Role of epigenetics and alterations in RNA metabolism in leukodystrophies.

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.

Terahertz and Infrared Plasmon Polaritons in PtTe2 Type-II Dirac Topological Semimetal.

Surface plasmon polaritons (SPPs) are electromagnetic excitations existing at the interface between a metal and a dielectric. SPPs provide a promising path in nanophotonic devices for light manipulation at the micro and nanoscale with applications in optoelectronics, biomedicine, and energy harvesting. Recently, SPPs are extended to unconventional materials like graphene, transparent oxides, superconductors, and topological systems characterized by linearly dispersive electronic bands. In this respect, 3D Dirac and Weyl semimetals offer a promising frontier for infrared (IR) and terahertz (THz) radiation tuning by topologically-protected SPPs. In this work, the THz-IR optical response of platinum ditelluride (PtTe2) type-II Dirac topological semimetal films grown on Si substrates is investigated. SPPs generated on microscale ribbon arrays of PtTe2 are detected in the far-field limit, finding an excellent agreement among measurements, theoretical models, and electromagnetic simulation data. The far-field measurements are further supported by near-field IR data which indicate a strong electric field enhancement due to the SPP excitation near the ribbon edges. The present findings indicate that the PtTe2 ribbon array appears an ideal active layout for geometrically tunable SPPs thus inspiring a new fashion of optically tunable materials in the technologically demanding THz and IR spectrum.

Optical properties of two-dimensional tin nanosheets epitaxially grown on graphene.

Heterostacks formed by combining two-dimensional materials show novel properties which are of great interest for new applications in electronics, photonics and even twistronics, the new emerging field born after the outstanding discoveries on twisted graphene. Here, we report the direct growth of tin nanosheets at the two-dimensional limit via molecular beam epitaxy on chemical vapor deposited graphene on Al2O3(0001). The mutual interaction between the tin nanosheets and graphene is evidenced by structural and chemical investigations. On the one hand, Raman spectroscopy indicates that graphene undergoes compressive strain after the tin growth, while no charge transfer is observed. On the other hand, chemical analysis shows that tin nanosheets interaction with sapphire is mediated by graphene avoiding the tin oxidation occurring in the direct growth on this substrate. Remarkably, optical measurements show that the absorption of tin nanosheets exhibits a graphene-like behavior with a strong absorption in the ultraviolet photon energy range, therein resulting in a different optical response compared to tin nanosheets on bare sapphire. The optical properties of ultra-thin tin films therefore represent an open and flexible playground for the absorption of light in a broad range of the electromagnetic spectrum and technologically relevant applications for photon harvesting and sensors.

Corrigendum: Newborn screening for X-linked adrenoleukodystrophy in Italy: diagnostic algorithm and disease monitoring.

[This corrects the article DOI: 10.3389/fneur.2022.1072256.].

Redox Imbalance in Neurological Disorders in Adults and Children.

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.

Anomalous Optical Properties of KTN:Li Ferroelectric Supercrystals.

We report a spectroscopic investigation of potassium-lithium-tantalate-niobate (KTN:Li) across its room-temperature ferroelectric phase transition, when the sample manifests a supercrystal phase. Reflection and transmission results indicate an unexpected temperature-dependent enhancement of average index of refraction from 450 nm to 1100 nm, with no appreciable accompanying increase in absorption. Second-harmonic generation and phase-contrast imaging indicate that the enhancement is correlated to ferroelectric domains and highly localized at the supercrystal lattice sites. Implementing a two-component effective medium model, the response of each lattice site is found to be compatible with giant broadband refraction.

Menkes disease complicated by concurrent ACY1 deficiency: A case report.

Introduction: Menkes disease is an X-linked recessive condition caused by mutations in the ATP7A gene, which leads to severe copper deficiency. Aminoacylase-1 deficiency is a rare inborn error of metabolism caused by homozygous or compound heterozygous variant in the ACY1 gene, characterized by increased urinary excretion of specific N-acetyl amino acids. Case presentation: We report an infant with neurological findings such as seizures, neurodevelopmental delay and hypotonia. Metabolic screening showed low serum copper and ceruloplasmin, and increased urinary excretion of several N-acetylated amino acids. Whole-exome sequencing analysis (WES) revealed the novel de novo variant c.3642_3649dup (p.Ala1217Aspfs*2) in the ATP7A gene, leading to a diagnosis of Menkes disease, and the simultaneous presence of the homozygous ACY1 variant c.1057C>T (p.Arg353Cys) causative of Aminoacylase-1 deficiency. Conclusion: Our patient had two rare conditions with different treatment courses but overlapping clinical features. The identified novel ATP7A mutation associated with Menkes disease expands the ATP7A gene spectrum.

