Nikos Protonotarios, MD and
Adalena Tsatsopoulou, MD.
From Yannis
Protonotarios Medical Center, Hora Naxos, Naxos 84300, Greece.
Address for
correspondence: Adalena Tsatsopoulou, MD, Yannis Protonotarios
Medical Center, Hora Naxos, Naxos 84300, Greece. E-mail:
adalena@altecnet.gr
Supported by European Community Research Contract #QLG1-CT-2000-01091
Key Words: Arrhythmogenic
right ventricular dysplasia/cardiomyopathy; Naxos disease; Cell
adhesions; Sudden death
Definition
Since 1995,
according to the World Health Organisation’s classification of
cardiomyopathies, Naxos disease has been considered as the recessive
form of arrhythmogenic right ventricular dysplasia/cardiomyopathy
(ARVD/C).1 It is a
stereotype association of ARVD/C with a cutaneous phenotype,
characterised by woolly hair and palmoplantar keratoderma.2
Epidemiology
Naxos disease
was first reported in 1986 by Protonotarios et al in patients
originating from the Hellenic island of Naxos.2,3 Apart from Naxos, cases have also been
reported from other Hellenic islands, as well as from Turkey, Israel
and Saudi Arabia.4 The
prevalence of the disease in Hellenic islands reaches 1:1000. A variety
of Naxos disease presenting at a younger age with more pronounced left
ventricular involvement has been described in families from India and
Ecuador (Carvajal syndrome). 5,6
Molecular Genetics
Genetic
studies have located two causative genes, encoding for the proteins
plakoglobin and desmoplakin. Plakoglobin and desmoplakin are proteins
of cell-cell adhesion.
A 2-base-pair deletion mutation
of the plakoglobin gene (Pk2157del2TG) truncating the C-terminal of the
protein causes Naxos disease.7
This mutation was identified in 13 families from Greece and in one
family from Turkey.4,8
The prevalence of heterozygous carriers is up to 5% of the Naxos
population (20,000 inhabitants). Heterozygotes present normal phenotype
except in a small minority who show woolly hair as well as a few
electrocardiographic or echocardiographic abnormalities not fulfilling
the criteria for ARVC.9 Two
different mutations of the desmoplakin gene (Dsp7901del1G and
DspG2375R), truncating the C-terminal of the protein, have been found
to underlie a similar cardiocutaneous syndrome in families from Ecuador
and Israel.10,11
Clinical presentation and natural
history
In patients
with Naxos disease woolly hair was apparent from birth (Figure 1A), whereas palmoplantar
keratoderma developed during the first year of life as soon as the
infant started to use the hands and feet (Figures 1B and 1C).9,12 In childhood the
patients were asymptomatic with no diagnostic cardiac findings. During
adolescence all affected members presented electrocardiographic and/or
echocardiographic abnormalities fulfilling the criteria for ARVC.13 Resting 12-lead electrocardiogram was
abnormal in more than 90% of patients.9
Electrocardiographic abnormalities included inverted T waves in leads
V1 to V3 or across the precordial leads (77%), QRS complex prolongation
in leads V1 to V3 (73%), epsilon waves (42%) (Figure 1E) and complete or
incomplete right bundle branch block (35%).9
Low voltage and/or flat T waves in left precordial leads were mostly
observed in severe right or biventricular involvement. Ventricular
extrasystoles of left bundle branch block configuration were recorded
in the majority of patients. Ventricular extrasystoles of right bundle
branch block configuration were less common. All patients presented
right ventricular structural/functional alterations; minor alterations,
consisting of mild dilatation or regional hypokinesia, were detected in
27% while major, consisting of severe dilatation, diffuse hypokinesia
and aneurysms mostly of the outflow tract, apex or inferior wall, were
detected in 73% of patients.9
In one fourth of patients left ventricular abnormalities ranging from
regional hypokinesia particularly of posterior wall or apex to diffuse
dilatation and global hypokinesia were detected.9
The
symptomatic presentation was usually with syncope and/or sustained
ventricular tachycardia during adolescence with a peak in young
adulthood.14 During
follow-up arrhythmic events occurred in half of the patients.9 The ECG during ventricular tachycardia
always showed a left bundle branch block pattern (Figure 1F) with a frontal plane axis
ranging from -30 to -60 degrees or +60 to +165 degrees. 14 The inducibility of sustained
monomorphic ventricular tachycardia in the electrophysiology laboratory
was high among those presenting with a clinical episode. Heart disease
progressed during time to the right or both ventricles. Congestive
heart failure developed in one fourth of patients at the end stage of
severe right or biventricular involvement.
The annual total cardiac
mortality rate was 3% and the annual sudden death mortality rate
reached 2.3%.9 Syncope, left
ventricular involvement and the appearance of symptoms and/or
structural progression before the age of 35 years were risk factors for
sudden death.9
Cardiac histology revealed the
typical pattern of ARVD/C15
with fibrofatty replacement of right
ventricular myocardium mainly in subepicardial and mediomural layers
being regionally transmural with formation of aneurysms.4,16 Surviving
myocytes surrounded by fibrosis were embedded within fatty tissue (Figure 1D). Involved left
ventricular myocardium showed fibrofatty or fibrous replacement.4 Lymphocyte infiltrates were observed
particularly when the biopsy was performed at the time of clinical
progression. Cardiac histology in one patient from Ecuador with the
Carvajal variant of Naxos disease differed only in that the fatty
component of replacement process was absent.17
Immunohistochemical
studies, showed that the signal of the mutated protein (plakoglobin or
desmoplakin) and the signal of connexin43 were diminished at
intercellular junctions.17,18
Figure 1: Naxos disease phenotype
of the skin and heart. Woolly hair (A)
and palmoplantar keratoderma (B
and C) are the principal
cutaneous abnormalities. The disease is expressed in the heart as
arrhythmogenic right ventricular dysplasia. Myocardial loss and
fibrofatty replacement of right ventricular myocardium (D) results in delayed activation
(epsilon waves on surface ECG) (E)
predisposing to reentrant ventricular arrhythmias (F).
Pathogenesis of ARVD/C in Naxos
disease
Myocardial
cells are differentiated bipolar cells coupled at intercalated discs
where adherence junctions, desmosomes and gap junctions are located.19 Adherence junctions and desmosomes
secure mechanical coupling while gap junctions serve electrical
coupling. Plakoglobin (γ-catenin) is the only known common component of
both adherence junctions and desmosomes functioning also as a signaling
molecule apart from its structural role in securing the intercellular
adhesion.20 At the
adherence junctions it is connected to the actin cytoskeleton and at
desmosomes to the intermediate filaments of desmin. Desmoplakin is also
a cytoplasmic protein of the desmosomes that interlinks plakoglobin or
plakophilin with desmin intermediate filaments. Defects in linking
sites of these proteins can interrupt the contiguous chain of cell
adhesion, particularly under conditions of increased mechanical stress
or stretch, leading to cell isolation and death, progressive loss of
myocardium and fibro-fatty replacement.4,7 The degree of participation of fat in
the repair process may be related to the rate of disease progression or
may be mutation specific.4
Surviving myocardial fibers within fibro-fatty tissue provide a slow
conduction substrate inducing re-entrant ventricular arrhythmias.21 Recent studies on Naxos disease
revealed that the genetically determined defect in cell adhesion
results in early gap junctions remodeling and altered electrical
coupling which may act synergically with the progressive pathologic
changes in myocardium contributing to a highly arrhythmogenic substrate.18
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