HCFC1 variants in the proteolysis domain are associated with X-linked idiopathic partial epilepsy: Exploring the underlying mechanism.

BACKGROUND: HCFC1 encodes transcriptional co-regulator HCF-1, which undergoes an unusual proteolytic maturation at a centrally located proteolysis domain. HCFC1 variants were associated with X-linked cobalamin metabolism disorders and mental retardation-3. This study aimed to explore the role of HCFC1 variants in common epilepsy and the mechanism underlying phenotype heterogeneity. METHODS: Whole-exome sequencing was performed in a cohort of 313 patients with idiopathic partial (focal) epilepsy. Functional studies determined the effects of the variants on the proteolytic maturation of HCF-1, cell proliferation and MMACHC expression. The role of HCFC1 variants in partial epilepsy was validated in another cohort from multiple centers. RESULTS: We identified seven hemizygous HCFC1 variants in 11 cases and confirmed the finding in the validation cohort with additional 13 cases and six more hemizygous variants. All patients showed partial epilepsies with favorable outcome. None of them had cobalamin disorders. Functional studies demonstrated that the variants in the proteolysis domain impaired the maturation by disrupting the cleavage process with loss of inhibition of cell growth but did not affect MMACHC expression that was associated with cobalamin disorder. The degree of functional impairment was correlated with the severity of phenotype. Further analysis demonstrated that variants within the proteolysis domain were associated with common and mild partial epilepsy, whereas those in the kelch domain were associated with cobalamin disorder featured by severe and even fatal epileptic encephalopathy, and those in the basic and acidic domains were associated with mainly intellectual disability. CONCLUSION: HCFC1 is potentially a candidate gene for common partial epilepsy with distinct underlying mechanism of proteolysis dysfunction. The HCF-1 domains played distinct functional roles and were associated with different clinical phenotypes, suggesting a sub-molecular effect. The distinct difference between cobalamin disorders and idiopathic partial epilepsy in phenotype and pathogenic mechanism, implied a clinical significance in early diagnosis and management.

SZT2 variants associated with partial epilepsy or epileptic encephalopathy and the genotype-phenotype correlation.

Background: Recessive SZT2 variants are reported to be associated with developmental and epileptic encephalopathy 18 (DEE-18) and occasionally neurodevelopment abnormalities (NDD) without seizures. This study aims to explore the phenotypic spectrum of SZT2 and the genotype-phenotype correlation. Methods: Trios-based whole-exome sequencing was performed in patients with epilepsy. Previously reported SZT2 mutations were systematically reviewed to analyze the genotype-phenotype correlations. Results: SZT2 variants were identified in six unrelated cases with heterogeneous epilepsy, including one de novo null variant and five pairs of biallelic variants. These variants had no or low frequencies in controls. All missense variants were predicted to alter the hydrogen bonds with surrounding residues and/or protein stability. The three patients with null variants exhibited DEE. The patients with biallelic null mutations presented severe DEE featured by frequent spasms/tonic seizures and diffuse cortical dysplasia/periventricular nodular heterotopia. The three patients with biallelic missense variants presented mild partial epilepsy with favorable outcomes. Analysis of previously reported cases revealed that patients with biallelic null mutations presented significantly higher frequency of refractory seizures and earlier onset age of seizure than those with biallelic non-null mutations or with biallelic mutations containing one null variant. Significance: This study suggested that SZT2 variants were potentially associated with partial epilepsy with favorable outcomes without NDD, expanding the phenotypic spectrum of SZT2. The genotype-phenotype correlation helps in understanding the underlying mechanism of phenotypic variation.

PRRT2 gene mutations associated with infantile convulsions induced by sucking and the genotype-phenotype correlation.

Introduction: PRRT2 is a major causative gene for self-limited familial neonatal-infantile epilepsy, paroxysmal kinesigenic dyskinesia, and paroxysmal kinesigenic dyskinesia with infantile convulsions. Voluntary movement trigger is prominent in adolescence and adulthood, but the triggers are unknown in infants. Methods: A gene panel designed for targeted next-generation sequencing (NGS) was used to screen genetic abnormalities in a cohort of 45 cases with infantile convulsions. The copy number variation was detected by a computational method based on the normalized depth of coverage and validated by a quantitative real-time polymerase chain reaction (RT-qPCR) method. The genotype-phenotype correlation of the PRRT2 mutation gene was analyzed. Results: A de novo heterozygous PRRT2 deletion was identified in a child who had infantile convulsions induced by vigorous sucking. Seizures happened during the change of feeding behavior from breast to formula, which led to hungry and vigorous sucking. Ictal electroencephalograms recorded seizures with focal origination, which provided direct evidence of epileptic seizures in infants with PRRT2 mutations. Seizures stopped soon after the feeding behavior was changed by reducing feeding interval time and extending feeding duration. Data reanalysis on our previously reported cases with PRRT2 mutations showed that six of 18 (33.3%) patients had infantile convulsions or infantile non-convulsion seizures during feeding. The mutations included two truncating mutations (c.579dupA/p.Glu194Argfs*6, and c.649dupC/p.Arg217Profs*8) that were identified in each of the three affected individuals. Conclusions: This study suggests that feeding, especially vigorous sucking, is potentially a trigger and highlights the significance of feeding behavior in preventing seizures in infants with PRRT2 mutations. Identification of PRRT2 haploinsufficiency mutations in the patients with infantile convulsions induced by sucking suggested a potential genotype-phenotype correlation.