Solid phase crystallization of amorphous silicon at the two-dimensional limit.

The epitaxy of silicene-on-Ag(111) renewed considerable interest in silicon (Si) when scaled down to the two-dimensional (2D) limit. This remains one of the most explored growth cases in the emerging 2D material fashion beyond graphene. However, out of a strict silicene framework, other allotropic forms of Si still deserve attention owing to technological purposes. Here, we present 2D Solid Phase Crystallization (SPC) of Si starting from an amorphous-Si on Ag(111) in atomic coverage to gain a crystalline-Si layer by post-growth annealing below 450 °C, namely Complementary Metal Oxide Semiconductor (CMOS) Back-End-of-Line (BEOL) thermal budget limit. Moreover, considering the benefit of the 2D-SPC scheme, we managed to write crystalline-Si pixels on the amorphous-Si matrix. Our in situ and ex situ analyses show that an in-plane interface or a lateral heterojunction between amorphous and crystalline-Si is formed. This amorphous-to-crystalline phase transformation suggests that 2D silicon may stem from an epitaxially grown layer and thermal self-organization/assembling.

Optical and thermal responses of silicene in Xene heterostructures.

Stabilization of silicene and preservation of its structural and electronic properties are essential for its processing and future integration into devices. The stacking of silicene on stanene, creating a Xene-based heterostructure, proves to be a viable new route in this respect. Here we demonstrate the effectiveness of a stanene layer in breaking the strong interaction between silicene and the Ag(111) substrate. The role of stanene as a 'buffer' layer is investigated by analyzing the optical response of epitaxial silicene through both power-dependent Raman spectroscopy and reflectivity measurements in the near infrared (NIR)-ultraviolet (UV) spectral range. Finally, we point out a Xene-induced shift of the silver plasma edge that paves the way for the development of a new approach to engineering the metal plasmonic response.

Complex neurodevelopmental disorder in a preterm child with unilateral cerebellar hemorrhage.

BACKGROUND: Cerebellar hemorrhage (CBH) represents the main form of direct cerebellar injury in preterm infants. Most CBHs occur bilaterally, while isolated unilateral hemorrhages are less frequent and often associated with focal atrophy. Limited and heterogeneous data exist on preterm birth, unilateral CBH and consequent long-term neurodevelopmental and non-motor outcomes. CASE REPORT: This is the case of a six-year-old child, born preterm, diagnosed with a complete atrophy of the right cerebellar hemisphere through brain MRI and presenting mild social atypies, visuo-perceptive and pragmatic language impairment, but only minor neurological signs. DISCUSSION: Despite the large extension of the patient's CBH neurological sequelae were mild, likely due to cerebellar plasticity, and only specific deficits in non-motor, behavioral and social skills were shown. Evidence exists on cerebellar contribution to dynamic visual information processing and to perceptual signals detection and prediction, that might explain the presence of non-motor signs.

Newborn screening for X-linked adrenoleukodystrophy in Italy: Diagnostic algorithm and disease monitoring.

Introduction: X-linked adrenoleukodystrophy (X-ALD) is the most common inherited peroxisomal disorder caused by variants in the ABCD1 gene. The main phenotypes observed in men with X-ALD are primary adrenal insufficiency, adrenomyeloneuropathy, and cerebral ALD (cALD). Cerebral ALD consists of a demyelinating progressive cerebral white matter (WM) disease associated with rapid clinical decline and is fatal if left untreated. Hematopoietic stem cell transplantation is the standard treatment for cALD as it stabilizes WM degeneration when performed early in the disease. For this reason, early diagnosis is crucial, and several countries have already implemented their newborn screening programs (NBS) with the assessment of C26:0-lysophosphatidylcholine (C26:0-LPC) values as screening for X-ALD. Methods: In June 2021, an Italian group in Lombardy launched a pilot study for the implementation of X-ALD in the Italian NBS program. A three-tiered approach was adopted, and it involved quantifying the values of C26:0-LPC and other metabolites in dried blood spots with FIA-MS/MS first, followed by the more specific ultra-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) technique and, finally, the genetic confirmation via focused NGS. Discussion: Genetically confirmed patients are set to undergo a follow-up protocol and are periodically evaluated to promptly start a specific treatment if and when the first signs of brain damage appear, as suggested by international guidelines. A specific disease monitoring protocol has been created based on literature data and personal direct experience. Conclusion: The primary aim of this study was to develop a model able to improve the early diagnosis and subsequent follow-up and timely treatment of X-ALD. Ethics: The study was approved by the local ethics committee. The research was conducted in the absence of any commercial or financial relationship that could be construed as a potential conflict of interest.

