Screening of the TMEM151A Gene in Patients With Paroxysmal Kinesigenic Dyskinesia and Other Movement Disorders.

Background: Paroxysmal kinesigenic dyskinesia (PKD) is a rare neurological disorder characterized by recurrent involuntary movements usually triggered by sudden movements. Mutations in the TMEM151A gene were found to be the causative factor of PKD in recent studies. It has also been revealed that loss-of-function is the mechanism by which TMEM151A mutations cause PKD. Methods: To investigate the genetic basis of PKD and broaden the clinical spectrum of the TMEM151A mutations, we recruited 181 patients of Chinese origin with movement disorders (MDs), including 39 PRRT2-negative PKD, 3 paroxysmal exercise-induced dyskinesia (PED), 2 paroxysmal non-kinesigenic dyskinesia (PNKD), 127 isolated dystonia, 8 choreas, and 2 myoclonus-dystonia syndromes. Whole-exome sequencing was applied to identify their possible disease-causing mutations. Then, Sanger sequencing was performed for validation and co-segregation analysis. Genetic analysis was also performed on additional family members of patients with TMEM151A mutations. Clinical manifestations of all PKD cases with mutations in TMEM151A reported, so far, were reviewed. Results: Two novel variants of the TMEM151A gene (NM_153266.4, NP_694998.1), c.627_643dup (p.A215Gfs*53) and c.627delG (p.L210Wfs*52), were identified in 2 patients with PKD by whole-exome sequencing and further Sanger sequencing. Both variants were inherited by the patients from their respective mothers. No mutation of the TMEM151A gene was found in the other type of movement disorders. In reviewing the clinical presentation of TMEM151A-related PKD, no statistically significant difference in the age of onset, family history, duration of attacks, laterality, and phenotype was found between genders. More male patients received treatment and had a good response. A higher proportion of female patients did not receive any treatment, possibly because they had a milder condition of the disease. Conclusions: This study further validated the role of TMEM151A in PKD. Future studies on protein function will be needed to ascertain the pathogenesis of TMEM151A in PKD.

Efficacy of systemic lidocaine on postoperative quality of recovery and analgesia after video-assisted thoracic surgery: A randomized controlled trial.

STUDY OBJECTIVE: Intraoperative systemic lidocaine has become widely accepted as an adjunct to general anesthesia, associated with opioid-sparing and enhanced recovery. We hypothesized that perioperative systemic lidocaine improves postoperative pain and enhances the quality of recovery (QoR) in patients following video-assisted thoracic surgery (VATS). DESIGN: Prospective, single-center, double-blind, randomized placebo-controlled clinical trial. SETTING: Single institution, tertiary university hospital. PATIENTS: Adult patients aged 18 to 65 undergoing VATS were eligible for participation. INTERVENTIONS: Patients enrolled in this study were randomized to receive either system lidocaine (a bolus of 1.5 mg kg-1, followed by an infusion of 2 mg kg-1 h-1 until the end of the surgical procedure) or identical volumes and rates of 0.9% saline. MEASUREMENTS: The primary outcome was a global QoR-15 score 24 h after surgery. Secondary outcomes included postoperative pain score, cumulative opioid consumption, emergence time, length of PACU stay, adverse events, and patient satisfaction. MAIN RESULTS: There was no difference in the global QoR-15 scores at 24 h postoperatively between the lidocaine and saline groups (median 117, IQR 113.5-124, vs. median 116, IQR 111-120, P = 0.067), with a median difference of 3 (95% CI 0 to 6, P = 0.507). Similarly, postoperative pain scores, postoperative cumulative opioid consumption, PACU length of stay, the occurrence of PONV, and patient satisfaction were comparable between the two groups (all P > 0.05). CONCLUSIONS: Our current findings do not support using perioperative systemic lidocaine as a potential strategy to improve postoperative pain and enhance QoR in patients undergoing VATS. TRIAL REGISTRATION: Chinese Clinical Trial Registry (identifier: ChiCTR1900027515).

Molecular expression and functional analysis of genes in children with temporal lobe epilepsy.

Temporal lobe epilepsy is the most common form of epilepsy. However, for this type of condition, antiseizure medication is not effective for children. As miRNAs are involved in the development of temporal lobe epilepsy in children, they may provide potential therapeutic approaches for treatment. The primary aim of this study was to explore the expression and function of miR-135a-5p in children with temporal lobe epilepsy. Hippocampal slices from either normal (control) children or children with temporal lobe epilepsy were used to detect the expression of miR-135a-5p and its target gene caspase activity and apoptosis inhibitor 1. To further explore the role of miR-135a-5p in the development of temporal lobe epilepsy in children, primary hippocampal neurons from newborn rats were cultured in vitro in a magnesium-free medium to mimic the temporal lobe epilepsy condition in children. The effect of transfection of miR-135a-5p inhibitor into cells was also assessed. Apoptosis and proliferation of hippocampus cells was respectively assessed by flow cytometry or 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The level of miR-135a-5p was significantly increased in both children with temporal lobe epilepsy and the epileptiform discharge model that employed newborn rat hippocampal neurons; whereas, the expression of caspase activity and apoptosis inhibitor 1 was downregulated by overexpression of miR-135a-5p. Moreover, miR-135a-5p mediated the pro-apoptotic effect of temporal lobe epilepsy via repressing caspase activity and apoptosis inhibitor 1 expression. Additionally, miR-135a-5p reduced cell survival in the temporal lobe epilepsy condition. Overexpression of miR-135a-5p induced cell apoptosis through inhibition of caspase activity and apoptosis inhibitor 1 expression and suppressed cell survival in children with temporal lobe epilepsy.

