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Introduction: The classic ketogenic diet (cKD) is an isocaloric, high fat, low-carbohydrate diet that induces the production of ketone bodies. High consumption of dietary fatty acids, particularly long-chain saturated fatty acids, could impair nutritional status and increase cardiovascular risk. The purpose of this study was to evaluate the long-term effects of a 5-year cKD on body composition, resting energy expenditure, and biochemical parameters in children affected by Glucose Transporter 1 Deficiency Syndrome (GLUT1DS)., Methods: This was a prospective, multicenter, 5-year longitudinal study of children with GLUT1DS treated with a cKD. The primary outcome was to assess the change in nutritional status compared with pre-intervention, considering anthropometric measurements, body composition, resting energy expenditure, and biochemical parameters such as glucose and lipid profiles, liver enzymes, uric acid, creatinine, and ketonemia. Assessments were conducted at pre-intervention and every 12 months of cKD interventions., Results: Ketone bodies increased significantly in children and adolescents, and remained stable at 5 years, depending on the diet. No significant differences were reported in anthropometric and body composition standards, as well as in resting energy expenditure and biochemical parameters. Bone mineral density increased significantly over time according to increasing age. Body fat percentage significantly and gradually decreased in line with the increase in body weight and the consequent growth in lean mass. As expected, we observed a negative trend in respiratory quotient, while fasting insulin and insulin resistance were found to decrease significantly after cKD initiation., Conclusion: Long-term adherence to cKD showed a good safety profile on anthropometric measurements, body composition, resting energy expenditure, and biochemical parameters, and we found no evidence of potential adverse effects on the nutritional status of children and adolescents., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 De Amicis, Leone, Pellizzari, Foppiani, Battezzati, Lessa, Tagliabue, Ferraris, De Giorgis, Olivotto, Previtali, Veggiotti and Bertoli.)

Background: GLUT1 deficiency syndrome is a rare, genetically determined neurological disorder for which Ketogenic Dietary Treatment represents the gold standard and lifelong treatment. Patient registries are powerful tools providing insights and real-world data on rare diseases., Objective: To describe the implementation of a national web-based registry for GLUT1-DS., Methods: This is a retrospective and prospective, multicenter, observational registry developed in collaboration with the Italian GLUT1-DS association and based on an innovative, flexible and configurable cloud computing technology platform, structured according to the most rigorous requirements for the management of patient's sensitive data. The Glut1 Registry collects baseline and follow-up data on the patient's demographics, history, symptoms, genotype, clinical, and instrumental evaluations and therapies., Results: Five Centers in Italy joined the registry, and two more Centers are currently joining. In the first two years of running, data from 67 patients (40 females and 27 males) have been collected. Age at symptom onset was within the first year of life in most (40, 60%) patients. The diagnosis was formulated in infancy in almost half of the cases (34, 51%). Symptoms at onset were mainly paroxysmal (mostly epileptic seizure and paroxysmal ocular movement disorder) or mixed paroxysmal and fixed symptoms (mostly psychomotor delay). Most patients (53, 79%) are currently under Ketogenic dietary treatments., Conclusions: We describe the principles behind the design, development, and deployment of the web-based nationwide GLUT1-DS registry. It represents a stepping stone towards a more comprehensive understanding of the disease from onset to adulthood. It also represents a virtuous model from a technical, legal, and organizational point of view, thus representing a possible paradigmatic example for other rare disease registry implementation., (© 2023. The Author(s).)

