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Neuromuscular Disorders 24 (2014) 648–650
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Case report

Atrio-ventricular block requiring pacemaker in patients with late onset

Pompe disease
Sabrina Sacconi a,⇑, Karim Wahbi b,c, Guillaume Theodore d, Jérémy Garcia a,
Leonardo Salviati e,f, Francßoise Bouhour g, Christophe Vial g, Denis Duboc b,
Pascal Laforêt c, Claude Desnuelle a
a
Neuromuscular Diseases Specialized Center, Archet 1 Hospital, CHU Nice, France
b
Cardiology Department, Cochin Hospital, APHP, Paris, France
c
Neuromuscular Diseases Specialized Center Paris Est, Groupe Hospitalier Pitié-Salpêtrière, APHP, Paris, France
d
Cardiology Department, Pasteur Hospital, CHU Nice, France
e
Clinical Genetics Unit, Department of Woman and Child Health, University of Padova, Padova, Italy
f
IRP città della Speranza, Padova, Italy
g
Electromyography and Neuromuscular Pathologies Department Lyon Est, Bron Hospitals, France

Received 17 January 2014; received in revised form 3 April 2014; accepted 11 April 2014

Abstract

Enzyme replacement therapy consistently improves cardiac function in infantile and juvenile onset patients with Pompe disease and
cardiomyopathy, but is apparently not effective in preventing rhythm disorders, an emerging cardiac phenotype in long term survivors. In
patients with late onset Pompe disease cardiomyopathy is an exceptional finding while heart rhythm disorders seem to be more frequent.
We retrospectively identified, among a cohort of 131 French late onset Pompe disease patients, four patients with severe atrio-ventricular
blocks requiring pacemaker implantation. These patients had no other risk factors for cardiovascular diseases or cardiomyopathy. In one
patient the atrioventricular block was discovered while still asymptomatic. Cardiac conduction defects are relatively rare in late onset
Pompe disease and may occur even in absence of cardiac symptoms or EKG abnormalities. However because of the possible
life-threatening complications associated with these conduction defects, cardiac follow-up in patients with late onset Pompe disease
should include periodical Holter-EKG monitoring.
Ó 2014 Elsevier B.V. All rights reserved.

Keywords: Late-onset Pompe disease; Pompe disease; Cardiomyopathy; Atrioventricular block; Pacemaker; Holter-EKG

1. Introduction accumulation of glycogen in muscle and other tissues.

Pompe disease (PD) MIM #232300 is an autosomal
recessive disorder caused by deficiency of acid
a-glucosidase (GAA – EC 3.2.1.20) and lysosomal
⇑ Corresponding author. Address: University Hospital of Nice,
Neuromuscular Diseases Specialized Center, Archet 1 Hospital, 151
Route de Saint Antoine de Ginestière, 06202 Nice, France. Tel.: +33 (0)
492 03 57 57; fax: +33 (0) 492 03 58 91.
E-mail address: sacconi@unice.fr (S. Sacconi).
Severe hypertrophic cardiomyopathy, ventricular
dysfunction, short PR interval, Wolff–Parkinson–White
syndrome have been described in the infantile and
juvenile form of this disease [1–3]. In these patients,
conduction defects and/or dysrythmia have been attributed
to the thickening and dilatation of cardiac wall due to
glycogen accumulation [4]. Long term survivors of infantile
onset Pompe disease patients display a complete resolution
of cardiomegaly shortly after the beginning of the enzyme
replacement therapy (ERT), but most of them suffer from

http://dx.doi.org/10.1016/j.nmd.2014.04.005
0960-8966/Ó 2014 Elsevier B.V. All rights reserved.
 S. Sacconi et al. / Neuromuscular Disorders 24 (2014) 648–650 649

cardiac arrhythmia that does not seem to respond to the
ERT [5].
In patients with late onset Pompe disease (LOPD)
cardiac involvement is far less frequent and less severe
[6,7], and there is a single report of a patient with cardiac
rhythm disturbances, which had significant impact on
prognosis [8]. Indeed, in these patients cardiomyopathy
seems to be a very rare finding [4,9], while rhythm disorders
are more common and have been described in absence of
cardiomyopathy [7].
Here, we describe four LOPD patients followed in
Neuromuscular Disease Specialized Centers in France
who developed severe life-threatening atrio-ventricular
(AV) conduction defects requiring the implantation of a
pacemaker (Table 1).
2. Case reports
These patients were identified among a cohort of 131
LOPD patients included the French national registry for
Pompe disease patients [10], collecting standardized data
on muscular, cardiac, respiratory, gastrointestinal and
central nervous system involvement. Cardiac follow up
for LOPD include annual EKG, echocardiography
examination and, if any abnormality appear at the EKG,
24 h Holter EKG. None of the patients in this cohort has
had pacemaker implantation within the last 5 years beside
the four patients we described in the present study, who
had no other risk factors for cardiovascular diseases nor
other relevant comorbidities.
The first patient (P1) presented at age 45 with lower limb
muscle weakness and was diagnosed with Pompe disease
(PD). At age 55, he developed respiratory insufficiency
and ERT was introduced. At age 57, EKG revealed a
2nd degree AV block, followed few months later by
syncopal 3rd degree AV block with pauses up to 5500 ms
which required permanent pacing.
The second patient (P2), a 42-year old man, was
diagnosed of PD at the age 30 because of weakness in
lower and upper limbs and involvement of paraspinal
and respiratory muscles. At age 35, EKG revealed sinus
tachycardia, without any prolongation of PR or QRS
intervals while Holter EKG revealed paroxysmal 3rd
degree AV block with pauses up to 5800 ms. A
pacemaker was implanted and ERT was started.
The third patient (P3) developed at age 30 lower limbs
weakness and respiratory insufficiency lading to the
diagnosis of PD. At age 35, ERT was introduced. At age