Lack of association between valproic acid response and polymorphisms of its metabolism, transport, and receptor genes in children with focal seizures.

OBJECTIVE: This study aims to describe the associations between genetic polymorphisms and therapeutic effect of valproic acid (VPA) in children with focal seizures. METHODS: Eighty-nine children with focal seizures on VPA therapy were enrolled. Patients' basic information, dosage regimens, and plasma concentrations were recorded. A 1-year follow-up was performed to evaluate the treatment response. Sixty-six single nucleotide polymorphisms involved in the metabolism, transport, and target receptor of VPA were identified, and their associations with VPA response were analyzed using logistic regression adjusted by various influence factors. Selected polymorphisms involved in the metabolism, transport, and target receptor of VPA were not associated with treatment effect in children with focal seizures. RESULTS: Three variants, rs9313892 (GABRA6, G > A, OR = 2.73, 95% CI 1.00 to 7.48, P = 0.051), rs4921195 (GABRA6, T > C, OR = 2.71, 95% CI 0.99 to 7.42, P = 0.053), and rs424740 (GABRG2, A > T, OR = 0.39, 95% CI 0.15 to 1.01, P = 0.053) had the potential to be associated with the VPA response. CONCLUSION: Selected genetic polymorphisms were not significantly associated with VPA response in children with focal seizures. However, three GABR variants showed potential to be associated with the response to VPA. Further and larger studies are warranted to confirm the results.

Effect of CYP2C19, UGT1A8, and UGT2B7 on valproic acid clearance in children with epilepsy: a population pharmacokinetic model.

PURPOSE: Valproic acid (VPA) is an important drug in seizure control with great inter-individual differences in metabolism and treatment effect. This study aims to identify the effects of genetic variants on VPA clearance in a population pharmacokinetic (popPK) model in children with epilepsy. METHODS: A total of 325 VPA plasma concentrations from 290 children with epilepsy were used to develop the popPK model by using the nonlinear mixed-effects modeling method. The one-compartment model was established to describe the pharmacokinetics of VPA. Twelve single nucleotide polymorphisms involved in the pharmacokinetics of VPA were identified by MassARRAY system and their effects on VPA clearance were evaluated. RESULTS: In the two final popPK models, inclusion of a combined genotype of four variants (rs1042597, rs28365062, rs4986893, and rs4244285), total daily dose (TDD), and body surface area (BSA) significantly reduced inter-individual variability for clearance over the base model. The inter-individual clearance equals to 0.73 × (TDD/628.92)0.59 × eUGT-CYP for TDD included model and 0.70 × (BSA/0.99)0.57 × eUGT-CYP for BSA included model. The precision of all parameters were acceptable (relative standard error < 32.81%). Bootstrap and visual predictive check results indicated that both two final popPK models were stable with acceptable predictive ability. CONCLUSION: TDD, BSA, and genotype might affect VPA clearance in children. The popPK models may be useful for dosing adjustment in children on VPA therapy.

Effects of UGT2B7, SCN1A and CYP3A4 on the therapeutic response of sodium valproate treatment in children with generalized seizures.

PURPOSE: This study aims to evaluate the associations between genetic polymorphisms and the effect of sodium valproate (VPA) therapy in children with generalized seizures. METHODS: A total of 174 children with generalized seizures on VPA therapy were enrolled. Steady-state trough plasma concentrations of VPA were analyzed. Seventy-six single nucleotide polymorphisms involved in the absorption, metabolism, transport, and target receptor of VPA were identified, and their associations with the therapeutic effect (seizure reduction) were evaluated using logistic regression adjusted by various influence factors. RESULTS: rs7668282 (UGT2B7, T > C, OR = 2.67, 95% CI: 1.19 to 5.91, P = 0.017) was more prevalent in drug-resistant patients than drug-responsive patients. rs2242480 (CYP3A4, C > T, OR = 0.27, 95% CI: 0.095 to 0.79, P = 0.017) and rs10188577 (SCN1A, T > C, OR = 0.40, 95% CI: 0.17 to 0.94, P = 0.035) were more prevalent in drug-responsive patients compared to drug-resistant patients. CONCLUSION: In children with generalized seizures on VPA therapy, polymorphisms of UGT2B7, CYP3A4, and SCN1A genes were associated with seizure reduction. Larger studies are warranted to corroborate the results.

Genetic polymorphisms and valproic acid plasma concentration in children with epilepsy on valproic acid monotherapy.

