Naxos Disease History

In 1986, an autosomal recessive cardiocutaneous syndrome of ARVC/D associated with woolly hair and palmoplantar keratoderma was first described in families from the Greek island of Naxos [8], from which the sydrome took the name of [9]. The autosomal recessive ARVC/D in Naxos disease is similar to autosomal dominant ARVC/D with respect to age and mode of clinical presentation, distribution of right ventricular and left ventricular involvement, electrocardiographic features, natural history, and histopathology [10-12].

Following the initial presentation, families with Naxos disease phenotype were reported from other areas of the world [13-19]. In some of these families, the cardiomyopathy presented with predominantly left ventricular involvement and early morbidity overlapping clinically with dilated cardiomyopathy [13,14]. This subtype of Naxos disease [20] was initially considered as a separate entity (Carvajal syndrome) [21].

Clinical Presentation

Woolly hair was a common finding in all affected members and it appeared at birth. Diffuse kerato-derma developed later in infancy or early childhood over the pressure areas of palms and soles (Fig. 2.1). Keratoderma was characterized histologically as nonepidermolytic [22] or epidermolytic [7]. Pem-phigous like vesicular lesions on palms, soles, and knees developed in some patients [16].

The cardiomyopathy usually presented with ventricular arrhythmias, electrocardiographic abnormalities, and structural alterations fulfilling the diagnostic criteria for ARVC/D [23]. The symptomatic presentation was usually with syncope and/or sustained ventricular tachycardia during adolescence and young adulthood [24]. Sudden death was the first disease manifestation in some cases. Heart disease progressed from the right to both ventricles. Left ventricular involvement ranging from regional hypokinesia, particularly of the posterior wall or apex, to global dilatation and diffuse hypokinesia was mostly related to the age of patients and to the rapidity of disease progression. Congestive heart failure developed in one fourth of patients as an end-stage feature of severe right or biventricular involvement [25]. In the Carvajal variant of Naxos disease, left ventricular involvement appeared during childhood, suggesting a rapid disease evolution.

Fig. 2.1 • Cutaneous phenotype in a homozygous carrier of plakoglobin mutation. Woolly hair (a), striate kerato-derma in the palm (b),diffuse keratoderma in the plantar areas (c)

Pathology

Cardiac pathology in patients with Naxos disease revealed typical features of ARVC/D (Fig. 2.2). The right ventricle showed extensive myocardial loss with fi-brofatty replacement at subepicardial and mediomur-

Fig. 2.2 • Gross pathology of the heart in a 33-year-old homozygous carrier of plako-globin mutation who died in severe heart failure while waiting for heart transplantation. (a) The right ventricular outflow tract seen from inside.Trans-mural myocardial loss with fatty replacement. (b) Posteroapical wall of the left ventricle. Myocardial loss with fatty replacement in subepicardial layers

Fig. 2.1 • Cutaneous phenotype in a homozygous carrier of plakoglobin mutation. Woolly hair (a), striate kerato-derma in the palm (b),diffuse keratoderma in the plantar areas (c)

al layers being regionally transmural with aneurysms [26]. Strands of surviving myocytes surrounded by fibrous tissue were embedded within adipocytes. Lymphocyte infiltrates were observed particularly when the biopsy was performed at the time of clinical progression. In patients with severe biventricular involvement, the left ventricle showed extensive myocardial loss with fib rofatty replacement mainly at subepicardial layers of the postero-apical wall.

Postmortem evaluation of the heart of an adolescent with Carvajal syndrome showed biventricular involvement [21]. The right ventricle was modestly dilated with aneurysms in the outflow tract, apex, and posterior wall, known as the "triangle of dysplasia". The left ventricle was markedly dilated with aneurysms on the posterior and anteroseptal wall. Microscopic examination showed areas of extensive myocardial loss and replacement fibrosis particularly in subepicardial layers, which is identical to the pathology in ARVC/D although without the fatty component.

Molecular Genetics The Way to Molecular Basis

The coexistence of cardiac and cutaneous abnormalities in Naxos disease suggested a common pathogenetic defect in two embryonically unrelated tissues [8]. The skin of the palms and soles as well as heart muscle are almost constantly subjected to mechanical stress or stretch demanding proper function of intercellular junctions. The identification of a mutation in the gene encoding plakoglobin, a key cell adhesion protein with a wide distribution among tissues including skin and myocardium, highlighted the patho-genesis of ARVC/D in Naxos disease [6]. Plakoglobin mutation led to consideration of ARVC/D as a disease potentially related to a cellular-adhesion defect. This finding stimulated research to find other genes encoding related proteins [27]. Since then, mutations in other desmosomal proteins including desmo-plakin, plakophilin-2, and desmoglein-2 have been recognized as causative genes in families with dominant ARVC/D [28-32].

Cell-Cell Junctions

Myocardial cells are differentiated bipolar cells coupled at intercalated discs where adherence junctions, desmosomes, and gap junctions are located [33]. Adherence junctions and desmosomes provide me chanical coupling, while gap junctions serve as electrical coupling. In desmosomes, plakoglobin, plakophilin-2, and desmoplakin anchor desmin intermediate filaments to transmembrane desmosomal cadherins (desmoglein and desmocollin). Plakoglo-bin and plakophilin-2 are armadillo proteins located at the outer dense plaque of desmosomes and binding with the N-terminal of desmoplakin and with the C-terminal of desmosomal cadherins. Desmoplakin is a larger dumbbell-shaped molecule which makes up the inner dense plaque with its middle coiled rod domain and binds via its C-terminal with desmin intermediate filaments [34]. Plakoglobin is the only desmosomal protein also found at adherens junctions, where it is involved in linking with the actin cy-toskeleton of adjacent myocardial cells [35]. Signaling to the nucleus and involvement in apoptotic mechanisms have also been attributed to plakoglobin [36]. The integrity of desmosomes is important in maintaining the normal function of gap-junction channels responsible for electrical coupling [37].

