Cardiovascular Pathology 60 (2022) 107453

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Cardiovascular Pathology
journal homepage: www.elsevier.com/locate/carpath

A case of endomyocardial biopsy-proven early stage cardiac

involvement in heterozygous Fabry disease ✩
Hiromitsu Kanamori, MD, PhD 1,∗, Akihiro Yoshida, MD, PhD 1, Hideo Sasai, MD, PhD 2,
Tatsuhiko Miyazaki, MD, PhD 3, Atsushi Mikami, MD, PhD 1, Hiroyuki Okura, MD, PhD 1
1
Department of Cardiology, Gifu University Graduate School of Medicine, Gifu, Japan
2
Department of Pediatrics, Gifu University Graduate School of Medicine, Gifu, Japan
3
Pathology Division, Gifu University Hospital, Gifu, Japan

a r t i c l e i n f o a b s t r a c t

Article history: Background: Fabry disease is a lysosomal disorder caused by a deficiency in α -galactosidase A. Heterozy-
Received 24 May 2022 gous female patients remain free of serious complications, including cardiovascular symptoms, until late
Revised 1 July 2022
in life. This often makes it difficult to decide on the best time to initiate treatment in female patients.
Accepted 12 July 2022
Still, it is important to initiate treatment before the disease progresses too far.
Case summary: We report the case of a 39-year-old asymptomatic female patient with Fabry disease [het-
Keywords: erozygous p.Arg301Pro (c.902 G>C) variant in the 6th exon of α -galactosidase A (NM_0 0 0169.3)]. After 8
Fabry disease years of follow-up, increased QRS voltage and strain T waves developed in the left precordial electrocar-
endomyocardial biopsy diogram leads in the absence of hypertension, left ventricular hypertrophy or ischemia. Echocardiography,
ECG abnormality
cardiac magnetic resonance, and coronary angiography showed normal findings. Through endomyocardial
microalbuminuria
biopsy, the patient was ultimately diagnosed with early stage cardiac involvement of her Fabry disease,
chaperon therapy
and chaperon therapy was initiated. Follow-up after one year revealed reduction of both the electrocar-
diogram abnormality and microalbuminuria, suggesting disease progression was halted.
Conclusion: This case highlights importance of prompt diagnosis of asymptomatic Fabry disease through
endomyocardial biopsy as well as the potential benefit of chaperon therapy.
© 2022 Elsevier Inc. All rights reserved.

1. Introduction diagnosed with the aid of an endomyocardial biopsy (EMB) at a

Fabry disease, a lysosomal disorder caused by a deficiency or
lack of α -galactosidase A (GLA), often produces cardiovascular and
renal complications. Cardiac involvement is a significant factor con-
tributing to a poor prognosis and is the most common cause of
death. Typically, heterozygous female patients remain free of seri-
ous complications until later in life than hemizygous male patients
[1]. However, the disease progresses silently in female patients, of-
ten making it difficult to decide on the best time to initiate treat-
ment. Chaperon therapy has recently proved effective in patients
with an amenable mutation without serious side effects [2]. We re-
port herein the case of an asymptomatic female patient who was
Abbreviations: EMB, endomyocardial biopsy; GLA, α -galactosidase A; ERT, en-
zyme replacement therapy; LVH, left ventricular hypertrophy; ECG, electrocardio-
gram; CMR, cardiac magnetic resonancec; lyso-Gb3, lyso-globotriaosylceramide;
LGE, late gadrinium enhancementl.
✩
No conflict of interest, financial or otherwise, is declared by the authors.
∗
Address for Correspondence: Hiromitsu Kanamori, MD, PhD, Department of Car-
diology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194,
Japan.
E-mail address: hk1973@gifu-u.ac.jp (H. Kanamori).
very early stage of cardiac involvement and was effectively treated
with migalastat, a pharmacological chaperon therapy agent.
2. Case report
2.1. History of presentation
A 39-year-old woman, the mother of a 10-year-old boy with
Fabry disease resulting from a hemizygous p.Arg301Pro (c.902
G>C) variant in the 6th exon of GLA (NM_0 0 0169.3), which en-
codes GLA, was referred to our department for evaluation by the
pediatrician treating her son. Her son has exhibited acroparesthe-
sia and hypohidrosis since the age of 6 and was diagnosed at 10.
He has been treated with enzyme replacement therapy (ERT) since
his diagnosis. On the other hand, our patient, who is heterozygous
for the same variant, was asymptomatic with no remarkable medi-
cal history: she exhibited no painful extremities, corneal dystrophy,
hypohidrosis or angiokeratomas. A chest X-ray showed a normal
cardiothoracic ratio without pleural effusion or pulmonary edema.
Echocardiography revealed normal cardiac function and left ven-
tricular (LV) wall thickness. Her electrocardiogram (ECG) showed

