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Pregabalin is prescribed for neuropathic pain. We report the first case of pregabalin toxicity in a hemodialysis patient and her successful treatment with hemodialysis. The patient was a 30-year-old woman on long-term hemodialysis therapy who experienced significant myoclonus of the arms and legs when her dose of pregabalin was mistakenly increased. The drug has 3 properties that contribute to making it amenable to removal by hemodialysis: relatively low molecular weight (159.23 Da), relatively low volume of distribution (0.5 L/kg), and not bound to plasma proteins. We achieved hemodialysis clearance of 88.8 mL/min, which was associated with resolution of symptoms immediately after hemodialysis. [ABSTRACT FROM AUTHOR]

Purpose: SRRM2 encodes the SRm300 protein, a splicing factor of the SR-related protein family characterized by its serine- and arginine-enriched domains. It promotes interactions between messenger RNA and the spliceosome catalytic machinery. This gene, predicted to be highly intolerant to loss of function (LoF) and very conserved through evolution, has not been previously reported in constitutive human disease., Methods: Among the 1000 probands studied with developmental delay and intellectual disability in our database, we found 2 patients with de novo LoF variants in SRRM2. Additional families were identified through GeneMatcher., Results: Here, we report on 22 patients with LoF variants in SRRM2 and provide a description of the phenotype. Molecular analysis identified 12 frameshift variants, 8 nonsense variants, and 2 microdeletions of 66 kb and 270 kb. The patients presented with a mild developmental delay, predominant speech delay, autistic or attention-deficit/hyperactivity disorder features, overfriendliness, generalized hypotonia, overweight, and dysmorphic facial features. Intellectual disability was variable and mild when present., Conclusion: We established SRRM2 as a gene responsible for a rare neurodevelopmental disease., Competing Interests: Conflict of Interest This work was carried out within the framework of Nantes University Medical Center activity without additional funding. One patient was diagnosed in the context of work in a private company (AiLife Diagnostics, Pearland, Texas). The other authors declare no conflicts of interest., (Copyright © 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Introduction: Whole-exome sequencing (WES) has identified de novo variants in chromatin remodelling genes in patients with neurodevelopmental disorders (NDD). We report on a novel genetic discovery in chromatin remodelling in patients with NDD who also have corpus callosum (CC) anomalies., Objective: To discover novel genes linked to both CC anomalies and NDD., Methods: Clinical WES was performed for evaluation of NDD, identifying five patients with de novo variants in SUPT16H , a subunit of the FACT (facilitates chromatin transcription) complex. The clinical phenotypes, genetic results and brain MRIs were obtained and systematically reviewed. In silico protein function predictions were assessed and allele frequencies in control populations were compared., Results: We identified four patients with de novo missense variants in SUPT16H and one patient with a de novo deletion including SUPT16H . These variants were not reported in the updated Genome Aggregation Database. When assayable, all protein products were predicted to be damaging. Symptoms included intellectual disability, autistic features, minor dysmorphic features and seizures. Anomalies of the CC were seen in all three patients with available brain imaging., Conclusion: Our findings implicate the gene SUPT16H in a novel disorder characterised by neurodevelopmental deficits and CC anomalies., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Mutations in sodium channel genes are highly associated with epilepsy. Mutation of SCN1A, the gene encoding the voltage gated sodium channel (VGSC) alpha subunit type 1 (Nav1.1), causes Dravet syndrome spectrum disorders. Mutations in SCN2A have been identified in patients with benign familial neonatal-infantile epilepsy (BFNIE), generalised epilepsy with febrile seizures plus (GEFS+), and a small number of reported cases of other infantile-onset severe intractable epilepsy. Here, we report three patients with infantile-onset severe intractable epilepsy found to have de novo mutations in SCN2A. While a causal role for these mutations cannot be directly established, these findings contribute to growing evidence that mutation of SCN2A is associated with a range of epilepsy phenotypes including severe infantile-onset epilepsy.

Goldenhar syndrome, also called hemifacial microsomia or oculo-auriculo-verterbal dysplasia (OAVS) (MIM 164210), is a birth defect involving the first and second branchial arch derivatives with an incidence of 1/5000. The variable phenotype includes mostly unilateral deformity of the external ear and small ipsilateral half of the face with epibulbar dermoid and vertebral anomalies. A genome-wide search in one family suggested linkage to a region of 10.7 cM on chromosome 14q32; however, no candidate genes have been identified. We report on a 9-month old with OAVS and a pericentric inversion of chromosome 14 which he inherited from his phenotypically normal mother. Fluorescence in-situ hybridization analysis with bacterial artificial chromosome clones from chromosome 14 showed the breakpoint on 14q maps distal to 14q21.2, thus confirming the cytogenetic breakpoints. In light of previous linkage studies mapping OAVS to 14q, we propose that the long arm breakpoint in our proband disrupted a potential candidate gene for OAVS resulting in his clinical phenotype.

