Hyperekplexia

Neurotransmitter-Gated Ion Channels At Fast Chemical Synapses: From Structure To Pathology

New Neuroimaging Findings in Patients with Molybdenum Cofactor Deficiency Type A: A Case Report and Literature Review

Introduction: Molybdenum cofactor deficiency (MoCD-A) is an extremely rare autosomal recessive disease that presents with intractable seizures. The diagnosis poses challenges due to the limited number of cases reported worldwide. Magnetic resonance imaging (MRI) is a useful diagnostic tool that can detect brain injury associated with the disorder. The prognosis of MoCD-A is poor partly because most cases are initially misdiagnosed as HIE (hypoxic ischemic encephalopathy), emphasizing the need for an early and accurate diagnosis to improve quality of life and provide adequate genetic counseling to avoid new cases in the future.

Case Report: This report presents a case of molybdenum cofactor deficiency type A (MoCD-A) caused by MOCS1 gene mutations. A male newborn was admitted on the 10th day of birth due to uncontrolled seizures and feeding difficulties. Brain MRI showed severe cerebral damage with multiple foci that did not enhance upon contrast administration. The diagnosis was confirmed by genetic analysis and the patient received rehabilitation. His parents also received genetic counseling. To the best of our knowledge, this is the first reported MoCD-A case that had enhanced MR imaging with Gd-DTPA (0.1 mmol/kg). In addition, we reviewed the clinical and neuroimaging features of 25 newborns diagnosed with MoCD-A, as documented in the existing literature.

Conclusion: MRI is crucial in the diagnosis of MoCD-A. A correct diagnosis can provide the family with timely genetic counseling to prevent future cases.

Respiratory Complications in the Inborn Errors of Metabolism

Inborn Errors of Metabolism (IEMs) are a large heterogeneous group of monogenic disorders that affect specific metabolic pathways. Although the clinical picture is variable and shows a multisystemic impairment, most of these defects encompass neurologic symptoms and signs. The respiratory involvement may represent a late-onset feature of a complex multisystemic disease or the only manifestation of an underlying IEM. The severity of the respiratory disease can range from mild aspecific symptoms, such as tachypnea and respiratory distress in response to metabolic acidosis, to severe conditions, such as respiratory failure and restrictive disease. This review aims to offer an overview of the principal IEMs with neurologic and respiratory involvement, highlighting the significance of early recognition and multidisciplinary management for optimal patient care.

A Review of Current and Prospective Treatments for Channelopathies, with a Focus on Gene and Protein Therapy

Reduced cell surface expression or the malfunctioning of ion channels gives rise to a group of disorders known as channelopathies. To treat the underlying cause, the delivery and/or expression of a functional ion channel into the cell membrane of the cell of interest is required. Unfortunately, for most channelopathies, current treatment options are only symptomatic and treatments that rectify the underlying damage are still lacking. Within this context, approaches that rely on gene and protein therapy are required. Gene therapy would allow the expression of a functional protein, provided that the cellular machinery in the diseased cell could correctly fold and traffic the protein to the cell membrane. Whereas protein therapy would allow the direct delivery of a functional protein, provided that the purification process does not affect protein function and a suitable delivery vehicle for targeted delivery is used. In this review, we provide an overview of channelopathies and available symptomatic treatments. The current state of gene therapy approaches mainly using viral vectors is discussed, which is followed by the role of nanomedicine in protein therapy and how nanomedicine could be exploited for the delivery of functional ion channels to diseased cells.

Diagnostic Approach and Treatment Regimens in Adult Patients Suffering from Antibody- mediated or Paraneoplastic Encephalitis

Identification of patients with antibody-mediated encephalitis poses a diagnostic challenge, and any delay in that aspect will increase the interval until the initiation of immunotherapy and may negatively affect the patient´s clinical outcome. Within this review, we focus on therapeutic strategies in antibody-mediated encephalitis and propose how to proceed with patients who are suspected of having encephalitis of unknown origin. We further briefly outline differences in the treatment of paraneoplastic and antibody-mediated encephalitis according to its pathomechanisms.

