the
number of patients in each age category shown
above each bar. All data are from patients not
treated with ERT at the time of their first stroke.
Sims et al
Stroke in Fabry Disease
791
who had strokes at ⬍30 years, particularly females, were
more likely than patients in the overall stroke population to
have experienced a stroke as their only clinical event (9 of 21
males, 42.9% and 6 of 9 females, 66.7%). Of these 30 young
patients, only 1 male and 1 female had experienced a renal or
3
100
Stroke Only
Stroke Before Renal or Cardiac Event
Renal or Cardiac Event Before Stroke
90
80
Percentage of Patients
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Figure 2. Incidence of stroke in Fabry Registry
patients and in the general U.S. population. Data
are expressed as number of strokes per personyear of follow-up time in 7 age categories. For
Fabry Registry patients with strokes, person-years
of follow-up was defined as the number of years
from birth to the date for first recorded stroke. For
Fabry Registry patients without strokes, personyears of follow-up was defined as the last available follow-up date during the natural history
period. Stroke incidence rates are shown in data
table below the graph. Data in parentheses indicate 95% confidence intervals for Fabry Registry
stroke incidence rates. *There were no Fabry Registry males in the 65 to ⬍75 year age group. None
of the 11 females in the 75 to ⬍85 year age group
experienced any strokes. Stroke incidence rates
among males and females age ⱖ35 years in the
general U.S. population are from the Framingham
Study.25 Stroke incidence rates in U.S. males and
females age 0 to ⬍35 years are from the American
Heart Association Statistics Committee and the
Stroke Statistics Subcommittee.26
6
70
60
42
50
11
26
6
9
40
25
30
19
4
14
12
3
2
20
1
10
0
1
Male Female
All Strokes
Male
Female
Stroke <30 yr
Male Female
Hemorrhagic
Figure 3. Occurrence of other clinical events in Fabry Registry
stroke patients by gender. Bar graphs indicate relative percentages of males and females who also experienced renal or cardiac events among all stroke patients, the subset of patients
⬍30 years at the time of their first stroke, and the subset of
patients with hemorrhagic strokes, as indicated. Patients who
experienced stroke as their only clinical event are shown in
black bars, patients who had a stroke as their first clinical event
are shown in dark gray bars, and patients who had a renal or
cardiac event before their first stroke are shown in light gray
bars. Data are expressed as relative percentages, with the number of patients in each group indicated above each bar. All
strokes occurred during the natural history period, but renal and
cardiac events may or may not have occurred during the natural
history period.
cardiac event before their first stroke. Among the 16 patients
who had hemorrhagic strokes, 6 of 13 males (46.2%) had
experienced a renal or cardiac event before their stroke. The
3 females who had hemorrhagic strokes each experienced
stroke as their only clinical event.
Patients’ renal and cardiac characteristics at the most
recently available follow-up examination after their first
stroke were also analyzed, as summarized in Table 2. Of
those for whom renal data were available, 49 of 82 males
(59.8%) and 12 of 47 females (25.5%) exhibited stage 3 to 5
chronic kidney disease. Of the 93 patients with echocardiographic data, 37 of 56 males (66.1%) and 22 of 37 females
(59.5%) had left ventricular hypertrophy.
Not surprisingly, patients who had strokes were much more
likely to have reported a medical history of various risk
factors for strokes, as compared to other patients in the Fabry
Registry. Compared to nonstroke patients, those who had
strokes were more likely to report TIAs (36.2% versus 5.4%),
arrhythmias (32.6% versus 12.7%), or hypertension (52.9%
versus 20.5%). As shown in Figure 4, similar percentages of
male and female stroke patients reported a history of TIAs.
Male stroke patients were more likely than females to have
reported a history of arrhythmias. A greater percentage of
females who had strokes reported a history of hypertension
(32 of 52, 61.5%), as compared to males (41 of 86, 47.7%).
Among the subpopulations of patients with strokes at ⬍30
years (all of whom had ischemic strokes) and those with
hemorrhagic strokes, the proportion of patients with a history
of TIAs or arrhythmias was generally similar to that observed
in the overall population of Fabry stroke patients (data not
shown). Patients with hemorrhagic strokes were more likely
to have reported a history of hypertension (11 of 16, 68.9%)
than patients with a stroke ⬍30 years (8 of 30, 26.7%).
Overall, 73 of 138 stroke patients (52.9%) had a history of
hypertension.
Discussion
The Fabry Registry has collected clinical data from 2446
Fabry patients. This large, international cohort provides a
792
Stroke
March 2009
Table 2.
