Genotype-phenotype correlations in RHOBTB2-associated neurodevelopmental disorders

PurposeMissense variants clustering in the BTB domain region of RHOBTB2 cause a developmental and epileptic encephalopathy with early-onset seizures and severe intellectual disability.MethodsBy international collaboration, we assembled individuals with pathogenic RHOBTB2 variants and a variable spectrum of neurodevelopmental disorders. By western blotting, we investigated the consequences of missense variants in vitro.ResultsIn accordance with previous observations, de novo heterozygous missense variants in the BTB domain region led to a severe developmental and epileptic encephalopathy in 16 individuals. Now, we also identified de novo missense variants in the GTPase domain in 6 individuals with apparently more variable neurodevelopmental phenotypes with or without epilepsy. In contrast to variants in the BTB domain region, variants in the GTPase domain do not impair proteasomal degradation of RHOBTB2 in vitro, indicating different functional consequences. Furthermore, we observed biallelic splice-site and truncating variants in 9 families with variable neurodevelopmental phenotypes, indicating that complete loss of RHOBTB2 is pathogenic as well.ConclusionBy identifying genotype-phenotype correlations regarding location and consequences of de novo missense variants in RHOBTB2 and by identifying biallelic truncating variants, we further delineate and expand the molecular and clinical spectrum of RHOBTB2-related phenotypes, including both autosomal dominant and recessive neurodevelopmental disorders.     

An angiographically occult arteriovenous malformation in the medial parietal lobe presenting as seizures of medial temporal lobe origin

We present an unusual case of a patient who was diagnosed with temporal lobe epilepsy and whose seizures were reduced markedly after excision of an angiographically occult arteriovenous malformation (AVM) located in the left medial parietal lobe. A 38-year-old man had complex partial seizures characterized by motionless staring with oroalimentary and behavioral automatisms since the age of 15 years. Magnetic resonance imaging (MRI) demonstrated a small lesion extending from the left posterior cingulate gyrus to the precuneus. There was no MRI evidence of mesial temporal sclerosis. Intracranial EEG recordings showed ictal onset from the left medial parietal lobe propagating to the medial temporal lobes. Clinical signs appeared when these discharges reached the temporal lobes. After excision of the lesion (which was histologically confirmed as an AVM), together with the marginal cortex, seizures were reduced significantly. Careful diagnostic evaluation of lesions such as the this one may reveal an epileptogenic lesion (zone) far from the region where scalp ictal discharges seem to arise. In our case, we hypothesize that false localization was due to propagation of ictal discharges from the parietal focus through the limbic system.     

Focal epileptic seizures ipsilateral to the tumour

Summary The authors report on six cases of cerebral tumours: three astrocytomas (two temporal and one frontal), two meningiomas (one parietal and one frontal), and a metastasis with a temporal location causing sensory-motor epileptic seizures ipsilateral to the lesion. The discussion includes comments on the pathogenesis of these manifestations viewed in the light of experimental and electrophysiological data, and on the hypotheses of the mirror focus, irritation of the supplementary motor and secondary somato-sensory areas, compression of the opposite hemisphere, and possible absence of decussation of the sensory-motor pathways. The false localization suggested by this type of paroxysmal seizures and their rare clinical occurrence is emphasized.     

非线性混合效应模型法估算癫(间)患者苯妥英群体药物动力学参数

目的 应用非线性混合效应模型法(NONMEM),估算癫癇患者苯妥英群体药物动力学参数,考察各因素对最大消除速率常数Vm(mg·d-1)及米氏常数Km(mg·L-1)的影响。方法 回顾性搜集56例门诊及住院癫癇患者服用苯妥英钠日剂量和血药浓度数据96对,并运行SAS程序进行计算。结果 患者的性别、年龄、体重、合并用药等对药物动力学参数均无显著性影响,Vm=(522.40±10.25)mg·d-1(513.14～630.63 mg·d-1),Km=(11.05±9.62)mg·L-1(1.90～34.83 mg·L-1)。血药浓度预测值与实测值相关性良好。结论 用非线性混合效应模型法估算癫癇患者苯妥英群体药物动力学参数方法可靠,值得推广。     

用群体药代动力学预测癫痫儿童丙戊酸钠血药浓度

目的 用群体药代动力(PPK)模型和贝叶斯法预测血药浓度。方法 用癫痫儿童丙戊酸钠PPK模型和USC~*PACK软件中的贝叶斯程序,对100例新癫痫患儿丙戊酸钠的血药浓度进行预测。将预测值与实测值做配对t检验,相关和回归分析,计算平均预测误差、预测误差的百分比、不同预测误差百分比的符合率及其95％可信区间、构成比和评价预测的准确程度。结果 预测值与实测值的相关系数为0.99,P<0.001,线性回归Y_(OBS)=0.99)Y_(PRED),决定系数为0.98,P<0.001;平均预测误差为-0.43μg·mL~(-1),预测误差百分比分别为5％,10％,15％,20％,25％,30％的符合率为62％,74％,82％,85％,89％,93％。结论 PPK模型和贝叶斯法可准确预测丙戊酸钠稳态血药浓度。     

