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doi: 10.1111/joim.12077
Long-term outcome of enzyme-replacement therapy in
advanced Fabry disease: evidence for disease progression
towards serious complications
F. Weidemann
1,2,
*, M. Niemann
1,2,
*, S. St€
ork
1,2
, F. Breunig
1
, M. Beer
3
, C. Sommer
4
, S. Herrmann
1,2
,
G. Ertl
1,2
& C. Wanner
1,2
From the
1
Department of Medicine, Divisions of Cardiology and Nephrology;
2
Comprehensive Heart Failure Center;
3
Institute of Radiology;
and
4
Department of Neurology, University of W€
urzburg, W €
urzburg, Germany
Abstract. Weidemann F, Niemann M, St€
ork S,
Breunig F, Beer M, Sommer C, Herrmann S, Ertl
G, Wanner C (Department of Medicine, Divisions of
Cardiology and Nephrology, University of Wu
¨rzburg,
Wu
¨rzburg, Germany; Comprehensive Heart Failure
Center, University of Wu
¨rzburg, Wu
¨rzburg, Germany;
Institute of Radiology, University of Wu
¨rzburg,
Wu
¨rzburg, Germany; Department of Neurology,
University of Wu
¨rzburg, Wu
¨rzburg, Germany). Long-
term outcome of enzyme-replacement therapy in
advanced Fabry disease: evidence for disease
progression towards serious complications. JIntern
Med 2013; 274: 331–341.
Objective. The long-term effects of enzyme-replace-
ment therapy (ERT) in Fabry disease are unknown.
Thus, the aim of this study was to determine
whether ERT in patients with advanced Fabry
disease affects progression towards ‘hard’ clinical
end-points in comparison with the natural course
of the disease.
Methods. A total of 40 patients with genetically
proven Fabry disease (mean age 40 9 years;
n=9 women) were treated prospectively with ERT
for 6 years. In addition, 40 subjects from the Fabry
Registry, matched for age, sex, chronic kidney
disease stage and previous transient ischaemic
attack (TIA), served as a comparison group. The
main outcome was a composite of stroke, end-stage
renal disease (ESRD) and death. Secondary out-
comes included changes in myocardial left ventric-
ular (LV) wall thickness and replacement fibrosis,
change in glomerular filtration rate (GFR), new TIA
and change in neuropathic pain.
Results. During a median follow-up of 6.0 years
(bottom and top quartiles: 5.1, 7.2), 15 events
occurred in 13 patients (n=7 deaths, n=4 cases
of ESRD and n=4 strokes). Sudden death
occurred (n=6) only in patients with documented
ventricular tachycardia and myocardial replace-
ment fibrosis. The annual progression of myocar-
dial LV fibrosis in the entire cohort was 0.6 0.7%.
As a result, posterior end-diastolic wall thinning
was observed (baseline, 13.2 2.0 mm; follow-up,
11.4 2.1 mm; P<0.01). GFR decreased by
2.3 4.6 mL min
1
per year. Three patients expe-
rienced a TIA. The major clinical symptom was
neuropathic pain (n=37), and this symptom
improved in 25 patients. The event rate was not
different between the ERT group and the untreated
(natural history) group of the Fabry Registry.
Conclusion. Despite ERT, clinically meaningful events
including sudden cardiac death continue to
develop in patients with advanced Fabry disease.
Keywords: dialysis, Fabry disease, prognosis, stroke,
sudden cardiac death, a-galactosidase A.
Introduction
Fabry disease is a rare X-linked lysosomal storage
disorder caused by deficiency of the enzyme a-
galactosidase A. The enzymatic deficit results in
progressive intracellular accumulation of globo-
triaosylceramide in different tissues with profound
clinical effects on the heart, kidneys and brain
[1–6]. Storage of globotriaosylceramide starts
before birth [7], and progressive organ failure leads
to early death in hemizygous male patients, typi-
cally at the age of 40–50 years [8–11]. Enzyme-
replacement therapy (ERT) with recombinant
a-galactosidase A substitutes for the missing
*The first two authors contributed equally.
