Central Dysmyelination in SSADH-Deficient Humans and Mice.

Objectives: Succinic semialdehyde dehydrogenase deficiency (SSADHD) is an inherited metabolic disorder characterized by an accumulation of γ-aminobutyric (GABA). In addition to its synaptic role as an inhibitory neurotransmitter, GABA also plays an important role in myelination. We aimed to investigate the relationship between GABA and myelination abnormalities in SSADHD patients and the mouse model.

Vigabatrin-associated brain abnormalities on MRI (VABAM) in children with epileptic spasms.

Background: The aim of this study was to identify risk factors and pattern of brain magnetic resonance imaging (MRI) changes in patients with vigabatrin-associated brain abnormalities on MRI (VABAM).

Methods: This retrospective observational study included patients who were treated with vigabatrin for epileptic spasms (ES). Patients who underwent at least one MRI during vigabatrin treatment were included.

Sex differences in seizure presentation in a Dravet syndrome mouse model.

Objectives: Dravet syndrome is an epileptic encephalopathy mostly because of haploinsufficiency of the SCN1A voltage-gated sodium channel subunit. Disease presentation (i.e.

Lower respiratory rate during sleep in children with angelman syndrome compared to age-matched controls.

Background: Angelman syndrome (AS) is a rare genetic neurodevelopmental disorder caused by the absence of a functional UBE3A gene, leading to developmental, behavioral, and medical challenges. Sleep disturbances, including sleep-disordered breathing, are common in AS. This study, for the first time, investigates nocturnal respiration in individuals with AS and healthy controls at home in a long term setting.

Clinical trials of prevention of acquired epilepsy: New proof-of-concept approach to restart trials.

Approximately 20% of epilepsy is caused by acute central nervous system insults such as traumatic brain injury (TBI), stroke, and infection. There is a latent period of weeks to years between the insult and epilepsy onset, which offers an opportunity to prevent epilepsy. No preventive treatments exist.

Phenotypic rescue via mTOR inhibition in neuron-specific Pten knockout mice reveals AKT and mTORC1-site specific changes.

Phosphatase and Tensin Homolog (PTEN) is a dual-specific protein and lipid phosphatase that regulates AKT and downstream signaling of the mechanistic target of rapamycin (mTOR). PTEN functions as a tumor suppressor gene whose mutations result in PTEN Hamartoma Tumor Syndrome (PHTS) characterized by increased cancer risk and neurodevelopmental comorbidity. Here, we generated a novel neuron-specific Pten knock-out mouse model (Syn-Cre/Pten HOM) to test the ability of pharmacologic mTOR inhibition to rescue Pten mutation-associated disease phenotypes in vivo and in vitro.

The neuropsychological profile of SSADH deficiency, a neurotransmitter disorder of GABA metabolism.

Background And Objectives: Succinic semialdehyde dehydrogenase deficiency (SSADHD) is an inherited metabolic disorder resulting in hyper-physiologic concentrations of the neurotransmitter γ-aminobutyrate (GABA). This study aims to provide the most comprehensive description, to date, of the neuropsychological profile of individuals with SSADHD and assess whether neuroimaging, neurophysiologic, and biochemical indices of cortical inhibition correlate with those of standardized behavioral tests.

Methods: Participants enrolled in the SSADHD Natural History Study underwent medical and neurological examinations, magnetic resonance imaging (MRI) and spectroscopy (MRS), biochemical tests of GABA and its related metabolites, transcranial magnetic stimulation (TMS), and gene expression quantification, as well as complete neuropsychological assessment including standardized measures for cognition, adaptive skills, motor function, receptive and expressive language, autism spectrum disorder, and behavior problems.

Alpha-Delta Ratio for Detection of Cerebral Injury and Stroke in Pediatric Extracorporeal Membrane Oxygenation.

Introduction: To assess the alpha-delta ratio (ADR) as a biomarker for cerebral injury and stroke in pediatric extracorporeal membrane oxygenation (ECMO).

