The genetic causes of epilepsies and developmental and epileptic encephalopathies (DEE) with onset in early childhood are increasingly recognized. Their outcomes vary from benign to severe disability. In this paper, we wished to retrospectively review the clinical, genetic, EEG, neuroimaging, and outcome data of patients experiencing the onset of epilepsy in the first three years of life, diagnosed and followed up in four Italian epilepsy centres (Epilepsy Centre of San Paolo University Hospital in Milan, Child Neurology and Psychiatry Unit of AUSL-IRCCS di Reggio Emilia, Pediatric Neurology Unit of Vittore Buzzi Children’s Hospital, Milan, and Child Neurology and Psychiatry Unit, IRCCS Mondino Foundation, Pavia). We included 168 patients (104 with monogenic conditions, 45 with copy number variations (CNVs) or chromosomal abnormalities, and 19 with variants of unknown significance), who had been followed up for a mean of 14.75 years. We found a high occurrence of generalized seizures at onset, drug resistance, abnormal neurological examination, global developmental delay and intellectual disability, and behavioural and psychiatric comorbidities. We also documented differing presentations between monogenic issues versus CNVs and chromosomal conditions, as well as atypical/rare phenotypes. Genetic early-childhood-onset epilepsies and DEE show a very wide phenotypic and genotypic spectrum, with a high risk of complex neurological and neuropsychiatric phenotypes.

Objective: Adenylosuccinate lyase (ADSL) deficiency is a rare inherited metabolic disorder with a wide phenotypic presentation, classically grouped into three types (neonatal, type I, and type II). We aim to better delineate the pathological spectrum, focusing on the electroclinical characteristics and phenotypic differences of patients with ADSL deficiency.Patients and Methods: Seven patients, from four different families, underwent serial electroencephalogram (EEG), clinical assessment, and neuroimaging. We also performed a systematic review of the cases published in the literature, summarizing the available clinical, neurophysiological, and genetic data.Results: We report seven previously unreported ADSL deficiency patients with long‐term follow‐up (10–34 years). From the literature review, we collected 81 previously reported cases. Of the included patient population, 58 % (51/88) were classified as having ADSL deficiency type I, 28% (25/88) as having type II, and 14% (12/88) as having neonatal. The most frequently reported pathogenic variants are p.R426H homozygous (19 patients), p.Y114H in compound heterozygosity (13 patients), and p.D430N homozygous (6 patients). In the majority (89.2%), disease onset was within the first year of life. Epilepsy is present in 81.8% of the patients, with polymorphic and often intractable seizures. EEG features seem to display common patterns and developmental trajectories: (i) poor general background organization with theta‐delta activity; (ii) hypsarrhythmia with spasms, usually adrenocorticotropic hormone‐responsive; (iii) generalized epileptic discharges with frontal or frontal temporal predominance; and (iv) epileptic discharge activation in sleep with an altered sleep structure. Imaging features present consistent findings of cerebral atrophy with frontal predominance, cerebellar atrophy, and white matter abnormalities among the three types.Significance: ADSL deficiency presents variable phenotypic expression, whose severity could be partially attributed to residual activity of the mutant protein. Although a precise phenotype‐genotype correlation was not yet feasible, we delineated a common pattern of clinical, neuroradiological, and neurophysiological features.

Background: Premature children are at increased risk of executive functions (EF) deficits and these difficulties persist into adolescence and adulthood, potentially undermining their development and academic achievements. The aim of the present randomized controlled trial (RCT) is to evaluate the efficacy of the Intendu trainer, an adaptive virtual reality platform, at ameliorating EF in preterm children. Methods: A single-center, RCT was conducted. The intervention group was exposed to game session with the Intendu software in addition to the standard of care in use in our center. The main outcome was the proportion of children with a 10-point increase in the processing speed quotient as measured by WPPSI–III after 4 weeks from the baseline assessment. Results: Forty-seven children born before 36 + 5 weeks were randomized to the experimental ( n = 24) or control arm ( n = 23). Five children were lost to follow-up. Thirteen of 23 children (56%) reached the main outcome in the experimental group and 5 of 19 (26%) in the control group ( P = 0.049, per-protocol analysis) with an absolute benefit increase (ABI) of 30% reconfirmed by the intention-to-treat analysis ( P = 0.022, ABI of 32%). Conclusion: Intendu brain-trainer showed promising short-term results on EF in pre-term children, however, larger studies with longer periods of follow-up are warranted to better investigate the role of this or similar technology in promoting better EF in preterm children.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with variable phenotypic expressions which has been associated with autonomic dysfunction. The cardiovascular system seems to be affected especially in the context of bulbar involvement. We describe four new cases of Tako-Tsubo syndrome (TTS) in ALS patients with an appraisal of the literature. We present a late-stage ALS patient with prominent bulbar involvement that presented TTS during hospitalization. We then retrospectively identify three additional ALS–TTS cases reporting relevant clinical findings. TTS cardiomyopathy has been observed in different acute neurological conditions, and the co-occurrence of ALS and TTS has already been reported. Cardiovascular autonomic dysfunctions have been described in ALS, especially in the context of an advanced diseases and with bulbar involvement. Noradrenergic hyperfunction linked to sympathetic denervation and ventilatory deficits coupled in different instances with a trigger event could play a synergistic role in the development of TTS in ALS. Sympathetic hyperfunctioning and ventilatory deficits in conjunction with cardiac autonomic nerves impairment may play a role in the development of TTS in a context of ALS.

Objective: We present the cases of two sisters, both harboring the same ALDH18A1 gene mutations, who presented with a complex clinical phenotype characterized by spastic paraparesis with ataxia, epileptic encephalopathy, severe psychomotor deficits, and behavioral abnormalities.Methods: Case description of two sisters with ALDH18A1 gene mutations.Results: The older patient, a 12‐year‐old girl, exhibited spastic paraparesis with ataxia, microcephaly, facial dysmorphisms, and severe intellectual disability, with an absence of verbal language. An electroencephalogram (EEG) revealed marked spike‐and‐wave activation during sleep (SWAS), although no clinically documented seizures were observed. The younger sister, who was 9 years old, displayed a similar clinical presentation, including spastic paraparesis with ataxia, microcephaly, dysmorphisms, however, she displayed slightly more severe intellectual deficits and polymorphic seizures. EEG revealed a SWAS pattern in this case. Magnetic resonance imaging scans in both cases showed only a thin corpus callosum. Whole exome sequencing unveiled the presence of two likely pathogenic variants in compound heterozygosity within the ALDH18A1 gene. Specifically, these variants included the splice site variant c.88 + 1c.88+1G>A of paternal origin and the variant c.1364c.1364T>C (p.Leu455Ser) of maternal origin. Both sisters displayed normal blood levels of ammonia, ornithine, citrulline, arginine, and other amino acids.Interpretation: These findings were compatible with ALDH18A1‐related HSP complicated with a clinical and EEG pattern reminiscent of DEE‐SWAS. We present the first report of DEE‐SWAS in ALDH18A1‐related HSP, expanding the clinical manifestations of this complex neurodevelopmental condition.