HLA Risk Alleles in Aromatic Antiepileptic Drug-Induced Maculopapular Exanthema.

To characterize human leukocyte antigen (HLA) loci as risk factors in aromatic antiepileptic drug-induced maculopapular exanthema (AED-MPE). A case-control study was performed to investigate HLA loci involved in AED-MPE in a southern Han Chinese population. Between January 2007 and June 2019, 267 patients with carbamazepine (CBZ), oxcarbazepine (OXC), or lamotrigine (LTG) associated MPE and 387 matched drug-tolerant controls from six centers were enrolled. HLA-A/B/C/DRB1 genotypes were determined using sequence-based typing. Potential risk alleles were validated by meta-analysis using data from different populations and in silico analysis of protein-drug interactions. HLA-DRB1*04:06 was significantly associated with OXC-MPE (p = 0.002, p c = 0.04). HLA-B*38:02 was associated with CBZ-MPE (p = 0.03). When pooled, HLA-A*24:02, HLA-A*30:01, and HLA-B*35:01 additionally revealed significant association with AED-MPE. Logistic regression analysis showed a multiplicative interaction between HLA-A*24:02 and HLA-B*38:02 in CBZ-MPE. Meta-analysis of data from different populations revealed that HLA-24*:02 and HLA-A*30:01 were associated with AED-MPE (p = 0.02 and p = 0.04, respectively). In silico analysis of protein-drug interaction demonstrated that HLA-A*24:02 and HLA-A*30:01 had higher affinities with the three aromatic AEDs than the risk-free HLA-A allele. HLA-DRB1*04:06 showed relatively specific high affinity with S-monohydroxy derivative of OXC. HLA-DRB1*04:06 is a specific risk allele for OXC-induced MPE in the Southern Han Chinese. HLA-A*24:02, possibly HLA-A*30:01, are common risk factors for AED-MPE. The multiplicative risk potential between HLA-A*24:02 and HLA-B*38:02 suggests that patients with two risk alleles are at greater risk than those with one risk allele. Inclusion of these HLA alleles in pre-treatment screening would help estimating the risk of AED-MPE.

Effect of adjuvant chemotherapy of ginsenoside Rg3 combined with mitomycin C and tegafur in advanced gastric cancer / 中华胃肠外科杂志

<p><b>OBJECTIVE</b>To evaluate the enhancing effects of ginsenoside Rg3 combined with mitomycin C and tegafur (MF) on postoperative chemotherapy in advanced gastric cancer.</p><p><b>METHODS</b>Seventy-one postoperative patients with advanced gastric cancer were randomly divided into two groups, the control group (n=33), which received treatment with only MF (Mitomycin C+Tegafur), and the trial group (n=38), which were treated with ginsenoside Rg3+MF. The serum VEGF levels in the control group and trial group were detected preoperatively and postoperatively, meanwhile, the serum VEGF levels in 30 healthy persons were detected as comparison. The relations between patients survival and serum VEGF levels were analyzed.</p><p><b>RESULTS</b>The levels of serum VEGF in advanced gastric cancer were higher than those in healthy persons [(297.8+/-129.6) pg/ml vs (212.3+/-67.5) pg/ml] (P<0.01), and were correlated with the depth of tumor invasion, lymph node metastasis, tumor size > 4 cm and TNM stage (P<0.05). Fourteen weeks after operation, the levels of serum VEGF in trial group decreased below those of preoperation and approached to normal range, while in the control group, the levels of serum VEGF decreased near those of preoperation only. The median survival of patients in trial group and control group were 40 and 25 months respectively. The survival rate of patients in trial group was significantly higher than that in control group (P=0.047).</p><p><b>CONCLUSION</b>The combined application of ginsenoside Rg3+MF chemotherapy can decrease the concentration of serum VEGF and improve the survival rate in advanced gastric cancer patients.</p>

Comprehensive analysis of 203 cases with abdominal cocoon / 中华胃肠外科杂志

<p><b>OBJECTIVE</b>To explore the clinical characteristics,diagnosis and treatment of abdominal cocoon.</p><p><b>METHODS</b>Clinical data of 203 cases with abdominal cocoon including 7 cases in our hospital and 196 cases reported in Chinese literature from January 1995 to June 2005 were analyzed retrospectively.</p><p><b>RESULTS</b>The male to female ratio was approximately 1.2:1. The mean age at diagnosis was 33 years. The main clinical manifestations included recurrent acute or chronic intestinal obstruction in 147 cases (72.4%), abdominal mass in 53 cases (26.1%). Of the 203 cases, abdominal plain X-ray were performed in 163, B-ultrasound in 85, CT in 68 and barium meal in 32 cases, however, only 6 cases (3.0%) were diagnosed as abdominal cocoon preoperatively. All the cases received operations included partial or total excision of the membrane and enterolysis in 172 cases (84.7%), together with bowel resection in 34 cases (16.7%) and appendectomy in 51 cases (25.1%). Postoperative complications included recurrent obstruction in 55, and death in 11 cases (5.4%).</p><p><b>CONCLUSIONS</b>The preoperative diagnosis of abdominal cocoon is difficult. Operations should be performed on the cases with intestine obstruction. Recurrent adhesive intestinal obstruction is the main postoperative complication.</p>