PURPOSE: The aim of the study is to evaluate the association between genetic polymorphisms and valproic acid (VPA) concentration to dose ratio in children with epilepsy on VPA monotherapy. METHODS: A total of 137 children, aged 3.5-18 years, (89 males and 48 females) with epilepsy on sustained-release VPA monotherapy were enrolled. Trough plasma concentrations of VPA at steady-state were measured using an AXSYM automatic immunity analyzer. The values were divided by body weight and total daily dose to calculate concentration to dose ratio of VPA (CDRV). Forty-eight single nucleotide polymorphisms involved in the pharmacokinetics of VPA were identified by MassARRAY system. The logarithmic transformed CDRV (lnCDRV) was normally distributed, and PLINK software was used to evaluate the association between genetic polymorphisms and lnCDRV using linear regression adjusted for gender and seizure type. RESULTS: rs28898617 (UGT1A3/4/5/6/7/8/9/10, BETA=0.32, P=0.0089) was significantly associated with higher lnCDRV. No other associations were found. CONCLUSIONS: In pediatric patients taking VPA monotherapy, rs28898617 was associated with a higher normalized VPA plasma concentration. Further studies are warranted to confirm the results.

Effects of UGT1A6 and GABRA1 on Standardized Valproic Acid Plasma Concentrations and Treatment Effect in Children With Epilepsy in China.

BACKGROUND: Valproic acid (VPA) is a widely used antiepileptic drug with acceptable safety and efficacy in treating pediatric patients with various kinds of seizures. However, interindividual variations in plasma concentrations and treatment effects of patients with epilepsy treated with VPA are observed. This study aimed to evaluate the effects of various genetic variations on normalized plasma concentration of VPA (NCVPA) and the treatment response in Chinese children with epilepsy administered with VPA. METHODS: Pediatric patients (3 months to 18 years old) with epilepsy, taking VPA therapy, were enrolled in the study. Important genetic variations of the pharmacokinetic and pharmacodynamic pathways of VPA were evaluated using the MassARRAY system (Sequenom). The associations of genetic variations with NCVPA/drug response and the mean value of NCVPA in responsive and resistant patients were evaluated using SPSS (17.0) and Plink (1.07) software. RESULTS: A total of 111 children with epilepsy (80 responsive and 31 resistant) were enrolled. rs28898617 (UGT1A6, A > G) was associated with an increase in NCVPA (ß = 5.31, 95% confidence interval = 0.78-9.83, P = 0.024); therefore, patients with this variation need a lower dose of VPA. rs2279020 (GABRA1, G > A) was associated with a decreased risk of developing VPA-resistant epilepsy (odds ratio = 0.42, 95% confidence interval = 0.21-0.84, P = 0.014). Similar NCVPA was observed in resistant and responsive patients (P = 0.257). CONCLUSIONS: rs28898617 (UGT1A6, A > G) variation was associated with an increase in NCVPA. rs2279020 (GABRA1, G > A) variation was associated with a decreased risk of developing VPA-resistant epilepsy. Resistant and responsive patients to VPA treatment had a similar mean value of NCVPA. The findings may help clinicians to adjust the dose and predict treatment effect for children with epilepsy receiving VPA treatment.

Risk factors and imaging characteristics of childhood stroke in china.

There are scarce reports of childhood stroke from China. Our objective was to describe the clinical spectrum, risk factors, and imaging characteristics of childhood stroke in China. Using a hospital discharge database, children with stroke who were first admitted from 2002 to 2011 were retrospectively enrolled. We identified 478 first admissions with childhood stroke, including 229 cases of ischemic stroke and 249 hemorrhagic stroke. Boys accounted for more than 60% in all stroke types (62.2% for ischemic stroke, intracerebral hemorrhage for 66.2%). The leading cause was moyamoya for ischemic stroke and arteriovenous malformations for intracerebral hemorrhage. Hemiplegia and headache were the most common presenting features. Internal carotid artery and middle cerebral artery were the most involved arteries according to imaging examination in the ischemic stroke. A total of 8 patients died of intracerebral hemorrhage. The prevalence of hemorrhagic stroke was more than that of ischemic stroke. As Western countries, arteriopathy was the most common cause of childhood stroke.

Mollaret meningitis associated with an intraspinal epidermoid cyst.

Mollaret meningitis, a benign recurrent aseptic disease, is known to be associated with intracranial epidermoid cysts. In this report, we describe a case of Mollaret meningitis caused by an intraspinal epidermoid cyst located at thoracic level 12. The patient's clinical manifestations and cerebrospinal fluid features were similar to those with bacterial meningitis characterized by predominant polymorphonuclear leukocytes. However, Mollaret cells, not bacteria, were identified in the patient's cerebrospinal fluid. The illness ceased after surgical resection of the cyst, and the cyst tissue was pathologically diagnosed as epidermoid. Therefore, an intraspinal epidermoid cyst can be etiologically associated with Mollaret meningitis and should be included in the differential diagnosis of recurrent aseptic meningitis.