Potential Biological Targets Prediction, ADME Profiling, and Molecular Docking Studies of Novel Steroidal Products from Cunninghamella blakesleana

Background: New potential biological targets prediction through inverse molecular docking technique is another smart strategy to forecast the possibility of compounds being biologically active against various target receptors.

Objective: In this case of designed study, we screened our recently obtained novel acetylenic steroidal biotransformed products [(1) 8- β-methyl-14-α-hydroxyΔ⁴tibolone (2) 9-α-HydroxyΔ⁴ tibolone (3) 8- β-methyl-11- β-hydroxyΔ⁴tibolone (4) 6- β-hydroxyΔ⁴tibolone, (5) 6- β-9-α-dihydroxyΔ⁴tibolone (6) 7- β-hydroxyΔ⁴tibolone)] from fungi Cunninghemella Blakesleana to predict their possible biological targets and profiling of ADME properties.

Methods: The prediction of pharmacokinetic properties, membrane permeability, and bioavailability radar properties was carried out by using Swiss target prediction and Swiss ADME tools, respectively. These metabolites were also subjected to predict the possible mechanism of action along with associated biological network pathways by using Reactome database.

Results: All the six screened compounds possessed excellent drug ability criteria and exhibited exceptionally excellent non-inhibitory potential against all five isozymes of the CYP450 enzyme complex, including CYP1A2, CYP2C19, CYP2C9, CYP2D6, and CYP3A4. All the screened compounds are lying within the acceptable pink zone of bioavailability radar and showing excellent descriptive properties. Compounds [1-4 & 6] are showing high BBB (Blood Brain Barrier) permeation, while compound 5 is exhibiting high HIA (Human Intestinal Absorption) property of (Egan Egg).

Conclusion: In conclusion, the results of this study smartly reveal that in-silico based studies are considered to provide robustness towards a rational drug design and development approach; therefore, in this way, it helps to avoid the possibility of failure of drug candidates in the later experimental stages of drug development phases.

Breath-Holding Spells in Pediatrics: A Narrative Review of the Current Evidence

Background: Breath-holding spells are common, frightening, but fortunately benign events. Familiarity with this condition is important so that an accurate diagnosis can be made.

Objective: To familiarize physicians with the clinical manifestations, diagnosis, evaluation, and management of children with breath-holding spells.

Methods: A PubMed search was completed in Clinical Queries using the key term "breath-holding spells". The search strategy included meta-analyses, randomized controlled trials, clinical trials, observational studies, and reviews. Only papers published in the English literature were included in this review. The information retrieved from the above search was used in the compilation of the present article.

Results: Breath-holding spells affect 0.1 to 4.6% of otherwise healthy young children. The onset is usually between 6 and 18 months of age. The etiopathogenesis is likely multifactorial and includes autonomic nervous system dysregulation, vagally-mediated cardiac inhibition, delayed myelination of the brain stem, and iron deficiency anemia. Breath-holding spells may be cyanotic or pallid. The former are usually precipitated by anger or frustration while the latter are more often precipitated by pain or fear. In the cyanotic type, the child usually emits a short, loud cry, which leads to a sudden involuntary holding of the breath in forced expiration. The child becomes cyanosed, rigid or limp, followed by a transient loss of consciousness, and a long-awaited inspiration and resolution of the spell. In the pallid type, crying may be minimal or “silent”. The apneic period in the pallid type is briefer than that in the cyanotic type prior to the loss of consciousness and posture. The episode in the pallid type then proceeds in the same manner as a cyanotic spell except that the child in the pallid type develops pallor rather than cyanosis. In both types, the entire episode lasts approximately 10 to 60 seconds. The spells usually disappear spontaneously by 5 years of age.

