Noninvasive Assessment of Hemodynamic Stress Distribution after Indirect Revascularization for Pediatric Moyamoya Vasculopathy

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Noninvasive Assessment of Hemodynamic Stress Distribution after Indirect Revascularization for Pediatric Moyamoya Vasculopathy

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Leucomalacia periventricolare ed encefalopatia epilettica con punte-onda continue in sonno lento

Children with cerebral palsy associated with periventricular leukomalacia frequently develop unprovoked epileptic seizures, with a reported incidence of 16.0% to 47%. Recently cases with early thalamic injury associated with continuous spike-waves during slow sleep syndrome (CSWSS) have been reported. The aim of this study was to investigate in a population of patients with a periventricular leukomalacia the presence of an activation of paroxysmal activities during sleep and their electroclinical characteristics

KCNT1-related epilepsies and epileptic encephalopathies: phenotypic and mutational spectrum

Variants in KCNT1, encoding a sodium-gated potassium channel (subfamily T member 1), have been associated with a spectrum of epilepsies and neurodevelopmental disorders. These range from familial autosomal dominant or sporadic sleep-related hypermotor epilepsy to epilepsy of infancy with migrating focal seizures (EIMFS) and include developmental and epileptic encephalopathies. This study aims to provide a comprehensive overview of the phenotypic and genotypic spectrum of KCNT1 mutation-related epileptic disorders in 248 individuals, including 66 previously unpublished and 182 published cases, the largest cohort reported so far. Four phenotypic groups emerged from our analysis: (i) EIMFS (152 individuals, 33 previously unpublished); (ii) developmental and epileptic encephalopathies other than EIMFS (non-EIMFS developmental and epileptic encephalopathies) (37 individuals, 17 unpublished); (iii) autosomal dominant or sporadic sleep-related hypermotor epilepsy (53 patients, 14 unpublished); and (iv) other phenotypes (six individuals, two unpublished). In our cohort of 66 new cases, the most common phenotypic features were: (i) in EIMFS, heterogeneity of seizure types, including epileptic spasms, epilepsy improvement over time, no epilepsy-related deaths; (ii) in non-EIMFS developmental and epileptic encephalopathies, possible onset with West syndrome, occurrence of atypical absences, possible evolution to developmental and epileptic encephalopathies with sleep-related hypermotor epilepsy features; one case of sudden unexplained death in epilepsy; (iii) in autosomal dominant or sporadic sleep-related hypermotor epilepsy, we observed a high prevalence of drug-resistance, although seizure frequency improved with age in some individuals, appearance of cognitive regression after seizure onset in all patients, no reported severe psychiatric disorders, although behavioural/psychiatric comorbidities were reported in ∼50% of the patients, sudden unexplained death in epilepsy in one individual; and (iv) other phenotypes in individuals with mutation of KCNT1 included temporal lobe epilepsy, and epilepsy with tonic-clonic seizures and cognitive regression. Genotypic analysis of the whole cohort of 248 individuals showed only missense mutations and one inframe deletion in KCNT1. Although the KCNT1 mutations in affected individuals were seen to be distributed among the different domains of the KCNT1 protein, genotype–phenotype considerations showed many of the autosomal dominant or sporadic sleep-related hypermotor epilepsy-associated mutations to be clustered around the RCK2 domain in the C terminus, distal to the NADP domain. Mutations associated with EIMFS/non-EIMFS developmental and epileptic encephalopathies did not show a particular pattern of distribution in the KCNT1 protein. Recurrent KCNT1 mutations were seen to be associated with both severe and less severe phenotypes. Our study further defines and broadens the phenotypic and genotypic spectrums of KCNT1-related epileptic conditions and emphasizes the increasingly important role of this gene in the pathogenesis of early onset developmental and epileptic encephalopathies as well as of focal epilepsies, namely autosomal dominant or sporadic sleep-related hypermotor epilepsy.Claudia M. Bonardi, Henrike O. Heyne, Martina Fiannacca, Mark P. Fitzgerald, Elena Gardella, Boudewijn Gunning, Kern Olofsson, Gaétan Lesca, Nienke Verbeek, Hannah Stamberger, Pasquale Striano, Federico Zara, Maria M. Mancardi, Caroline Nava, Steffen Syrbe, Salvatore Buono, Stephanie Baulac, Antonietta Coppola, Sarah Weckhuysen, An-Sofie Schoonjans, Berten Ceulemans, Catherine Sarret, Tobias Baumgartner, Hiltrud Muhle, Vincent des Portes, Joseph Toulouse, Marie-Christine Nougues, Massimiliano Rossi, Geneviève Demarquay, Dorothée Ville, Edouard Hirsch, Hélène Maurey, Marjolaine Willems, Julitta de Bellescize, Cecilia Desmettre Altuzarra, Nathalie Villeneuve, Fabrice Bartolomei, Fabienne Picard, Frauke Hornemann, David A. Koolen, Hester Y. Kroes, Chiara Reale, Christina D. Fenger, Wen-Hann Tan, Leanne Dibbens, David R. Bearden, Rikke S. Møller, and Guido Rubbol

