Temporal lobe connects regression and macrocephaly to autism spectrum disorders

Interictal electroencephalogram (EEG) abnormalities are frequently associated with autism spectrum disorders (ASD), although their relationship with the clinical features of ASD, particularly the regressive onset, remains controversial. The aim of this study was to investigate whether the characteristics of interictal EEG abnormalities might help to distinguish and predict definite phenotypes within the heterogeneity of ASD. We reviewed the awake and sleep interictal EEGs of 220 individuals with idiopathic ASD, either with or without a history of seizures. EEG findings were analyzed with respect to a set of clinical variables to explore significant associations. A brain morphometry study was also carried out on a subgroup of patients. EEG abnormalities were seen in 154/220 individuals (70 %) and were mostly focal (p < 0.01) with an anterior localization (p < 0.001). They were detected more frequently during sleep (p < 0.01), and were associated with a regressive onset of ASD (p < 0.05), particularly in individuals with focal temporal localization (p < 0.05). This association was also stronger in regressive patients with concurrent macrocephaly, together with a relative volumetric reduction of the right temporal cortex (p < 0.05). Indeed, concurrence of temporal EEG abnormalities, regression and macrocephaly might possibly define a distinct endophenotype of ASD. EEG-based endophenotypes could be useful to untangle the complexity of ASD, helping to establish anatomic or pathophysiologic subtypes of the disorder

Gain-of-function defects of astrocytic Kir4.1 channels in children with autism spectrum disorders and epilepsy

Dysfunction of the inwardly-rectifying potassium channels Kir4.1 (KCNJ10) represents a pathogenic mechanism contributing to Autism-Epilepsy comorbidity. To define the role of Kir4.1 variants in the disorder, we sequenced KCNJ10 in a sample of affected individuals, and performed genotype-phenotype correlations. The effects of mutations on channel activity, protein trafficking, and astrocyte function were investigated in Xenopus laevis oocytes, and in human astrocytoma cell lines. An in vivo model of the disorder was also explored through generation of kcnj10a morphant zebrafish overexpressing the mutated human KCNJ10. We detected germline heterozygous KCNJ10 variants in 19/175 affected children. Epileptic spasms with dysregulated sensory processing represented the main disease phenotype. When investigated on astrocyte-like cells, the p.R18Q mutation exerted a gain-of-function effect by enhancing Kir4.1 membrane expression and current density. Similarly, the p.R348H variant led to gain of channel function through hindrance of pH-dependent current inhibition. The frequent polymorphism p.R271C seemed, instead, to have no obvious functional effects. Our results confirm that variants in KCNJ10 deserve attention in autism-epilepsy, and provide insight into the molecular mechanisms of autism and seizures. Similar to neurons, astrocyte dysfunction may result in abnormal synaptic transmission and electrical discharge, and should be regarded as a possible pharmacological target in autism-epilepsy. Supplementary information accompanies this paper in the files section.peer-reviewe

Die schwierige Versöhnung

This volume is the result of collaboration between historians and scientific institutions in Austria and Italy. It covers two major topics: the bilateral contacts in the 20th century between the two neighbouring countries and the role of the South Tyrol question in this relationship. In the Rome-Vienna-Bolzano triangle, the most important intersections of this continuously maintained relationship are illuminated and central questions of recent European history are examined: the treatment of national minorities, the work of authoritarian regimes as well as democratization and the process of European integration. The aim of this volume is to map the current state of research, to open up possible new fields of research and to give new impulses to the historiographical dialogue between Rome and Vienna.; Dieser Band ist das Ergebnis der Zusammenarbeit zwischen Historikern und wissenschaftlichen Einrichtungen in Österreich und Italien. Er umfasst zwei große Themenbereiche: die bilateralen Kontakte im 20. Jahrhundert zwischen den beiden Nachbarländern sowie die Rolle der Südtirolfrage in diesem Verhältnis. Im Dreieck Rom-Wien-Bozen werden die wichtigsten Schnittpunkte dieser fortwährend aufrechterhaltenen Beziehung beleuchtet und zentrale Fragen der jüngsten europäischen Geschichte untersucht: der Umgang mit nationalen Minderheiten, das Wirken autoritärer Regimes sowie die Demokratisierung und der Prozess der europäischen Integration. Ziel dieses Bandes ist es, den derzeitigen Forschungsstand abzubilden, mögliche neue Forschungsfelder zu eröffnen und dem historiografischen Dialog zwischen Rom und Wien neue Impulse zu verleihen

Autism-Epilepsy Phenotype: Clinical and EEG clustering and genotype-phenotype correlation