ª2013 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of The Association for the Publication of the Journal of Internal Medicine 331
This is an open access article under the terms of the Creative Commons Attribution License,
which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Original Article
enzyme and is administered intravenously every
2 weeks. Two short-term clinical phase III trials
have demonstrated that ERT is safe and well
tolerated and is able to remove the microvascular
deposits of globotriaosylceramide in biopsies of
kidney, skin and heart of most patients with Fabry
disease [12, 13]. A phase IV clinical trial over a
median observation period of 18.5 months pro-
vided proof that ERT can slow the progression
towards serious cardiac, renal and cerebrovascular
complications [14]. Data from the Fabry Outcome
Survey Registry on 5 years of treatment with ERT
demonstrated a reduction in left ventricular hyper-
trophy and stabilization of kidney function in
subgroups of patients [15]. However, the effects of
long-term ERT on ‘hard’ clinical end-points includ-
ing Fabry disease-related death remain unknown.
The aim of the current study was to examine the
effects of ERT in patients with Fabry disease on
progression towards the end-points long-term
survival and cause-specific death, compared with
the natural course of the disease.
Methods
Study population and protocol
Since the initiation of the W€
urzburg Fabry Disease
Centre in 2001, 180 patients with genetically
proven Fabry disease (73 male, 107 female) have
been registered and are monitored regularly at the
centre. In this cohort, ERT was initiated in 74
patients. Here, we report on the clinical course and
outcome of all consecutive patients (n=40) with
genetically confirmed Fabry disease (for gene
mutations see Supplementary Table S1) who have
been treated for at least 5 years at a dose of
1mgkg
1
body weight with recombinant a-galac-
tosidase A (agalsidase beta; Fabrazyme, Genzyme,
a Sanofi company, Cambridge, MA, USA) or died
during the observation period. Patients were fol-
lowed up to the time-point when they had to switch
to agalsidase alpha because of agalsidase beta
shortage due to viral contamination at manufac-
turing [16]. In general, most of these patients were
relatively old and already advanced with respect to
disease progression at baseline because ERT was
not available before 2001. Thus, for these patients,
this was the earliest opportunity to receive treat-
ment with a-galactosidase A.
None of the patients had previously received infu-
sions of recombinant a-galactosidase A. Before the
first infusion (baseline) and at annual intervals, a
complete medical history was taken, and cardiac,
renal and neurological evaluations were per-
formed. Here, we report data from the baseline
and final visits. The cardiac and renal results after
1 and 3 years of observation have been reported
previously [17–19].
Cardiac assessment was performed using echocar-
diography (morphology), strain rate (SR) imaging
(regional myocardial function), 24-h Holter electro-
cardiogram (ventricular tachycardia) and magnet
resonance imaging (MRI) with late enhancement
(LE) imaging (myocardial fibrosis). Kidney function,
that is, glomerular filtration rate (GFR), was mea-
sured by
99
Tc-DTPA clearance, and proteinuria
was assessed using 24-h urine collection.
The study conformed to the principles outlined in
the Declaration of Helsinki. Written informed con-
sent was obtained from all patients. The authors
had full access to and take complete responsibility
for the integrity of the data. Genzyme Corporation
sponsors the Fabry Registry, maintains the data-
base and has provided support for the analysis of
the control group of patients from the Fabry
Registry. All authors have read and approved the
manuscript as written.
Standard echocardiography
Left ventricular end-diastolic dimension as well as
end-diastolic thickness of the posterior wall and the
septum were measured using standard M-mode
echocardiographic methods in parasternal long-
axis images (GE Vingmed Vivid 7, Horten, Norway;
3.5 MHz). Left ventricular (LV) myocardial mass was
calculated using the Devereux formula. Ejection
fraction was calculated using the modified Simpson
method. Blood pool pulsed Doppler of the mitral
valve inflow was used to extract the ratio of early to
late diastolic flow velocity and the deceleration time.
Strain rate imaging
Real-time two-dimensional colour Doppler data
were recorded from the interventricular septum
and the LV lateral wall using standard apical four-
chamber views to evaluate longitudinal function
(GE Vingmed Vivid 7, Horten, Norway; 3.5 MHz).
All data were analysed using dedicated software
(Echopac
; GE Ultrasound, Horten, Norway).
Longitudinal SR curves of the mid-apical septum
and the basal–mid-lateral wall were extracted and
peak systolic SR was derived. These longitudinal
F. Weidemann et al. Enyzme-replacement therapy in Fabry disease
332 ª2013 The Authors. Journal of Internal Med icine published by John Wiley & Sons Ltd on behalf of The Association for the Publication of the Journal of Internal Medicine
Journal of Internal Medicine, 2013, 274; 331–341
segments were chosen on the basis of experience
gained in earlier studies of Fabry disease cardio-
myopathy: fibrosis usually starts in the basal–
mid-lateral wall and is not typically observed in the
mid-apical septum [20–22]. All echocardiographic
data were analysed blinded to the time-point of
visit and to the degree of fibrosis.
