Accepted Manuscript
Title: Ischemic stroke due to hypoperfusion in a patient with a previously
unrecognized danon disease
Author: Marco Marino, Olimpia Musumeci, Giuseppe Paleologo, Maria
Cucinotta, Alba Migliorato, Carmelo Rodolico, Antonio Toscano
PII:
DOI:
Reference:

S0960-8966(16)30883-5
http://dx.doi.org/doi: 10.1016/j.nmd.2016.09.025
NMD 3271

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Neuromuscular Disorders

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12-8-2016
29-9-2016
30-9-2016

Please cite this article as: Marco Marino, Olimpia Musumeci, Giuseppe Paleologo, Maria
Cucinotta, Alba Migliorato, Carmelo Rodolico, Antonio Toscano, Ischemic stroke due to
hypoperfusion in a patient with a previously unrecognized danon disease, Neuromuscular
Disorders (2016), http://dx.doi.org/doi: 10.1016/j.nmd.2016.09.025.
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Ischemic stroke due to hypoperfusion in a patient with a previously unrecognized Danon
disease

Marco Marinoa, Olimpia Musumecia, Giuseppe Paleologob, Maria Cucinottaa, Alba Miglioratoa,
Carmelo Rodolicoa, Antonio Toscanoa.
a

Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy

b

Department of Cardiovascular Diseases, Papardo - Piemonte Hospital, Messina, Italy

Corresponding author: Antonio Toscano
Email address: atoscano@unime.it
Full postal address: UOC Neurologia e Mal. Neuromuscolari, Department of Clinical and
Experimental Medicine, AOU Policlinico “G. Martino”, Via Consolare Valeria N° 1, 98125
Messina, Italy
Phone numbers: +390902213500

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Highlights


We report on a Danon patient with HCM and ischemic stroke.



Stroke is a rare complication of Danon disease, usually due to cardioembolism.



Haemodynamic stroke is an alternative cause of stroke in Danon disease.



Danon disease should be considered in patients with stroke and HCM.

Abstract
Danon disease, an X-linked multisystemic disorder, is due to deficiency of Lysosome-Associated
Membrane Protein 2 (LAMP2). It is usually characterized by hypertrophic cardiomyopathy, mental
retardation and skeletal myopathy, sometimes also with atypical features. A 20-year-old man with
cognitive impairment was admitted to the Emergency Room because of a sudden chest pain. ECG
showed Wolff-Parkinson-White syndrome; echocardiography revealed hypertrophic
cardiomyopathy, and, shortly after, he experienced a cardiac arrest followed by an occipital
ischemic stroke. On neurological examination, he complained of visual loss, and diffuse muscle
wasting and weakness were also unexpectedly noted. Electromyography evidenced a myopathic
pattern and a peripheral neuropathy. A muscle biopsy disclosed vacuolar myopathy with glycogen
storage; immunohistochemical studies demonstrated a LAMP-2 deficiency. LAMP2 molecular
analysis identified a de “novo” mutation (p. Q353X). This patient with a neglected Danon disease,
experienced an unusual complication as a stroke due to cerebral hypoperfusion after cardiac arrest
caused by WPW syndrome.
Keywords: Ischemic stroke; Danon disease; brain hypoperfusion; “de novo” mutation

Introduction
Danon disease is a rare X-linked dominant disorder (Xq24-q25) due to mutations in the gene
encoding for Lysosome Associated Membrane Protein-2 (LAMP- 2B isoform) [1]. In 1981, this
disorder was first described as “Lysosomal glycogen storage disease with normal acid maltase” [2].
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In fact, its morphological hallmarks in skeletal and cardiac muscles were cytoplasmic vacuoles
containing autophagic material and glycogen storage, mimicking Pompe disease but with normal
acid maltase activity. Men usually are affected but also women can be symptomatic manifesting
with a mild late-onset heart involvement or, sometimes, with a severe course almost
indistinguishable from the male pattern [3]. The clinical phenotype is often characterized by a
clinical triad: hypertrophic cardiomyopathy (HCM), mental retardation and skeletal myopathy, but
sometimes HCM can be the first evidence of the disease as well as exercise intolerance, persistent
hyperCKemia [4] or ECG abnormalities, often sustained by Wolff-Parkinson-White (WPW)
syndrome [5-6].
Recently, retinopathy, neuropathy and gastrointestinal involvement have also been reported, as less
usual clinical features [7]. Cerebrovascular complications are quite rare: to our knowledge, only
three cases of stroke of cardioembolic origin have been described [8].
However, juvenile ischemic stroke (JIS) represents 15% of all ischemic vascular events. Causes are
quite heterogeneous as arteriopathies (i.e. the carotid artery dissection) or congenital heart diseases
but JIS has also been reported in some monogenic disorders as cerebral autosomal dominant
arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), Fabry disease,
MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) etc [9].
We report, herein, a young man with a neglected history of Danon disease, who developed an
ischemic stroke after a cardiac arrest sustained by WPW syndrome [10].