Epilepsy and EEG abnormalities are frequently associated with Autism Spectrum Disorders (ASD), defining a condition termed “Autism-Epilepsy Phenotype” (AEP). The lack of clear conclusions about this relationship reflects the complexity and heterogeneity of the disorder and its presumed multifactorial pathophysiology. This strong comorbidity also suggests that ASD, epilepsy and EEG abnormalities may share common genetic or pathophysiologic underpinnings which deserve to be further investigated. The first aim of this PhD was therefore to perform a full clinical and EEG characterization of a large sample of idiopathic ASD individuals, in order to pinpoint distinctive endophenotypic subgroups within the autism-epilepsy comorbidity. We found that seizures are associated with severe intellectual disability, and not with autism severity. Interestingly, tall stature seems to be a phenotypic ‘‘biomarker’’ of susceptibility to EEG abnormalities or late onset epilepsy in ASD and, when concurring with macrocephaly, predisposes to early onset seizures. The EEG characterization, conducted by reviewing the awake and sleep interictal recordings of 220 individuals in our sample, either with or without history of seizures, showed a significant association between EEG abnormalities, type of onset of ASD (regressive versus non regressive) and somatic features. The second aim of this PhD was to carry out genetic studies on specific endophenotypic subgroups, through a candidate gene approach. In particular, we focused on the association of macrocephaly, ASD and epilepsy (or EEG abnormalities) and screened for mutations of two genes previously reported to be associated with autism and macrocephaly (GLIALCAM and PTEN). Whilst we detected in GLIALCAM several single nucleotide variants without clear pathogenic effects, we found a novel PTEN heterozygous frameshift mutation in one patient with “extreme” macrocephaly, autism, intellectual disability and seizures, confirming PTEN as a major candidate gene in the ASD-macrocephaly endophenotype and suggesting that the PTEN/AKT/mTOR pathway should deserve to be investigated in autism-epilepsy comorbidity. Finally, following the report of gain-of-function mutations of KCNJ10 (Kir4.1) in epilepsy and ASD by our research group, we aimed at further defining whether defects of genes encoding astrocytic Kir channels, KCNJ10 (Kir4.1), KCNJ2 (Kir2.1), KCNJ16 (Kir5.1), underlie the disorder, and performing genotype-phenotype correlation

The spreading of the invasive Italian wall lizard on vulcano, the last Island inhabited by the critically endangered Aeolian wall lizard

The Aeolian Wall Lizard (Podarcis raffoneae) is an endemic species of the Aeolian Archipelago of Italy (Mediterranean Sea). Its distribution is limited to three islets and two relict populations on a relatively large island: Vulcano (a population on the summit of Gran Cratere volcano and another on Capo Grosso promontory). The critically endangered Aeolian Wall Lizard is threatened by the introduction of the Italian Wall Lizard (Podarcis siculus), which successfully competes and hybridizes with the endemic lizard. The invasive lizard is widespread on Vulcano, although the literature does not provide the exact distribution. Our first aim was updating the distribution of the Italian Wall Lizard on Vulcano, with special attention to the last enclaves of the Aeolian Wall Lizard. Our second purpose was investigating the factors determining this distribution range. In the spring of 2016, we surveyed the Italian Wall Lizard distribution on Vulcano, considering 10 human-related and 10 natural areas, including Gran Cratere volcano and Capo Grosso promontory. We recorded the presence of the invasive Italian Wall Lizard in each survey area. As a consequence, the Aeolian Wall Lizard populations of Vulcano face an imminent extinction risk. The main factors increasing the presence probability of this invasive lizard on Vulcano were the nearness to the harbor (the introduction gateway) and the urbanization degree (the invasion pathway). Therefore, we suggest the implementation of a control plan simultaneously acting on the areas of sympatry (mostly Capo Grosso promontory), the introduction gateway (Vulcano harbor), and the source populations (urban areas)

I disturbi depressivi nell’età prescolare

Obiettivo: Fornire un contributo alla clinica della depressione nell’età prescolare, con particolare attenzione alla costellazione sintomatologica, ai pattern di relazione genitore-bambino, al livello di funzionamento emotivo ed all’incidenza di eventi stressanti. Metodo: Il campione è costituito da 12 bambini di età compresa tra 11 e 56 mesi per i quali è stata effettuata la diagnosi di Depressione attraverso l’applicazione della CD:0-3R. Alcuni dati sono stati poi confrontati con un gruppo di controllo costituito da bambini, equiparabili per numero, sesso ed età. Risultati: Tutti i bambini hanno ricevuto una diagnosi di Disturbo depressivo NAS; nella relazione genitore-bambino prevale una tendenza al disturbo (PIRGAS, media, 53.18); sono stati riscontrati 1 o 2 life events nel 63% dei casi con un’influenza sul funzionamento emotivo e sociale nel 45% dei bambini. Alla CBCL si evidenzia una media di valori borderline nell’area esternalizzante, mentre al PSI i punteggi rientrano nel range della normalità. Il confronto con il gruppo di controllo ha mostrato differenze significative sia alla CBCL che al PSI. Discussione: Il Disturbo Depressivo in età prescolare appare oggi un’entità clinica sufficientemente definita, anche se alcuni criteri introdotti nella CD:0- 3R non sono risultati applicabili. È stato tuttavia possibile individuare una costellazione sintomatologica ricorrente sull’Asse I e un andamento specifico degli altri Assi (Asse II, IV e V) che consente di ipotizzare un “circuito patogeno ricorrente”. Viene infine segnalata l’importanza di validare le ipotesi diagnostiche con studi di follow-up