Pseudoxanthoma Elasticum (PXE) is a rare inheritable disease as an autosomal recessive trait affecting the connective tissue. The pathology is characterized by ectopic mineralization and fragmentation of elastic fibers, following the deposition of calcium and other minerals, with consequent alterations to the skin, eyes and cardiovascular system. Skin manifestations are the first clinical signs and consist of small yellow papules on the nape, on the sides of the neck and in the areas of flexion, which gradually join into larger plaques giving the skin a pebbled appearance. The characteristic ocular manifestations of the disease are peau d'orange, patches of the retina that can progress into angioid streaks, and angioid strips. In the later stages of the disease, choroidal neovascularization, subretinal fibrosis, atrophy of the retinal pigment epithelium and retinal hemorrhages can occur, which can lead to partial or complete loss of vision. Calcification can also affect the cardiovascular system, in particular small and medium-sized arteries, causing a reduction in the vessels with the consequent possibility of heart attack, small strokes and, above all, intermittent claudicatio, pain due to poor blood circulation in the arteries. PXE is an inheritable disease as an autosomal recessive trait and this means that both parents must be carriers in order to transmit the mutated ABCC6 gene to their child, therefore, it may be important to undergo genetic counseling that provides information on the nature and implications of the type of inheritable variant. There are also numerous systemic and dermatological disorders that present clinical and histological characteristics similar to PXE thus generating diagnostic doubts. For this reason, it becomes very important to make a differential diagnosis. The gene responsible for the onset of the disease is the ABCC6 gene, mainly expressed in the liver and proximal tubules of the kidney and, at a very low level, in the tissues involved in the PXE. In particular, the mutations responsible for the disease found on the ABCC6 gene are nonsense, missense and frameshit mutations. Transgenic knock out (KO) mice have been developed to better understand the pathogenetic mechanisms of PXE and to test potential treatment modalities. The Abcc6 - / - mouse therefore represents the reference model system, in that it presents part of the genetic and histopathological characteristics of PXE patients. So far there is no specific treatment for this pathology, but effective therapies for ocular complications are currently available, for which the only stage of the disease in which therapy is possible and indicated is at the moment in which choroidal neovascularization develops. In recent years, however, several approaches have been developed to counteract the manifestations of PXE, mainly using Abcc6 - / - mice as a model. Many studies have shown that the magnesium content in the diet is able to prevent ectopic mineralization. A further study has suggested the possibility of clinical use of oral phosphate binders such as sevelamer hydrochloride, although the effectiveness of these drugs in countering the clinical manifestations of PXE still requires several clinical studies. Another potential way to prevent ectopic mineralization is the administration of fetuin-A and pyrophosphate, important anti-mineralization factors. In this context, early diagnosis of the disease is indispensable, which can allow for timely therapy. Furthermore, a correct lifestyle, which mainly consists of a healthy diet and tobacco abstinence, could limit the severity of the pathology. New potential treatments for PXE and new technologies to perfect any gene therapy are also being developed.
Lo Pseudoxanthoma Elasticum (PXE) è una rara malattia ereditabile come tratto autosomico recessivo che interessa il tessuto connettivo. La patologia è caratterizzata da mineralizzazione ectopica e frammentazione delle fibre elastiche, in seguito a deposizione di calcio e altri minerali, con conseguenti alterazioni a pelle, occhi e sistema cardiovascolare. Le manifestazioni cutanee sono i primi segni clinici e consistono in piccole papule gialle sulla nuca, sui lati del collo e nelle aree di flessione, che progressivamente si uniscono in placche più grandi dando alla pelle un aspetto a ciottoli. Le manifestazioni oculari caratteristiche della malattia sono peau d'orange, chiazze della retina che possono progredire in striature angioidi, e strisce angioidi. Nelle fasi successive della malattia può verificarsi neovascolarizzazione coroideale, fibrosi subretinale, atrofia dell'epitelio pigmentato retinico ed emorragie retiniche che possono portare ad una perdita parziale o completa della vista. La calcificazione può influenzare anche il sistema cardiovascolare, in particolare le arterie di piccole e medie dimensioni, provocando una riduzione dei vasi con conseguente possibilità di infarto, piccoli ictus e, soprattutto, claudicatio intermittente, ovvero dolore dovuto alla cattiva circolazione del sangue nelle arterie. Il PXE è una malattia ereditabile come tratto autosomico recessivo e ciò significa che entrambi i genitori devono essere portatori per poter trasmettere il gene ABCC6 mutato al figlio, quindi, può essere importante sottoporsi ad una consulenza genetica che fornisca informazioni sulla natura e le implicazioni del tipo di variante ereditabile. Vi sono inoltre numerosi disturbi sistemici e dermatologici che presentano caratteristiche cliniche e istologiche simili al PXE generando di conseguenza dubbi diagnostici. Per questo motivo, diventa molto importante procedere ad una diagnosi differenziale. Il gene responsabile dell'insorgenza della malattia è il gene ABCC6. In particolare, le mutazioni responsabili del PXE riscontrate sul gene ABCC6 sono mutazioni nonsenso, missenso e