Renal and Cardiac Disease Characteristics of Fabry Registry Stroke Patients by Gender
Parameter
Males With Strokes
Females With Strokes
82
47
Estimated glomerular filtration rate (eGFR), n
All Patients With Strokes
129
Mean eGFR, ml/min/1.73 m2 (SD)
56.0 (39.43)
76.4 (39.87)
63.4 (40.65)
Median (range)
48.8 (4.2, 233.7)
75.7 (7.2, 260.7)
64.3 (4.2, 260.7)
eGFR Categories
Normal or Stage 1 to 2 chronic kidney disease
33 (40.2)
35 (74.5)
68 (52.7)
49 (59.8)
12 (25.5)
61 (47.3)
(eGFRⱖ60 mL/min/1.73 m2), n (%)
Stage 3 to 5 chronic kidney disease (eGFR⬍60
mL/min/1.73 m2), n (%)
Left posterior wall thickness, n
56
37
93
Mean thickness, mm (SD)
13.8 (4.39)
13.0 (3.21)
13.5 (3.96)
Median (range)
13.0 (5.0, 26.0)
12.5 (8.0, 19.0)
13.0 (5.0, 26.0)
Left posterior wall thickness categories
Normal range (⬍12 mm), n (%)
19 (33.9)
15 (40.5)
34 (36.6)
Left ventricular hypertrophy (ⱖ12 mm), n (%)
37 (66.1)
22 (59.5)
59 (63.4)
unique resource to study various characteristics of these
patients, including stroke incidence rates and risk factors
associated with stroke. Stroke is associated with significant
morbidity and high mortality in Fabry patients. A better
understanding of the clinical history and phenotype of Fabry
patients with stroke may help to identify patients at higher
risk of suffering a stroke and allow for more proactive
management, including aggressive blood pressure control,
70
34
Medical History
No Medical History
Unknown / Not Reported
60
32
45
27
Percentage of Patients
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Stroke patients are those with recorded stroke events during the natural history time period, i.e., before the start of ERT. Renal and
cardiac data shown represent most recent recorded value after patients’ first stroke, which may or may not have occurred during
Natural History time period. The Modification of Diet in Renal Disease (MDRD) simplified equation was used to estimate glomerular
filtration rate (eGFR) from serum creatinine levels.32 SD indicates standard deviation.
41
50
37
36
40 32
31
18
18
30
14
18
20
7
10
4
10
8
2
0
Male
Female
TIA
Male
Female
Arrhythmia
Male
Female
Hypertension
Figure 4. Medical history of various risk factors in Fabry Registry stroke patients. Bar graphs indicate relative percentages of
males and females with strokes who also reported a history of
TIAs, arrhythmias, or hypertension at the time they enrolled in
the Fabry Registry, as indicated. Black bars indicate patients
with strokes who also reported these risk factors, dark gray
bars indicate patients with stroke who did not report these risk
factors, and light gray bars indicate patients who had not
reported this information or for whom this information was
unknown. Data are expressed as relative percentages, with the
number of patients in each group indicated above each bar.
Note that these risk factors may have occurred either before or
after a patient’s first stroke.
antiplatelet or anticoagulation prophylactic treatment. Evaluation of comorbid prothrombotic risk factors may also identify those with higher thromboembolic stroke risk.
These analyses evaluated data from 138 patients who
experienced strokes before ERT. The mean age at first stroke
for Fabry patients was considerably younger than that of the
general U.S. population. As in the general population,25,26 the
incidence of stroke increased with increasing age in Fabry
Registry patients. The incidence of stroke during each decade
was markedly higher among Fabry patients, compared to the
general population. Although it is well known that Fabry
patients have a high risk of stroke,1–3,27 this is the first study
to systematically analyze the rates of stroke events in a large
Fabry population and to evaluate the clinical characteristics
of these stroke patients.
The fact that 4.3% of the females in the Fabry Registry had
experienced a stroke supports the growing body of evidence
that heterozygous females develop substantial symptoms and
signs of Fabry disease and are at risk of premature death.3,13
Males experienced first strokes at an earlier age than females
(median age 39.0 years versus 45.7 years, respectively),
which is consistent with males typically exhibiting more
severe and earlier signs and symptoms of Fabry disease.3,13
However, 17% of females who had strokes experienced their
first stroke before 30 years, including 1 female at age 19.8
years.
Sixty-one of the 133 stroke patients (45.9%) for whom data
were available experienced their first stroke before being
diagnosed with Fabry disease. In these 61 patients, the
median time from first stroke to diagnosis was 4.8 years (data
not shown). This highlights the need for greater awareness
and earlier diagnosis, before the major clinical manifestations
of Fabry disease occur. Most patients, particularly females
and patients ⬍30 years, either had their first stroke before any
renal or cardiac events or did not have any other clinical
Sims et al
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events. Thus, many Fabry patients may not exhibit obvious
major signs of the disease before a stroke occurs.