MRI
Routine MRI with gadolinium was carried out as
part of the standard assessment for patients at the
W€
urzburg Fabry disease centre. The LE technique
(8 mm slice thickness, breath-hold, short heart
axis) was applied to detect changes in tissue
integrity in the LV myocardium [22]. Images were
acquired using an inversion recovery sequence
(field of view 240 9320 mm
2
; matrix 165 9256).
Short axis views at the basal, mid and apical
segments, covering the entire ventricle, were used
to quantify the LE area (if present) by manual
tracing. Applying this technique to a standard
17-segment model, every LV segment was evalu-
ated for the occurrence of myocardial replacement
fibrosis. A ratio of LE to complete LV cardiac mass
was calculated [23]. All MRI data were analysed
blinded to the time-point of visit.
Definitions of outcome
The main outcome variable was defined as a
composite of stroke, end-stage renal disease and
initiation of dialysis and death.
Other cardiac outcomes were change in LV wall
thickness (for morphology), change in peak systolic
SR (for regional LV function), new ventricular
tachycardia (for malignant arrhythmias) and
change in LE-positive volume (for LV fibrosis).
Kidney damage and kidney function were assessed
by change in GFR and change in proteinuria.
Neurological outcomes were defined as any new
onset of transient ischaemic attack (TIA) or
changes in neuropathic pain and hypohidrosis.
Comparison group
After the approval of ERT as an efficacious and safe
treatment option by the relevant authorities under
the Orphan Drug Act, prospective randomized trials
became largely impossible because of ethical con-
siderations. Thus, we made use of the Fabry Registry
(ClinicalTrials.gov Identifier: NCT00196742), an
ongoing, international, multicentre, observational
database that monitors natural history of the
disease course and outcomes of patients with Fabry
disease. The Fabry Registry began enrolling patients
in April 2001 and included case records in the
database for 4171 patients as of 6 January 2012
[24]. All patients with Fabry disease are eligible to
enrol, regardless of age, gender, symptoms or
treatment with ERT from any commercial source.
We selected data from 40 adult subjects included in
the Fabry Registry, matched to individuals in the
treated group by year of birth, gender, previous TIA
and chronic kidney disease (CKD) stage. These 40
patients were not treated with ERT because of
problems with reimbursement in their countries of
residence. Characteristics of this untreated
comparison group are shown in Supplementary
Table S2.
Data analysis
Data are presented as mean standard devia-
tion, median (bottom and top quartiles) or num-
bers (percentage), as appropriate. Baseline and
follow-up values were compared using paired
t-test or Fisher’s exact test, as appropriate. For
prognostic analyses, a Cox proportional hazard
regression was used. The proportionality assump-
tion was checked by visual inspection and no
violation was found. Statistical interaction was
examined by introducing the respective product
term in the model. Predictors of the combined
end-point were sought amongst the clinical char-
acteristics shown in the tables, using a P-value of
0.1 in univariable analyses. For multivariable
analysis, the backstep likelihood criterion was
used (P
in
=0.05; P
out
=0.1). SPSS (version 19.0.1;
SPSS Inc, Chicago, IL, USA) was used for statis-
tical analysis.
Results
Patients
The baseline characteristics of all patients with
Fabry disease, and subgroups with and without
the main outcome, are presented in Table 1. The
major clinical limitation at baseline was neuro-
pathic pain, which was found in 37 patients. The
40 ERT-treated patients originated from 25 differ-
ent families with Fabry disease. Only two families
share the same stop codon mutation in exon 5 (for
gene mutations see Supplementary Table S1). The
mean a-galactosidase A activity assessed in white
blood cells was 0.21 0.12 nmol min
1
per mg in
women and 0.03 0.01 nmol min
1
per mg in
F. Weidemann et al. Enyzme-replacement therapy in Fabry disease
ª2013 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of The Association for the Publication of the Journal of Internal Medicine 333
Journal of Internal Medicine, 2013, 274; 331–341
men (the normal value is >0.4 nmol min
1
per mg).
At baseline, 19 patients were treated with angio-
tensin-converting enzyme (ACE) inhibitors or
angiotensin receptor blockers. During follow-up,
all but six patients (with no documented protein-
uria prior to or during the study) underwent
titration of the ACE inhibitors or angiotensin
receptor blockers.