https://doi.org/10.1016/j.carpath.2022.107453
1054-8807/© 2022 Elsevier Inc. All rights reserved.
H. Kanamori, A. Yoshida, H. Sasai et al.
Fig. 1. Time course of changes in the patient’s electrocardiogram at 39 (A), 47 (B), and 48 (C) years old, respectively. Shown are ST-segment changes at first reference (A) and
before (B) and after (C) 12 months of treatment. Repolarization abnormalities appeared in leads II, III, aVf and V2-V6 (B). After 1-year of chaperon therapy, the repolarization
abnormalities were diminished, particularly in leads II, III, aVf and V2-V6 (C).
normal conduction velocities and an absence of left ventricular
high voltage (Fig. 1A). Blood and urine examination yielded nearly
normal findings. She was therefore followed up carefully and reg-
ularly without medication.
Eight years later she remained asymptomatic, but her ECG re-
vealed short PR intervals with increased QRS voltages and ST seg-
ment/T wave alterations in limb leads II, III and aVf, and in the
left precordial leads V2-V6. (Fig. 1B). The increased LV voltage
and change in repolarization without a change in wall thickness
suggested myocardial degeneration consistent with Fabry disease
[3,4].
2.2. Diagnosis
The patient did not exhibit hypertension during the follow-up
period. Her arterial blood pressure was 92/60 mmHg, and echocar-
diography revealed normal cardiac function with no hypertrophy
(Fig. 2A-E). Cardiac magnetic resonance (CMR) imaging revealed no
myocardial hypertrophy, edema or fibrosis (Fig. 2F and G). Coro-
nary angiography showed no organic stenosis. This patient had no
2
Cardiovascular Pathology 60 (2022) 107453
manifest cardiac signs other than the abnormal ECG. Although no
overt renal dysfunction or proteinuria was seen, microalbuminuria
[albumin-to-creatinine ratio (Alb/Cr) 64.1 mg/gCr (normal range:
≤30 mg/gCr)] was detected. The patient exhibited normal GLA ac-
tivity, 23.99 pmol/punch/hr (normal range: ≥11.27 pmol/punch/hr);
however, her blood lyso-globotriaosylceramide (lyso-Gb3) level, a
useful metabolic biomarker, was elevated to 15.1 ng/mL (normal
range: 0.28-0.56 ng/mL).
Based on those findings, the patient was categorized as hav-
ing the cardiac variant of Fabry disease [1]. To assess progression
of the cardiac involvement at the cellular level, we performed an
EMB. Under light microscopy, moderate interstitial and perivascu-
lar fibrosis was observed. Notably, a mosaic pattern of vacuolated
hypertrophied myocytes reflecting lyonization (X-inactivation) was
also observed (Fig. 3A and B). This mosaic pattern of normal and
vacuolated cells is caused by random embryonic inactivation of ei-
ther X-chromosome followed by clonal proliferation thereafter. It
is characteristic of heterozygous female Fabry disease patients. Un-
der electron microscopy, abundant lamellar bodies with a myelin-
like configuration were observed within myocytes and the en-
H. Kanamori, A. Yoshida, H. Sasai et al. Cardiovascular Pathology 60 (2022) 107453