Methods: Retrospective study of children aged >44 weeks gestation to 21 years monitored with continuous electroencephalography during ECMO. The interhemispheric ADR difference between the left and right hemisphere was calculated per hour.

Enhancement of Glutamate Uptake as Novel Antiseizure Approach: Preclinical Proof of Concept.

Objective: Excitotoxicity is a common hallmark of epilepsy and other neurological diseases associated with elevated extracellular glutamate levels. Thus, here, we studied the protective effects of (R)-AS-1, a positive allosteric modulator (PAM) of glutamate uptake in epilepsy models.

Methods: (R)-AS-1 was evaluated in a range of acute and chronic seizure models, while its adverse effect profile was assessed in a panel of standard tests in rodents.

The role of parvalbumin interneuron dysfunction across neurodegenerative dementias.

Parvalbumin-positive (PV+) basket neurons are fast-spiking, non-adapting inhibitory interneurons whose oscillatory activity is essential for regulating cortical excitation/inhibition balance. Their dysfunction results in cortical hyperexcitability and gamma rhythm disruption, which have recently gained substantial traction as contributing factors as well as potential therapeutic targets for the treatment of Alzheimer's Disease (AD). Recent evidence indicates that PV+ cells are also impaired in Frontotemporal Dementia (FTD) and Dementia with Lewy bodies (DLB).

A comparison of the antiepileptogenic efficacy of two rationally chosen multitargeted drug combinations in a rat model of posttraumatic epilepsy.

Post-traumatic epilepsy (PTE) is a recurrent and often drug-refractory seizure disorder caused by traumatic brain injury (TBI). No single drug treatment prevents PTE, but preventive drug combinations that may prophylax against PTE have not been studied. Based on a systematic evaluation of rationally chosen drug combinations in the intrahippocampal kainate (IHK) mouse model of acquired epilepsy, we identified two multi-targeted drug cocktails that exert strong antiepileptogenic effects.

Case report: Tremor in the placebo condition of a blinded clinical trial of intermittent theta-burst stimulation for cocaine use disorder.

We report a case of a new-onset, persistent tremor that developed during a clinical trial (NCT02927236) of intermittent theta burst stimulation [iTBS, a form of repetitive magnetic transcranial magnetic stimulation (rTMS)] for cocaine use disorder. Although the participant exhibited an exceptionally strong clinical response, subsequent unblinding revealed that they received sham iTBS. This case highlights the potential for strong functional neurological placebo responses in rTMS trials, and functional disorders might be a marker of a placebo response.

Zebrafish models of candidate human epilepsy-associated genes provide evidence of hyperexcitability.

Hundreds of novel candidate human epilepsy-associated genes have been identified thanks to advancements in next-generation sequencing and large genome-wide association studies, but establishing genetic etiology requires functional validation. We generated a list of >2,200 candidate epilepsy-associated genes, of which 48 were developed into stable loss-of-function (LOF) zebrafish models. Of those 48, evidence of seizure-like behavior was present in 5 (, , , , and ).

Clinical and molecular outcomes from the 5-Year natural history study of SSADH Deficiency, a model metabolic neurodevelopmental disorder.

Background: Succinic semialdehyde dehydrogenase deficiency (SSADHD) represents a model neurometabolic disease at the fulcrum of translational research within the Boston Children's Hospital Intellectual and Developmental Disabilities Research Centers (IDDRC), including the NIH-sponsored natural history study of clinical, neurophysiological, neuroimaging, and molecular markers, patient-derived induced pluripotent stem cells (iPSC) characterization, and development of a murine model for tightly regulated, cell-specific gene therapy.

Methods: SSADHD subjects underwent clinical evaluations, neuropsychological assessments, biochemical quantification of γ-aminobutyrate (GABA) and related metabolites, electroencephalography (standard and high density), magnetoencephalography, transcranial magnetic stimulation, magnetic resonance imaging and spectroscopy, and genetic tests. This was parallel to laboratory molecular investigations of in vitro GABAergic neurons derived from induced human pluripotent stem cells (hiPSCs) of SSADHD subjects and biochemical analyses performed on a versatile murine model that uses an inducible and reversible rescue strategy allowing on-demand and cell-specific gene therapy.

