Chitinase-3-like protein 1 may be a potential biomarker in patients with drug-resistant epilepsy.

The mechanisms of the pathogenesis of epilepsy remain unclear. Recent research shows that the inflammatory process occurring in the brain may be a common and critical mechanism of seizures. Chitinase-3-like protein 1 (CHI3L1 or YKL-40) is a newly discovered inflammatory factor. We aimed to evaluate the role of YKL-40 as a biomarker for epilepsy. 124 subjects were classified as control group (n = 23), new-diagnosis epilepsy group (NDE, n = 34), drug responsive epilepsy group (DPE, n = 37), and drug-resistant epilepsy group (DRE, n = 30) YKL-40 was measured by ELISA in serum and cerebrospinal fluid (CSF). The concentrations of serum and CSF YKL-40 and its diagnostic accuracy for epilepsy were analysed. Patients with DRE had higher concentrations of YKL-40 in serum and CSF, while patients with NDE and DPE had increased YKL-40 levels in CSF but not serum in comparison with control. Moreover, serum and CSF YKL-40 provide high diagnostic accuracy for DRE. YKL-40 may play a possible pathogenic role in epilepsy. YKL-40 may represent a potential biomarker of brain inflammation in patients with DRE.

The effect of NR4A1 on APP metabolism and tau phosphorylation.

Alzheimer's disease (AD) is characterized by senile plaques (SP) composed of ß-amyloid protein (Aß) and neurofibrillary tangles (NFTs) composed of intracellular hyperphosphorylated tau. Recently, nuclear receptor subfamily 4 group A member 1 (NR4A1) was implicated in synaptic plasticity, long-term memory formation, suggesting that it may play a role in the pathophysiology of AD. Here, we showed that the expression of NR4A1 was significantly increased in the hippocampus of APP/PS1 transgenic mice. In addition, NR4A1 overexpression in HT22 cells up-regulated APP and BACE1 levels, down-regulated ADAM10 expression, and promoted amyloidogenesis as indicated by decreased α-CTF levels and elevated ß-CTF levels. Furthermore, a raised level of phospho-tau (p-tau, S396) was accompanied by p-GSK3ß (S9) expression reducing, but total tau, p-tau (S262 and T231), CDK5 and ERK remained unchanged in NR4A1-overexpressing cells. Collectively, our results suggest that NR4A1 promotes the amyloidogenic processing of APP by regulating ADAM10 and BACE1 expression in HT22 cells; as well as NR4A1 accelerates tau hyperphosphorylation by GSK3ß signal. Therefore, NR4A1 may play an important role in the pathogenesis of AD.

Patients with neutral lipid storage disease with myopathy (NLSDM) in Southwestern China.

OBJECTIVES: Neutral lipid storage disease with myopathy (NLSDM) is a rare metabolic myopathy occurring owing to mutations in the patatin like phospholipase domain containing 2 (PNPLA2) gene. Till date, less than 50 patients with PNPLA2 mutations have been reported. In this study, we describe the clinical, pathological, and genetic findings, and muscle magnetic resonance imaging (MRI) changes in four Chinese patients with NLSDM. PATIENTS AND METHODS: Peripheral blood smears were stained using Wright's stain. Muscle biopsies, muscle MRI, and sequence analysis of PNPLA2 gene were performed. RESULTS: All patients exhibited slowly progressive myopathy during adulthood. Cardiomyopathy, sensorineural hearing loss, hepatic adipose infiltration, and hypertriglyceridemia were observed in some patients. Jordan's anomaly was detected in the blood smears of all patients. Muscle biopsies revealed the presence of massive lipid droplets and rimmed vacuoles in two patients. MR images of the lower lumbar, pelvis, and lower extremities showed the involvement of posterior compartment muscles. The anterior compartment muscles were found to be less affected. Gene analysis for PNPLA2 revealed an identical homozygous mutation c.757 + 1G > T in all patients. CONCLUSION: Patients with NLSDM display clinical heterogeneities despite sharing the same mutation (c.757 + 1G > T) of the PNPLA2 gene, may suggest a founder effect in the region.

A Missense Mutation in Epsilon-subunit of Acetylcholine Receptor Causing Autosomal Dominant Slow-channel Congenital Myasthenic Syndrome in a Chinese Family.

BACKGROUND: Congenital myasthenic syndromes are a group of rare disorders that are clinically and genetically heterogeneous and caused by mutations in the genes encoding proteins of the neuromuscular junction. Here, we described a Chinese family that presented with phenotypes of classic slow-channel congenital myasthenic syndrome (SCCMS). METHODS: Clinical characteristics and electrophysiological features of three patients from a Chinese family were examined, and next-generation sequencing followed by direct sequencing was carried out. RESULTS: The patients revealed variability in clinical and electrophysiological features. However, weakness, scoliosis, and repetitive-compound muscle action potential were found in all affected members in the family. A heterozygous C>T missense mutation at nucleotide 865 in acetylcholine receptor epsilon-subunit (CHRNE) gene that causes a leucine-to-phenylalanine substitution at position 289 (L289F) was found. CONCLUSIONS: We reported a SCCMS family of Chinese origin. In the family, classical clinical phenotype with phenotypic variability among different members was found. Genetic testing could help diagnose this rare disease.

