Long-term evolution of the electroclinical phenotype in Mowat-Wilson syndrome: data from a 40 patients cohort

Background: La sindrome di Mowat-Wilson (SMW) è una patologia genetica legata ad aploinsufficienza del gene ZEB2. L’epilessia connota la sindrome essendo descritta nel 75%-80% dei pazienti; tuttavia ad oggi pochi studi si sono concentrati sulla descrizione del fenotipo elettroclinico in questa condizione. In particolare, non è finora stata chiarita l’evoluzione a lungo termine dell’epilessia in SMW e le casistiche descritte sono spesso rappresentate da un campione numericamente esiguo. Scopo: valutare l’evoluzione a lungo termine del fenotipo elettroclinico nella SMW individuando anche gli eventuali approcci terapeutici più efficaci. Indagare correlazioni fenotipo/genotipo e chiarire i meccanismi etiopatogenici alla base dell’epilessia fornendo utile feed-back alla ricerca di laboratorio. Pazienti e Metodi: Studio longitudinale retrospettivo di coorte coinvolgente 40 pazienti con diagnosi confermata geneticamente di Sindrome di Mowat-Wilson (22 femmine: 18 maschi) seguiti in follow-up per una durata media del follow-up 11,3 anni. Sono stati centralizzati i dati clinici inerenti l’epilessia ed i tracciati elettroencefalografici, revisionati in cieco da due esperti epilettologi dell’età pediatrica. La popolazione è stata suddivisa in tre fasce d’età, i dati clinici/elettroencefalografici sono stati raccolti per ciascuna di esse quando possibile e confrontati statisticamente. Risultati: ottenuta coorte più numerosa mai descritta finora in termini di epilessia nella SMW, con più prolungato follow-up che ha permesso di evidenziare definito fenotipo elettroclinico età dipendente, sovrapponibile nei diversi pazienti. Conclusioni:L’epilessia è stata descritta per la prima volta nella totalità dei pazienti in età scolare unitamente ad alcune sue caratteristiche di immediato valore nella gestione clinica dei pazienti. Confermata etiologia genetica dell’epilessia con possibilità di ipotizzare più chiaramente coinvolgimento dei circuiti cerebrali cortico-sottocorticali. Non emersa chiara correlazione genotipo-fenotipo. Individuate, con i limiti di uno studio osservazionale, terapie farmacologiche maggiormente efficaci.Background: Mowat-Wilson Syndrome (MWS) is a genetic disease related to ZEB2 gene. The underlying mechanism is haploinsufficiency in the majority of patients linked to loss of function mutations. Rare ZEB2 missense mutations have also been described expanding the clinical phenotype. Epilepsy is a cardinal feature of both MWS and ZEB2 mutations. To date, few studies have focused on the electroclinical phenotype in MWS. In particular no long-term follow-up data are available. Aim: to describe the long-term evolution of the electroclinical phenotype in MWS and suggest the most effective treatment. To investigate the possible pathogenic mechanisms of epilepsy in patients with ZEB2 mutations. Methods: longitudinal cohort study. We analyse data of 40 patients (22 females; 18 males) with genetically confirmed MWS, aged 2-31 years (mean age 12,8; median 13,9) at last examination, with mean follow-up of 11 years. Results: all the patients aged >5 years present epilepsy that appears clearly defined and similar across our sample cases. A clear age dependent pattern has been identified. As previously supposed, the involvement of cortical-subcortical circuits appears to be crucial and we can provide solid data on the genetic etiology of epilepsy in MWS. Some antiepileptic drugs seem to be more effective preliminarily. Conclusion: for the first time in literature, the long-term evolution of the electroclinical phenotype has been described in a significant sample of patients with MWS. We also delineate a few therapeutic implications that need to be confirmed with further studies. Moreover, our data suggest some possible assumptions about the pathogenic mechanism of epilepsy in ZEB2 mutations. A next desirable research step should be to evaluate gene expression profiling of GABAergic interneurons derived from cells of MWS patients through induced pluripotent stem cells

Diversidad de parasitoides primarios y secundarios del pulgón Myzus persicae (Hemiptera, Aphididae) en el duraznero Prunus persica (Rosales, Rosaceae) en la provincia de Mendoza, Argentina