Conclusion: Although breath-holding spells are benign, they can be quite distressing to the parents. Confident reassurance and frank explanation are the cornerstones of treatment. Underlying cause, if present, should be treated. Interventions beyond iron supplementation may be considered for children with severe and frequent breath-holding spells which have a strong impact on the lifestyle of both the child and family.

Treatment of Epileptic Encephalopathies

Background: Epileptic encephalopathies represent the most severe epilepsies, with onset in infancy and childhood and seizures continuing in adulthood in most cases. New genetic causes are being identified at a rapid rate. Treatment is challenging and the overall outcome remains poor. Available targeted treatments, based on the precision medicine approach, are currently few.

Objective: To provide an overview of the treatment of epileptic encephalopathies with known genetic determinants, including established treatment, anecdotal reports of specific treatment, and potential tailored precision medicine strategies.

Method: Genes known to be associated to epileptic encephalopathy were selected. Genes where the association was uncertain or with no reports of details on treatment, were not included. Although some of the genes included are associated with multiple epilepsy phenotypes or other organ involvement, we have mainly focused on the epileptic encephalopathies and their antiepileptic treatments.

Results: Most epileptic encephalopathies show genotypic and phenotypic heterogeneity. The treatment of seizures is difficult in most cases. The available evidence may provide some guidance for treatment: for example, ACTH seems to be effective in controlling infantile spams in a number of genetic epileptic encephalopathies. There are potentially effective tailored precision medicine strategies available for some of the encephalopathies, and therapies with currently unexplained effectiveness in others.

Conclusions: Understanding the effect of the mutation is crucial for targeted treatment. There is a broad range of disease mechanisms underlying epileptic encephalopathies, and this makes the application of targeted treatments challenging. However, there is evidence that tailored treatment could significantly improve epilepsy treatment and prognosis.

Inhibitors of Glycine Transporter-1: Potential Therapeutics for the Treatment of CNS Disorders

Glycine acts as an inhibitory neurotransmitter at glycine receptor (GlyR)-enriched synapses and as an obligatory co-agonist at the N-methyl-D-aspartate (NMDA) receptor, where it facilitates neuronal excitation. Two high-affinity and substrate selective transporters, glycine transporter-1 and glycine transporter-2 (GlyT-1 and GlyT-2), regulate extracellular glycine concentrations within the CNS and as such, play critical roles in maintaining a balance between inhibitory and excitatory neurotransmission. GlyT-1 inhibition has been extensively examined as a potential means by which to treat several CNS disorders that include schizophrenia, depression, anxiety, obsessive compulsive disorder (OCD), and addiction. More recently, preclinical studies have emerged that indicate the approach may also promote neuroprotection, provide a pharmacotherapeutic strategy for autism spectrum disorders (ASDs), and treat symptomology associated with pain, Parkinson’s disease, and epilepsy. This review examines the pharmacological aspects of GlyT-1 inhibition and describes drug discovery and development efforts toward the identification of novel inhibitors.

Studies on Chloride Channels and their Modulators

The prime roles of mutations in the genes, encoding chloride ion channels, in various human diseases of muscle, kidney, bone and brain, such as congenital myotonia, myotonic dystrophy, cystic fibrosis, osteopetrosis, epilepsy, glioma, etc., have been well established. Chloride ion channels are also responsible for glioma progression in brain and malaria parasite in red blood cells. The present article thus emphasises on the various diseases associated with chloride channel regulation and their modulators. Studies on various chloride channels and their modulators have been discussed in detail.

Inhibition of glycine transporter 1: The yellow brick road to new schizophrenia therapy?