Main outcome
The median follow-up time for survivors treated
with ERT was 6.0 years (bottom and top quartiles:
5.1, 7.2). There were 15 events (death, stroke and
end-stage renal disease) in 13 patients (Table 1).
Seven patients (all male) died during follow-up due
to infection (n=1) or sudden cardiac death (n=6)
at a mean age of 53 6.8 years (range 42–
61 years). These seven patients had received ERT
on average for 60 32 months (range 10–
104 months). One patient had received an implant-
able cardioverter defibrillator (ICD) 2 years prior to
death, with several documented episodes of ven-
tricular tachycardia adequately abolished by the
device. All patients who died because of cardiac
arrest had ventricular tachycardia according to
Holter ECG. Four had a sustained and two a
nonsustained episode. In one of these patients,
ventricular tachycardia was recorded by online
monitoring during multiple in-hospital resuscita-
tions. According to echocardiographic appearance,
all six patients had hypertrophic cardiomyopathy
and demonstrated at least two LE-positive seg-
ments loco typico, indicating advanced myocardial
fibrosis (Fig. 1). One patient experienced a fatal
event due to sepsis, which is not typical of Fabry
disease. Prior to death, one patient had a stroke
and another had a stroke prior to end-stage renal
disease (Table 2).
Four other patients (all male) progressed to end-
stage renal disease and initiation of dialysis at the
ages of 33, 41, 43 and 47 years. Three of the four
already had moderate to severe CKD (GFR of 22, 33
and 47 mL min
1
) and proteinuria (2.3, 2.3 and
6.6 g per day) at first presentation; haemodialysis
was started after 3, 6 and 6 years on ERT. The last
of the four patients progressed to dialysis within
Table 1 Baseline characteristics of all patients with Fabry disease
All Pts (n=40)
Pts with events
(main outcome) (n=13)
Pts without events
(main outcome) (n=27)
Age (years) 40 9458389
Sex (male/female) 31/9 12/1 19/8
Weight (kg) 72 12 72 14 71 10
Height (cm) 175 9 178 7 174 9
Heart rate (min
1
)6410 64 11 65 11
Systolic BP (mmHg) 127 15 126 17 127 15
Diastolic BP (mmHg) 79 11 80 11 78 11
Atrial fibrillation (n, %) 3 (8) 2 (15) 1 (4)
Angina pectoris (n, %) 13 (33) 7 (54) 6 (22)
Dyspnoea (n, %) 19 (48) 7 (54) 12 (44)
Glomerular filtration rate (mL min
1
)8528 61 25 94 22
Proteinuria (g) 0.63 0.96 2.4 2.2 0.5 0.6
Dialysis (n, %) 7 (18) 4 (31) 3 (11)
Kidney transplantation (n, %) 4 (10) 2 (15) 2 (7)
Stroke (n, %) 3 (8) 3 (23) 0 (0)
TIA (n, %) 3 (8) 0 (0) 3 (11)
Neuropathic pain (n, %) 37 (93) 11 (85) 26 (96)
Hypohidrosis (n, %) 33 (83) 11 (85) 22 (82)
Pts, patients; BP, blood pressure; TIA, transient ischaemic attack.
Data are given as mean SD or numbers (%).
F. Weidemann et al. Enyzme-replacement therapy in Fabry disease
334 ª2013 The Authors. Journal of Internal Med icine published by John Wiley & Sons Ltd on behalf of The Association for the Publication of the Journal of Internal Medicine
Journal of Internal Medicine, 2013, 274; 331–341
4 years declining from a baseline GFR of
81 mL min
1
associated with proteinuria (3.1 g
per day) (Table 2).
Four patients (three male and one female) devel-
oped a stroke during follow-up at age 41, 46, 54
and 60 years, respectively (Table 2). Only one of
these patients experienced a TIA before the onset of
stroke; all had myocardial fibrosis and advanced
cardiomyopathy. Subsequent thrombo-embolism
due to atrial fibrillation was suspected in two of
the four patients.
In univariate Cox regression analysis, the following
variables were associated with the occurrence of
the combined end-point [hazard ratio (HR); 95%
confidence interval (CI)]: LE (5.17; 1.13–23.62),
cardiac mass (per 10 g: 1.12; 1.03–1.23), GFR (per
mL min
1
: 0.98; 0.97–0.99), previous cerebro-
vascular accident (4.36; 1.14–16.64), New York
Heart Association (NYHA) functional class (per
class: 2.22; 0.93–5.26) and proteinuria (per 1 g:
1.31; 0.97–1.75). In multivariable analysis, only
NYHA functional class (per class: 2.74; 1.13–
6.66; P=0.025) and proteinuria (per 1 g: 1.47;
1.05–2.05; P=0.026) remained independently
predictive.