Parental Distress in the Time of COVID-19: A Cross-Sectional Study on Pediatric Patients with Neuropsychiatric Conditions during Lockdown.

The lockdown due to the COVID-19 pandemic has had adverse psychological effects on children and parents. While parenting is essential for positive development, increased parental distress has interfered with children's wellbeing. In our study, we aimed to identify the predictors of parental distress in families of children with neuropsychiatric disorders during lockdown. Seventy-seven parents of children with neuropsychiatric disorders were asked to fill three online questionnaires (a socio-demographic questionnaire, the Child Behavior Checklist (CBCL) and Parental-Stress-Index (PSI-4-SF) to explore the relationship between parental distress, emotional/behavioral problems in children and quarantine-related factors through univariate analyses and multiple mediation models. Significant positive associations between CBCL-internalizing-problems and all PSI-4-SF subscales, and between CBCL-externalizing-problems and "Difficult Child" subscales were found. "Parent-Child Dysfunctional Interaction" subscale and teachers-child relationship quality resulted negatively associated, as well as the "Difficult Child" subscale and peers-child relationship quality. The effect of teachers-child relationship quality on "Parent-Child Dysfunctional Interaction" was mediated by children internalizing problems, while the effect of peers-child relationship quality on "Difficult Child" by the child internalizing/externalizing problems. Internalizing problems in children with neuropsychiatric disorders were among the strongest predictors of parental stress during lockdown, mediating the indirect effects of quarantine-related factors, thus suggesting the importance of their detection during and after emergency situations to provide assistance and reduce parenting pressure.

Clinical, molecular and glycophenotype insights in SLC39A8-CDG.

BACKGROUND: SLC39A8, a gene located on chromosome 4q24, encodes for the manganese (Mn) transporter ZIP8 and its detrimental variants cause a type 2 congenital disorder of glycosylation (CDG). The common SLC39A8 missense variant A391T is associated with increased risk for multiple neurological and systemic disorders and with decreased serum Mn. Patients with SLC39A8-CDG present with different clinical and neuroradiological features linked to variable transferrin glycosylation profile. Galactose and Mn supplementation therapy results in the biochemical and clinical amelioration of treated patients. RESULTS: Here, we report clinical manifestations, neuroradiological features and glycophenotypes associated with novel SLC39A8 variants (c.1048G > A; p.Gly350Arg and c.131C > G; p.Ser44Trp) in two siblings of the same Italian family. Furthermore, we describe a third patient with overlapping clinical features harbouring the homozygous missense variant A391T. The clinical phenotype of the three patients was characterized by severe developmental disability, dystonic postural pattern and dyskinesia with a more severe progression of the disease in the two affected siblings. Neuroimaging showed a Leigh syndrome-like pattern involving the basal ganglia, thalami and white matter. In the two siblings, atrophic cerebral and cerebellum changes consistent with SLC39A8-CDG were detected as well. Serum transferrin isoelectric focusing (IEF) yielded variable results with slight increase of trisialotransferrin isoforms or even normal pattern. MALDI-MS showed the presence of hypogalactosylated transferrin N-glycans, spontaneously decreasing during the disease course, only in one affected sibling. Total serum N-glycome depicted a distinct pattern for the three patients, with increased levels of undergalactosylated and undersialylated precursors of fully sialylated biantennary glycans, including the monosialo-monogalacto-biantennary species A2G1S1. CONCLUSIONS: Clinical, MRI and glycosylation features of patients are consistent with SLC39A8-CDG. We document two novel variants associated with Leigh syndrome-like disease presentation of SLC39A8-CDG. We show, for the first time, a severe neurological phenotype overlapping with that described for SLC39A8-CDG in association with the homozygous A391T missense variant. We observed a spontaneous amelioration of transferrin N-glycome, highlighting the efficacy of MS-based serum glycomics as auxiliary tool for the diagnosis and clinical management of therapy response in patients with SLC39A8-CDG. Further studies are needed to analyse more in depth the influence of SLC39A8 variants, including the common missense variant, on the expression and function of ZIP8 protein, and their impact on clinical, biochemical and neuroradiological features.

