small molecules

2026-09-10 | Recurrent homozygous GLRB p.Arg472Ter variant in Palestinian hereditary hyperekplexia: a retrospective genotype–phenotype case series of nine children

Abstract Background Hereditary hyperekplexia is a treatable neurogenetic disorder of impaired glycinergic inhibition that may present neonatally with exaggerated startle, generalized stiffness, and life-threatening tonic apneic spells. Data from Palestine remain limited. We aimed to describe the clinical spectrum, molecular findings, diagnostic course, neurodevelopmental outcome, and treatment response of children with genetically confirmed GLRB-related hyperekplexia in the West Bank. Methods We conducted a retrospective descriptive case series of children evaluated in pediatric neurology clinics between 2015 and 2024. Medical records, electroencephalography, brain magnetic resonance imaging, final clinical genetic reports, medication history, complications, and follow-up data were reviewed. Molecular testing had been performed by targeted Sanger sequencing or whole exome sequencing. Data were summarized descriptively. Results Nine children from seven unrelated families were included: five males (55.6%) and four females (44.4%). All nine (100%) carried the homozygous GLRB c.1414 C > T (p.Arg472Ter) variant and presented from the first day of life with excessive startle, generalized stiffness, tonic apneic spells, and a positive nose tap test. Consanguinity was documented in eight (88.9%), family history in four (44.4%), and a previous alternative diagnosis in five (55.6%), including epilepsy in four (44.4%). EEG was normal in all eight tested patients, and brain MRI was normal in all five imaged patients. Among the eight survivors, seven (87.5%) had a documented developmental concern. Clonazepam was used in all nine patients; tonic apneic spells disappeared or improved in seven (77.8%). Conclusions This series documents a consistent neonatal phenotype and repeated identification of the same GLRB variant across unrelated Palestinian families, with variable developmental and treatment outcomes. Because population-based ascertainment and haplotype analysis were not performed, the findings should not be interpreted as evidence of population frequency or a founder effect. Early clinical recognition, genetic confirmation, individualized clonazepam management, and structured developmental follow-up are important.

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2026-09-09 | Induced epileptic seizures in larval zebrafish reveal a synaptic modulation associated with the post-ictal state.

Epilepsy patients suffer from spontaneous and recurrent seizures. In some cases, after seizures, a transient post-ictal state associated with cognitive deficits develops. Moreover, seizure-induced alterations in brain structure and function may give rise to neurological comorbidities associated with epilepsy. Nevertheless, the mechanisms underlying neurological comorbidities in epilepsy broadly and the post-ictal state specifically are not well understood. Here we used a well-established model of acutely induced seizures in larval zebrafish to reveal how seizures modulate a neural circuit implementing a specific sensorimotor transformation, the escape response. Using in vivo calcium imaging, we found that the responsivity of Mauthner cells, hindbrain command-like neurons that normally evoke fast and strong escape responses, to startling stimuli was reduced following seizures. Moreover, we observed a global reduction in post-seizure responsivity of neurons to the stimuli and in spontaneous neural activity. To identify structural correlates of these changes, we used expansion microscopy to characterize synaptic inputs to the Mauthner cells. Using this approach, we discovered that seizures increased the density of receptors in glycinergic inhibitory synapses onto these cells, expected to increase synaptic strength. This enhancement may compensate for the lack of GABAergic inhibition during the seizure. In addition, inducing the disassembly of glycinergic synapses by post-seizure strychnine treatment, reversed the effect of reduced neural responsivity. Put together, these data show that, at both the synaptic and circuit levels, inhibitory drive is strengthened after seizure termination, giving rise to a post-ictal state similar to that defined in humans. Consequently, sensory sensitivity is reduced, and post-seizure behavioural deficits are expected. These results reveal a potential target for pharmacological interventions that may mitigate neurological deficits in epilepsy when the seizures themselves cannot be prevented.

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2026-01-24 | A case of childhood hyperekplexia due to a novel nonsense variant in the GLRA1 gene.

