Clinical and biological progress over 50 years in Rett syndrome

In the 50 years since Andreas Rett first described the syndrome that came to bear his name, and is now known to be caused by a mutation in the methyl-CpG-binding protein 2 (MECP2) gene, a compelling blend of astute clinical observations and clinical and laboratory research has substantially enhanced our understanding of this rare disorder. Here, we document the contributions of the early pioneers in Rett syndrome (RTT) research, and describe the evolution of knowledge in terms of diagnostic criteria, clinical variation, and the interplay with other Rett-related disorders. We provide a synthesis of what is known about the neurobiology of MeCP2, considering the lessons learned from both cell and animal models, and how they might inform future clinical trials. With a focus on the core criteria, we examine the relationships between genotype and clinical severity. We review current knowledge about the many comorbidities that occur in RTT, and how genotype may modify their presentation. We also acknowledge the important drivers that are accelerating this research programme, including the roles of research infrastructure, international collaboration and advocacy groups. Finally, we highlight the major milestones since 1966, and what they mean for the day-to-day lives of individuals with RTT and their families

cancro colorettale: uno sguardo di genere

Per lungo tempo la medicina è stata improntata da un lato dal considerare l’uomo modello e misura della salute e della malattia anche per la donna e, dall’altro, dal considerare la salute delle donne essenzialmente legata alla loro funzione sessuale/riproduttiva. Per sottolineare l’eccessiva attenzione al binomio mammella/apparato ginecologico, che porta a sottovalutare pericoli epidemiologicamente più rilevanti per la salute femminile, è stato coniato il termine di “sindrome del bikini”. Il carcinoma colo rettale (KCR) è una delle neoplasie più frequenti nelle donne dei Paesi industrializzati e, in Italia, è al secondo posto, dopo il carcinoma della mammella. Tuttavia, un nostro recente studio ha confermato alcune segnalazioni della letteratura riguardo la loro minor attenzione al suo screening rispetto ad altre neoplasie meno frequenti (utero, ovaio). Le donne dimostrano di sottostimare il rischio di KCR nel loro sesso anche a causa di una informazione non adeguata che le raggiunge sia dai media che dai medici stessi. Differenze di genere sono segnalate anche riguardo alcune caratteristiche del KCR che, nelle donne, sembra insorgere qualche anno più tardi che nell’uomo, localizzarsi in tratti diversi del grosso intestino, mostrare particolari aspetti anatomo-patologici e, forse, una prognosi diversa. Si è ipotizzato che tali differenze siano legate all’influenza degli ormoni femminili sulla nascita e sullo sviluppo della neoplasia: comunque determinatesi, dovrebbero essere prese in considerazione per ottimizzare i protocolli. Tuttavia, altri studi segnalano che le donne giungono alla diagnosi più tardi degli uomini, hanno più spesso interventi d’urgenza e neoplasie in stadio avanzato. Altri ancora segnalano che le donne hanno trattamenti meno standardizzati e, a parità di stadio, vengono sottoposte meno degli uomini a terapia adiuvante post-operatoria. E’ evidente che tali differenze sono più difficilmente attribuibili ad una specifica fisiologia e che anche influenze socio-culturali hanno il loro peso e la stessa medicina le sue responsabilità. Tra queste, il non considerare la possibile differenza dei sintomi nei due sessi, l’attribuire troppo spesso il dolore addominale delle donne a fenomeni legati al ciclo mestruale o al colon irritabile, la stessa scarsa attenzione delle donne alla loro salute perché eccessivamente investite della cura della famiglia, come risulta anche da un nostro studio sulle campagne di screening gratuite offerte dalla Regione Toscana secondo il quale i motivi più spesso addotti dalle donne per rifiutare l’invito sono difficoltà logistiche ed impegni familiari. Da tutte queste considerazioni emerge la necessità che sia la medicina che la politica si impegnino a verificare se davvero esistono rischi aggiuntivi sesso-specifici per la salute delle donne ed a rimuoverli

Epigenetic and copy number variation analysis in retinoblastoma by MS-MLPA.