Case report
The proband was a 20-year-old boy, born from consanguineous parents with no family history of
neuromuscular disorders. Since childhood, he showed cognitive impairment and behavioural
disturbances. At 18 years of age, he started to complain of fatigue and progressive difficulty in
walking, climbing stairs and rising from a seated position; he also showed weight loss and increased
levels of transaminases (GOT 235 U/l, GPT 219 U/l).
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At 19 years of age, he was admitted to the Emergency Room because of sudden dyspnoea and chest
pain. ECG showed paroxysmal supraventricular tachycardia (PSVT), short P-R interval and delta
waves (preexcitation condition), due to WPW syndrome (Fig 1 A), which was acutely treated with
amiodarone infusion and, subsequently, with direct-current shock at 120 J. Echocardiography
revealed a severe global left ventricular hypertrophy, mainly at the interventricular septum (IVS)
(IVS: 23 mm- n.v. 11 mm) with a strongly depressed systolic function (ejection fraction (E.F. –
20/25 %). In absence of intramural thrombus or dilated ventricular chambers, the clinical pattern
suggested a severe HCM with generalized left ventricular hypokinesia. A continuous treatment with
beta-blockers and oral amiodarone was maintained for several months to prevent paroxysmal
episodes of atrial flutter; in the mean time, subcutaneous low-weight-molecular heparin injection
was also started. Despite this therapy, he still complained of some episodes of atrial flutter, which
were sensitive to electrical direct-current cardioversion.
Unfortunately, at 20 years of age, during a new episode of PSVT, he experienced a cardiac arrest
which, although immediately treated in the emergency room by cardio-pulmonary resuscitation
manoeuvre, determined a severe ischemic stroke causing bilateral visual loss because of acute
cerebral hypoperfusion. Meanwhile, no other prominent neurological deficits were observed. He
was immediately admitted to a Neurological Unit: on examination, marked visual loss was evident
as well as a mild spasticity of the four limbs and weak deep tendon reflexes but, surprisingly, a
diffuse muscle wasting and weakness of the four limbs with a “stocking and glove” hypoesthesia
was also noticed. Then, referred to our Neuromuscular Center, he was studied more thoroughly.
Neuropsychological tests confirmed the cognitive impairment.
A brain MRI, with T1, T2 and FLAIR-weighted images, evidenced bilateral hyperintense signals in
occipital and parietal lobes as a sub-acute phase of an ischemic injury (Fig. 1 C, D, E). However, it
was not possible to perform additional studies such as MR angiography, carotid ultrasonography
and SPECT because of the critical condition of the patient. Blood tests revealed persistently
increased values of ALT 244 U/l (n.v. 15- 45), AST 243 U/l (n.v. 30- 65), LDH 875 U/l (n.v. 844