Epilepsy in LAMA2-related muscular dystrophy: A systematic review of the literature.

Epilepsy is a common, often severe, feature of LAMA2-related muscular dystrophy (LAMA2-RD) and could represent its onset and main manifestation, even in the absence of overt muscle involvement. To date, there is no systematic characterization of epilepsy in LAMA2-RD, and its impact on neurodevelopment and on the clinical course remains poorly established. In view of this knowledge gap, we conducted a systematic review of the literature and, as an illustrative example, reported the clinical case of a boy with late-onset LAMA2-related limb-girdle muscular dystrophy presenting with severe epilepsy. Our analyses of the literature data revealed a mean age at first seizure of 8 years, with significant differences between early- versus late-onset disease (5.78 ± 4.11 and 9.00 ± 2.65 years, respectively; p = 0.0007), and complete versus partial merosin deficiency (5.33 ± 3.70 and 10.36 ± 5.49 years, respectively; p = 0.0176). A generalized onset was the most common seizure presentation, regardless of merosin expression levels or the timing of muscular distrophy onset. Cortical malformations were not significantly associated with an earlier epilepsy onset, and were found to be quasi-significantly associated with a greater incidence of focal, or focal and generalized, onset seizures. No clear conclusions could be reached on the electrophysiological and neurodevelopmental features of the disorder, or on the relative efficacy of anti-epileptic treatments; further research on these aspects is needed. This systematic review helps to show that epilepsy in LAMA2-RD may be more than an ancillary manifestation of the disease, but rather one of its core features. A targeted and prompt electroencephalographic and epilepsy assessment, in addition to the specific neuromuscular workup, is therefore mandatory in early clinical management to pursue the best possible outcome for affected children.

Optical Properties of Stanene-like Nanosheets on Al2O3(0001): Implications for Xene Photonics.

Stanene is one of the most intriguing two-dimensional (2D) materials because of its nontrivial topological properties. Here, the optical properties from THz to UV of molecular beam deposited tin nanosheets on Al2O3(0001) are reported. The experimental absorption coefficient cannot be described in terms of metallic tin or tin oxides. Nonetheless, a similar optical behavior was predicted by theory for freestanding stanene, thus suggesting the formation of the 2D tin nanosheets with stanene-like properties. These findings show that 2D tin bears appealing optical properties in a broad range of the electromagnetic spectrum, thus paving the way to Xenes-based nanophotonics.

Behavioural and Emotional Changes during COVID-19 Lockdown in an Italian Paediatric Population with Neurologic and Psychiatric Disorders.

On 11 March 2020, a national lockdown was imposed by the Italian government to contain the spread of COVID19 disease. This is an observational longitudinal study conducted at Fondazione Stella Maris (FSM), Italy to investigate lockdown-related emotional and behavioural changes in paediatric neuropsychiatric population. Families having children (1.5-18 years) with neuropsychiatric disorders referred to FSM have been contacted and proposed to fulfil two online questionnaires (General questionnaire and Child Behaviour Check List (CBCL)) to (i) compare (paired two-sample t-tests) the CBCL scores during lockdown with previous ones, and (ii) investigate the influence (multiple linear regression models) of variables such as age, diagnosis grouping (neurological, neurodevelopmental, emotional, and behavioural disorders) and financial hardship. One hundred and forty-one parents fulfilled the questionnaires. Anxiety and somatic problems increased in 1.5-5 years subpopulation, while obsessive-compulsive, post-traumatic and thought problems increased in 6-18 years subpopulation. In the regression models, younger age in the 1.5-5 years subpopulation resulted as "protective" while financial hardship experienced by families during lockdown was related to psychiatric symptoms increasing in the 6-18 years subpopulation. Some considerations, based on first clinical impressions, are provided in text together with comments in relation to previous and emerging literature on the topic.