Secondary outcomes
The organ-specific outcomes (cardiac, renal and
cerebral) are summarized in Table 3. The last
available information is reported for patients who
died.
(a) (b)
(c) (d)
Fig. 1 Example of data from a typical patient with Fabry disease who died during follow-up. (a) Echocardiographic four-
chamber view with hypertrophy of the left ventricular septum and thinning of the lateral wall (arrow). (b) Magnetic
resonance image showing short axis view with a late enhancement-positive segment in the posterolateral wall (arrow) of the
left ventricle. (c) Strain-rate curve (for the evaluation of regional myocardial function) extracted from the basal left ventricular
lateral wall over one heart cycle showing reduced regional myocardial function (reduced first systolic strain-rate peak) and a
second strain-rate peak shortly after aortic valve closure as a typical sign of myocardial fibrosis. (d) Section of a 24-h Holter
electrocardiogram showing a typical ventricular tachycardia with a heart rate of 160 beats per min. AVC, aortic valve
closure; LV, left ventricle; SR, strain rate.
F. Weidemann et al. Enyzme-replacement therapy in Fabry disease
ª2013 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of The Association for the Publication of the Journal of Internal Medicine 335
Journal of Internal Medicine, 2013, 274; 331–341
Both septal and posterior end-diastolic wall thick-
ness decreased significantly, but longitudinal sys-
tolic SR increased in the septum (not significantly)
and decreased significantly in the lateral wall. Two
patients developed a new LE-positive segment loco
typico. The annual progression of LV fibrosis was
0.6 0.7% (men: 0.7 0.7%; women: 0.2
0.3%). During follow-up, four patients received an
ICD because of sustained (n=3) or nonsustained
(n=1) ventricular tachycardia. Subsequent
episodes of adequately terminated ventricular
tachycardia were recorded by the ICDs in three of
these four patients. Two other patients who exhib-
ited nonsustained ventricular tachycardia were
scheduled to receive implantation of an ICD after
the observation period had ended (i.e. at the time
the dosage was decreased or they switched to
another source of ERT). Almost all patients with
documented ventricular tachycardia had hypertro-
phic cardiomyopathy with myocardial fibrosis, but
ventricular tachycardia was never detected in
patients without LE.
During follow-up, GFR decreased by 2.3
4.6 mL min
1
per year (men: 2.4 5.0 mL min
1
per year; women: 1.9 3.3 mL min
1
per year). In
patients without proteinuria (<150 mg per day) at
baseline (n=14), GFR remained stable over time
(baseline 88 mL min
1
; follow-up 88 mL min
1
).
Four out of the five patients who had proteinuria
>2 g per day at baseline progressed to end-stage
renal disease. Kidney function in the remaining
patient also worsened and GFR decreased from 48
to 27 mL min
1
.
Only three patients developed a TIA during follow-
up. Neuropathic pain was frequently observed at
baseline (n=37), but improved markedly in 25
patients. Likewise, hypohidrosis improved in 14
patients, but to a lesser degree.
Natural course of Fabry disease
Nine of the 40 matched ERT-na€
ıve patients from
the Fabry Registry were female (23%). Further
characteristics of this comparison group are shown
in Supplementary Table S2. During the median
life-time follow-up of 45 years (bottom and top
quartiles: 38, 52 years), 10 patients developed a
stroke (25%), 11 patients (28%) progressed to end-
stage renal disease with initiation of dialysis and
two patients died (5%). Because two patients
experienced several events, only 21 events that
occurred in more than half of the cohort were
included in the main outcome analysis. Over a
median life-time follow-up 44 years (quartiles: 39,
Table 2 Baseline characteristics of all patients with Fabry disease with a main outcome event
Patient (sex) Type of event
Age at ERT
start (years)
GFR at baseline
(mL min
1
)
ERT Time to
event (months)
1 (male) Sepsis and death 41 81 12
2 (male) Cardiac death 45 81 75
3 (male) Cardiac death 46 ESRD
a
10
4 (male) Cardiac death 51 81 77
5 (male) Cardiac death 51 ESRD
a
72
6 (male) Cardiac death 53 48 104
7 (male) Cardiac death and
stroke
39 ESRD
a
68
15
8 (male) Stroke 54 43 6
9 (female) Stroke 56 95 42
10 (male) Stroke and
ESRD
41 47 70
72
11 (male) ESRD 29 81 46
12 (male) ESRD 37 22 72
13 (male) ESRD 38 33 35
ERT, enzyme-replacement therapy; GFR, glomerular filtration rate; ESRD, end-stage renal disease.
a
Patients with ESRD at baseline were treated with maintenance haemodialysis.