Recessive Mutations

To date, one plakoglobin mutation and three desmo-plakin mutations have been implicated in recessive ARVC/D (Table 2.1).

A 2-base pair deletion mutation in plakoglobin (2157del2TG) was identified in 13 Greek families and one Turkish family with Naxos disease. This deletion causes a frameshift and premature termination of translation resulting in a truncated protein at the C-terminal domain [6].

A deletion mutation in desmoplakin (7901del1G) was identified in 3 Ecuadorian families with Carvajal syndrome [7]. This deletion causes a premature stop codon leading to a truncated desmoplakin missing the last domain of the C-terminal.

A missense mutation in desmoplakin (G2375R) was identified in one Arab family from Jerusalem [16]. This mutation leads to Gly2375Arg substitution in the C-terminal of the protein.

A nonsense mutation in desmoplakin (C3799T) in association with a polymorphism in plakoglobin (T2089A) was found to cause a severe form of car-diocutaneous syndrome in a Turkish family [19]. This mutation leads to loss of most of the desmo-plakin isoform 1 particularly affecting the C-termi-nal area.

Genetic investigation in two Arab families from Israel and one family from Saudi Arabia with cardio-cutaneous syndrome excluded mutations in the already-described desmosomal protein genes [15,18].

Table 2.1 • Genotype-phenotype features in recessive ARVC/D

Mutation

PG_2157del2(TG)

DP_7901del1(G)

DP_G2375R

DP_C3799T, PG_T2089A

Country of origin

Greece (13),

Ecuador (3)

Israel (1)

Turkey (1)

(No. of families)

Turkey (1)

Cutaneous phenotype

Hair abnormalities

WH

WH

WH

WH

Skin disorder

PPK

PPK

Pemphigous-like

PPK

Cardiomyopathy

Age at earliest

diagnosis (years)

13

8

16

3

Structural

Predominantly RV

Predominantly LV

RV involvement

Severe RV and LV

characteristics

involvement

involvement

involvement

Major arrhythmia

SVT

NSVT

SVT

NSVT

Major clinical events

SYNC, HF, SD

HF, SD

SD

HF

HF,heart failure; LV, left ventricular; NSVT,non-sustained ventricular tachycardia;PPK,palmoplantar keratoderma;RV,right ventricular; SD, sudden death; SVT, sustained ventricular tachycardia; SYNC, syncope;WH, woolly hair.

Genotype-Phenotype Plakoglobin Mutation

Recessive ARVC/D due to plakoglobin mutation is 100% penetrant by adolescence [23]. All homozygotes have hair and skin phenotype from infancy (Table 2.1). The right ventricle is always involved, initially with localized kinetic abnormalities at the triangle of dysplasia: the outflow tract, posterior wall, and apex. With disease progression, the right ventricle becomes dilated and hypokinetic. The left ventricle is involved later; 10% of patients have left ventricular involvement by the second decade of life, while 60% of those who survive to the fifth decade of life develop left ventricular involvement. Clinical events are usually related to episodes of sustained ventricular tachycardia of left bundle branch block morphology. Arrhythmic storms are accompanied by step-wise structural progression [24]. The involved myocardium reveals myocyte loss with fibrofatty replacement mainly at subepicardial and mediomural layers occasionally associated with inflammatory infiltrates [26]. On immunohistology the signal for plakoglobin and connexin 43 (the main gap junctional protein in ventricular myocardium) is diminished at intercellular junctions [37].

Desmoplakin Mutations

Dominant desmoplakin mutations that cause non-syndromic ARVC/D truncate either the N- or the

C-terminal of the protein and result in distinctive cardiac phenotypes [28]. When the N-terminal is affected, particularly the plakoglobin binding site of desmoplakin in the outer dense plaque, the pheno-type is typical for ARVC/D with respect to electro-cardiographic and structural abnormalities [29]. Truncation of the molecule in the inner dense plaque results in a broader cardiac phenotype, occasionally with predominantly left ventricular involvement [3].

The identified desmoplakin mutations that cause recessive ARVC/D affect the C-terminal of the protein at the inner dense plaque of desmosomes and result in skin and hair phenotype similar to that of plako-globin mutation and a broadened cardiac phenotype (Table 2.1) [3, 7,16,19]. Left ventricular involvement predominates when the mutation is predicted to disrupt the desmin-binding site at the C-terminal of desmo-plakin [7,19]. More than 90% of those affected showed left ventricular involvement by childhood or adolescence and early development of heart failure [19,38].

Histopathologic features of a heart homozygote for 7901del1G desmoplakin mutation were similar to those of the plakoglobin mutation, although the fatty component of the usual right ventricular replacement process was absent [21]. The immunohistochemical signal for plakoglobin, desmoplakin, and desmin at the level of intercalated disks was diminished [21].

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