Background: A severe multisystem inflammatory syndrome in children (MIS-C) related to SARS-CoV-2 has been described after infection. A limited number of reports have analyzed the long-term complications related to pro-inflammatory status in MIS-C. We evaluated multiorgan impairment at the 6-month follow-up in MIS-C., Methods: We enrolled 33 pediatric patients consecutively hospitalized for MIS-C and monitored for almost 6 months. The inter-relationship of patient's features and disease severity at admission with long term complications was studied by multivariate analysis., Results: Endo-metabolic derangement, cardiac injury, respiratory, renal and gastrointestinal manifestations and neurological involvement are part of the initial presentation. The most abnormalities appear to resolve within the first few weeks, without significant long term dysfunction at the 6-months follow-up, except for endocrine (non-thyroidal illness syndrome in 12.1%, insulin resistance in 21.2%) and neurological system (27.3% cognitive or psychological, behavioral, adaptive difficulties). Endocrine and heart involvement at admission represent a significant factor on the long term sequelae; however no association between severity score and long-term outcome was noted., Conclusions: The severity of initial clinical presentation may be associated to organ domain, however it is not related to long term sequelae. The prevalent organ restoration supports a predominant indirect immune-mediated injury triggered by a systemic inflammatory response; however a direct damage due to the viral entry could be not excluded. Eventhought our preliminary results seem to suggest that MIS-C is not a long-term risk condition for children health, a longer follow-up is mandatory to confirm this hypothesis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Zuccotti, Calcaterra, Mannarino, D'Auria, Bova, Fiori, Verduci, Milanese, Marano, Garbin, Zirpoli, Fabiano, Carlucci, Olivotto, Gianolio, De Santis, Pelizzo, Zoia, Dilillo and Biganzoli.)

GLUT1 deficiency syndrome (GLUT1DS1; OMIM #606777) is a rare genetic metabolic disease, characterized by infantile-onset epileptic encephalopathy, global developmental delay, progressive microcephaly, and movement disorders (e.g., spasticity and dystonia). It is caused by heterozygous mutations in the SLC2A1 gene, which encodes the GLUT1 protein, a glucose transporter across the blood-brain barrier (BBB). Most commonly, these variants arise de novo resulting in sporadic cases, although several familial cases with AD inheritance pattern have been described. Twenty-seven Italian pediatric patients, clinically suspect of GLUT1DS from both sporadic and familial cases, have been enrolled. We detected by trios sequencing analysis 25 different variants causing GLUT1DS. Of these, 40% of the identified variants (10 out of 25) had never been reported before, including missense, frameshift, and splice site variants. Their structural mapping on the X-ray structure of GLUT1 strongly suggested the potential pathogenic effects of these novel disease-related mutations, broadening the genotypic spectrum heterogeneity found in the SLC2A1 gene. Moreover, 24% is located in a vulnerable region of the GLUT1 protein that involves transmembrane 4 and 5 helices encoded by exon 4, confirming a mutational hotspot in the SLC2A1 gene. Lastly, we investigated possible correlations between mutation type and clinical and biochemical data observed in our GLUT1DS cohort, revealing that splice site and frameshift variants are related to a more severe phenotype and low CSF parameters.

Background: Glut1 deficiency syndrome (Glut1-DS) is a rare metabolic encephalopathy. Familial forms are poorly investigated, and no previous studies have explored aspects of Glut1-DS over the course of life: clinical pictures, intelligence, life achievements, and quality of life in adulthood. Clinical, biochemical and genetic data in a cohort of familial Glut1-DS cases were collected from medical records. Intelligence was assessed using Raven's Standard Progressive Matrices and Raven's Colored Progressive Matrices in adults and children, respectively. An ad hoc interview focusing on life achievements and the World Health Organization Quality of Life Questionnaire were administered to adult subjects., Results: The clinical picture in adults was characterized by paroxysmal exercise-induced dyskinesia (PED) (80%), fatigue (60%), low intelligence (60%), epilepsy (50%), and migraine (50%). However, 20% of the adults had higher-than-average intelligence. Quality of Life (QoL) seemed unrelated to the presence of PED or fatigue in adulthood. An association of potential clinical relevance, albeit not statistically significant, was found between intelligence and QoL. The phenotype of familial Glut1-DS in children was characterized by epilepsy (83.3%), intellectual disability (50%), and PED (33%)., Conclusion: The phenotype of familial Glut1-DS shows age-related differences: epilepsy predominates in childhood; PED and fatigue, followed by epilepsy and migraine, characterize the condition in adulthood. Some adults with familial Glut1-DS may lead regular and fulfilling lives, enjoying the same QoL as unaffected individuals. The disorder tends to worsen from generation to generation, with new and more severe symptoms arising within the same family. Epigenetic studies might be useful to assess the phenotypic variability in Glut1-DS., (© 2022. The Author(s).)

