Neuromuscular junction disorders: Experimental models and pathophysiological mechanisms.

Located between skeletal muscle fibers and motoneurons, the neuromuscular junction is a chemical synapse essential for the transmission of information from nervous system to skeletal muscle. There are many diseases related to neuromuscular junction dysfunction, including myasthenia gravis, Lambert­Eaton myasthenic syndrome, congenital myasthenic syndromes, amyotrophic lateral sclerosis, and spinal muscular atrophy. The pathophysiological mechanisms of these diseases have been investigated using many animal models. Among them, mouse models are the most commonly used and have provided the majority of current data. Moreover, advances in human induced pluripotent stem cell technology has resulted in new opportunities to study neuromuscular junction disorders from both patients and healthy individuals. Currently, patient­specific induced pluripotent stem cells derived from motor neurons have begun to be studied. These studies will help us achieve a more comprehensive understanding of diseases related to neuromuscular junction disorders. We will describe the research models of neuromuscular junction disorders and provide an overview of recent key findings.

Late-onset multiple acyl-CoA dehydrogenase deficiency with cardiac syncope: A case report.

BACKGROUND: Multiple acyl-CoA dehydrogenase deficiency (MADD) is an uncommon autosomal recessive disorder of mitochondrial fatty acid beta-oxidation. Syncope is a transient loss of consciousness due to acute global cerebral hypoperfusion. Late-onset MADD with syncope has not been reported previously. CASE SUMMARY: We report a 17-year-old girl with exercise intolerance and muscle weakness. She felt palpitation and shortness of breath after short bouts of exercise. She also suffered from a transient loss of consciousness many times. Muscle biopsy showed lipid storage. Genetic mutation analysis indicated a compound heterozygous mutation c.250G > A (p.A84T) and c.872T > G (p.V291G) in the ETFDH gene. The results of Holter electrocardiogram monitoring showed supraventricular tachycardia when the patient experienced a loss of consciousness. After treatment with riboflavin and carnitine, muscle weakness and palpitation symptoms improved rapidly. No loss of consciousness occurred, and the Holter electrocardiogram monitoring was normal. CONCLUSION: Late-onset MADD with supraventricular tachycardia can cause cardiac syncope. Carnitine and riboflavin supplement were beneficial for treating the late-onset MADD with cardiac syncope. Attention should be paid to the prevention of cardiac syncope when diagnosing late-onset MADD.

No association of four candidate genetic variants in MnSOD and SYNIII with Parkinson's disease in two Chinese populations.

BACKGROUND: The manganese superoxide dismutase (MnSOD) gene, which encodes a chief reactive oxygen species (ROS) scavenging enzyme, has been reported to be associated with the risk of developing sporadic Parkinson's disease (PD) in some Asian races and the synapsin III (SYN3) gene with some neuropsychiatric diseases. OBJECTIVE: To explore the associations between the MnSOD and SYN III variations and PD in two Chinese populations from mainland China and Singapore. METHODS: We recruited 2342 subjects including 1200 sporadic PD patients and 1142 healthy controls from two independent Asian countries. Using a case-control methodology, we genotyped the single nucleotide polymorphisms (SNP) in MnSOD (rs4880) and SYN III (rs3788470, rs3827336, rs5998557) to explore the associations with risk of PD. RESULTS: The results showed the genotype distributions and minor allele frequencies (MAF) of MnSOD (rs4880) and SYN III (rs3788470, rs3827336, rs5998557) were not significantly different between PD patients and healthy controls in mainland China and Singapore, as well as in merged populations. CONCLUSIONS: The variations of MnSOD (rs4880) and SYN III (rs3788470, rs3827336, rs5998557) were not major risk factors for PD among Chinese, at least in our study populations.

Genetic association study between STK39 and CCDC62/HIP1R and Parkinson's disease.

BACKGROUND: The first large-scale meta-analysis of published genome-wide association studies (GWAS) in Parkinson's disease (PD) identified 5 new genetic loci (ACMSD, STK39, MCCC1/LAMP3, SYT11, and CCDC62/HIP1R). Very recently, a large-scale replication and heterogeneity study also reported that STK39 and CCDC62/HIP1R increased risk of PD in Asian and Caucasian populations. However, their roles still remain unclear in a Han Chinese population from mainland China. METHODS: We examined genetic associations of STK39 rs2102808 and CCDC62/HIP1R rs12817488 with PD susceptibility in a Han Chinese population of 783 PD patients and 725 controls. We also performed further stratified analyses by the age of onset and accomplished in-depth clinical characteristics analyses between the different genotypes for each locus. RESULTS: No significant differences were observed in the minor allele frequency (MAF) among cases and controls at the two loci (STK39 rs2102808: OR = 1.06, 95% CI = 0.91, 1.23, P = 0.467; CCDC62/HIP1R rs12817488: OR = 0.88, 95% CI = 0.76, 1.01, P = 0.072). Subgroup analyses by the age of onset also showed no significant differences among different subgroups of the two loci. In addition, minor allele carriers cannot be distinguished from non-carriers based on their clinical features at the two loci. CONCLUSIONS: We are unable to demonstrate the association between STK39 and CCDC62/HIP1R and PD susceptibility in a Han Chinese population from mainland China. Additional replication studies in other populations and functional studies are warranted to better validate the role of the two new loci in PD risk.