Diversity of primary and secondary parasitoids of the aphid Myzus persicae (Hemiptera, Aphididae) in peach Punus persica (Rosales, Rosaceae) in the province of Mendoza, Argentina. Mendoza is the highest stone fruit producer and the main industrial peach producer for Argentina. Myzus persicae, known as the green peach aphid or the peach–potato aphid, is one of the main pests that affect this crop. Hymenoptera parasitoids of the Braconidae family stand out as one of the most efficient groups of natural enemies of this pest. The objectives of this study were to determine the natural parasitoidism of this peach aphid and to know the diversity of parasitoids associated with this pest. During the years 2015/2016, weekly collections were made from September to December of shoots with aphids that might or might not show signs of parasitoidism. The percentage of parasitoidism and the frequency and relative abundance of the parasitoids were calculated. The percentage of average parasitoidism per shoot was close to 20%. About the peach–M. persicae association nine species of primary parasitoids and four species of secondary parasitoids were recorded. Aphidius colemani was the dominant species within the primary parasitoids.Fil: Mazitelli, Emilia. Instituto Nacional de Tecnología Agropecuaria; ArgentinaFil: Aquino, Daniel Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Estudios Parasitológicos y de Vectores. Universidad Nacional de La Plata. Facultad de Ciencias Naturales y Museo. Centro de Estudios Parasitológicos y de Vectores; ArgentinaFil: Gallardo, Fabiana Edith. Universidad Nacional de La Plata. Facultad de Ciencias Naturales y Museo. División Entomología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Recce, Vanina. Universidad Nacional de La Plata. Facultad de Ciencias Naturales y Museo. División Entomología; Argentina. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas; ArgentinaFil: Ricci, Mónica. Universidad Nacional de La Plata. Facultad de Ciencias Agrarias y Forestales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Organ Stiffness in the Work-Up of Myelofibrosis and Philadelphia-Negative Chronic Myeloproliferative Neoplasms

To define the role of spleen stiffness (SS) and liver stiffness (LS) in myelofibrosis and other Philadelphia (Ph)-negative myeloproliferative neoplasms (MPNs), we studied, by ultrasonography (US) and elastography (ES), 70 consecutive patients with myelofibrosis (MF) (no.43), essential thrombocythemia (ET) (no.10), and polycythemia vera (PV) (no.17). Overall, the median SS was not different between patients with MF and PV (p = 0.9); however, both MF and PV groups had significantly higher SS than the ET group (p = 0.011 and p = 0.035, respectively) and healthy controls (p < 0.0001 and p = 0.002, respectively). In patients with MF, SS values above 40 kPa were significantly associated with worse progression-free survival (PFS) (p = 0.012; HR = 3.2). SS also correlated with the extension of bone marrow fibrosis (BMF) (p < 0.0001). SS was higher in advanced fibrotic stages MF-2, MF-3 (W.H.O. criteria) than in pre-fibrotic/early fibrotic stages (MF-0, MF-1) (p < 0.0001) and PFS was significantly different in the two cohorts, with values of 63% and 85%, respectively (p = 0.038; HR = 2.61). LS significantly differed between the patient cohort with MF and healthy controls (p = 0.001), but not between the patient cohorts with ET and PV and healthy controls (p = 0.999 and p = 0.101, respectively). We can conclude that organ stiffness adds valuable information to the clinical work-up of MPNs and could be employed to define patients at a higher risk of progression

New Species in the Old World: Europe as a Frontier in Biodiversity Exploration, a Test Bed for 21st Century Taxonomy

The number of described species on the planet is about 1.9 million, with ca. 17,000 new species described annually, mostly from the tropics. However, taxonomy is usually described as a science in crisis, lacking manpower and funding, a politically acknowledged problem known as the Taxonomic Impediment. Using data from the Fauna Europaea database and the Zoological Record, we show that contrary to general belief, developed and heavily-studied parts of the world are important reservoirs of unknown species. In Europe, new species of multicellular terrestrial and freshwater animals are being discovered and named at an unprecedented rate: since the 1950s, more than 770 new species are on average described each year from Europe, which add to the 125,000 terrestrial and freshwater multicellular species already known in this region. There is no sign of having reached a plateau that would allow for the assessment of the magnitude of European biodiversity. More remarkably, over 60% of these new species are described by non-professional taxonomists. Amateurs are recognized as an essential part of the workforce in ecology and astronomy, but the magnitude of non-professional taxonomist contributions to alpha-taxonomy has not been fully realized until now. Our results stress the importance of developing a system that better supports and guides this formidable workforce, as we seek to overcome the Taxonomic Impediment and speed up the process of describing the planetary biodiversity before it is too late

Mowat-Wilson syndrome : growth charts

Background Mowat-Wilson syndrome (MWS; OMIM #235730) is a genetic condition caused by heterozygous mutations or deletions of theZEB2gene. It is characterized by moderate-severe intellectual disability, epilepsy, Hirschsprung disease and multiple organ malformations of which congenital heart defects and urogenital anomalies are the most frequent ones. To date, a clear description of the physical development of MWS patients does not exist. The aim of this study is to provide up-to-date growth charts specific for infants and children with MWS. Charts for males and females aged from 0 to 16 years were generated using a total of 2865 measurements from 99 MWS patients of different ancestries. All data were collected through extensive collaborations with the Italian MWS association (AIMW) and the MWS Foundation. The GAMLSS package for the R statistical computing software was used to model the growth charts. Height, weight, body mass index (BMI) and head circumference were compared to those from standard international growth charts for healthy children. Results In newborns, weight and length were distributed as in the general population, while head circumference was slightly smaller, with an average below the 30th centile. Up to the age of 7 years, weight and height distribution was shifted to slightly lower values than in the general population; after that, the difference increased further, with 50% of the affected children below the 5th centile of the general population. BMI distribution was similar to that of non-affected children until the age of 7 years, at which point values in MWS children increased with a less steep slope, particularly in males. Microcephaly was sometimes present at birth, but in most cases it developed gradually during infancy; many children had a small head circumference, between the 3rd and the 10th centile, rather than being truly microcephalic (at least 2 SD below the mean). Most patients were of slender build. Conclusions These charts contribute to the understanding of the natural history of MWS and should assist pediatricians and other caregivers in providing optimal care to MWS individuals who show problems related to physical growth. This is the first study on growth in patients with MWS.Peer reviewe

