SNUPN deficiency causes a recessive muscular dystrophy due to RNA mis-splicing and ECM dysregulation.

SNURPORTIN-1, encoded by SNUPN, plays a central role in the nuclear import of spliceosomal small nuclear ribonucleoproteins. However, its physiological function remains unexplored. In this study, we investigate 18 children from 15 unrelated families who present with atypical muscular dystrophy and neurological defects. Nine hypomorphic SNUPN biallelic variants, predominantly clustered in the last coding exon, are ascertained to segregate with the disease. We demonstrate that mutant SPN1 failed to oligomerize leading to cytoplasmic aggregation in patients' primary fibroblasts and CRISPR/Cas9-mediated mutant cell lines. Additionally, mutant nuclei exhibit defective spliceosomal maturation and breakdown of Cajal bodies. Transcriptome analyses reveal splicing and mRNA expression dysregulation, particularly in sarcolemmal components, causing disruption of cytoskeletal organization in mutant cells and patient muscle tissues. Our findings establish SNUPN deficiency as the genetic etiology of a previously unrecognized subtype of muscular dystrophy and provide robust evidence of the role of SPN1 for muscle homeostasis.

The Role of Video-EEG Monitoring in Lesch-Nyhan Syndrome.

Introduction: Lesch-Nyhan syndrome (LNS) is a rare genetic disease secondary to a HPRT1 mutation on chromosome X. It is characterized by dystonia, developmental delay, hyperuricemia and self-harming behaviours. The HPRT enzyme is implicated in the purine salvage pathway. The deficiency of HPRT results in accumulation of uric acid. There have been some cases associated with epilepsy, but it still remains a rare occurrence in LNS patients. Case presentation: We describe the case of a 20-month-old male patient with a heterozygous HPRT1 mutation c11_17del.p (Arg4Leufs*4) associated with LNS. The child associated epileptic seizures mistaken by his parents as non-epileptic sleep events associated with apnea. Seizures were discovered secondary to a polygraphic long-time sleep video-electroencephalography (EEG) monitoring. The dystonic movements and epileptic seizures responded to Levetiracetam, but the management of the behavioural disorder remained a challenge. Conclusion:Lesch-Nyhan syndrome is a rare inherited metabolic disease and its pathogenesis is not fully known, which makes the treatment management very difficult. Despite the fact that epilepsy is uncommon in LNS children, it should always be considered as part of the differential diagnosis in movement disorders. Therefore, long-term video-EEG monitoring is recommended as well as a detailed patient history to identify possible clinical/subclinical epileptic seizures that require treatment.

Case report: Tackling the complexities of an extremely premature newborn with intrauterine growth restriction and congenital metabolic disorders through a multidisciplinary approach.

Background and objectives: The premature birth of a newborn can present a complex challenge for healthcare providers, particularly in cases of extreme prematurity combined with intrauterine growth restriction and multiple metabolic deficiencies. In this report, we aim to shed light on the difficulties and considerations involved in the management of such a case. In addition, our study is aimed to raise awareness of the importance of a multidisciplinary team in managing an extreme premature case with multiple comorbidities. Case presentation and main findings: We present the case of a 28-week premature female newborn with very low birth weight (660 g, percentile <10%) and intrauterine growth restriction. She was born through emergency cesarean delivery due to maternal Hemolysis, Elevated Liver enzymes, and Low Platelet count (HELLP) syndrome and had a high-risk pregnancy (spontaneous twin pregnancy, with one fetus stopping development at 16 weeks and maternal hypertension). In the first hours of life, she presented with persistent hypoglycemia requiring progressive glucose supplementation up to 16 g/kg/day to maintain normal blood glucose levels. The baby then showed favorable progress. However, from days 24 to 25, hypoglycemia recurred and did not respond to glucose boluses or supplementation in both intravenous and oral feeds, leading to the suspicion of a congenital metabolic disorder. Endocrine and metabolic screenings led to suspicion of primary carnitine deficiency and a deficiency in hepatic form of carnitine-palmitoyltransferase type I (CPT1) on the second screening. Conclusion and clinical implications: The study highlights rare metabolic anomalies that can be due to both organ and system immaturity and delayed enteral feeding and excessive use of antibiotics. The clinical implications of this study emphasize the need for careful monitoring and comprehensive care of premature infants to prevent and manage potential metabolic abnormalities by neonatal metabolic screening.