frameshit. Per comprendere meglio i meccanismi patogenetici del PXE e per testare potenziali modalità di trattamento sono stati sviluppati topi knock out (KO) transgenici. Il topo Abcc6-/- rappresenta quindi il sistema modello di riferimento, in quanto presenta parte delle caratteristiche genetiche e istopatologiche dei pazienti PXE. Finora non esiste un trattamento specifico per questa patologia, ma attualmente sono disponibili terapie efficaci per le complicanze oculari, per le quali l'unico stadio della malattia in cui è possibile e indicata la terapia è nel momento in cui si sviluppa neovascolarizzazione coroideale. Negli ultimi anni, tuttavia, sono stati sviluppati diversi approcci per contrastare le manifestazioni del PXE, usando principalmente topi Abcc6-/- come modello. Molti studi hanno dimostrato che il contenuto di magnesio nella dieta è in grado di prevenire la mineralizzazione ectopica. Un ulteriore studio ha suggerito la possibilità di uso clinico di leganti orali di fosfato come il sevelamer cloridrato, anche se l’efficacia di questi farmaci nel contrastare le manifestazioni cliniche di PXE richiede ancora diversi studi clinici. Un altro potenziale modo per prevenire la mineralizzazione ectopica vede la somministrazione di fetuin-A e pirofosfato, importanti fattori anti-mineralizzazione. In questo contesto risulta essere indispensabile una diagnosi precoce della malattia, la quale può consentire una terapia tempestiva. Inoltre, un corretto stile di vita, che consiste principalmente in una dieta sana e nell'astinenza da tabacco, potrebbe limitare la gravità della patologia. Sono inoltre in fase di sviluppo nuovi trattamenti potenziali per il PXE e nuove tecnologie per perfezionare un’eventuale terapia genica.
PSEUDOXANTHOMA ELASTICUM : UNA PATOLOGIA RARA DEL TESSUTO CONNETTIVO
FEDERICI, RACHELE
2019/2020
Abstract
Pseudoxanthoma Elasticum (PXE) is a rare inheritable disease as an autosomal recessive trait affecting the connective tissue. The pathology is characterized by ectopic mineralization and fragmentation of elastic fibers, following the deposition of calcium and other minerals, with consequent alterations to the skin, eyes and cardiovascular system. Skin manifestations are the first clinical signs and consist of small yellow papules on the nape, on the sides of the neck and in the areas of flexion, which gradually join into larger plaques giving the skin a pebbled appearance. The characteristic ocular manifestations of the disease are peau d'orange, patches of the retina that can progress into angioid streaks, and angioid strips. In the later stages of the disease, choroidal neovascularization, subretinal fibrosis, atrophy of the retinal pigment epithelium and retinal hemorrhages can occur, which can lead to partial or complete loss of vision. Calcification can also affect the cardiovascular system, in particular small and medium-sized arteries, causing a reduction in the vessels with the consequent possibility of heart attack, small strokes and, above all, intermittent claudicatio, pain due to poor blood circulation in the arteries. PXE is an inheritable disease as an autosomal recessive trait and this means that both parents must be carriers in order to transmit the mutated ABCC6 gene to their child, therefore, it may be important to undergo genetic counseling that provides information on the nature and implications of the type of inheritable variant. There are also numerous systemic and dermatological disorders that present clinical and histological characteristics similar to PXE thus generating diagnostic doubts. For this reason, it becomes very important to make a differential diagnosis. The gene responsible for the onset of the disease is the ABCC6 gene, mainly expressed in the liver and proximal tubules of the kidney and, at a very low level, in the tissues involved in the PXE. In particular, the mutations responsible for the disease found on the ABCC6 gene are nonsense, missense and frameshit mutations. Transgenic knock out (KO) mice have been developed to better understand the pathogenetic mechanisms of PXE and to test potential treatment modalities. The Abcc6 - / - mouse therefore represents the reference model system, in that it presents part of the genetic and histopathological characteristics of PXE patients. So far there is no specific treatment for this pathology, but effective therapies for ocular complications are currently available, for which the only stage of the disease in which therapy is possible and indicated is at the moment in which choroidal neovascularization develops. In recent years, however, several approaches have been developed to counteract the manifestations of PXE, mainly using Abcc6 - / - mice as a model. Many studies have shown that the magnesium content in the diet is able to prevent ectopic mineralization. A further study has suggested the possibility of clinical use of oral phosphate binders such as sevelamer hydrochloride, although the effectiveness of these drugs in countering the clinical manifestations of PXE still requires several clinical studies. Another potential way to prevent ectopic mineralization is the administration of fetuin-A and pyrophosphate, important anti-mineralization factors. In this context, early diagnosis of the disease is indispensable, which can allow for timely therapy. Furthermore, a correct lifestyle, which mainly consists of a healthy diet and tobacco abstinence, could limit the severity of the pathology. New potential treatments for PXE and new technologies to perfect any gene therapy are also being developed.È consentito all'utente scaricare e condividere i documenti disponibili a testo pieno in UNITESI UNIPV nel rispetto della licenza Creative Commons del tipo CC BY NC ND.
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https://hdl.handle.net/20.500.14239/24538