Objective: To discuss the results of the KETASER01 trial and the reasons for its failure, particularly in view of future studies., Methods: KETASER01 is a multicenter, randomized, controlled, open-label, sequentially designed, non-profit Italian study that aimed to assess the efficacy of ketamine compared with conventional anesthetics in the treatment of refractory convulsive status epilepticus (RCSE) in children., Results: During the 5-year recruitment phase, a total of 76 RCSEs treated with third-line therapy were observed in five of the 10 participating Centers; only 10 individuals (five for each study arm; five females, mean age 6.5 ± 6.3 years) were enrolled in the KETASER01 study. Two of the five patients (40%) in the experimental arm were successfully treated with ketamine and two of the five (40%) children in the control arm, where successfully treated with thiopental. In the remaining six (60%) enrolled patients, RCSE was not controlled by the randomized anesthetic(s)., Significance: The KETASER01 study was prematurely halted due to low eligibility of patients and no successful recruitment. No conclusions can be drawn regarding the objectives of the study. Here, we discuss the KETASER01 results and critically analyze the reasons for its failure in view of future trials., (© 2022 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Pathogenic variants in gamma-aminobutyric acid type A receptor subunit alpha1 (GABRA1) is a protein coding gene that has been associated with a broad phenotypic spectrum of epilepsies. These have ranged from mild generalized forms to early-onset severe epileptic encephalopathies. Both in mild and in severe forms, tonic-clonic and myoclonic seizures with generalized spike and wave discharges and photoparoxysmal responses are common clinical manifestations. We present the case of a 14-year-old girl referred to our clinic with uncontrolled epilepsy. She was found to carry a heterozygous variant (c.335G > A) in GABRA1, already described in the literature and classified as "pathogenic" according to ACMG guidelines. The patient showed severe drug resistance with seizures often triggered by photic stimulation. The introduction of perampanel therapy led to overall reduction of the focal and generalized myoclonic seizures and complete clinical control of the light-triggered seizures. To our knowledge this is the first report of perampanel efficacy in photosensitive epilepsy, and in particular in the presence of a GABRA1 variant. New evidence is needed to confirm our findings in this case., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 Published by Elsevier Inc.)

Background: The etiology of pediatric-onset multiple sclerosis is unknown although putative genetic and environmental factors appear to be involved. Among children multiple sclerosis onset occurs closer to the susceptibility window thank in adults and the exposure to etiological environmental factors is more informative. An Italian multicentre case-control study (the PEDiatric Italian Genetic and enviRonment ExposurE, PEDIGREE study ) was designed to investigate environmental exposures in pediatric-onset multiple sclerosis and their interaction with genetics., Objectives: To collect evidence on exposures to environmental risk factors in pediatric-onset multiple sclerosis, a questionnaire was developed for the Italian population (PEDIGREE Questionnaire) and is presented., Methods: PEDIGREE Questionnaire develops from an existing tool used in case-control studies on pediatric-onset multiple sclerosis in US Americans, and was translated, adapted and tested for the contents perceived relevance, acceptability, feasibility and reliability in a population of Italian pediatric subjects and their parents recruited from clinics and general population., Results: PEDIGREE Questionnaire contents were overall deemed relevant by the study population, acceptable for 100% participants and feasible for at least 98%. PEDIGREE Questionnaire degree of reliability ranged 56% to 72%., Conclusion: PEDIGREE Questionnaire proves to be an efficient tool to assess environmental exposures in the Italian pediatric population. We encourage the dissemination of population-specific questionnaires and shared methodology to optimize efforts in MS etiological research., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2021.)