The Importance of Implementing a Transition Strategy for Patients with Muscular Dystrophy: From Child to Adult-Insights from a Tertiary Centre for Rare Neurological Diseases.

Progress in the field of muscular dystrophy (MD) using a multidisciplinary approach based on international standards of care has led to a significant increase in the life expectancy of patients. The challenge of transitioning from pediatric to adult healthcare has been acknowledged for over a decade, yet it continues to be a last-minute concern. Currently, there is no established consensus on how to evaluate the effectiveness of the transition process. Our study aimed to identify how well patients are prepared for the transition and to determine their needs. We conducted a descriptive, cross-sectional study on 15 patients aged 14 to 21 years. The patients completed a sociodemographic and a Transition Readiness Assessment Questionnaire (TRAQ). We also analyzed the comorbidities of these patients. Our study revealed that only 46.7% of the patients had engaged in a conversation with a medical professional, namely, a child neurologist, about transitioning. A total of 60% of the participants expressed having confidence in their self-care ability. However, the median TRAQ score of 3.6 shows that these patients overestimate themselves. We emphasize the necessity for a slow, personalized transition led by a multidisciplinary team to ensure the continuity of state-of-the-art care from pediatric to adult healthcare services and the achievement of the highest possible quality of life for these patients.

Autosomal Dominant Hypocalcemia Type 1 and Neonatal Focal Seizures.

Autosomal dominant hypocalcemia type 1 (ADH1) is a rare form of hypoparathyroidism that is characterized by gain-of-function mutations in the CASR gene, which provides instructions for producing the protein called calcium-sensing receptor (CaSR). Hypocalcemia in the neonatal period has a wide differential diagnosis. We present the case of a female newborn with genetic hypoparathyroidism (L125P mutation of CASR gene), hypocalcemia, and neonatal seizures due to the potential correlation between refractory neonatal seizures and ADH1. Neonatal seizures were previously described in patients with ADH1 but not in association with the L125P mutation of the CASR gene. Prompt diagnosis and management by a multidisciplinary and an appropriate therapeutic approach can prevent neurological and renal complications.

The State of the Art of Pediatric Multiple Sclerosis.

Multiple sclerosis (MS) represents a chronic immune-mediated neurodegenerative disease of the central nervous system that generally debuts around the age of 20-30 years. Still, in recent years, MS has been increasingly recognized among the pediatric population, being characterized by several peculiar features compared to adult-onset disease. Unfortunately, the etiology and disease mechanisms are poorly understood, rendering the already limited MS treatment options with uncertain efficacy and safety in pediatric patients. Thus, this review aims to shed some light on the progress in MS therapeutic strategies specifically addressed to children and adolescents. In this regard, the present paper briefly discusses the etiology, risk factors, comorbidities, and diagnosis possibilities for pediatric-onset MS (POMS), further moving to a detailed presentation of current treatment strategies, recent clinical trials, and emerging alternatives. Particularly, promising care solutions are indicated, including new treatment formulations, stem cell therapies, and cognitive training methods.

Functional Neurological Disorder-Old Problem New Perspective.

Functional neurological disorder (FND) is a common issue in the pediatric population. The concept and our understanding of functional neurological disorders have changed over the past years, and new etiologic models and treatment plans have been explored. Knowledge about FND in the pediatric population, however, is lacking. The aim of this review is to provide an update on pediatric functional neurological disorder. We conducted a literature search of PubMed and SCOPUS databases and reviewed a total of 85 articles to gain insight into the current understanding of FND etiology, diagnosis, treatment, and prognosis in children and adolescents. Functional and high resolution MRI revealed abnormal connectivity and structural changes in patients with functional symptoms. The diagnostic criteria no longer require the presence of a psychological factor and instead focus on a rule-in diagnosis. Treatment of FND includes a clear communication of the diagnosis and the support of a multidisciplinary team. Although FND typically has a poor prognosis, better outcomes appear to have been achieved in children and young adults. We conclude that pediatric functional neurological disorder is a prevalent pathology and that this patient population has additional specific needs compared to the adult population.

An Overview of Oxidative Stress, Neuroinflammation, and Neurodegenerative Diseases.