Hyperekplexia is a rare hereditary neurological disorder characterized by an exaggerated startle response and generalized rigidity. It is frequently misdiagnosed as epilepsy, leading to unnecessary treatment. We report a case of mild hyperekplexia caused by a novel GLRA1 mutation, highlighting the diagnostic value of genetic testing in atypical presentations. An 18-month-old girl presented with recurrent episodes of vacant staring and limb rigidity triggered by sudden sounds or tactile stimuli over the past 2 months. She had a history of 3 febrile seizures but normal development. Physical examination revealed hypersensitivity to external stimuli, but the nose-tap test was negative. Routine metabolic studies, brain magnetic resonance imaging, and electroencephalogram were normal. Whole-exome sequencing identified a de novo heterozygous nonsense variant c.593G > A (p.Trp198Ter) in the GLRA1 gene, confirming the diagnosis of hyperekplexia. Given the confirmed diagnosis and the mild nature of the symptoms, the previously prescribed antiepileptic drug (levetiracetam) was discontinued. Clonazepam was not initiated due to the mild severity of the condition. At the 8-month follow-up, the patient remained seizure-free with minimal non-epileptic stimulus-induced symptoms. Her growth and psychomotor development were normal. This case expands the phenotypic spectrum of GLRA1-related hyperekplexia to include mild phenotypes with a negative nose-tap test. It underscores the critical role of whole-exome sequencing in distinguishing hyperekplexia from epilepsy, thereby avoiding inappropriate antiepileptic therapy.

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2025-04-22 | Lethal Interactions of neuronal networks in epilepsy mediated by both synaptic and volume transmission indicate approaches to prevention.

Neuronal network interactions are important in normal brain physiology and also in brain disorders. Many mesoscopic networks, including the auditory and respiratory network, mediate a single brain function. Macroscopic networks, including the locomotor network, central autonomic network (CAN), and many seizure networks involve interactions among multiple mesoscopic networks. Network interactions are mediated by neuroactive substances, acting via synaptic transmission, which mediate rapid interactions between networks. Slower, but vitally important network interactions, are mediated by volume transmission. Changes in the interactions between networks, mediated by neuroactive substances, can significantly alter network function and interactions. The acoustic startle response involves interactions between auditory and locomotor networks, and also includes brainstem reticular formation (BRF) nuclei, which participate in many different networks. In the fear-potentiated startle paradigm this network interacts positively with the amygdala, induced by conditioning. Seizure networks can interact negatively with the respiratory network, which becomes lethal in sudden unexpected death in epilepsy (SUDEP), a tragic emergent property of the seizure network. SUDEP models that exhibit audiogenic seizures (AGSz) involve interactions between the auditory and locomotor networks with BRF nuclei. In the DBA/1 mouse SUDEP model the AGSz network interacts negatively with the respiratory network, resulting in postictal apnea. The apnea is lethal unless the CAN is able to initiate autoresuscitation. These network interactions involve synaptic transmission, mediated by GABA and glutamate and volume transmission mediated by adenosine, CO2 and serotonin. Altering these interaction mechanisms may prevent SUDEP. These epilepsy network interactions illustrate the complex mechanisms that can occur among neuronal networks.

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2023-12-06 | Neuroprotectant Activity of Novel Water-Soluble Synthetic Neurosteroids on Organophosphate Intoxication and Status Epilepticus-Induced Long-Term Neurological Dysfunction, Neurodegeneration, and Neuroinflammation.

Organophosphates (OP) and nerve agents are potent neurotoxic compounds that cause seizures, status epilepticus, brain injury or death. There are persistent long-term neurological and neurodegenerative effects that manifest months to years after the initial exposure. Current antidotes are ineffective in preventing these long-term neurobehavioral and neuropathological changes. Additionally, there are few effective neuroprotectants for mitigating the long-term effects of acute OP intoxication. We have pioneered neurosteroids as novel anticonvulsants and neuroprotectants for OP intoxication and seizures. In this study, we evaluated the efficacy of two novel synthetic, water-soluble neurosteroids; valaxanolone (VX) and lysaxanolone (LX), in combating the long-term behavioral and neuropathological impairments caused by acute OP intoxication and SE. Animals were exposed to the OP compound diisopropylfluorophosphate (DFP), and were treated with VX or LX in addition to midazolam at 40-min post-exposure. The extent of neurodegeneration along with various behavioral and memory deficits were assessed at 3 months post-exposure. VX significantly reduced deficits of aggressive behavior, anxiety, memory, and depressive-like traits in control (DFP-exposed, midazolam-treated) animals; VX also significantly prevented the DFP-induced chronic loss of NeuN(+) principal neurons and PV(+) inhibitory neurons in the hippocampus and other regions. Additionally, VX-treated animals exhibited a reduced inflammatory response with decreased GFAP(+) astrogliosis and IBA1(+) microgliosis in the hippocampus, amygdala, and other regions. Similarly, LX showed significant improvement in behavioral and memory deficits, coupled with reducing neurodegeneration and neuroinflammation. Together, these results demonstrate the neuroprotectant effects of the novel synthetic neurosteroids in mitigating the long-term neurological dysfunction and neurodegeneration associated with OP exposure. Significance Statement Survivors of nerve agents and OP exposures suffer from long-term neurological deficits. Currently, there is no specific drug therapy for mitigating the impact of OP exposure. However, novel synthetic neurosteroids that activate tonic inhibition provide a viable option for treating OP intoxication. The data from this study indicates the neuroprotective effects of synthetic, water-soluble neurosteroids for attenuation of long-term neurological deficits after OP intoxication. These findings establish VX and LX as potent and efficacious neuroprotectants suitable for injectable dosing.