Fig. 2. Echocardiographic imaging of the left ventricle in the apical [two-, three-, and four-chamber (A, B, and C, respectively)] view and pulse wave doppler of the transmitral
flow (D). IVS, intraventricular septum (9 mm); LVPW, left ventricular posterior wall (10 mm); LVEF, left ventricular ejection fraction (74%). The transmitral doppler shows
the normal pattern for A-wave and E-wave velocities (E/A ratio 1.73). Left ventricular global longitudinal strain visualized through automated function imaging revealed a
normally ranged strain pattern. The global longitudinal strain average was -23.6% (E). Cardiac magnetic resonance imaging in short axis views. Black blood myocardial T2
mapping (F) and late gadolinium enhancement (G) showed an absence of left ventricular hypertrophy, tissue edema, inflammation and fibrosis.

3
H. Kanamori, A. Yoshida, H. Sasai et al. Cardiovascular Pathology 60 (2022) 107453

Fig. 3. Endomyocardial biopsy. Photomicrographs of hematoxylin and/or eosin-(A) and Masson’s trichrome-stained (B) sections showing interlacing fibrosis and a mosaic
pattern, which is consistent with the presence of both normal cardiomyocytes (white arrow heads) and affected cardiomyocytes (black arrow heads) showing prominent
vacuolization. Normal cardiomyocytes (right cluster) and affected cardiomyocytes (left cluster) are shown side by side in (A’). Bars: 100 μm. Electron micrographs show large
numbers of myeloid bodies, called “zebra bodies” (arrows), within cardiomyocytes (C) and the endocardium (D). A’ and D’ are enlargements of the boxed areas in A and D,
respectively. Bars: 1 μm. Mt, mitochondria, Mf, myofibril; IC, intercalated disc; End, endocardium.

docardium, indicating accumulation of glycosphingolipids due to
Fabry disease progression (Fig. 3C and D).
2.3. Management
The patient was administrated migalastat, an oral small-
molecule pharmacological chaperone therapy agent, which sta-
bilizes amenable misfolded GLA mutants [2]. After 12 months
of treatment, the patient had experienced no side effects, but
GLA activity had increased (34.79 pmol/punch/hr or 145% of pre-
treatment value, Table 1), her blood lyso-Gb3 level had decreased
by nearly half (8.74 ng/mL, 58% of that before treatment, ibid.), and
urinary microalbumin excretion was also reduced by about half
(Alb/Cr: 33.6 mg/gCr, 52% of the level before treatment). Echocar-