Oxidative stress has been linked with a variety of diseases, being involved in the debut and/or progress of several neurodegenerative disorders. This review intends to summarize some of the findings that correlate the overproduction of reactive oxygen species with the pathophysiology of Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Oxidative stress was also noted to modify the inflammatory response. Even though oxidative stress and neuroinflammation are two totally different pathological events, they are linked and affect one another. Nonetheless, there are still several mechanisms that need to be understood regarding the onset and the progress of neurodegenerative diseases in order to develop efficient therapies. As antioxidants are a means to alter oxidative stress and slow down the symptoms of these neurodegenerative diseases, the most common antioxidants, enzymatic as well as non-enzymatic, have been mentioned in this paper as therapeutic options for the discussed disorders.

Neurotransmitters-Key Factors in Neurological and Neurodegenerative Disorders of the Central Nervous System.

Neurotransmitters are molecules that amplify, transmit, and convert signals in cells, having an essential role in information transmission throughout the nervous system. Hundreds of such chemicals have been discovered in the last century, continuing to be identified and studied concerning their action on brain health. These substances have been observed to influence numerous functions, including emotions, thoughts, memories, learning, and movements. Thus, disturbances in neurotransmitters' homeostasis started being correlated with a plethora of neurological and neurodegenerative disorders. In this respect, the present paper aims to describe the most important neurotransmitters, broadly classified into canonical (e.g., amino acids, monoamines, acetylcholine, purines, soluble gases, neuropeptides) and noncanonical neurotransmitters (e.g., exosomes, steroids, D-aspartic acid), and explain their link with some of the most relevant neurological conditions. Moreover, a brief overview of the recently developed neurotransmitters' detection methods is offered, followed by several considerations on the modulation of these substances towards restoring homeostasis.

Recent Advances in Managing Spinal Intervertebral Discs Degeneration.

Low back pain (LBP) represents a frequent and debilitating condition affecting a large part of the global population and posing a worldwide health and economic burden. The major cause of LBP is intervertebral disc degeneration (IDD), a complex disease that can further aggravate and give rise to severe spine problems. As most of the current treatments for IDD either only alleviate the associated symptoms or expose patients to the risk of intraoperative and postoperative complications, there is a pressing need to develop better therapeutic strategies. In this respect, the present paper first describes the pathogenesis and etiology of IDD to set the framework for what has to be combated to restore the normal state of intervertebral discs (IVDs), then further elaborates on the recent advances in managing IDD. Specifically, there are reviewed bioactive compounds and growth factors that have shown promising potential against underlying factors of IDD, cell-based therapies for IVD regeneration, biomimetic artificial IVDs, and several other emerging IDD therapeutic options (e.g., exosomes, RNA approaches, and artificial intelligence).

Current Strategies to Enhance Delivery of Drugs across the Blood-Brain Barrier.

The blood-brain barrier (BBB) has shown to be a significant obstacle to brain medication delivery. The BBB in a healthy brain is a diffusion barrier that prevents most substances from passing from the blood to the brain; only tiny molecules can pass across the BBB. The BBB is disturbed in specific pathological illnesses such as stroke, diabetes, seizures, multiple sclerosis, Parkinson's disease, and Alzheimer's disease. The goal of this study is to offer a general overview of current brain medication delivery techniques and associated topics from the last five years. It is anticipated that this review will stimulate readers to look into new ways to deliver medications to the brain. Following an introduction of the construction and function of the BBB in both healthy and pathological conditions, this review revisits certain contested questions, such as whether nanoparticles may cross the BBB on their own and if medications are selectively delivered to the brain by deliberately targeted nanoparticles. Current non-nanoparticle options are also discussed, including drug delivery via the permeable BBB under pathological circumstances and the use of non-invasive approaches to improve brain medication absorption.

Novel Strategies for Spinal Cord Regeneration.

A spinal cord injury (SCI) is one of the most devastating lesions, as it can damage the continuity and conductivity of the central nervous system, resulting in complex pathophysiology. Encouraged by the advances in nanotechnology, stem cell biology, and materials science, researchers have proposed various interdisciplinary approaches for spinal cord regeneration. In this respect, the present review aims to explore the most recent developments in SCI treatment and spinal cord repair. Specifically, it briefly describes the characteristics of SCIs, followed by an extensive discussion on newly developed nanocarriers (e.g., metal-based, polymer-based, liposomes) for spinal cord delivery, relevant biomolecules (e.g., growth factors, exosomes) for SCI treatment, innovative cell therapies, and novel natural and synthetic biomaterial scaffolds for spinal cord regeneration.

GRIN2A Variant in A 3-Year-Old-An Expanding Spectrum?