F. Weidemann et al. Enyzme-replacement therapy in Fabry disease
336 ª2013 The Authors. Journal of Internal Med icine published by John Wiley & Sons Ltd on behalf of The Association for the Publication of the Journal of Internal Medicine
Journal of Internal Medicine, 2013, 274; 331–341
51 years), there was no significant difference in the
main outcome between the control group (natural
course of the disease) and the ERT group in Cox
regression adjusted for sex (HR 1.48; 95% CI 0.72–
3.06; P=0.284). Figure 2 shows time to first event
(stroke, renal death or all-cause mortality for the
ERT and control Registry groups) stratified by sex;
life-time follow-up was derived from Cox regression
analysis. No interaction between group and sex
was found (P>0.3).
Discussion
Recombinant human alpha-galactosidase A ther-
apy for Fabry disease received orphan drug
designation approval in 2001 after clinical studies
demonstrated tissue clearance of the substrate
and symptom relief in patients [12, 13]. Subse-
quent clinical studies focused on organ and heart
function and identified groups of patients with
nonuniform responses to treatment [14, 15, 17,
19, 24, 25]. The success of treatment was depen-
dent on the severity of organ involvement and was
essentially a function of age [14, 15, 19]. Here, we
report disease progression beyond cardiac and
renal damage occurring in 35% of the present
cohort after 6.0 years of uninterrupted treatment
with the licensed dose of algasidase beta. The
main finding in this patient cohort was sudden
cardiac death, explained by progressive replace-
ment fibrosis in the heart and subsequent ven-
tricular arrhythmia. We postulate that a similar
Table 3 Organ-specific outcomes (n=40)
Baseline Follow-up P-value*
Heart
Septum (mm) 13.5 2.0 11.9 1.8 <0.0001
PWT (mm) 13.2 2.0 11.4 2.1 <0.0001
LV mass (g) 270 87 224 71 <0.0001
LVEDD (mm) 49 5496 0.883
EF (%) 64 6637 0.692
E/A 1.3 0.4 1.2 0.4 0.061
DT (ms) 225 60 217 63 0.383
SR septum (s
1
) 1.3 0.2 1.4 0.3 0.365
SR lateral (s
1
) 0.9 0.3 0.7 0.3 <0.0001
Pts with fibrosis (n) 29 31 0.797
Pts with new
fibrosis (n)
–2–
Fibrosis in
relation to LV (%)
1.7 2.7 3.7 4.0 <0.0001
Pts with new VT (n)–12 –
Kidney
GFR (mL min
1
)8528 73 39 0.003
Proteinuria
(mg per day)
633 961 209 215 0.018
Brain
New TIA (n)–3–
Any neuropathic
pain (n)
37 21 0.0001
Pts with improved
pain (n)
–25 –
Analgesic
medication (n)
16 16 0.999
Hypohidrosis (n) 33 24 0.046
Pts with improved
hypohidrosis (n)
–14 –
PWT, posterior wall thickness; LV, left ventricle; LVEDD,
left ventricular end-diastolic diameter; EF, ejection
fraction; E/A, ratio of early to late diastolic flow velocity;
DT, deceleration time; SR, strain rate; Pts, patients; VT,
ventricular tachycardia; GFR, glomerular filtration rate;
TIA, transient ischaemic attack.
The last value available from the latest follow-up was
carried forward for patients who died.
*Paired t-test or Fisher’s exact test, as appropriate.
1.0
0.8
0.6
Time to first event
0.4 ERT, female
ERT, male
Registry, female
Registry, male
0.2
0.0
010 20 30
Life-time follow-up (years)
40 50 60
Fig. 2 Incidence of stroke, haemodialysis or death in 40
subjects treated with enzyme-replacement therapy (ERT)
for a period of at least 5 years (ERT group) versus 40
subjects from the Fabry Registry matched for year of birth,
sex, chronic kidney disease stage and previous transient
ischaemic attack. Unadjusted graphs from Cox regression
plots are shown for both sexes (n =9 women per group).