Table 1
Clinical features of adult onset Pompe disease patients.
Patient Sex Age at onset GAA activity Genetics Muscle Respiratory
(on lymphocytes)
Mutation Muscle involvement Spirometry FVC NIV
P1 M 45 1.0 lkat/kg prot c.32-13T>G Lower limb proximal weakness Seated 94% No
NV: 7.3–13.5 ex18_del Supine 66%
P2 M 30 0.5 lkat/kg prot c.32-13T>G Lower and upper limb proximal weakness Seated 11% Yes
NV: 4.9–13.3 p.G219R Supine10%
P3 M 30 0.9 lkat/kg prot c.32-13T>G Lower limb proximal weakness Seated 75% No
NV: 7.3–13.5 ex18_del Supine 65%
P4 F 32 1.3 lkat/kg prot c.32-13T>G Lower and upper limb proximal weakness Seated 65% No
NV: 7.3–13.5 p.D489N
Patient Cardiac involvement Age at
introduction
Family history of Risk Symptoms EKG Echocardiography Holter Cardiac Age at
of ERT
cardiac problems factors ECG electrophysiological permanent
study pacing (years)
(years)
P1 No. One affected None Sudden 2nd degree Normal 3rd degree HV interval = 74 ms 57 55
brother without syncope AV block EF:74% AV block
cardiac symptoms
P2 Nocturnal sudden None Exercise Sinus Normal 3rd degree Normal 35 35
death of brother dyspnea Tachycardia EF:70% AV block
with PD muscular
symptoms
P3 No None None 2nd degree Normal 3rd degree HV interval = 77 ms 37 35
AV block EF:75% AV block
P4 No None Sudden Long QT Normal 2nd degree ND 47 46
syncope EF:70% AV blocks
(2/1 and
Mobitz II)
GAA, glucosidase alpha acid; NV, normal value; NIV, non invasive ventilation; PM, pacemaker; FVC, forced vital capacity; AV, atrioventricular; EF,
ejection fraction; ERT, enzyme replacement therapy.
650 S. Sacconi et al. / Neuromuscular Disorders 24 (2014) 648–650
37, EKG showed 2nd degree AV block. Six months later,
he developed 3rd degree AV block with a ventricular
frequency of 42 bpm requiring the implantation of a
pacemaker. He died at age 42 of a traumatic injury.
The last patient (P4) was diagnosed with PD because of
lower and upper limb girdle muscle weakness presenting at
age 32; ERT was introduced at age 46. One year later she
presented several episodes of syncope. EKG was normal
except for the presence of long QT, but Holter EKG
revealed 2nd degree AV block with pauses up to 6000 ms
requiring pacemaker implantation.
3. Discussion
The mean age of pacemaker implantation in these
patients was 44 (±10). In contrast with the few case
reports described in literature of PD patients needing a
pacemaker implantation [3,4,8,9], the LOPD patients we
describe had normal echocardiography, without any
evidence of myocardial involvement. AV conduction
blocks were not associated to pre-excitation syndrome.
P1 and P4 were symptomatic (both experienced syncopes
which prompted a complete cardiac examination). P3 was
completely asymptomatic and 3rd degree AV block was
discovered at the annual follow-up EKG, while in P2,
exercise dyspnea was attributed to respiratory insufficiency
since EKG and echocardiography were normal. AV
conduction block was discovered only after systematic
Holter EKG monitoring.
AV conduction blocks were not associated with specific
GAA genotypes, and its appearance seems to be
unpredictable during disease progression. P1, P3, P4 were
receiving enzyme replacement therapy which does not
seem to prevent the appearance of conduction defects. Its
pathogenesis is not clear, even though in some of the
previously reported cases, glycogen infiltration of the
myocardium and His bundle was reported [4]. In P1,
myocardial biopsy performed during surgery for pacemaker
implantation, did not reveal any glycogen accumulation.
However, in analogy with PD cases with normal muscle
biopsy, the negativity of myocardial biopsy in this patient
could result from the lack of sensitivity of this technique.
It is also possible that other factors may be involved in
the development of this complication. In particular, the
coexistence of important respiratory failure (see P3) may
have a role in the appearance or in the worsening of
heart conduction disturbances. Apparently, ERT has no
protective effect on AV conduction block development,
since three of our four patients (P1, P3 and P4) were
receiving the ERT before the onset of symptoms. No other
cases with disturbances of cardiac conduction involvement
were found in the French late-onset PD registry (which
includes 131 patients), confirming the low frequency of this
complication that can be estimated in our cohort at 3%
(95% CI 0.1–6%). 3rd degree AV block are extremely rare
in general population with an overall prevalence of 0.04%
and frequency of 0.05% [11]. Larger cohort studies are
needed to confirm the association and the exact prevalence
of AV conduction blocks in LOPD. Nevertheless, since AV
blocks may result in potentially life-threatening situations,
we suggest that a complete cardiac follow-up, including
Holter EKG monitoring, should be performed regularly
in LOPD patients.
Acknowledgments
We would like to thank for their contribution in data
collection and manuscript critical revision Kenza Laloui,
Pauline Lahaut and Catherine Caillaud. All these
collaborators had no relevant conflict of interest.
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