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246), CK 358 U/l (n.v. 39- 308) and CK-MB 9.6 U/l (n.v. 0- 3.6). Myoglobin was also increased
(943 ng/ml n.v. 10- 92), Hemostatic parameters, like prothrombin time (PT), INR, activated partial
thromboplastin time (aPTT), fibrinogen and antithrombin were normal. Brain natriuretic peptide
(Pro-BNP), a proven marker for the diagnosis of heart failure, was quite elevated (9004 pg/ml - n.v.
0-125). Arterial blood-gas analysis was normal whereas chest X-rays documented a right basal
consolidation, bilateral hilar congestion and cardiomegaly. Spirometry was not performed because
of poor patient cooperation.
Heart MRI showed a severe left ventricular hypertrophy, mainly at lateral and posterior walls (Fig.
1 B).
An EMG revealed a prominent myopathic pattern whereas electroneurography (ENG) also detected
a reduction of MCVs and SCVs, more diffuse in the lower limbs, and compatible with a diagnosis
of a sensorymotor demyelinating neuropathy.
A biopsy from the left vastus lateralis muscle revealed an increased variability of muscle fibers size
whose majority (65-70%) contained vacuoles PAS and acid phosphatase positive with increased
glycogen storage. Immunostaining with antibodies against LAMP-2 and LIMP-1, two lysosomal
membrane proteins, demonstrated absent immunoreactivity of LAMP-2, whereas LIMP-1 strong
reaction was present within intracytoplasmatic vacuoles (Fig. 2).
LAMP-2 gene molecular genetic analysis was performed by direct sequencing of all coding regions
using a set of primers previously described [11]. Sequence analysis revealed the presence of a
nonsense mutation c.1057C>T in exon 8, which introduced a premature stop codon at position 353
(p.Q353X) in the LAMP-2. This change was not detected in the proband’s parents, brothers and
sisters and consequently, that DNA variant was considered a “de novo” mutation.
Patient clinical situation remained very severe: after 3 weeks, the cardiac condition deteriorated as
well as blood gas analysis which showed a metabolic acidosis and hyperlactatemia. He died because
of cardiorespiratory failure. No autopsy studies were performed because there was no family
consensus.
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Discussion
Danon disease is a multisystemic disorder, often characterized by vacuolar myopathy, mental
retardation and hypertrophic cardiomyopathy (HCM). The X-linked nature of inheritance accounts
for the different clinical severity between men and women. In men, disease onset occurs earlier than
in women; heart involvement may require transplantation in the second or third decade, but
sometimes this disease leads to an early sudden death [7].
In 2002, Sugie et al. reviewed 38 genetically confirmed cases (20 men and 18 women) and provided
a comprehensive description of the typical clinical and pathological features as myopathy,
hypertrophic cardiomyopathy, mental retardation, high CK values, epato-splenomegaly and ECG
alterations [12]. Since then, other cases have been recorded and recently Boucek et al. reported
additional less usual clinical features as visual problems, muscle cramping, peripheral neuropathy
and gastrointestinal involvement manifesting with chronic abdominal pain, constipation and
diarrhoea [7]. Ischemic stroke is quite a rare complication of Danon disease (see Table 1): in 2008,
Spinazzi et al described three juvenile/adult cases with HCM who complained of cardioembolic
strokes, caused by atrial fibrillation (AF) [8]. They suggested that embolic events could be related
to either paroxysmal or chronic AF, severely depressing the ejection fraction. Juvenile ischemic
stroke (JIS) is a heterogeneous multifactorial disorder which occurs in subjects under 45-50 years of
age. In young adults, cardioembolism (patent foramen ovale, rheumatic valvular heart disease,
congenital cardiac diseases and dilative cardiomyopathy) and cervico-cephalic arterial dissection
are the main aetiological factors, but other genetic conditions have been reported to cause a JIS. In
connective tissue disorders, cerebrovascular complications are due to intracranial aneurysms, artery
dissection and spontaneous rupture of large and medium-sized arteries. Other rarer single-gene
disorders have been described as CADASIL, Fabry disease, Sickle-cell disease, MELAS, Marfan
syndrome and Ehlers-Danlos syndrome type IV [13], but only some of them may present a