Glutamate, the major excitatory neurotransmitter, plays a ubiquitous role in most aspects of normal brain functioning. Its indispensable position is paradoxically doubled by a high excitotoxic potential following disruption of its dynamic equilibrium. Several lines of evidence have suggested the involvement of the glutamatergic N-methyl-D-aspartate receptor (NMDAR) in learning, memory formation, and human cognition. Furthermore, NMDARs play a pivotal role in various neuropsychiatric disorders, recently being identified as an important locus for disease-associated genomic variation. The GRIN2A gene encodes the NMDAR's GluN2A subunit. Genetic alterations of GRIN2A result in phenotypic pleiotropy, predisposing to a broad range of epilepsy syndromes, with an elusive and unpredictable evolution and response to treatment. The archetypal GRIN2A-related phenotype comprises the idiopathic focal epilepsies (IFEs), with a higher incidence of GRIN2A mutants among entities at the more severe end of the spectrum. We report the case of a patient heterozygous for GRIN2A, c.1081C>T, presenting with febrile convulsions and later superimposed atonic seizures, expressive language delay, and macrocephaly. As the number of reported GRIN2A variants is continuously increasing, the phenotypic boundaries gradually grow faint. Therefore, it is fundamental to maintain an acute critical awareness of the possible genetic etiology of different epilepsy syndromes. So far, therapeutic strategies rely on empirical observations relating genotypes to specific drugs, but the overall success of treatment remains unpredictable. Deciphering the functional consequences of individual GRIN2A variants could lead to the development of precision therapeutic approaches for patients carrying NMDAR mutations.

The Role of Polysomnography in Identifying Sleep Disorders in Children with Migraine.

Migraine pathophysiology and sleep share common neural pathways, and there are clinical as well as paraclinical observations, which lead to the hypothesis of an association between migraine and sleep disorders. The objective of this study consisted of the evaluation of a possible correlation between migraine and sleep disorders in children, as reflected by sleep architecture and electroencephalographic patterns. Eighteen patients aged five to seventeen were recruited for the migraine group, and sixteen age-matched patients with no criteria for migraine or any underlying organic disorder, diagnosed with emotional disorders, were enrolled in the control group. All patients underwent inpatient full night polysomnographic recordings, the results of which were analyzed using appropriate statistical methods. Patients in the migraine group had decreased REM sleep (p = 0.049) and increased N1 sleep (p = 0.018) percentages, compared to the control group. Also, more arousals (p = 0.011) and lower sleep latency (p = 0.029) were noted in the migraine group. A statistically significant association was observed between migraine and sleep disorders when the latter was defined with respect to normal values of polysomnographic parameters published in studies conducted on healthy children. Polysomnography can be a useful tool for studying sleep in pediatric migraine patients. The results of this study can be regarded as a starting point for a better understanding of the complex role of sleep in the developing brain and of eventual intricacies with migraine pathophysiological mechanisms.

Pediatric Autoimmune Encephalitis: Practical Aspects.

Autoimmune encephalitis is an inflammatory condition of the central nervous system that may involve a widely variable spectrum of clinical features. It can be divided into two main groups: with antibodies against intracellular antigens and with antibodies against surface antigens. The main clinical presentation is characterized by psychiatric symptoms, movement disorders and seizures. The differential diagnosis process should mainly consist of excluding infectious or other causes of encephalitis. Brain imagining, cerebrospinal fluid analysis and serology for a wide range of antibodies should lead to the diagnosis of a specific type of autoimmune encephalitis. Considering the fact that the disease may be paraneoplastic, appropriate tumor screening should be performed. Once the autoimmune etiology is established, treatment consists mainly of escalating immune therapies.

Antioxidant Therapies for Neuroprotection-A Review.

Although moderate concentrations of reactive oxygen species (ROS) and reactive nitrogen species (RNS) are crucial for various physiological processes within the human body, their overproduction leads to oxidative stress, defined as the imbalance between the production and accumulation of ROS and the ability of the body to neutralize and eliminate them. In the brain, oxidative stress exhibits significant effects, due to its increased metabolical activity and limited cellular regeneration. Thus, oxidative stress is a major factor in the progressive loss of neurons structures and functions, leading to the development of severe neurodegenerative disorders. In this context, recent years have witnessed tremendous advancements in the field of antioxidant therapies, with a special emphasis for neuroprotection. The aim of this paper is to provide an overview of the oxidative stress and antioxidant defense mechanisms and to present the most recent studies on antioxidant therapies for neuroprotection.