Apart from antibiotic treatment in bacterial meningitis supportive therapy including dexamethasone is widely used. In investigations on the pathogenesis of bacterial meningitis we previously demonstrated that Streptococcus suis (S. suis), a relevant cause of bacterial meningitis in pigs and humans, affects porcine choroid plexus epithelial cell (PCPEC) barrier function. The choroid plexus epithelium constitutes the structural basis of the blood-CSF barrier. Now, we investigated the role of tight junction proteins and the actin cytoskeleton of PCPEC in correlation to barrier function after S. suis infection and analyzed the influence of dexamethasone. S. suis caused massive rearrangement of the tight junction proteins ZO-1, occludin and claudin-1, caused loss of actin at the apical cell pole and induced basolateral stress fiber formation. Moreover, tight junctions were shifted from the Triton X insoluble to the Triton X soluble fraction, and additionally occludin was dephosphorylated and degraded. Infection with S. suis leads to an inflammatory response exemplified by the induction of tumor necrosis factor (TNF) alpha and matrix metalloproteinase (MMP)-3 gene activation, which correlated with phosphorylation of extracellular signal regulated kinases (ERKs). Importantly, dexamethasone significantly prevented S.suis-induced protein and morphological tight junction alterations and attenuated ERK activation and MMP-3 expression. It especially improved the barrier function by preventing tight junction protein reorganization and degradation. In the pathogenesis of bacterial meningitis protection of blood-CSF barrier by dexamethasone may prevent the penetration of bacteria and leukocytes into the CSF.

Phenylketonuria (PKU) is an inborn error of amino acid metabolism. Phenylalanine hydroxylase (PAH) mutations resulting reduced enzyme levels lead to accumulation of phenylalanine (Phe) in brain, if Phe diet is not restricted. Patients with PKU show neurophysiological abnormalities including demyelination and cognitive defect. How PAH defect causes events seen in PKU is not obvious. Therefore, expression analysis was performed in the brain of a mouse model for PKU. Microarray expression profile of the brain showed lower expression of myocilin (Myoc) in the PKU mouse. Reduced expression of Myoc was further confirmed by one-step real-time RT-PCR. Western blotting analysis of the brain using equal quantities of protein showed a thin band in PKU compared to a prominent band in the wild type brain. In addition, expression of genes associated with transcription was found to be altered in the PKU mouse brain as observed by microarray analysis. These data suggest that PAH defect alters other genes expression likely to contribute neurophysiological abnormalities seen in the mouse, if documented also in patients with PKU.

Streptococcus suis capsular type 2 is an important agent of diseases including meningitis among pigs worldwide, and is also a zoonotic agent. The barrier function of the choroid plexus epithelium that constitutes the structural basis for the blood-cerebrospinal fluid (CSF) barrier has not been elucidated yet in bacterial meningitis. We investigated the influence of various S. suis isolates on the barrier function of cultured porcine choroid plexus epithelial cells with respect to the transepithelial resistance and paracellular [(3)H]-mannitol flux. Preferentially apical application of S. suis isolates significantly decreased transepithelial resistance and significantly increased paracellular [(3)H]-mannitol flux in a time-, dose- and strain-dependent manner. Viable S. suis isolates caused cytotoxicity determined by lactate dehydrogenase assay and electron microscopy, whereas S. suis sonicates and UV-inactivated S. suis did not cause cytotoxicity. The observed effects on porcine choroid plexus epithelial cells barrier function could not exclusively be ascribed to known virulence factors of S. suis such as suilysin. In conclusion, S. suis isolates induce loss of blood-cerebrospinal fluid barrier function in an in vitro model. Thus, S. suis may facilitate trafficking of bacteria and leucocytes across the blood-cerebrospinal fluid barrier. The underlying mechanisms for the barrier breakdown have yet to be determined.

Patients with protruding aortic atheroma containing mobile emboli are at risk for peripheral emboli and stroke. This risk may possibly be reduced by anticoagulation, but whether or not such patients have an increased prevalence of thrombotic risk factors has not been previously determined. Twenty-two patients were studied (11 with protruding thoracic aortic atheromas and superimposed mobile thrombi on transesophageal echocardiography were compared to 11 age-matched controls). The authors evaluated activated protein C resistance (APC-R) by measuring the prolongation of the partial thromboplastin time (PTT) in response to activated protein C (APC). Concentrations of fibrinogen, antithrombin III (AT III), factor II, factor V, and D-dimer were also determined in all patients. There was significant resistance to APC (a smaller prolongation in PTT) in patients with atheromas and thrombi. They also had significantly higher concentrations of factor II. Factor V and fibrinogen were higher, and AT III lower, in patients than in controls; however, these latter differences did not reach statistical significance. Patients with aortic atheroma and mobile thrombi may have an increased prevalence of thrombotic risk factors. There is significantly increased resistance to activated protein C in patients with protruding atheroma and mobile thrombi in their thoracic aorta. There was also a trend toward elevated fibrinogen, homocysteine, and apo (a) concentrations as well as lower antithrombin III concentrations in these patients.

Lewis, Fischer 344, and Sprague-Dawley rats were implanted with electrodes in the medial forebrain bundle and trained to lever press for brain stimulation reward using a rate-frequency curve-shift electrical brain stimulation paradigm based on a series of 16 pulse frequencies ranging from 25 to 141 Hz in descending order. Once reward thresholds were stable, rats were given 1.0 mg/kg delta 9-tetrahydrocannabinol (delta 9-THC), the psychoactive constituent in marijuana and hashish, or vehicle, by intraperitoneal injection. Lewis rats showed the most pronounced delta 9-THC-induced enhancement of brain reward functions. Sprague-Dawley rats showed an enhancement of brain reward functions that was approximately half that seen in Lewis rats. Brain reward functions in Fischer 344 rats were unaffected by delta 9-THC at the dose tested. These results are consistent with previous work showing Lewis rats to be highly sensitive to the rewarding properties of a variety of drugs of abuse, including opiates, cocaine, and alcohol, while Fischer 344 rats are relatively less sensitive. They extend such previous findings to cannabinoids, and further suggest that genetic variations to other cannabinoid effects may also exist.