Increased osteopontin in muscle and serum from patients with idiopathic inflammatory myopathies.

OBJECTIVES: Osteopontin (OPN) is a non-traditional pro-inflammatory cytokine and is involved in muscle regeneration and inflammation. The aim of this study was to investigate the expression of OPN in skeletal muscle and serum of patients with IIMs. METHODS: 45 patients with IIMs (27 with PM and 18 with DM) were included in the study. Patients received initial prednisone therapy (1-1.5 mg/kg/day) without other immunosuppressive agents. Muscle biopsies were taken before start of treatment and serum samples were collected from each patient before and after corticosteroid treatment. The expression of OPN in skeletal muscle was using immunofluorescence staining and western blotting. Serum OPN levels were detected by enzyme-linked immunosorbent assays (ELISA). RESULTS: OPN expression was increased in muscle samples from IIM patients compared to control muscle. The serum level of OPN was significantly higher in IIM patients than in controls. Moreover, the serum concentrations in the DM subgroup were significantly higher compared to the PM groups. Serum OPN levels positively correlated with creatinine kinase (CK), C-reactive protein (CRP) in PM and DM patients, respectively. After corticosteroid treatment, serum OPN levels decreased significantly in steroid responders compared to baseline, but no significant decrease was observed in steroid non-responders. CONCLUSIONS: OPN is increased in patients with DM and PM, both in muscle and serum. OPN may play an important role in the pathogenesis of IIMs. Moreover, serum OPN may be a potential biomarker for this illness, and changes in serum OPN may provide an index of therapeutic efficacy.

Increased levels of HSPA5 in the serum of patients with inflammatory myopathies--preliminary findings.

Endoplasmic reticulum (ER) stress is suggested to play an important role in the pathogenesis of myositis recently. The aim of this study was to investigate the serum concentration of an ER stress-specific chaperone protein HSPA5 in patients with inflammatory myopathies. Forty-five patients (27 with polymyositis (PM) and 18 with dermatomyositis (DM)) were included in the study, and all received prednisone therapy. Serum samples were collected from each patient before and after prednisone treatment. Serum HSPA5 levels were detected by enzyme-linked immunosorbent assays. The serum level of HSPA5 was significantly higher in myositis patients than in controls. In addition, the concentrations in the DM subgroup were significantly higher than in the PM groups. Serum HSPA5 levels were positively correlated with creatine kinase (CK) and C-reactive protein (CRP) in PM patients. In patients with DM, the serum HSPA5 concentrations were also found significantly correlated with CK, but not with CRP. After prednisone treatment, serum HSPA5 levels significantly decreased compared to baseline in steroid responders, but no marked decrease was observed in steroid non-responders. Serum HSPA5 is increased in patients with DM and PM. Increased concentrations of HSPA5 in serum may reflect the enhanced ER stress in muscle tissue. Decrease in serum HSPA5 levels appears in patients with clinical remission; therefore, HSPA5 may be a potential biomarker for inflammatory myopathies.

A novel mutation in GJB1 (c.212T>G) in a Chinese family with X-linked Charcot-Marie-Tooth disease.

Gap junction protein beta 1 (GJB1) gene mutations lead to X-linked Charcot-Marie-Tooth (CMTX) disease. We investigated a Chinese family with CMTX and identified a novel GJB1 point mutation. Clinical and electrophysiological features of the pedigree were examined, and sequence alterations of the coding region of GJB1 that encode connexin32 were determined by direct sequencing. Sequence alignment of the mutation site was performed using Clustal W. Mutation effects were analysed using PolyPhen-2, SIFT and Mutation Taster software. The three-dimensional structures of the mutant and wild-type proteins were predicted by modeling with SWISS MODEL online software. The affected family members displayed typical Charcot-Marie-Tooth phenotypes, but phenotypic heterogeneity was observed. Nerve conduction velocities of all affected patients were slow. Sequencing of GJB1 revealed a heterozygous T>G missense mutation at nucleotide 212 in the proband, the proband's mother and the proband's daughter. The affected male sibling of the proband displayed a hemizygous missense mutation with T>G transition at the identical position on the GJB1 gene. This mutation resulted in an amino acid change from isoleucine to serine that was predicted to lead to tertiary structural alterations that would disrupt the function of the GJB1 protein. A novel point mutation in GJB1 was detected, expanding the spectrum of GJB1 mutations known to be associated with CMTX.