Nanomaterial-Based Approaches for Neural Regeneration.

Mechanical, thermal, chemical, or ischemic injury of the central or peripheral nervous system results in neuron loss, neurite damage, and/or neuronal dysfunction, almost always accompanied by sensorimotor impairment which alters the patient's life quality. The regenerative strategies for the injured nervous system are currently limited and mainly allow partial functional recovery, so it is necessary to develop new and effective approaches for nervous tissue regenerative therapy. Nanomaterials based on inorganic or organic and composite or hybrid compounds with tunable physicochemical properties and functionality proved beneficial for the transport and delivery/release of various neuroregenerative-relevant biomolecules or cells. Within the following paragraphs, we will emphasize that nanomaterial-based strategies (including nanosized and nanostructured biomaterials) represent a promising alternative towards repairing and regenerating the injured nervous system.

Contrast Agents Delivery: An Up-to-Date Review of Nanodiagnostics in Neuroimaging.

Neuroimaging is a highly important field of neuroscience, with direct implications for the early diagnosis and progression monitoring of brain-associated diseases. Neuroimaging techniques are categorized into structural, functional and molecular neuroimaging, each possessing advantages and disadvantages in terms of resolution, invasiveness, toxicity of contrast agents and costs. Nanotechnology-based approaches for neuroimaging mostly involve the development of nanocarriers for incorporating contrast agents or the use of nanomaterials as imaging agents. Inorganic and organic nanoparticles, liposomes, micelles, nanobodies and quantum dots are some of the most studied candidates for the delivery of contrast agents for neuroimaging. This paper focuses on describing the conventional modalities used for imaging and the applications of nanotechnology for developing novel strategies for neuroimaging. The aim is to highlight the roles of nanocarriers for enhancing and/or overcome the limitations associated with the most commonly utilized neuroimaging modalities. For future directions, several techniques that could benefit from the increased contrast induced by using imaging probes are presented.

Neuronanomedicine: An Up-to-Date Overview.

The field of neuronanomedicine has recently emerged as the bridge between neurological sciences and nanotechnology. The possibilities of this novel perspective are promising for the diagnosis and treatment strategies of severe central nervous system disorders. Therefore, the development of nano-vehicles capable of permeating the blood⁻brain barrier (BBB) and reaching the brain parenchyma may lead to breakthrough therapies that could improve life expectancy and quality of the patients diagnosed with brain disorders. The aim of this review is to summarize the recently developed organic, inorganic, and biological nanocarriers that could be used for the delivery of imaging and therapeutic agents to the brain, as well as the latest studies on the use of nanomaterials in brain cancer, neurodegenerative diseases, and stroke. Additionally, the main challenges and limitations associated with the use of these nanocarriers are briefly presented.

Nanomaterials for Drug Delivery to the Central Nervous System.

The intricate microstructure of the blood-brain barrier (BBB) is responsible for the accurate intrinsic regulation of the central nervous system (CNS), in terms of neuronal pathophysiological phenomena. Any disruption to the BBB can be associated with genetic defects triggering or with local antigenic invasion (either neurotoxic blood-derived metabolites and residues or microbial pathogens). Such events can be further related to systemic inflammatory or immune disorders, which can subsequently initiate several neurodegenerative pathways. Any degenerative process related to the CNS results in progressive and yet incurable impairment of neuronal cells. Since these particular neurons are mostly scanty or incapable of self-repair and regeneration processes, there is tremendous worldwide interest in novel therapeutic strategies for such specific conditions. Alzheimer's and Parkinson's diseases (AD and PD, respectively) are conditions found worldwide, being considered the most rampant degenerative pathologies related to CNS. The current therapy of these conditions, including both clinical and experimental approaches, mainly enables symptom management and subsidiary neuronal protection and even less disease regression. Still, a thorough understanding of the BBB pathophysiology and an accurate molecular and sub-molecular management of AD and PD will provide beneficial support for more specific and selective therapy. Since nanotechnology-derived materials and devices proved attractive and efficient platforms for modern biomedicine (including detection, imaging, diagnosis, medication, restoration and regeneration), a particular approach for AD and PD management relies on nanoparticle-based therapy. In this paper we will discuss relevant aspects related to the BBB and its impact on drug-based treatment and emphasize that nanoparticles are suitable and versatile candidates for the development of novel and performance-enhanced nanopharmaceuticals for neurodegenerative conditions therapy.