Two genes causally involved in refractory epilepsy with mental retardation, cyclin-dependent kinase-like 5 and aristaless-related homeobox, could account for at least some forms of early onset epileptic encephalopathy that still lack etiological explanation. With the aim of investigating the specific pathogenic involvement of the 2 genes, we have conducted a clinical and molecular study in 80 patients with epileptic encephalopathy of unknown etiology and onset within the first year of life, regardless of the presence of other clinical features or the definition of a precise epileptologic syndrome. A total of 8 different disease-causing mutations were detected in our population, confirming the pivotal role of these genes in the pathogenesis of the epileptic encephalopathies in infancy. Early key clinical and electroencephalographic phenotypical features identified in these patients can contribute to more precise and early diagnoses. This work provides a better phenotypic characterization and more stringent clinical indications for the molecular test.

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Cornelia de Lange syndrome (CdLS), Rubinstein-Taybi syndrome (RSTS), and KBG syndrome are three distinct developmental human disorders. Variants in seven genes belonging to the cohesin pathway, NIPBL, SMC1A, SMC3, HDAC8, RAD21, ANKRD11, and BRD4, were identified in about 80% of patients with CdLS, suggesting that additional causative genes remain to be discovered. Two genes, CREBBP and EP300, have been associated with RSTS, whereas KBG results from variants in ANKRD11. By exome sequencing, a genetic cause was elucidated in two patients with clinical diagnosis of CdLS but without variants in known CdLS genes. In particular, genetic variants in EP300 and ANKRD11 were identified in the two patients with CdLS. EP300 and ANKRD11 pathogenic variants caused the reduction of the respective proteins suggesting that their low levels contribute to CdLS-like phenotype. These findings highlight the clinical overlap between CdLS, RSTS, and KBG and support the notion that these rare disorders are linked to abnormal chromatin remodeling, which in turn affects the transcriptional machinery.

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Background and ObjectivesWe sought to identify early factors associated with relapse and outcome in paediatric-onset myelin oligodendrocyte glycoprotein antibody-associated disorders (MOGAD).MethodsIn a multicenter retrospective cohort of pediatric MOGAD (≤18 years), onset features and treatment were compared in patients with monophasic vs relapsing disease (including cases with follow-up ≥12 months after onset or relapse at any time) and in patients with final Expanded Disability Status Scale (EDSS) 0 vs ≥1 at last follow-up (including cases with follow-up >3 months after last event or EDSS0 at any time). Multivariable logistic regression models were used to evaluate factors associated with relapsing disease course and EDSS ≥ 1 at final follow-up.ResultsSeventy-five children were included (median onset age 7 years; median 30 months of follow-up). Presentation with acute disseminated encephalomyelitis was more frequent in children aged 8 years or younger (66.7%, 28/42) than in older patients (30.3%, 10/33) (p= 0.002), whereas presentation with optic neuritis was more common in children older than 8 years (57.6%, 19/33) than in younger patients (21.4%, 9/42) (p= 0.001). 40.0% (26/65) of patients relapsed. Time to first relapse was longer in children aged 8 years or younger than in older patients (median 18 vs 4 months) (p= 0.013). Factors at first event independently associated with lower risk of relapsing disease course were immunotherapy <7 days from onset (6.7-fold reduced odds of relapsing course, OR 0.15, 95% CI 0.03–0.61,p= 0.009), corticosteroid treatment for ≥5 weeks (6.7-fold reduced odds of relapse, OR 0.15, 95% CI 0.03–0.80,p= 0.026), and abnormal optic nerves on onset MRI (12.5-fold reduced odds of relapse, OR 0.08, 95% CI 0.01–0.50,p= 0.007). 21.1% (15/71) had EDSS ≥ 1 at final follow-up. Patients with a relapsing course had a higher proportion of final EDSS ≥ 1 (37.5%, 9/24) than children with monophasic disease (12.8%, 5/39) (p= 0.022, univariate analysis). Each 1-point increment in worst EDSS at onset was independently associated with 6.7-fold increased odds of final EDSS ≥ 1 (OR 6.65, 95% CI 1.33–33.26,p= 0.021).DiscussionAt first attack of pediatric MOGAD, early immunotherapy, longer duration of corticosteroid treatment, and abnormal optic nerves on MRI seem associated with lower risk of relapse, whereas higher disease severity is associated with greater risk of final disability (EDSS ≥ 1).