While pharmacological blockade of dopamine D2 receptor can effectively suppress the psychotic or positive symptoms of schizophrenia, there is no satisfactory medication for the negative and cognitive symptoms of schizophrenia in spite of the proliferation of second generation antipsychotic drugs. Excitements over a new class of third generation antipsychotics that might possibly fill this urgent medical need have been prompted by the recent development of glycine transporter 1 (GlyT1) inhibitors. The impetus of this novel pharmacological strategy stems directly from the prevailing hypothesis that negative and cognitive symptoms are attributable to the hypofunction of glutamatergic signalling via the N-methyl-D-aspartate (NMDA) receptor in the brain. Inhibition of GlyT1 reduces clearance of extra-cellular glycine near NMDA receptor-containing synapses, and thereby increases baseline occupancy of the glycine-B site at the NR1 subunit of the NMDA receptor, which is a prerequisite of channel activation upon stimulation by the excitatory neurotransmitter glutamate. Pharmacological inhibition of GlyT1 is expected to boost NMDA receptor function and therefore alleviate persistent negative and cognitive symptoms without excessive risk of excitotoxicity associated with direct NMDA receptor agonists. The recently completed phase III clinical trials of the Roche compound, bitopertin (a.k.a. RG1678 or RO-4917838) had initially raised hope that this new class of drugs might represent the first successful translation of the glutamate hypothesis of schizophrenia to the clinic. However, the outcomes of the multi-centre bitopertin clinical trials have been disappointing. The present review seeks to examine this promise through a critical survey of the latest clinical and preclinical findings on the therapeutic potential of GlyT1 inhibition or down-regulation.

Interaction of Different Proteins with GABA_A Receptor and their Modulatory Effect on Inhibitory Neural Transmission Leads to Epilepsy

γ-aminobutyric acid type A receptors (GABA_ARs) are key players in the mediation of synaptic inhibition in the mammalian brain. Several proteins have a significant role in the complex trafficking mechanisms of GABA_ARs to and from the neuronal surface. Proper trafficking maintain number and localization of GABA_AR at the neuronal surface which is necessary for inhibitory neuronal transmission. Among many other proteins, recently identified molecular motor protein KIF5A is also involved in the GABA_AR trafficking by interacting with GAB_ARP protein. Deletion in the KIF5A can impair transportation mechanism of GABA_AR, while an inappropriate inhibitory GABA_AR mediated neuronal transmission leads to epilepsy. In this article, we discussed the dynamic regulation of GABA_AR, role of different proteins in GABA_AR trafficking, clustering and endocytosis by direct interaction with GABA_AR or interaction through adaptor proteins linked with microtubules and also the dysregulation of GABA_AR trafficking in epilepsy. It is concluded that various proteins are involved in the GABA_AR trafficking; mutation or any other change in the interacting proteins can reduce the GABA_AR trafficking and also reduces their cell surface expression which may lead to epilepsy.

The Different Ways through Which Specificity Works in Orthosteric and Allosteric Drugs

Currently, there are two types of drugs on the market: orthosteric, which bind at the active site; and allosteric, which bind elsewhere on the protein surface, and allosterically change the conformation of the protein binding site. In this perspective we argue that the different mechanisms through which the two drug types affect protein activity and their potential pitfalls call for different considerations in drug design. The key problem facing orthosteric drugs is side effects which can occur by drug binding to homologous proteins sharing a similar binding site. Hence, orthosteric drugs should have very high affinity to the target; this would allow a low dosage to selectively achieve the goal of target-only binding. By contrast, allosteric drugs work by shifting the free energy landscape. Their binding to the protein surface perturbs the protein surface atoms, and the perturbation propagates like waves, finally reaching the binding site. Effective drugs should have atoms in good contact with the ‘right’ protein atoms; that is, the contacts should elicit propagation waves optimally reaching the protein binding site target. While affinity is important, the design should consider the protein conformational ensemble and the preferred propagation states. We provide examples from functional in vivo scenarios for both types of cases, and suggest how high potency can be achieved in allosteric drug development.