托吡酯预防动物热性惊厥的实验研究

目的:观察托吡酯预防动物热性惊厥发作的疗效与毒副反应。方法:60只对热惊厥敏感的Wistar大鼠,随机分为两组,分别按4或8mg/(k·d)的剂量灌服托吡酯20d后,观察其热性惊厥敏感性改变情况和毒副反应。结果:Wistar大鼠用药后,在热水浴中发生惊厥的时间分别从(247.8±84.9)s、(243.4±99.4)s延长到(353.6±79.3)s、(329.2±78.1)s(t分别为3.07、3.59,P均<0.01);发生惊厥的持续时间分别从(283.0±112.3)s、(298.3±84.0)s缩短到(178.9±84.8)s、(230.3±74.0)s(t分别为3.33、4.18,P均<0.01);热惊厥发生程度也明显减轻,分别从2.9±0.9、2.7±0.7降低到1.8±0.9、1.3±0.9(t分别为4.89、6.65,P均<0.01);热惊厥控制率达95%(57/60,P<0.01);不良反应发生率虽然较高为65.0%(39/60),但表现轻微,而引起动物死亡等严重不良反应发生却只有16.7%(10/60),两者相比差异非常显著(χ2=29.1,P<0.01),而血常规和肝肾功均无异常改变。结论:托吡酯用于预防动物热性惊厥的发生具有剂量较小,疗效高,安全性较好等优点。     

L-精氨酸、L-硝基精氨酸对红藻氨酸诱导大鼠癫痫及其海马结构中iNOS mRNA表达的影响

目的　观察诱导型一氧化氮合酶 (iNOS)在红藻氨酸(KA)癫痫大鼠海马内的表达及L 精氨酸 (L Arg)和L 硝基精氨酸 (L NNA)慢性干预的影响。方法　采用惊厥剂量的KA(1 0mg·kg- 1 )诱导大鼠癫痫发作 ,以NOS抑制剂L NNA(50mg·kg- 1 )和NO前体L Arg(40mg·kg- 1 )进行干预 ,对大鼠的癫痫发作行为及KA后不同时间点的海马内i NOSmRNA ,通过RT PCR观察其表达。结果　KA可使动物发生时间相关性癫痫发作 ,L NNA预处理后使KA诱导的癫痫发作明显加重 ,而L Arg预处理后使KA诱导的癫痫发作减弱。iNOSmRNA在KA处理后 3h开始有微弱的表达 ,且随着时间的延长逐渐增加 ,2 4h达到最高水平 ,2d及3d时未见表达 ,但 7d时又出现高表达 ;经L NNA预处理的动物 ,KA后 1h其海马结构中未出现iNOSmRNA ,但L Arg预处理后再给予KA后 1h ,可见微弱的iNOSmRNA表达。结论　红藻氨酸给药后一定时间 ,癫痫大鼠海马结构中可出现iNOSmRNA表达 ,L Arg慢性干预也有一定影响     

红藻氨酸诱导癫痫发作大鼠海马结构中EAAC-1变化

目的 研究谷氨酸转运蛋白亚型（ＥＡＡＣ－１）在红藻氨酸（ＫＡ）诱导癫痫发作大鼠海马结构中的变化。方法 用红藻氨酸诱导的复杂部分性癫痫模型,将２０只ＳＤ大鼠随机分为３,６,１２,４８ｈ及对照５组,用免疫蛋白印记法（Ｗｅｓｔｅｒｎ ｂｌｏｔ）观察ＥＡＡＣ－１在海马结构上的变化。结果 ＫＡ注射后３ｈ海马ＥＡＡＣ－１开始减少,６ｈ显著减少,１２ｈ后ＥＡＡＣ－１逐渐恢复。结论 ＥＡＡＣ－１表达的调控可能与Ｋ     

Effect of gastrin-releasing peptide on rat hippocampal extracellular GABA levels and seizures in the audiogenic seizure-prone DBA/2 mouse

Gastrin-releasing peptide (GRP), a selective agonist for the BB(2) subtype of bombesin receptor, is reported to depolarise GABAergic interneurons in the stratum oriens layer of the hippocampus. Such an action might lead to increased extracellular levels of GABA in the hippocampus, and result in an anti-convulsant effect with this peptide. We have tested this hypothesis by determining the effect of GRP on extracellular levels of GABA in the ventral hippocampus of the freely moving rat using in vivo microdialysis, and by intracerebroventricular (i.c.v.) administration of GRP to audiogenic seizure-prone DBA/2 mice prior to exposure to the noise of an electric bell. Following local perfusion in the ventral hippocampus by reverse dialysis GRP (10 microM) significantly raised levels of GABA in the recovered dialysates by approximately 40%. In the seizure studies, GRP (30-300 ng) increased the latency to tonic seizure, the number of mice convulsing and reduced the incidence of lethality. In both dialysis and seizure studies, the effects of GRP were blocked by the selective BB(2) receptor antagonist, [D-Phe(6), Leu-NHEt(13)]bombesin (6-13). These experiments provide further functional evidence that activation of the BB(2) receptor may modulate neurotransmission in the hippocampus, and that this action may confer anti-convulsant properties on agonists acting at the BB(2) receptor in the brain.