Mutation screening of the PRRT2 gene for benign epilepsy with centrotemporal spikes in Chinese mainland population.

Proline-rich transmembrane protein 2 gene (PRRT2) mutations are reported to cause common paroxysmal neurological disorders and show a remarkable pleiotropy. Benign epilepsy with centrotemporal spikes (BECTS) is considered to be the most common epilepsy syndrome in childhood. It is placed among the idiopathic localization related epilepsies. Recently, it was reported that a girl with a PRRT2 mutation c.649_650insC developed infantile focal epilepsy with bilateral spikes which resembled the rolandic spikes. Hereby we performed a comprehensive genetic mutation screening of PRRT2 gene in a cohort of 53 sporadic BECTS patients. None of the 53 sporadic BECTS patients and other 250 controls carried mutations including c.649_650insC in PRRT2. Our data indicated that the PRRT2 mutations might most likely not be associated with BECTS in Chinese mainland population.

Increase of the plasma α-synuclein levels in patients with multiple system atrophy.

Multiple system atrophy, a sporadic neurodegenerative disease, is characterized by the presence of high numbers of glial cytoplasmic inclusions mainly formed by α-synuclein protein, which is encoded by the SNCA gene. To date, however, few studies have investigated the plasma α-synuclein levels in patients with multiple system atrophy. We studied plasma α-synuclein concentrations by using an enzyme-linked immunosorbent assay in 74 patients with multiple system atrophy and 90 healthy controls. The plasma α-synuclein levels were significantly elevated in patients who had multiple system atrophy compared with the control group (P = 0.000). In a subgroup of 48 patients who had probable multiple system atrophy, there was a weakly negative correlation between plasma α-synuclein levels and subscores on Unified Multiple System Atrophy Rating Scale item VI (r(s) = -0.307; P = 0.034). Plasma α-synuclein levels were elevated in patients with multiple system atrophy, and these levels may be decreased with the development of disease.

Altered immune pathways in patients of temporal lobe epilepsy with and without hippocampal sclerosis.

Over the past decades, the immune responses have been suspected of participating in the mechanisms for epilepsy. To assess the immune related pathway in temporal lobe epilepsy (TLE), we explored the altered immune pathways in TLE patients with and without hippocampal sclerosis (HS). We analyzed RNA-seq data from 3 TLE-HS and 3 TLE-nonHS patients, including identification of differentially expressed RNA, function pathway enrichment, the protein-protein interaction network and construction of ceRNA regulatory network. We illustrated the immune related landscape of molecules and pathways on human TLE-HS. Also, we identified several differential immune related genes like HSP90AA1 and SOD1 in TLE-HS patients. Further ceRNA regulatory network analysis found SOX2-OT connected to miR-671-5p and upregulated the target gene SPP1 in TLE-HS patients. Also, we identified both SOX2-OT and SPP1 were significantly upregulated in five different databases including TLE-HS patients and animal models. Our findings established the first immune related genes and possible regulatory pathways in TLE-HS patients and animal models, which provided a novel insight into disease pathogenesis in both patients and animal models. The immune related SOX2-OT/miR-671-5p/SPP1 axis may be the potential therapeutic target for TLE-HS.

The single nucleotide polymorphism Rs12817488 is associated with Parkinson's disease in the Chinese population.

A recent meta-analysis of datasets from five of the published Parkinson's disease (PD) genome-wide association studies implicated the single nucleotide polymorphism (SNP) rs12817488 in coiled-coil domain containing 62 (CCDC62)/huntingtin interacting protein 1 related (HIP1R) as a risk factor for PD. We conducted a case-control study to evaluate the possible association between rs12817488 and PD in Chinese people. All patients (515 PD patients and 518 age and sex-matched controls) were successfully genotyped using polymerase chain reaction restriction fragment length polymorphism analysis. We observed that the rs12817488 polymorphism is associated with PD (p=0.003) and that the genotype and allele frequencies showed a difference between late-onset PD patients and male controls (p=0.025 and p=0.007, respectively). However, there was no difference in the early-onset PD patients and controls. We found a difference in the genotype and allele frequencies between the male PD patients and the male controls (p=0.034 and p=0.017, respectively). However, there was no difference in females. Patients with the A allele were susceptible to PD in both dominant (GA+AA versus GG; odds ratio [OR] 1.365, 95% confidence interval [CI] 1.041-1.788) and recessive (AA versus GG+GA; OR 1.606, 95% CI 1.194-2.158) models. Therefore, our findings support the conclusion that the rs12817488 in CCDC62/HIP1R polymorphism may increase the risk of PD in the Chinese Han population.

Genetic diagnosis of two dopa-responsive dystonia families by exome sequencing.

Dopa-responsive dystonia, a rare disorder typically presenting in early childhood with lower limb dystonia and gait abnormality, responds well to levodopa. However, it is often misdiagnosed with the wide spectrum of phenotypes. By exome sequencing, we make a rapid genetic diagnosis for two atypical dopa-responsive dystonia pedigrees. One pedigree, presented with prominent parkinsonism, was misdiagnosed as Parkinson's disease until a known mutation in GCH1 (GTP cyclohydrolase 1) gene (NM_000161.2: c.631_632delAT, p.Met211ValfsX38) was found. The other pedigree was detected with a new compound heterozygous mutation in TH (tyrosine hydroxylase) gene [(NM_000360.3: c.911C>T, p.Ala304Val) and (NM_000360.3: c.1358G>A, p.Arg453His)], whose proband, a pregnant woman, required a rapid and less-biased genetic diagnosis. In conclusion, we demonstrated that exome sequencing could provide a precise and rapid genetic testing in the diagnosis of Mendelian diseases, especially for diseases with wide phenotypes.

Using next-generation sequencing as a genetic diagnostic tool in rare autosomal recessive neurologic Mendelian disorders.

Next-generation sequencing was used to investigate 9 rare Chinese pedigrees with rare autosomal recessive neurologic Mendelian disorders. Five probands with ataxia-telangectasia and 1 proband with chorea-acanthocytosis were analyzed by targeted gene sequencing. Whole-exome sequencing was used to investigate 3 affected individuals with Joubert syndrome, nemaline myopathy, or spastic ataxia Charlevoix-Saguenay type. A list of known and novel candidate variants was identified for each causative gene. All variants were genetically verified by Sanger sequencing or quantitative polymerase chain reaction with the strategy of disease segregation in related pedigrees and healthy controls. The advantages of using next-generation sequencing to diagnose rare autosomal recessive neurologic Mendelian disorders characterized by genetic and phenotypic heterogeneity are demonstrated. A genetic diagnostic strategy combining the use of targeted gene sequencing and whole-exome sequencing with the aid of next-generation sequencing platforms has shown great promise for improving the diagnosis of neurologic Mendelian disorders.