Gene replacement therapies for inherited disorders of neurotransmission: Current progress in succinic semialdehyde dehydrogenase deficiency.

Neurodevelopment is a highly organized and complex process involving lasting and often irreversible changes in the central nervous system. Inherited disorders of neurotransmission (IDNT) are a group of genetic disorders where neurotransmission is primarily affected, resulting in abnormal brain development from early life, manifest as neurodevelopmental disorders and other chronic conditions. In principle, IDNT (particularly those of monogenic causes) are amenable to gene replacement therapy via precise genetic correction.

Consensus guidelines for the diagnosis and management of succinic semialdehyde dehydrogenase deficiency.

Succinic semialdehyde dehydrogenase deficiency (SSADHD) (OMIM #271980) is a rare autosomal recessive metabolic disorder caused by pathogenic variants of ALDH5A1. Deficiency of SSADH results in accumulation of γ-aminobutyric acid (GABA) and other GABA-related metabolites. The clinical phenotype of SSADHD includes a broad spectrum of non-pathognomonic symptoms such as cognitive disabilities, communication and language deficits, movement disorders, epilepsy, sleep disturbances, attention problems, anxiety, and obsessive-compulsive traits.

Zebrafish models of candidate human epilepsy-associated genes provide evidence of hyperexcitability.

Hundreds of novel candidate human epilepsy-associated genes have been identified thanks to advancements in next-generation sequencing and large genome-wide association studies, but establishing genetic etiology requires functional validation. We generated a list of >2200 candidate epilepsy-associated genes, of which 81 were determined suitable for the generation of loss-of-function zebrafish models via CRISPR/Cas9 gene editing. Of those 81 crispants, 48 were successfully established as stable mutant lines and assessed for seizure-like swim patterns in a primary F screen.

Background EEG Suppression Ratio for Early Detection of Cerebral Injury in Pediatric Cardiac Arrest.

Background: Our objective was to assess the utility of the 1-h suppression ratio (SR) as a biomarker of cerebral injury and neurologic prognosis after cardiac arrest (CA) in the pediatric hospital setting.

Methods: Prospectively, we reviewed data from children presenting after CA and monitored by continuous electroencephalography (cEEG). Patients aged 1 month to 21 years were included.

Glymphatic dysfunction coincides with lower GABA levels and sleep disturbances in succinic semialdehyde dehydrogenase deficiency.

Succinic semialdehyde dehydrogenase deficiency (SSADHD) is an inherited metabolic disorder of γ-aminobutyrate (GABA) catabolism. Cerebral waste clearance along glymphatic perivascular spaces depends on aquaporin 4 (AQP4) water channels, the function of which was shown to be influenced by GABA. Sleep disturbances are associated independently with SSADHD and glymphatic dysfunction.

Synaptic BMAL1 phosphorylation controls circadian hippocampal plasticity.

The time of day strongly influences adaptive behaviors like long-term memory, but the correlating synaptic and molecular mechanisms remain unclear. The circadian clock comprises a canonical transcription-translation feedback loop (TTFL) strictly dependent on the BMAL1 transcription factor. We report that BMAL1 rhythmically localizes to hippocampal synapses in a manner dependent on its phosphorylation at Ser [pBMAL1(S42)].

Shortened Motor Evoked Potential Latency in the Epileptic Hemisphere of Children With Focal Epilepsy.

Purpose: Motor evoked potential (MEP) amplitude and latency are acquired routinely during neuronavigated transcranial magnetic stimulation, a method of functional mapping of the motor cortex before epilepsy surgery. Although MEP amplitude is routinely used to generate a motor map, MEP latency in patients with focal epilepsy has not been studied systematically. Given that epilepsy may alter myelination, we tested whether intrinsic hand muscle MEPs obtained from the hemisphere containing a seizure focus differ in latency from MEPs collected from the opposite hemisphere.