Oxygen is a central molecule for numerous metabolic and cytophysiological processes, and, indeed, its imbalance can lead to numerous pathological consequences. In the human body, the brain is an aerobic organ and for this reason, it is very sensitive to oxygen equilibrium. The consequences of oxygen imbalance are especially devastating when occurring in this organ. Indeed, oxygen imbalance can lead to hypoxia, hyperoxia, protein misfolding, mitochondria dysfunction, alterations in heme metabolism and neuroinflammation. Consequently, these dysfunctions can cause numerous neurological alterations, both in the pediatric life and in the adult ages. These disorders share numerous common pathways, most of which are consequent to redox imbalance. In this review, we will focus on the dysfunctions present in neurodegenerative disorders (specifically Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis) and pediatric neurological disorders (X-adrenoleukodystrophies, spinal muscular atrophy, mucopolysaccharidoses and Pelizaeus–Merzbacher Disease), highlighting their underlining dysfunction in redox and identifying potential therapeutic strategies.

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.

The prevalence of pediatric obesity is rising rapidly worldwide, and “omic” approaches are helpful in investigating the molecular pathophysiology of obesity. This work aims to identify transcriptional differences in the subcutaneous adipose tissue (scAT) of children with overweight (OW), obesity (OB), or severe obesity (SV) compared with those of normal weight (NW). Periumbilical scAT biopsies were collected from 20 male children aged 1–12 years. The children were stratified into the following four groups according to their BMI z-scores: SV, OB, OW, and NW. scAT RNA-Seq analyses were performed, and a differential expression analysis was conducted using the DESeq2 R package. A pathways analysis was performed to gain biological insights into gene expression. Our data highlight the significant deregulation in both coding and non-coding transcripts in the SV group when compared with the NW, OW, and OB groups. A KEGG pathway analysis showed that coding transcripts were mainly involved in lipid metabolism. A GSEA analysis revealed the upregulation of lipid degradation and metabolism in SV vs. OB and SV vs. OW. Bioenergetic processes and the catabolism of branched-chain amino acids were upregulated in SV compared with OB, OW, and NW. In conclusion, we report for the first time that a significant transcriptional deregulation occurs in the periumbilical scAT of children with severe obesity compared with those of normal weight or those with overweight or mild obesity.

Since the initial description of glucose transporter-1 deficiency syndrome (Glut1-DS) the phenotype of the condition has expanded, even leading to the recognition of atypical manifestations. We report on eight patients with Glut1-DS who experienced at least one episode of acute focal neurological deficits. We conducted a retrospective analysis, collecting clinical, electrophysiological, neuroradiological, and genetic information. We focused in particular on three well-documented cases. Among 42 patients with Glut1-DS, eight individuals aged between six and 38 years presented with an acute onset of neurological disturbances: dysarthria/aphasia, oral dyskinesia, swallowing difficulties, paresthesia, facial palsy, hemi/monoplegia, vomiting, headache, and behavioral disturbances. When performed, magnetic resonance imaging (MRI) revealed signs of venous congestion and hypoperfusion and electroencephalography showed focal contralateral slowing. Deficits were transient in all patients but one. Four patients (50%) were on a ketogenic diet (KD), and two of these patients had lower than usual ketonemia levels during the episode. In two patients, MRI demonstrated the presence of an ischemic brain lesion. In Glut1-DS, stroke-like episodes are a recurrent manifestation, particularly during early adulthood, and they were reported in 19% of the patients in our cohort. Stroke mimics should be considered a key feature of Glut1-DS, as other paroxysmal disorders. It remains to be established whether a KD can prevent the recurrence of episodes and, if so, at what level of ketosis. Further observations are needed to confirm the correlation between Glut1-DS and ischemic stroke.

Leukodystrophies are a class of rare heterogeneous disorders which affect the white matter of the brain, ultimately leading to a disruption in brain development and a damaging effect on cognitive, motor and social‐communicative development. These disorders present a great clinical heterogeneity, along with a phenotypic overlap and this could be partially due to contributions from environmental stimuli. It is in this context that there is a great need to investigate what other factors may contribute to both disease insurgence and phenotypical heterogeneity, and novel evidence are raising the attention toward the study of epigenetics and transcription mechanisms that can influence the disease phenotype beyond genetics. Modulation in the epigenetics machinery including histone modifications, DNA methylation and non‐coding RNAs dysregulation, could be crucial players in the development of these disorders, and moreover an aberrant RNA maturation process has been linked to leukodystrophies. Here, we provide an overview of these mechanisms hoping to supply a closer step toward the analysis of leukodystrophies not only as genetically determined but also with an added level of complexity where epigenetic dysregulation is of key relevance.This article is categorized under: Regulatory RNAs/RNAi/Riboswitches > Regulatory RNA RNA in Disease and Development > RNA in Disease RNA in Disease and Development > RNA in Development

Background: Newborn screening (NBS) is a preventive healthcare program aiming at identifying the inborn errors of metabolism (IEMs) in asymptomatic infants to reduce the risk of severe complications. The aim of this study was to report the first years (2016–2020) of the expanded NBS program in the Lombardy region, Italy. Methods: Dried blood spots were collected from newborns’ heels at 48–72 h after birth. FIA-MS/MS was performed to evaluate specific biochemical markers. Genetic confirmation was achieved via Sanger or NGS on newborns and reported to a clinical reference center (CRC). Results: A total of 343,507 newborns were tested; 1414/343,507 resulted as positive to NBS and were reported to the CRC. A total of 209 newborns were diagnosed with IEMs: 206 infants received a diagnosis of IEM through NBS, confirmed by genetic analysis; three neonates were not positive to NBS but were subsequentially diagnosed with IEMs. A total of 1208/343,507 were false positive cases. Twenty-seven types of IEMs were diagnosed in 209 patients: 111 newborns were affected by aminoacidemias, 11 by urea cycle disorders, 27 by organic acidemias, 34 by fatty acid oxidation disorders, and 26 by secondary conditions. Conclusions: We report here for the first time the IEM incidence and distribution in the Lombardy region in the first five years of NBS.