Where stroke type was reported, 86.8% of first strokes
were ischemic and 13.9% were hemorrhagic. This proportion
is similar to that observed in the general population of stroke
patients,25,26 though hemorrhagic strokes were more common
in Fabry males (16.9%) than in females (6.8%). Glycolipid
deposition within intracerebral blood vessels would be predicted to put patients at risk for ischemic stroke, but the
finding that 16 patients had hemorrhagic strokes was somewhat unexpected. Vertebrobasilar dolichoectasia, which is
primarily associated with ischemic strokes, has also been
linked with hemorrhagic strokes, particularly in patients with
hypertension.28 Dolichoectasia of the basilar artery has been
reported in Fabry disease.29,30 Though hypertension was more
prevalent in the subset of patients with hemorrhagic strokes,
none of these patients exhibited hemorrhage within the
vertebrobasilar region.
Various risk factors were identified among Fabry stroke
patients. The 3 risk factors most strongly associated with
stroke were a history of TIAs, arrhythmias, or hypertension.
Similar proportions of males and females reported a history
of TIAs, whereas arrhythmia was more prevalent in male
stroke patients and hypertension was more strongly associated with stroke in females. Thus, Fabry patients who
experience TIAs, hypertension, or arrhythmia are at risk of
stroke, and management should be proactive and specifically
targeted in those who experience these premonitory events.
However, patients who do not exhibit these signs may still be
at risk of stroke, as many patients who experienced a stroke
did not report any of these risk factors. Although it has not
been demonstrated that ERT can prevent strokes, it has been
shown to ameliorate many of the major signs and symptoms
of Fabry disease,4 –9 and patients at risk of stroke should also
be considered for treatment with ERT.
The precise pathological mechanisms underlying strokes in
patients with Fabry disease are uncertain, though various
abnormalities in cerebral blood flow and in intracranial vessel
walls have been identified (reviewed in19). In addition,
characteristic white matter lesions are very common in
patients with Fabry disease, and the prevalence of white
matter lesions among these patients grows with increasing
age (reviewed in10). As mentioned, Fabry patients can have
dolichoectasia of the basilar artery.29,30 Finally, microvascular
cerebral abnormalities were detected in 2 male Fabry patients
during childhood (ages 8 and 11 years), when they showed no
clinical evidence of renal or cardiac disease.31 In future
studies, detailed analyses of cerebral MRI data may provide
valuable information for predicting which patients are at high
risk for strokes.
The finding that nearly half of these patients experienced
their first stroke before diagnosis is contrary to the conventional view of the “classical” progression of Fabry disease,
namely that early symptoms (ie, hypohidrosis, neuropathic
pain, and gastrointestinal dysfunction) begin in childhood and
that major end-organ events (ie, renal dysfunction or cardiovascular disease preceding stroke) occur during the fourth or
fifth decades of life.3,27 Although many patients do exhibit the
classical type of gradual disease progression, it is possible at
Stroke in Fabry Disease
793
least some who have strokes experience less severe “early
symptoms” of the disease, and therefore go undiagnosed until
they have a stroke. Indeed, patients who had strokes, particularly females, reported experiencing symptoms at an older
age than Fabry Registry patients without strokes. Accordingly, patients with strokes were also diagnosed at a much
later age. Furthermore, many patients with cryptogenic
strokes (4.9% of males and 2.4% of females) were found to
have undiagnosed Fabry disease.16 Because most Fabry
Registry patients did not report other major clinical signs
before their first stroke (ie, cardiovascular or renal dysfunction), physicians must be vigilant for cerebrovascular risk
factors and complications in all Fabry patients, even those
who do not exhibit substantial cardiovascular or renal disease.
It is imperative that Fabry patients are diagnosed as early as
possible, particularly given the possibility of this relatively
“silent progression” to stroke. All patients should be closely
followed and evaluated to monitor the progression of Fabry
disease, and patients who experience TIAs, arrhythmia, or
hypertension should be considered at risk of stroke and
management and therapy adjusted accordingly.
Acknowledgments
The authors thank the many patients who have agreed to participate
in the Fabry Registry as well as the physicians and research
coordinators who have entered clinical data on these patients. We
also acknowledge Dana Beitner-Johnson, PhD, Fanny O’Brien, PhD,
and Marta Cizmarik, MS (Genzyme Corporation, Cambridge, MA)
for assistance with manuscript writing and statistical analyses.
Sources of Funding
The Fabry Registry is sponsored by Genzyme Corporation. K.S.,
M.B., and P.L. serve on the Genzyme-sponsored North American
Fabry Registry Board of Advisors. J.P. serves as a Latin American
Fabry Registry Coordinator.
Disclosures
None.
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Stroke in Fabry Disease Frequently Occurs Before Diagnosis and in the Absence of Other
Clinical Events: Natural History Data From the Fabry Registry
Katherine Sims, Juan Politei, Maryam Banikazemi and Philip Lee
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Stroke. 2009;40:788-794; originally published online January 15, 2009;
doi: 10.1161/STROKEAHA.108.526293
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