F. Weidemann et al. Enyzme-replacement therapy in Fabry disease
ª2013 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of The Association for the Publication of the Journal of Internal Medicine 337
Journal of Internal Medicine, 2013, 274; 331–341
mechanism accounts for the documented progres-
sion to renal death and stroke. Thus, ERT could
not fully prevent development of fibrosis and
organ failure in more than a third of this cohort
with Fabry disease during a period of nearly
6 years.
The safety and efficacy of ERT were shown in two
initial studies [12, 13]. Eng et al. [12] demon-
strated in a randomized, double-blind, placebo-
controlled study that ERT resulted in histological
clearance of the deposits of globotriaosylceramide
from the heart, kidney and skin. Subsequently,
clinical short-term follow-up studies in relatively
small cohorts or registries of patients with Fabry
disease focused on the impact of ERT on organ
function. These studies also showed an improve-
ment in Fabry disease-related symptoms, and the
results suggested a stabilization of kidney function
and a reduction in LV hypertrophy [17–19, 24, 25].
Similarly, the current long-term follow-up study
confirms that typical Fabry disease-related symp-
toms such as neuropathic pain and hypohidrosis
improve over time in most patients. Focusing on
organ-related outcomes, it was shown in a ran-
domized controlled trial with a median observation
time of 18.5 months that ERT slowed the progres-
sion towards cardiac, renal and cerebrovascular
complications [14]. It is interesting that in this trial
in patients with advanced renal involvement, ERT
had no impact on progression of the disease,
whereas substantial improvement could be
observed in those with mild renal involvement
[14]. Furthermore, Germain et al. provided proof
that, amongst patients with Fabry disease, a sub-
population with impaired renal function (reduced
GFR, proteinuria and glomerulosclerosis) at base-
line has a less favourable outcome and may
develop renal progression despite treatment with
ERT [26, 27]. By contrast, using natural history
data from the Fabry Outcome Survey database
(sponsored by Shire Human Genetic Therapies,
Lexington, MA, USA), it was shown that pain and
quality of life improved, LV mass decreased and the
rate of loss of kidney function declined after
5 years of ERT [15].
Finally, the results of the current systematic long-
term follow-up study, focusing primarily on cardiac
death, renal death and stroke demonstrate that the
three main target organs of Fabry disease cannot
be prevented from failing, despite ERT. Thus, in the
advanced stages of Fabry disease, specific treat-
ment can decrease symptoms, but not prevent
progression towards organ damage and subse-
quently death. Slowing the progression of the
disease by ERT may still be an important option,
given the heterogeneity of disease development
between men and women and even amongst indi-
viduals within the same families. It is possible that
because the present cohort is older than previously
studied patient groups and thus at a later stage of
disease, ERT may be less effective. The average age
of patients who reached the stage of renal replace-
ment therapy was 33–47 years. Patients who died
were 42–61 years old; this is similar to the age
range of those who experienced a stroke: progres-
sion of this orphan disease appears to be a function
of age without any subtle slowing of development
with treatment. Early treatment, that is, as early as
possible during adulthood, may be recommended,
but treatment success may only be recognized, if at
all, after decades of ERT. Potentially, we see
progression of the disease as a function of age
without the chance to detect subtle changes of
retardation in this orphan disease. Advocating
earlier treatment, that is, as early as possible
during adulthood, may be the recommendation of
choice, but similarly we could evaluate treatment
success, if at all, only after decades of treatment.
It has been demonstrated previously that ERT
improves regional myocardial function and reduces
LV hypertrophy during the first 3 years of treat-
ment [15, 18, 19, 24]. Patients in the present study
also showed a significant reduction in septal and
posterior wall thickness. We propose that a
decrease in septal wall thickness is required for
treatment to be considered successful. Takenaka
and coworkers suggested that a reduction in pos-
terior wall thickness probably reflects myocardial
fibre dropout and wall thinning due to progressive
fibrosis with subsequent reduction in regional LV
myocardial function [28]. Despite ERT, the annual
progression of LV fibrosis was 0.7 0.7% in men
and 0.2 0.3% in women. Subsequent develop-
ment of malignant ventricular tachycardia appears
to be the consequence of ongoing myocardial
fibrosis, which is consistent with the findings of
the autopsy study by Takenaka et al. [28]. Of
interest, ventricular tachycardia was not detected
in any patients without LV fibrosis.