4
H. Kanamori, A. Yoshida, H. Sasai et al.
Table 1
Effect of 1-year chaperon therapy on GLA activity, renal function, and cardiac function
Pre treatment
Plasma a-GLA activity, pmol/punch/hr 23.99
Plasma Lyso-Gb3, ng/mL 15.1
eGFR, mL/min/1.73m2 87.3
Serum Creatinine, mg/dL 0.58
Albuminuria, Alb/Cr, mg/gCr 64.1
Echocardiography
IVSth, mm 9 8
PWth, mm 10
LVDd, mm 47
LVEF 74
GLS% -23.6
MV E/A ratio 1.73
a-GLA, galactosisase A; Lyso-Gb3, lyso-globotriaosylceramide; eGFR, estimated glomerular filtration rate; IVSth, intra-
ventricular septum thickness; PWth, posterior wall thickness; LVDd, left ventricular end-diastolic diameter; LVEF, left
ventricular ejection fraction; GLS, global longitudinal strain.
diography revealed her cardiac function and geometry to be un-
changed (Table 1). In addition, her ECG showed a reduction in
the ST segment abnormality (Fig. 1C). At the most recent follow-
up, in 2022, the patient was asymptomatic with no change in
her ECG. These findings indicate disease progression was halted,
despite the relatively short treatment period. We plan to main-
tain her on chaperon therapy. However, careful follow-up will be
needed.
3. Discussion
Patients with Fabry disease can present with cardiovascular
and/or renal pathophysiology. Because these patients inherit a
mutated gene on their X chromosome, heterozygous female pa-
tients present with a wide spectrum of disease complications [1].
Our patient presented with a newly developed ECG abnormality
in the ST segment in the absence of hypertension, LV hypertro-
phy or ischemia. An ECG strain pattern is mainly observed in fe-
male patients, irrespective of left ventricular hypertrophy (LVH) [5].
This strain pattern may reflect early-stage myocardial fibrosis. Late
gadrinium enhancement (LGE) of CMR is useful for detecting fibro-
sis in female patients, even those with little or no LVH [4–6]. Our
patient was negative for LGE; however, EMB revealed mild cardiac
fibrosis, suggesting the cardiac involvement of her Fabry disease
was at a very early stage. Recently developed quantitative meth-
ods, such as T1 mapping, enables detection of mild fibrosis [7,8].
ERT or chaperon therapy is indicated for female patients with later
onset Fabry disease, but it is often difficult to decide when to ini-
tiate treatment in asymptomatic patients. According to guidelines,
ERT should be considered if there is any laboratory, histological or
imaging evidence of injury to the heart or kidneys attributable to
Fabry disease, even in the absence of other typical Fabry symp-
toms [9]. Long-term data show that ERT has beneficial effects but
also has drawbacks. For instance, it requires intravenous adminis-
tration every 2 weeks, and inhibitory antibodies develop in some
patients. Recently, chaperon therapy with migalastat has proved
effective for patients with an amenable mutation. The drug sta-
bilizes the altered enzyme, thereby diminishing the accumulation
of pathogenic cellular substances. Migalastat is administered orally
every other day and has no serious side effects [2]. Our patient
has an amenable mutation that was previously reported to be a
classical type of Fabry disease [10]. She did not exhibit cardiac hy-
pertrophy or fibrosis, despite moderate pathological findings. The
therapeutic goal was to inhibit disease progression caused by the
accumulation of harmful substances. In our case, ECG changes and
decreased microalbuminuria correlated with a therapeutic effect
against Fabry disease. The reduction in ECG abnormality was par-
alleled by an increase in GLA activity and reductions in blood lyso-
5
Cardiovascular Pathology 60 (2022) 107453
Post 1-year treatment Normal range
34.79 ≥11.27
8.74 0.28-0.56
89.5 ≥90
0.56 0.46-0.79
33.6 ≤30
9
49
73
-22.3
1.39
Gb3 and microalbuminuria. We suggest that ECG changes could be
a useful marker of disease progression and therapeutic efficacy in
Fabry disease patients with cardiac involvement.
4. Conclusion
There is no consensus regarding the best time to initiate chap-
eron therapy in asymptomatic heterozygous Fabry disease patients,
but we have added another case to the literature to emphasize
the importance of prompt diagnosis through EMB when a patient
with Fabry disease presents a newly developed ECG abnormality.
Early administration of chaperon therapy could promise a favorable
prognosis for pre-symptomatic Fabry disease patients.
Ethics
Written informed consent was obtained from the patient for
publication of this case report. This genetic research was approved
by the ethics committee of Gifu University Graduate School of
Medicine (Approval number: 29-210). The investigation conformed
to the principles outlined in the Declaration of Helsinki (BMJ 1964;
ii 177).
Funding
We received no funds from anywhere to support this study.
Acknowledgments
We thank Akiho Kimura, Kazuho Niwa, Tomoko Niwa and Akiko
Tsujimoto at Gifu University; Drs. Nagisa Miyazaki and Yasuaki
Hotta at Asahi University for their assistance; and Drs. Kimitoshi
Nakamura and Ken Momosaki at the Department of Pediatrics, Fac-
ulty of Life Sciences, Kumamoto University for our patient’s GLA
gene test.
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