Retinoblastoma is the most common primary intraocular malignancy in children. Two step inactivation of RB1 (M1-M2) represents the key event in the pathogenesis of retinoblastoma but additional genetic and epigenetic events (M3-Mn) are required for tumor development. In the present study, we employed Methylation Specific Multiplex Ligation Probe Assay to investigate methylation status and copy number changes of 25 and 39 oncosuppressor genes, respectively. This technique was applied to analyse 12 retinoblastomas (5 bilateral and 7 unilateral) and results were compared to corresponding normal retina. We identified hypermethylation in seven new genes: MSH6 (50%), CD44 (42%), PAX5 (42%), GATA5 (25%), TP53 (8%), VHL (8%) and GSTP1 (8%) and we confirmed the previously reported hypermethylation of MGMT (58%), RB1 (17%) and CDKN2 (8%). These genes belong to key pathways including DNA repair, pRB and p53 signalling, transcriptional regulation, protein degradation, cell-cell interaction, cellular adhesion and migration. In the same group of retinoblastomas, a total of 29 copy number changes (19 duplications and 10 deletions) have been identified. Interestingly, we found deletions of the following oncosuppressor genes that might contribute to drive retinoblastoma tumorigenesis: TP53, CDH13, GATA5, CHFR, TP73 and IGSF4. The present data highlight the importance of epigenetic changes in retinoblastoma and indicate seven hypermethylated oncosuppressors never associated before to retinoblastoma pathogenesis. This study also confirms the presence of copy number variations in retinoblastoma, expecially in unilateral cases (mean 3 ± 1.3) where these changes were found more frequently respect to bilateral cases (mean 1.4 ± 1.1)

p53 Arg72Pro and MDM2 309 SNPs in hereditary retinoblastoma.

The tumor suppressor p53 and its negative regulator MDM2 have crucial roles in a variety of cellular functions such as the control of the cell cycle, senescence, genome stability and apoptosis, and are frequently deregulated in carcinogenesis. Previous studies have highlighted the contribution of the common functional polymorphisms p53 p.Arg72Pro and MDM2 309SNP to the risk of both common cancers and Li-Fraumeni syndrome. Their possible role in retinoblastoma has recently been addressed by Castéra et al, who however only studied the MDM2 309SNP. Here, for the first time, we analyzed both single nucleotide polymorphisms (SNPs) in a case-control study of 111 Italian hereditary retinoblastoma patients. We found a significant association of the p53 Pro/Pro genotype with the disease (odds ratio=3.58, P=0.002). The MDM2 309SNP showed a weak negative association of allele G that deserves further investigation. These findings further support the hypothesis that genetic variability of the p53 pathway contributes to the individual susceptibility to retinoblastoma, as shown for Li-Fraumeni syndrome and a variety of non-hereditary cancers

p53 Arg72Pro and MDM2 309 SNPs in hereditary retinoblastoma

The tumor suppressor p53 and its negative regulator MDM2 have crucial roles in a variety of cellular functions such as the control of the cell cycle, senescence, genome stability and apoptosis, and are frequently deregulated in carcinogenesis. Previous studies have highlighted the contribution of the common functional polymorphisms p53 p.Arg72Pro and MDM2 309SNP to the risk of both common cancers and Li-Fraumeni syndrome. Their possible role in retinoblastoma has recently been addressed by Castéra et al, who however only studied the MDM2 309SNP. Here, for the first time, we analyzed both single nucleotide polymorphisms (SNPs) in a case-control study of 111 Italian hereditary retinoblastoma patients. We found a significant association of the p53 Pro/Pro genotype with the disease (odds ratio=3.58, P=0.002). The MDM2 309SNP showed a weak negative association of allele G that deserves further investigation. These findings further support the hypothesis that genetic variability of the p53 pathway contributes to the individual susceptibility to retinoblastoma, as shown for Li-Fraumeni syndrome and a variety of non-hereditary cancers