Background and Objectives: Purine-rich element-binding protein A ( PURA ) gene encodes Pur-α, a conserved protein essential for normal postnatal brain development. Recently, a PURA syndrome characterized by intellectual disability, hypotonia, epilepsy, and dysmorphic features was suggested. The aim of this study was to define and expand the phenotypic spectrum of PURA syndrome by collecting data, including EEG, from a large cohort of affected patients., Methods: Data on unpublished and published cases were collected through the PURA Syndrome Foundation and the literature. Data on clinical, genetic, neuroimaging, and neurophysiologic features were obtained., Results: A cohort of 142 patients was included. Characteristics of the PURA syndrome included neonatal hypotonia, feeding difficulties, and respiratory distress. Sixty percent of the patients developed epilepsy with myoclonic, generalized tonic-clonic, focal seizures, and/or epileptic spasms. EEG showed generalized, multifocal, or focal epileptic abnormalities. Lennox-Gastaut was the most common epilepsy syndrome. Drug refractoriness was common: 33.3% achieved seizure freedom. We found 97 pathogenic variants in PURA without any clear genotype-phenotype associations., Discussion: The PURA syndrome presents with a developmental and epileptic encephalopathy with characteristics recognizable from neonatal age, which should prompt genetic screening. Sixty percent have drug-resistant epilepsy with focal or generalized seizures. We collected more than 90 pathogenic variants without observing overt genotype-phenotype associations., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Glucose transporter type I deficiency syndrome (GLUT1DS) is an encephalopathic disorder due to a chronic insufficient transport of glucose into the brain. PET studies in GLUT1DS documented a widespread cortico-thalamic hypometabolism and a signal increase in the basal ganglia, regardless of age and clinical phenotype. Herein, we captured the pattern of functional connectivity of distinct striatal, cortical, and cerebellar regions in GLUT1DS (10 children, eight adults) and in healthy controls (HC, 19 children, 17 adults) during rest. Additionally, we explored for regional connectivity differences in GLUT1 children versus adults and according to the clinical presentation. Compared to HC, GLUT1DS exhibited increase connectivity within the basal ganglia circuitries and between the striatal regions with the frontal cortex and cerebellum. The excessive connectivity was predominant in patients with movement disorders and in children compared to adults, suggesting a correlation with the clinical phenotype and age at fMRI study. Our findings highlight the primary role of the striatum in the GLUT1DS pathophysiology and confirm the dependency of symptoms to the patients' chronological age. Despite the reduced chronic glucose uptake, GLUT1DS exhibit increased connectivity changes in regions highly sensible to glycopenia. Our results may portrait the effect of neuroprotective brain strategy to overcome the chronic poor energy supply during vulnerable ages., (© 2019 The Authors. Human Brain Mapping published by Wiley Periodicals, Inc.)

Purpose: To provide imaging biomarkers of generalized spike-and-wave discharges (GSWD) in patients with GLUT1 deficiency syndrome (GLUT1DS)., Methods: Eighteen GLUT1DS patients with pathogenetic mutation in SLC2A1 gene were studied by means of Video-EEG simultaneously recorded with functional MRI (VideoEEG-fMRI). A control group of sex and age-matched patients affected by Genetic Generalized Epilepsy (GGE) with GSWD were investigated with the same protocol. Within and between groups comparison was performed as appropriated. For GLUT1DS, correlations analyses between the contrast of interest and the main clinical measurements were provided., Results: EEG during fMRI revealed interictal GSWD in 10 GLUT1DS patients. Group-level analysis showed BOLD signal increases at the premotor cortex and putamen. With respect to GGE, GLUT1DS patients demonstrated increased neuronal activity in the putamen, precuneus, cingulate cortex, SMA and paracentral lobule. Whole-brain correlation analyses disclosed a linear relationship between the GSWD-related BOLD changes and the levels of glycorrhachia at diagnosis over the sensory-motor cortex and superior parietal lobuli., Conclusion: The BOLD dynamics related to GSWD in GLUT1DS are substantially different from typical GGE showing the former an increased activity in the premotor-striatal network and a decrease in the thalamus. The revealed hemodynamic maps might represent imaging biomarkers of GLUT1DS, being potentially useful for a precocious diagnosis of this genetic disorder.

