EEG at onset and MRI predict long-term clinical outcome in Aicardi syndrome

Descriptions of electroencephalographic (EEG) patterns in Aicardi syndrome (AIC) have to date referred to small cohorts of up to six cases and indicated severe derangement of electrical activity in all cases. The present study was conducted to describe the long-term EEG evolution in a larger AIC cohort, followed for up to 23 years, and identify possible early predictors of the clinical and EEG outcomes

A clustering of heterozygous missense variants in the crucial chromatin modifier WDR5 defines a new neurodevelopmental disorder

WDR5 is a broadly studied, highly conserved key protein involved in a wide array of biological functions. Among these functions, WDR5 is a part of several protein complexes that affect gene regulation via post-translational modification of histones. We collected data from 11 unrelated individuals with six different rare de novo germline missense variants in WDR5; one identical variant was found in five individuals and another variant in two individuals. All individuals had neurodevelopmental disorders including speech/language delays (n = 11), intellectual disability (n = 9), epilepsy (n = 7), and autism spectrum disorder (n = 4). Additional phenotypic features included abnormal growth parameters (n = 7), heart anomalies (n = 2), and hearing loss (n = 2). Three-dimensional protein structures indicate that all the residues affected by these variants are located at the surface of one side of the WDR5 protein. It is predicted that five out of the six amino acid substitutions disrupt interactions of WDR5 with RbBP5 and/or KMT2A/C, as part of the COMPASS (complex proteins associated with Set1) family complexes. Our experimental approaches in Drosophila melanogaster and human cell lines show normal protein expression, localization, and protein-protein interactions for all tested variants. These results, together with the clustering of variants in a specific region of WDR5 and the absence of truncating variants so far, suggest that dominant-negative or gain-of-function mechanisms might be at play. All in all, we define a neurodevelopmental disorder associated with missense variants in WDR5 and a broad range of features. This finding highlights the important role of genes encoding COMPASS family proteins in neurodevelopmental disorders

Basal Ganglia Dysmorphism in Patients With Aicardi Syndrome

none63noOBJECTIVE: Aiming to detect associations between neuroradiologic and EEG evaluations and long-term clinical outcome in order to detect possible prognostic factors, a detailed clinical and neuroimaging characterization of 67 cases of Aicardi syndrome (AIC), collected through a multicenter collaboration, was performed. METHODS: Only patients who satisfied Sutton diagnostic criteria were included. Clinical outcome was assessed using gross motor function, manual ability, and eating and drinking ability classification systems. Brain imaging studies and statistical analysis were reviewed. RESULTS: Patients presented early-onset epilepsy, which evolved into drug-resistant seizures. AIC has a variable clinical course, leading to permanent disability in most cases; nevertheless, some cases presented residual motor abilities. Chorioretinal lacunae were present in 86.56% of our patients. Statistical analysis revealed correlations between MRI, EEG at onset, and clinical outcome. On brain imaging, 100% of the patients displayed corpus callosum malformations, 98% cortical dysplasia and nodular heterotopias, and 96.36% intracranial cysts (with similar rates of 2b and 2d). As well as demonstrating that posterior fossa abnormalities (found in 63.63% of cases) should also be considered a common feature in AIC, our study highlighted the presence (in 76.36%) of basal ganglia dysmorphisms (never previously reported). CONCLUSION: The AIC neuroradiologic phenotype consists of a complex brain malformation whose presence should be considered central to the diagnosis. Basal ganglia dysmorphisms are frequently associated. Our work underlines the importance of MRI and EEG, both for correct diagnosis and as a factor for predicting long-term outcome. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with AIC, specific MRI abnormalities and EEG at onset are associated with clinical outcomes.mixedMasnada S.; Pichiecchio A.; Formica M.; Arrigoni F.; Borrelli P.; Accorsi P.; Bonanni P.; Borgatti R.; Bernardina B.D.; Danieli A.; Darra F.; Deconinck N.; De Giorgis V.; Dulac O.; Gataullina S.; Giordano L.; Guerrini R.; La Briola F.; Mastrangelo M.; Montomoli M.; Mortilla M.; Osanni E.; Parisi P.; Perucca E.; Pinelli L.; Romaniello R.; Severino M.; Vigevano F.; Vignoli A.; Bahi-Buisson N.; Cavallin M.; Accogli A.; Burgeois M.; Capra V.; Chaves-Vischer V.; Chiapparini L.; Colafati G.; D'Arrigo S.; Desguerre I.; Doco-Fenzy M.; d'Orsi G.; Epitashvili N.; Fazzi E.; Ferretti A.; Fiorini E.; Fradin M.; Fusco C.; Granata T.; Johannesen K.M.; Lebon S.; Loget P.; Moller R.S.; Montanaro D.; Orcesi S.; Quelin C.; Rebessi E.; Romeo A.; Solazzi R.; Spagnoli C.; Uebler C.; Zara F.; Arzimanoglou A.; Veggiotti P.Masnada, S.; Pichiecchio, A.; Formica, M.; Arrigoni, F.; Borrelli, P.; Accorsi, P.; Bonanni, P.; Borgatti, R.; Bernardina, B. D.; Danieli, A.; Darra, F.; Deconinck, N.; De Giorgis, V.; Dulac, O.; Gataullina, S.; Giordano, L.; Guerrini, R.; La Briola, F.; Mastrangelo, M.; Montomoli, M.; Mortilla, M.; Osanni, E.; Parisi, P.; Perucca, E.; Pinelli, L.; Romaniello, R.; Severino, M.; Vigevano, F.; Vignoli, A.; Bahi-Buisson, N.; Cavallin, M.; Accogli, A.; Burgeois, M.; Capra, V.; Chaves-Vischer, V.; Chiapparini, L.; Colafati, G.; D'Arrigo, S.; Desguerre, I.; Doco-Fenzy, M.; D'Orsi, G.; Epitashvili, N.; Fazzi, E.; Ferretti, A.; Fiorini, E.; Fradin, M.; Fusco, C.; Granata, T.; Johannesen, K. M.; Lebon, S.; Loget, P.; Moller, R. S.; Montanaro, D.; Orcesi, S.; Quelin, C.; Rebessi, E.; Romeo, A.; Solazzi, R.; Spagnoli, C.; Uebler, C.; Zara, F.; Arzimanoglou, A.; Veggiotti, P

Basal ganglia dysmorphism in patients with Aicardi syndrome

Aiming to detect associations between neuroradiologic and EEG evaluations and long-term clinical outcome in order to detect possible prognostic factors, a detailed clinical and neuroimaging characterization of 67 cases of Aicardi syndrome (AIC), collected through a multicenter collaboration, was performed