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Rigato, Ilaria (2009) Correlazione gentotipo-fenotipo in pazienti affetti da cardiomiopatia aritmogena del ventricolo destro portatori di mutazioni di geni codificanti per le proteine di giunzione intercellulare. [Ph.D. thesis]

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Abstract (english)

Background: Arrhymogenic Right Ventricular Cardiomyopathy (ARVC) is an inherited primary heart muscle disease characterized by progressive myocardial atrophy and progressive fibrofatty tissue replacement. Familiar occurrence with an autosomal dominant pattern of inheritance and variable penetrance is proven, although recessive forms exist. ARVC affects primarily the right ventricle even if a left ventricular involvement is frequently described. The disease often presents with ventricular arrhythmias that can also lead to sudden death. A recent molecular classification defines ARVC as a “Desmosomal Cardiomyopathy” due to the identification of causative mutations in genes encoding for components of the desmosome, the specialized intercellular junctions that anchor intermediate filaments to the cytoplasmatic membrane in adjoining cells. This defect in desmosome components seems to predispose to myocyte detachment and death. Available genotype-phenotype correlation studies analysed the phenotypic features associated with mutations of a single disease-gene, although a comparison among clinical phenotype of patients with mutation on different genes is still missing.
Objectives we sought to provide a detailed analysis of the genotype-phenotype correlation in subjects carrying a causative mutation of the different disease-genes encoding for desmosome components (Plakophillin2-PKP2, Desmoglein2-DSG2, Desmoplakin-DSP, Desmoglein2-DSG2, Multiple mutations-MM)
Materials and Methods a total of 38 families (257 patients-128 women and 129 men- mean age at first evaluation 35±18 years) affected by ARVC and in whom mutations of a known ARVC-gene has been identified were analysed. The study population was divided into 4 groups according to the disease-gene: PKP2 (n=46), DSP (n=37), DSG2 (n=59) and those with MM (n=28). The instrumental and clinical features detected at first and at last examination were compared. Clinical evaluation included a detailed familial pedigree, medical history, 12- lead ECG, signal-averaged ECG, two-dimensional echocardiography, 24-hour ambulatory ECG monitoring. Moreover, in selected cases a cardiac magnetic resonance with gadolinium injection was performed.
Results: a total of 170 patients was found to carry a mutation in a desmosomal gene (DSP=59, PKP2= 46, DGS2=37,MM=22 had). Moreover, 48% of patients fulfilled the established diagnostic criteria of ARVC (M/F 2,8/1). Analysis of clinical and instrumental data showed a greater extent of the disease in PKP2 and MM groups, defined a larger right ventricular dimensions and more frequent left ventricular involvement. During follow- up patients carrying a DSP mutation showed a greater progression of the disease, with particular regard to the left ventricle. Nonetheless, survival analysis didn't show a significant difference of major events in patients carrying distinct genes mutations.
Conclusions: the study demonstrated the presence of gene-specific features in ARVC patients, with particular regard to right ventricular dilatation and left ventricular involvement. Nevertheless the prognosis doesn't seem to be different among mutation carriers of different genes. Thus the genetic characterization seems not to modify the therapeutic strategies and the risk stratification of patients. Finally, the different clinical expression of this disease in subjects carrying the same mutation suggests a possible role of modifying factor in the clinical phenotype.

Abstract (italian)