Objectives: To provide insight into the pathophysiology of idiopathic childhood occipital epilepsies (ICOEs), by mapping the contribution of retinotopic visual areas to the generation and sustainment of epileptic activity., Methods: Thirteen patients affected by ICOEs (mean age = 10.9 years) underwent a video electroencephalography-functional magnetic resonance imaging (EEG-fMRI) study. A flexible-related fMRI analysis was applied to estimate the shape of the blood oxygen level-dependent (BOLD) response in each patient. Second-level analysis was performed using the interictal EEG discharge (IED)-specific response shape for the ICOE group. The resulting fMRI t-maps were warped to the Population-Average, Landmark- and Surface-based (PALS)-B12 atlas in Caret. For localization purposes, functional results were plotted and compared against 19 retinotopic areas for each hemisphere. A correlation analysis was performed between the hemodynamic maps and electroclinical variables., Results: The shape of the group-averaged hemodynamic response in ICOE patients showed an earlier time-to-peak and a more pronounced undershoot than the canonical hemodynamic response function (HRF). The random-effect analysis showed positive hemodynamic changes in the bilateral temporooccipital network. With regard to the retinotopic subdivision of the visual cortex, the primary visual area was consistently spared. Conversely, an extensive involvement of the occipitotemporal cortex, including the fusiform gyrus, and the occipitoparietal areas was observed. Moreover, a linear relationship was detected between the occipital spike-density and BOLD increases at the postcentral gyrus and temporooccipital cortex., Significance: Our data indicate that both the ventral and dorsal visual pathways are involved in spike generation in ICOEs, to extents that vary between patients, and reinforce the concept of benign childhood seizure susceptibility syndrome as a substrate for ICOEs. Finally, these results underscore the need for appropriate neuropsychological testing in these children, aimed at revealing selective impairments in functions subserved by both visual pathways., (Wiley Periodicals, Inc. © 2016 International League Against Epilepsy.)

Purpose: GLUT1 deficiency syndrome is a treatable neurological disorder characterized by developmental delay, movement disorders and epilepsy. It is caused by mutations in the SLC2A1 gene inherited as an autosomal dominant trait with complete penetrance, even if most detected SCL2A1 mutations are de novo. Our aim is to present a wide series of Italian patients to highlight the differences among subjects with de novo mutations and those with familial transmission., Methods: We present clinical and genetic features in a series of 22 GLUT1DS Italian patients. Our patients were classified in two different groups: familial cases including GLUT1DS patients with genetically confirmed affected relatives and sporadic cases with detection of SLC2A1 de novo mutation., Results: We found remarkable differences in the severity of the clinical picture regarding the type of genetic inheritance (sporadic versus familial): sporadic patients were characterized by an earlier epilepsy-onset and higher degree of intellectual disability. No significant differences were found in terms of type of movement disorder, whilst Paroxysmal Exertion-induced Dyskinesia (PED) is confirmed to be the most characteristic movement disorder type in GLUT1DS. In familial cases the clinical manifestation of the disease was particularly variable and heterogeneous, also including asymptomatic patients or those with minimal-symptoms., Conclusion: The finding of a "mild" phenotype in familial GLUT1DS gives rise to several questions: the real incidence of the disease, treatment option with ketogenic diet in adult patients and genetic counseling., (Copyright © 2014 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)