Results from previous trials have demonstrated
that ERT has no impact on proteinuria and
improvement of kidney function [14, 15, 17, 26,
27, 29–31]. In the present study, the annual
decrease in GFR was 2.3 4.6 mL min
1
resulting
F. Weidemann et al. Enyzme-replacement therapy in Fabry disease
338 ª2013 The Authors. Journal of Internal Med icine published by John Wiley & Sons Ltd on behalf of The Association for the Publication of the Journal of Internal Medicine
Journal of Internal Medicine, 2013, 274; 331–341
in substantial loss of kidney function over time.
Intense antiproteinuric therapy through blockade
of the renin–angiotensin system (RAS) is recom-
mended to reduce proteinuria [31]. Despite ERT,
we could not prevent end-stage renal failure
in most patients with baseline proteinuria above
2 g per day. Nevertheless, RAS blockade is advis-
able in patients with Fabry disease with overt
proteinuria.
Cryptogenic stroke is an established complication
of Fabry disease [2, 32–34]. The current findings
suggest that ERT cannot prevent TIA or strokes.
Only one treated patient developed a TIA before a
stroke. Our data suggest that it is important to
focus on severe neurological complications as a
consequence of the severity of cardiomyopathy and
cardiac thrombo-embolism. Diagnostic procedures
should rule out atrial fibrillation on a routine basis
in order to prevent strokes of cardiac origin
because of the availability of preventive measures
such as anticoagulation.
The current findings indicate that patients with
advanced Fabry disease should undergo a compre-
hensive organ staging at routine intervals, as
recommended by current guidelines [16, 35].
Experience from patients with other chronic pro-
gressive diseases may be applied to those with
Fabry disease. The amount of proteinuria and the
level of myocardial replacement fibrosis are helpful
prognostic indicators to motivate the initiation of
adjunctive therapies to prevent major complica-
tions of Fabry disease.
Although the observation period was long, the size
of the cohort was relatively small. Registries would
provide the opportunity to collect solid outcome
data from larger groups, but the comprehensive
collection of data from LE imaging, SR imaging,
assessment of ventricular tachycardia and tracer
studies of renal function is a major challenge.
Nevertheless, the follow-up time of 6 years may
compensate partly for the sample size as at
least one major event was recorded in 35% of
patients.
In the current study, it was not possible to include
a randomized control group. Because of ethical
considerations as stated above, patients at a sim-
ilar stage of disease could not be deprived of a
therapy considered to be effective. To compensate,
we used carefully matched registry data from
subjects following the natural course of the dis-
ease; however, due to the observational nature of
the data, careful interpretation is recommended.
It was initially intended that our cohort study com-
prising 180 individual patients would continue for
longer than 6 years. The advent of enzyme shortage
from September 2009 forced us to terminate the
study as most patients were initially treated with
low-dose agalsidase beta and were then switched to
licensed doses of agalsidase alfa. The present data
may have an important impact when the supply of
agalsidase beta is restored and triage strategies can
provide enzyme to those who need it most.
In conclusion, ERT in patients with advanced
Fabry disease did not prevent progression towards
fatal organ failure and death. These results sup-
port the rationale for early treatment of patients
with Fabry disease.
Conflict of interest statement
F. Weidemann, M. Niemann and F. Breunig have
received speaker honoraria from Genzyme and
Shire Corporation. F. Weidemann and C. Wanner
are members of the Fabry Registry European Board
of Advisors and have received travel assistance and
speaker honoraria. Research grants were given by
Genzyme and Shire Corporation.
Acknowledgements
We thank the patients who agreed to participate in
the study through enrolment in the Fabry Registry
and the physicians and research coordinators
(especially Katharina Baumg€
artner and Johannes
Kr€
amer) who provided clinical data on these
patients. We also acknowledge our colleagues at
Genzyme Corporation (Cambridge, MA, USA), espe-
cially J. Alexander Cole, DSc, MPH, for assistance
with statistical analysis of the cohort of subjects in
the Fabry Registry.
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Correspondence: Frank Weidemann, Medizinische Klinik und
Poliklinik I, Universit€
atsklinik W€
urzburg, Oberd€
urrbacherstr. 6,
D-97080 W€
urzburg, Germany.
(fax: +49 931 201639191; e-mail: weidemann_f@medizin.
uniwuerzburg.de).
F. Weidemann et al. Enyzme-replacement therapy in Fabry disease
340 ª2013 The Authors. Journal of Internal Med icine published by John Wiley & Sons Ltd on behalf of The Association for the Publication of the Journal of Internal Medicine
Journal of Internal Medicine, 2013, 274; 331–341