The European union’s 2010 target: Putting rare species in focus

P. 167-185The European Union has adopted the ambitious target of halting the loss of biodiversity by 2010. Several indicators have been proposed to assess progress towards the 2010 target, two of them addressing directly the issue of species decline. In Europe, the Fauna Europaea database gives an insight into the patterns of distribution of a total dataset of 130,000 terrestrial and freshwater species without taxonomic bias, and provide a unique opportunity to assess the feasibility of the 2010 target. It shows that the vast majority of European species are rare, in the sense that they have a restricted range. Considering this, the paper discusses whether the 2010 target indicators really cover the species most at risk of extinction. The analysis of a list of 62 globally extinct European taxa shows that most contemporary extinctions have affected narrow-range taxa or taxa with strict ecological requirements. Indeed, most European species listed as threatened in the IUCN Red List are narrow-range species. Conversely, there are as many wide-range species as narrow-range endemics in the list of protected species in Europe (Bird and Habitat Directives). The subset of biodiversity captured by the 2010 target indicators should be representative of the whole biodiversity in terms of patterns of distribution and abundance. Indicators should not overlook a core characteristic of biodiversity, i.e. the large number of narrow-range species and their intrinsic vulnerability. With ill-selected indicator species, the extinction of narrowrange endemics would go unnoticedS

The Action Mechanism of the Myc Inhibitor Termed Omomyc May Give Clues on How to Target Myc for Cancer Therapy

Recent evidence points to Myc – a multifaceted bHLHZip transcription factor deregulated in the majority of human cancers – as a priority target for therapy. How to target Myc is less clear, given its involvement in a variety of key functions in healthy cells. Here we report on the action mechanism of the Myc interfering molecule termed Omomyc, which demonstrated astounding therapeutic efficacy in transgenic mouse cancer models in vivo. Omomyc action is different from the one that can be obtained by gene knockout or RNA interference, approaches designed to block all functions of a gene product. This molecule – instead – appears to cause an edge-specific perturbation that destroys some protein interactions of the Myc node and keeps others intact, with the result of reshaping the Myc transcriptome. Omomyc selectively targets Myc protein interactions: it binds c- and N-Myc, Max and Miz-1, but does not bind Mad or select HLH proteins. Specifically, it prevents Myc binding to promoter E-boxes and transactivation of target genes while retaining Miz-1 dependent binding to promoters and transrepression. This is accompanied by broad epigenetic changes such as decreased acetylation and increased methylation at H3 lysine 9. In the presence of Omomyc, the Myc interactome is channeled to repression and its activity appears to switch from a pro-oncogenic to a tumor suppressive one. Given the extraordinary therapeutic impact of Omomyc in animal models, these data suggest that successfully targeting Myc for cancer therapy might require a similar twofold action, in order to prevent Myc/Max binding to E-boxes and, at the same time, keep repressing genes that would be repressed by Myc

Phenotype and genotype of 87 patients with Mowat-Wilson syndrome and recommendations for care

Mowat-Wilson syndrome (MWS) is a rare intellectual disability/multiple congenital anomalies syndrome caused by heterozygous mutation of the ZEB2 gene. It is generally underestimated because its rarity and phenotypic variability sometimes make it difficult to recognize. Here, we aimed to better delineate the phenotype, natural history, and genotype-phenotype correlations of MWS.MethodsIn a collaborative study, we analyzed clinical data for 87 patients with molecularly confirmed diagnosis. We described the prevalence of all clinical aspects, including attainment of neurodevelopmental milestones, and compared the data with the various types of underlying ZEB2 pathogenic variations.ResultsAll anthropometric, somatic, and behavioral features reported here outline a variable but highly consistent phenotype. By presenting the most comprehensive evaluation of MWS to date, we define its clinical evolution occurring with age and derive suggestions for patient management. Furthermore, we observe that its severity correlates with the kind of ZEB2 variation involved, ranging from ZEB2 locus deletions, associated with severe phenotypes, to rare nonmissense intragenic mutations predicted to preserve some ZEB2 protein functionality, accompanying milder clinical presentations.ConclusionKnowledge of the phenotypic spectrum of MWS and its correlation with the genotype will improve its detection rate and the prediction of its features, thus improving patient care.GENETICS in MEDICINE advance online publication, 4 January 2018; doi:10.1038/gim.2017.221