On the Involvement of H2S in Nitroso Signaling and Other Mechanisms of H2S Action

Both endogenously produced and exogenously administered H2S exert numerous biological effects. However, the molecular mechanisms underlying these effects are not fully understood. This review surveys the biological effects of H2S and summarizes the molecular mechanisms of H2S action. It focuses on the role of H2S/HS--induced NO release from nitroso compounds, modulation of ion channels and the antioxidant and radical properties of H2S in the molecular mechanism of its effects. The potential involvement of H2S in nitroso signaling underlying its diverse biological effects is also discussed.

Autoimmune Channelopathies of the Nervous System

Ion channels are complex transmembrane proteins that orchestrate the electrical signals necessary for normal function of excitable tissues, including the central nervous system, peripheral nerve, and both skeletal and cardiac muscle. Progress in molecular biology has allowed cloning and expression of genes that encode channel proteins, while comparable advances in biophysics, including patch-clamp electrophysiology and related techniques, have made the functional assessment of expressed proteins at the level of single channel molecules possible. The role of ion channel defects in the pathogenesis of numerous disorders has become increasingly apparent over the last two decades. Neurological channelopathies are frequently genetically determined but may also be acquired through autoimmune mechanisms. All of these autoimmune conditions can arise as paraneoplastic syndromes or independent from malignancies. The pathogenicity of autoantibodies to ion channels has been demonstrated in most of these conditions, and patients may respond well to immunotherapies that reduce the levels of the pathogenic autoantibodies. Autoimmune channelopathies may have a good prognosis, especially if diagnosed and treated early, and if they are non-paraneoplastic. This review focuses on clinical, pathophysiologic and therapeutic aspects of autoimmune ion channel disorders of the nervous system.

Molecular Pharmacology of the Glycine Receptor Chloride Channel

The glycine receptor (GlyR) Cl- channel belongs to the cysteine-loop family of ligand-gated ion channel receptors. It is best known for mediating inhibitory neurotransmission in motor and sensory reflex circuits of the spinal cord, although glycinergic synapses are also present in the brain stem, cerebellum and retina. Extrasynaptic GlyRs are widely distributed throughout the central nervous system and they are also found in sperm and macrophages. A total of 5 GlyR subunits (α1-4 and β) have been identified. Embryonic receptors comprise α2 homomers whereas adult receptors comprise predominantly α1β heteromers in a 2:3 stoichiometry. Notably, the α3 subunit is present in synaptic GlyRs that mediate inhibitory neurotransmission onto spinal nociceptive neurons. These receptors are specifically inhibited by inflammatory mediators, implying a role for α3-containing GlyRs in inflammatory pain sensitisation. Because molecules that increase GlyR current may have clinical potential as muscle relaxant and peripheral analgesic drugs, this review focuses on the molecular pharmacology of GlyR potentiating substances. Of all GlyR potentiating substances identified to date, we conclude that 5HT3R antagonists such as tropisetron offer the most promise as therapeutic lead compounds. However, one problem is that that virtually all known GlyR potentiating compounds, including tropisetron analogues, lack specificity for the GlyR. Another is that almost nothing is known about the pharmacological properties of α3-containing GlyRs, which is the subtype of choice for targeting by novel antinociceptive agents. These issues need to be addressed before GlyR-specific therapeutics can be developed.

The Patch Clamp Technique in Ion Channel Research

To understand the pathogenesis of a given ion channel disorder, knowledge of the mutation alone is insufficient, instead, the description of the associated functional defect is decisive. The patch clamp technique enables to achieve this both in native tissue as well as heterologous expression systems. By this technique, structure-function relationships of ion channels were elucidated that not only support the homology already suggested by amino acid alignments of different channel types, but that also pointed to regions important for gating, ion selectivity, or subunit interaction. Currently, effort is being made to develop automation of the technique which will result in a cost-effective, fast, and highly accurate method to test for drug actions on high throughput scales. This review contains an overview of channel structures, channel diseases, and methods to study channel function by the patch clamp technique.