Introduzione: la Cardiomiopatia Aritmogena del Ventricolo Destro (Arrythmogenic Right Ventricular Cardiomyopaty: ARVC) è una malattia ereditaria del muscolo cardiaco, spesso familiare, caratterizzata da un’atrofia miocardica progressiva con sostituzione fibro-adiposa. Il coinvolgimento ventricolare destro è predominante e più evidente ma anche il ventricolo sinistro viene colpito dalla malattia in maniera significativa. Clinicamente si manifesta con aritmie ventricolari che possono portare anche a morte improvvisa. Una recente classificazione molecolare definisce l’ARVC una “Cardiomiopatia delle giunzioni intercellulari” o “Cardiomiopatia Desmosomiale”, dato che i geni-malattia codificano per proteine delle giunzioni intercellulari (desmosomi e giunzioni adherens) con rimodellamento dei dischi intercalari, così da rendere i miociti più suscettibili allo stress parietale con morte miocellulare e sostituzione fibroadiposa . Gli studi di correlazione genotipo- fenotipo finora eseguiti hanno esaminato il fenotipo dei pazienti portatori dei vari geni malattia, senza tuttavia paragonare gli aspetti clinici di pazienti portatori di mutazioni genetiche a carico di geni diversi.
Scopo dello Studio: lo studio si propone di eseguire una correlazione genotipo- fenotipo in soggetti affetti e nei familiari non affetti dalla malattia, portatori di mutazioni di geni che codificano per le proteine desmosomiali finora identificati nella nostra casistica (Plakofillina-2: PKP2; Desmogleina-2: DSG2; Desmoplachina: DSP)
Materiali e Metodi: abbiamo studiato le famiglie di 38 probandi affetti da ARVC per un totale di 257 soggetti (128 femmine e 129 maschi età media 35±18 anni). I soggetti analizzati sono stati suddivisi in 3 gruppi in base alla alterazione genetica individuata (PKP2, DSP e DSG2); un quarto gruppo comprendeva pazienti portatori di una mutazione multipla (MM). Sono stati raccolti i dati relativi alla prima visita e all’ultima visita di follow-up. Il protocollo di studio prevedeva l’anamnesi personale e familiare, l’ecocardiografia mono e bidimensionale color Doppler, l’elettrocardiogramma di base, i SAECG (potenziali tardivi ad alta risoluzione), l’ECG Holter delle 24h. In casi selezionati si acquisivano i dati di Risonanza Magnetica Cardiaca.
Risultati: un totale di 170 (51%) soggetti è risultato essere portatore di mutazione genetica. Si trattava di mutazioni della DSP (n.59), PKP2 (n. 46), DSG2 (n.37) e di doppie mutazioni (MM= n.28). Una diagnosi clinica con i criteri della Task Force era possibile nel 48% dei soggetti con mutazione, con una netta prevalenza maschile (M/F 2,8/1). L’analisi dei dati clinico- strumentali mostrava alla prima visita una maggiore estensione della malattia, in termini di dilatazione del ventricolo destro e di interessamento del ventricolo sinistro, nei soggetti portatori di mutazione PKP2 e MM. Durante il follow up i pazienti con mutazione DSP mostravano una maggiore progressione della malattia in particolare a carico del ventricolo sinistro. L’analisi di sopravvivenza non mostrava differenze significative nei pazienti portatori di mutazioni dei diversi geni.
Conclusioni: I dati ottenuti evidenziano delle caratteristiche gene- specifiche dell’ARVC in particolare al grado di dilatazione del ventricolo destro e del coinvolgimento ventricolare sinistro. Tuttavia la prognosi non sembra essere diversa nei portatori di mutazioni di geni diversi. Pertanto al momento attuale la caratterizzazione genetica non modifica l’approccio clinico- diagnostico e la stratificazione del rischio nei pazienti. La diversa espressione clinica della malattia in famiglie portatrici della stessa mutazione suggeriscono che il fenotipo è in larga misura influenzato anche da fattori ambientali.

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EPrint type:Ph.D. thesis
Tutor:Nava, Andrea and Bauce, Barbara
Ph.D. course:Ciclo 21 > Scuole per il 21simo ciclo > SCIENZE MEDICHE, CLINICHE E SPERIMENTALI > SCIENZE CARDIOVASCOLARI
Data di deposito della tesi:01 February 2009
Anno di Pubblicazione:2009
Key Words:Cardiomiopatia, genetica, geni.diagnosi, morte improvvisa
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/11 Malattie dell'apparato cardiovascolare
Struttura di riferimento:Dipartimenti > pre 2012 - Dipartimento di Scienze Medico Diagnostiche e Terapie Speciali
Codice ID:1879
Depositato il:01 Feb 2009
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