6

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neuromuscular involvement. In Pompe disease, cerebral aneurisms and cerebrovascular
abnormalities have been recently described [14], but paroxysmal heart disorders are very rare [15].
Our patient developed an ischemic stroke due to cerebral hypoperfusion after a cardiac arrest caused
by WPW syndrome (see Table 1) which is known to produce a rapid conduction of atrial fibrillation
over the accessory connection to the ventricle, precipitating ventricular fibrillation [5, 6, 16]. The
brain ischemic mechanism was indirectly confirmed by MRI features, which documented bilateral
ischemic lesions at the watershed areas (Fig. 1 C, D, E). Susceptibility of the watershed (WS) areas
to ischemic injury is due to their location in “distal fields”, where perfusion pressure is lower and
consequently, episodes of severe hypotension could cause bilateral WS infarcts. [17, 18]. This case
suggests that, apart from cardioembolic events, a hemodynamic mechanism due to hypoperfusion,
could be considered as an alternative cause of stroke in Danon disease which provoked acute visual
loss.
On the other hand, ocular problems, in Danon disease, are usually due to maculopathy or
retinopathy, characterized by a diffuse cone-rod dystrophy with a salt and pepper appearance of the
mid peripheral retina and severe visual loss [19].
Peripheral neuropathy has rarely been characterized in previous reports: Sugie et al, in 2002,
described presence of distal atrophy in lower limbs and pes cavus with normal nerve conduction
studies in three patients [12]; in 2004, Laforet et al. reported a patient with a mild axonal
polyneuropathy, mimicking a Charcot-Marie-Tooth disease [20]. In the present case, a sensorymotor demyelinating peripheral neuropathy, further limiting patient motor activities, was
demonstrated by clinical and electrophysiological studies.
Unfortunately, due to the low cultural status of the patient’s relatives, the “myopathic condition”
was ignored for a long time. Consequently, the diagnosis of Danon disease was quite delayed and
patient’s clinical condition progressively worsened, also because of severe heart failure. Previous
studies in Danon disease as well in other myopathies, i.e. Duchenne muscular dystrophy (DMD) or
Becker muscular dystrophy (BMD), have demonstrated that heart transplantation can successfully
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improve survival and quality of life, although interventional procedure is seldom performed because
of the severe clinical status of these patients[1,21, 22]. In the last few years, new techniques, like
left ventricular assist device (LVAD) implantation, have been developed improving cardiac output,
alleviating heart failure and ameliorating the quality of life [23]. Consequently, in young males with
progressive cardiomyopathy and/or heart arrhythmias as in Danon disease, physicians should pay
attention to the possibility of a timely cardiac transplantation or LVAD implantation since the
patient’s general conditions are not yet so jeopardized.
In conclusion, this case suggests that in young patients with an undiagnosed myopathy and a
prominent HCM, Danon disease should be seriously considered in the differential diagnosis.

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Acknowledgements
We thank all the staff of the Neurology and Neuromuscular Disorders Unit of the University of
Messina, Italy as well as the Department of Cardiovascular Diseases of “Papardo-Piemonte
Azienda” of Messina for their clinical and technical assistance.
We also would like to thank Telethon for grant “GUP13013” that made possible this study

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and adolescents. Neurology 2013; 81: 1089-1097
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cardiomyopathy (Danon disease). Nature 2000; 406: 906-910
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confirmed Danon disease. Neurology 2002; 58: 1773-1778
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14) Montagnese F, Musumeci O, Toscano A et al. Intracranial arterial abnormalities in patients with
late onset Pompe disease (LOPD). J Inherit Metab Dis. 2016 Feb 1.
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late onset Pompe disease. Neuromuscular Disorders 2014 Jul; 24 (7): 648-50
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17) Klijn CJM, Kappelle LJ et al. Haemodynamic stroke: clinical features, prognosis and
management. Lancet neurology 2010; 9: 1008-1017
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Clinical Implications. Cerebral Journal of Vascular and Interventional Neurology 2008; 1: 65-69
19) Schorderet DF, Munire FL, et al. Retinopathy in Danon disease. Arch Ophthalmology.
2007;125:231-236
20) Laforet P, Charron P, Sebillon P et al. Charcot- Marie- Tooth features and maculopathy in a
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Figure Legends
Fig. 1- ECG: (A) bizarre QRS waves widening of QRS complex and ST changes, suggestive of
Wolff-Parkinson-White syndrome
Heart MRI: (B) severe hypertrophy of left ventricle posterior wall
Brain MRI: T1 (C), T2 (D) and FLAIR (E) -weighted images: bilateral hyperintense signals
in occipital and parietal lobes as a subacute phase of an ischemic insult.
Fig 2 - Muscle biopsy: (A) PAS stain: fiber size variability; several fibers (65-70%) contain vacuoles
with glycogen storage, (B) focus of increased acid phosphatase activity,
(C) immunohistochemistry for LAMP2 showing an absence of the protein and (D) an over
expression of LIMP1 protein.

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Table 1: Summary of 4 patients with Danon disease that developed an ischemic stroke
Patient

Cardiomyopathy

Age at

Signs and/or

history

onset

symptoms at onset

Ictus origin

Central nervous system
involvement after
cerebral accident

Patient 1

+

9

Scleral jaundice and

Cardioembolic

increased liver enzymes
Patient 2

+

20

Easy fatigability and

hemiparesis
Cardioembolic

dyspnea
Patient 3

+

26

Palpitations and easy

Motor aphasia and right

Aphasia and right
hemiplegia

Cardioembolic

fatigability

Transient aphasia, right
facial deficit and
hemisensory loss

Our case

-

18

Weight loss, easy

Haemodinamic

Bilateral visual loss

fatigability and
elevated liver enzymes

13

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