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proteins

2023-10-30 | Dual Role of Dysfunctional Asc-1 Transporter in Distinct Human Pathologies, Human Startle Disease, and Developmental Delay

Human startle disease is associated with mutations in distinct genes encoding glycine receptors, transporters or interacting proteins at glycinergic synapses in spinal cord and brainstem. However, a significant number of diagnosed patients does not carry a mutation in the common genes GLRA1 , GLRB , and SLC6A5 . Recently, studies on solute carrier 7 subfamily 10 ( SLC7A10 ; Asc-1, alanine-serine-cysteine transporter) knock-out (KO) mice displaying a startle disease-like phenotype hypothesized that this transporter might represent a novel candidate for human startle disease. Here, we screened 51 patients from our patient cohort negative for the common genes and found three exonic (one missense, two synonymous), seven intronic, and single nucleotide changes in the 5′ and 3′ untranslated regions (UTRs) in Asc-1. The identified missense mutation Asc-1 G307R from a patient with startle disease and developmental delay was investigated in functional studies. At the molecular level, the mutation Asc-1 G307R did not interfere with cell-surface expression, but disrupted glycine uptake. Substitution of glycine at position 307 to other amino acids, e.g., to alanine or tryptophan did not affect trafficking or glycine transport. By contrast, G307K disrupted glycine transport similar to the G307R mutation found in the patient. Structurally, the disrupted function in variants carrying positively charged residues can be explained by local structural rearrangements because of the large positively charged side chain. Thus, our data suggest that SLC7A10 may represent a rare but novel gene associated with human startle disease and developmental delay.

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2015-12-18 | Up-Regulation of Excitatory Amino Acid Transporters EAAT1 and EAAT2 by ß-Klotho

Klotho, a transmembrane protein expressed in chorioid plexus of the brain, kidney, and several other tissues, is required for inhibition of 1,25(OH)2D3 formation by FGF23. The extracellular domain of Klotho protein could be cleaved off, thus being released into blood or cerebrospinal fluid. At least in part by exerting β-glucuronidase activity, soluble klotho regulates several ion channels and carriers. Klotho protein deficiency accelerates the appearance of age related disorders including neurodegeneration and muscle wasting and eventually leads to premature death. The present study explored the effect of Klotho protein on the excitatory glutamate transporters EAAT1 (SLC1A3) and EAAT2 (SLC1A2), Na+ coupled carriers clearing excitatory amino acids from the synaptic cleft and thus participating in the regulation of neuronal excitability.cRNA encoding EAAT1 or EAAT2 was injected into Xenopus laevis oocytes and glutamate (2 mM)-induced inward current (IGlu) taken as measure of glutamate transport. Measurements were made without or with prior 24 h treatment with soluble ß-Klotho protein (30 ng/ml) in the absence and presence of β-glucuronidase inhibitor D-saccharic acid 1,4-lactone monohydrate (DSAL,10 µM).IGlu was observed in EAAT1 and in EAAT2 expressing oocytes but not in water injected oocytes. In both, EAAT1 and EAAT2 expressing oocytes IGlu was significantly increased by treatment with soluble ß-Klotho protein, an effect reversed by DSAL. Treatment with ß-klotho protein increased significantly the maximal transport rate without significantly modifying the affinity of the carriers.ß-Klotho up-regulates the excitatory glutamate transporters EAAT1 and EAAT2 and thus participates in the regulation of neuronal excitation.

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