Clinical spectrum and genotype-phenotype correlations in PRRT2 Italian patients

none32noPrrt2 is a neuron-specific protein expressed at axonal and pre-synaptic domains, involved in synaptic neurotransmitter release and modulation of intrinsic excitability. Mutations in PRRT2 cause a spectrum of autosomal dominant paroxysmal neurological disorders including epilepsy, movement disorders, and hemiplegic migraine and show incomplete penetrance and variable expressivity. We assessed the diagnostic rate of PRRT2 in a cohort of Italian patients with epilepsy and/or paroxysmal kinesigenic dyskinesia (PKD) and evaluated genotype-phenotype correlations. Clinical data were collected using a structured questionnaire. Twenty-seven out of 55 (49.1%) probands carried PRRT2 heterozygous pathogenic variants, including six previously known genotypes and one novel missense mutation. A family history of epilepsy starting in the first year of life and/or PKD was strongly suggestive of a PRRT2 pathogenic variant. Epilepsy patients harbouring PRRT2 pathogenic variants showed earlier seizure onset and more frequent clusters compared with PRRT2-negative individuals with epilepsy. Moreover, we did also identify individuals with PRRT2 pathogenic variants with atypical age at onset, i.e. childhood-onset epilepsy and infantile-onset PKD. However, the lack of a clear correlation between specific PRRT2 genotypes and clinical manifestations and the high incidence of asymptomatic carriers suggest the involvement of additional factors in modulating expressivity of PRRT2-related disorders. Finally, our study supports the pleiotropic and multifaceted physiological role of PRRT2 gene which is emerging from experimental neuroscience.mixedBalagura G.; Riva A.; Marchese F.; Iacomino M.; Madia F.; Giacomini T.; Mancardi M.M.; Amadori E.; Vari M.S.; Salpietro Damiano V.; Russo A.; Messana T.; Vignoli A.; Chiesa V.; Giordano L.; Accorsi P.; Caffi L.; Orsini A.; Bonuccelli A.; Santucci M.; Vecchi M.; Vanadia F.; Milito G.; Fusco C.; Cricchiutti G.; Carpentieri M.; Margari L.; Spalice A.; Beccaria F.; Benfenati F.; Zara F.; Striano P.Balagura, G.; Riva, A.; Marchese, F.; Iacomino, M.; Madia, F.; Giacomini, T.; Mancardi, M. M.; Amadori, E.; Vari, M. S.; Salpietro Damiano, V.; Russo, A.; Messana, T.; Vignoli, A.; Chiesa, V.; Giordano, L.; Accorsi, P.; Caffi, L.; Orsini, A.; Bonuccelli, A.; Santucci, M.; Vecchi, M.; Vanadia, F.; Milito, G.; Fusco, C.; Cricchiutti, G.; Carpentieri, M.; Margari, L.; Spalice, A.; Beccaria, F.; Benfenati, F.; Zara, F.; Striano, P

Abrogation of MAP4K4 protein function causes congenital anomalies in humans and zebrafish.

We report 21 families displaying neurodevelopmental differences and multiple congenital anomalies while bearing a series of rare variants in mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4). MAP4K4 has been implicated in many signaling pathways including c-Jun N-terminal and RAS kinases and is currently under investigation as a druggable target for multiple disorders. Using several zebrafish models, we demonstrate that these human variants are either loss-of-function or dominant-negative alleles and show that decreasing Map4k4 activity causes developmental defects. Furthermore, MAP4K4 can restrain hyperactive RAS signaling in early embryonic stages. Together, our data demonstrate that MAP4K4 negatively regulates RAS signaling in the early embryo and that variants identified in affected humans abrogate its function, establishing MAP4K4 as a causal locus for individuals with syndromic neurodevelopmental differences