Early-onset epileptic encephalopathy caused by a reduced sensitivity of Kv7.2 potassium channels to phosphatidylinositol 4,5-bisphosphate

Kv7.2 and Kv7.3 subunits underlie the M-current, a neuronal K(+) current characterized by an absolute functional requirement for phosphatidylinositol 4,5-bisphosphate (PIP(2)). Kv7.2 gene mutations cause early-onset neonatal seizures with heterogeneous clinical outcomes, ranging from self-limiting benign familial neonatal seizures to severe early-onset epileptic encephalopathy (Kv7.2-EE). In this study, the biochemical and functional consequences prompted by a recurrent variant (R325G) found independently in four individuals with severe forms of neonatal-onset EE have been investigated. Upon heterologous expression, homomeric Kv7.2 R325G channels were non-functional, despite biotin-capture in Western blots revealed normal plasma membrane subunit expression. Mutant subunits exerted dominant-negative effects when incorporated into heteromeric channels with Kv7.2 and/or Kv7.3 subunits. Increasing cellular PIP(2) levels by co-expression of type 1γ PI(4)P5-kinase (PIP5K) partially recovered homomeric Kv7.2 R325G channel function. Currents carried by heteromeric channels incorporating Kv7.2 R325G subunits were more readily inhibited than wild-type channels upon activation of a voltage-sensitive phosphatase (VSP), and recovered more slowly upon VSP switch-off. These results reveal for the first time that a mutation-induced decrease in current sensitivity to PIP(2) is the primary molecular defect responsible for Kv7.2-EE in individuals carrying the R325G variant, further expanding the range of pathogenetic mechanisms exploitable for personalized treatment of Kv7.2-related epilepsies

Comparing the responses of countries and National Health Systems to the COVID-19 pandemic: a critical analysis with a case-report series

This review aimed to compare the different responses of countries to the pandemic, their National Health Systems, and their impact on citizens’ health. This work aimed to create a narrative plot that connects different discussion points and suggests organizational solutions and strategic choices in the face of the pandemic. In particular, this work focused on public health organizations, specifically the European Union and vaccination politics. It is also based on a case report series (about the United States, Germany, Vietnam, New Zealand, Cuba, and Italy), where each country has responded differently to the pandemic in terms of political decisions such as vaccination type, information to citizens, dealings with independent experts, and other specific country factors. In comparing the various models of care systems response to the pandemic, it emerges that: we have found some (few) good practices, but without global coordination, and this is obviously not enough. It is now quite clear that there cannot be a “good answer” in a single nation. Uncoordinated local responses cannot counter a global phenomenon. The second point is that the general context must be considered from a strategic point of view. With the threat of new pandemics (but also of health disasters linked to climate change, pollution, and wars), humanity finds itself at the crossroads between investing in a “democratic” management of international bodies but without power (and at the mercy of the need for funds with consequent conflicts) or in some new leadership proposals that advocate efficiency and problem-solving (and that would probably be able to implement it) but that would place processes totally outside of the public’s control

I mobility scooter: da ausili per la mobilità di disabili e anziani a nuovi veicoli per una mobilità sostenibile? Una normativa comunque da rifare

I mobility scooter, in particolare quelli cabinati, sono potenzialmente un ausilio formidabile per la mobilità a breve e medio raggio delle persone sia abili che disabili, con innegabili benefici anche per il traffico urbano e l’ambiente, ma a condizione di una drastica revisione normativa. La modifica all’art. 46 del Codice della Strada intervenuta nel 2010, che ha demandato genericamente la definizione delle “macchine per uso di invalidi” (non considerate veicoli) a “vigenti disposizioni comunitarie” (che invece equiparano i mobility scooter ad autoveicoli), sembra aver sortito un risultato opposto al suo intento chiarificatore, con implicazioni finanche inquietanti per quanto riguarda la possibilità che i mobility scooter siano effettivamente ammessi a circolare in aree aperte al pubblico. Il recente decreto per la sperimentazione su strada dei dispositivi per la micromobilità elettrica, che ha ignorato il dispositivo obiettivamente più versatile, sicuro e “serio”, ha perso una grande occasione, ma si può ancora rimediare. La loro classificazione come “veicoli” adatti sia agli abili che ai disabili – anche ai sensi dell’orientamento comunitario – ed una specifica regolamentazione della loro circolazione nelle aree pubbliche attraverso una serie di modifiche al Codice della Strada, al suo Regolamento di attuazione ed al decreto per la sperimentazione su strada dei dispositivi di micromobilità elettrica, nonché l’individuazione di un organismo di controllo e informazione, porrebbero facilmente fine ad un pericoloso vuoto normativo ed alla confusione e disinformazione che ne sono derivate, favorendo finalmente la meritata diffusione dei mobility scooter: ciò contribuirebbe anche ad abbattere i costi d’acquisto dei moderni e versatili scooter cabinati, ancora relativamente elevati seppur inferiori a quelli di un’autovettura elettrica, a tutto vantaggio delle categorie spesso non abbienti per cui questi dispositivi sono stati originariamente concepiti

Neuronal Ablation of CoA Synthase Causes Motor Deficits, Iron Dyshomeostasis, and Mitochondrial Dysfunctions in a CoPAN Mouse Model

COASY protein-associated neurodegeneration (CoPAN) is a rare but devastating genetic autosomal recessive disorder of inborn error of CoA metabolism, which shares with pantothenate kinase-associated neurodegeneration (PKAN) similar features, such as dystonia, parkinsonian traits, cognitive impairment, axonal neuropathy, and brain iron accumulation. These two disorders are part of the big group of neurodegenerations with brain iron accumulation (NBIA) for which no effective treatment is available at the moment. To date, the lack of a mammalian model, fully recapitulating the human disorder, has prevented the elucidation of pathogenesis and the development of therapeutic approaches. To gain new insights into the mechanisms linking CoA metabolism, iron dyshomeostasis, and neurodegeneration, we generated and characterized the first CoPAN disease mammalian model. Since CoA is a crucial metabolite, constitutive ablation of the Coasy gene is incompatible with life. On the contrary, a conditional neuronal-specific Coasy knock-out mouse model consistently developed a severe early onset neurological phenotype characterized by sensorimotor defects and dystonia-like movements, leading to premature death. For the first time, we highlighted defective brain iron homeostasis, elevation of iron, calcium, and magnesium, together with mitochondrial dysfunction. Surprisingly, total brain CoA levels were unchanged, and no signs of neurodegeneration were present

De novo gain-of-function variants in KCNT2 as a novel cause of developmental and epileptic encephalopathy.

Variants in several potassium channel genes have been found in developmental and epileptic encephalopathies (DEE). We report two females with de novo variants in KCNT2 with West syndrome followed by Lennox-Gastaut syndrome or with DEE with migrating focal seizures. After in vitro analysis suggested quinidine-responsive gain-of-function effects, we treated one of the girls with quinidine add-on therapy and achieved marked clinical improvements. This suggests that the new spectrum of KCNT2-related disorders do not only share similar phenotypic and in vitro functional and pharmacological features with previously known KCNT1-related disorders but also represents a further example for possible precision medicine approaches. This article is protected by copyright. All rights reserved