Association between asymptomatic carotid stenosis and cognitive function: a systematic review.

BACKGROUND: Asymptomatic carotid stenosis (CS), traditionally considered clinically silent, may be an independent risk factor for a cognitive impairment. METHODS: To determine whether an association exists between asymptomatic CS and cognitive function, we systematically reviewed the literature in the Cochrane Library, MEDLINE, EMBASE and the China National Knowledge Infrastructure databases. RESULTS: A total of 8 cross-sectional studies and 2 community-based cohort studies were included, comprising 763 participants in the CS group and 6308 participants in the non-CS group. All but one study supported the association between asymptomatic CS and cognitive impairment. Pooled analysis identified older age (2 studies) and cerebral hypoperfusion (2 studies) as additional factors in patients with asymptomatic CS that may linked to cognitive decline. CONCLUSIONS: These results suggest that rather than being clinically silent, asymptomatic CS may be associated with cognitive impairment, and this should be further investigated in high-quality studies.

SNCA rs356219 variant increases risk of sporadic Parkinson's disease in ethnic Chinese.

Alpha-synuclein gene (SNCA) polymorphisms have been associated with Parkinson's disease (PD). A recently published genome-wide association study (GWAS) meta-analysis from the USA and Europe found a strong association between SNCA rs356219 and PD. Considering the population-specific heterogeneity, we investigated the role of SNCA rs356219 as PD susceptibility in a large Han Chinese population of 685 patients and 569 controls. The SNCA rs356219-G allele was found to increase the risk to develop PD (OR = 1.81, 95% CI: 1.54-2.13, P = 5.71E-13). The meta-analysis revealed that the frequency of AG + GG genotypes higher in PD than in control subjects (OR = 1.85, 95% CI: 1.56-2.19, P = 0.00001) in the Asian population. PD patients with AG + GG genotypes were associated with earlier age at onset compared with those with AA genotype. No such significant association was observed in the clinical presentation for gender, age at onset, and onset symptoms. Our study provides strong support for the susceptibility role of SNCA rs356219 in sporadic PD in a Han Chinese population from mainland China and the meta-analysis also revealed a similar finding in the Asian population.

GSK3ß reduces risk of sporadic Parkinson's disease in ethnic Chinese.

Genetic variability of glycogen synthase kinase-3ß (GSK3ß) may be linked to Parkinson's disease (PD). Its role in ethnic Chinese population is still unclear. We examined the association between GSK3ß variation and PD in a Han Chinese population from mainland China. Using a case-control methodology, we genotyped the single nucleotide polymorphism (SNP) in GSK3ß (rs334558) to investigate the association with risk of PD. A total of 1,280 ethnic Han Chinese study subjects comprising 761 sporadic PD patients and 519 controls were recruited. The T allele of a promoter SNP rs334558 was found to reduce the risk of PD (OR = 0.82, 95% CI: 0.696-0.960, P = 0.014). Patients with CT + TT genotypes have a reduced risk of PD compared to those with CC genotype (OR = 0.61, 95% CI: 0.477-0.776, P = 6.09E-5). In addition, we demonstrated that CT + TT subjects cannot be distinguished from CC subjects based on their clinical features. Our data suggest that rs334558 variant in GSK3ß reduces the risk of PD in a Han Chinese population from mainland China. Further studies of large series of subjects are necessary to fully elucidate the true role of GSK3ß in PD.

Genetic analysis of LRRK2 A419V variant in ethnic Chinese.

Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) are the most common causes of autosomal dominant and sporadic forms of Parkinson's disease (PD). The A419V variant has been suggested to be a potential risk variant but its role among Chinese is unclear. We genotyped LRRK2 A419V variant to investigate the association with risk of PD. A total of 1314 subjects comprising 729 patients with PD and 585 controls were genotyped. Twenty-two (3.0%) patients were heterozygous carriers for the A419V variant, and the frequency was higher compared with controls (0.7%, p = 0.003). The association was seen among the younger age group (early onset PD patients vs. controls: p = 0.0005), but was not significant among the older age group (late onset PD patients vs. controls: p = 0.17). We showed a significant association of LRRK2 A419V variant among early onset PD in the ethnic Han Chinese population but not among late onset PD. Further replication studies in additional Chinese and other Asian cohorts will be important to address its potential pathophysiologic role.

GWAS-linked GAK locus in Parkinson's disease in Han Chinese and meta-analysis.

Genome-wide association studies of Parkinson's disease (PD) have recently identified a new susceptibility locus GAK (PARK17) (rs1564282 variant) in subjects of European ancestry. Its role in other races is still unclear. The potential differences of the clinical characteristics between carriers and non-carriers have not been examined in detail. Using a case-control methodology, we analyzed the GAK rs1564282 variant in an ethnic Han Chinese population and conducted a meta-analysis combining our result and available published data. A total of 1,574 ethnic Han Chinese study subjects comprising 812 sporadic PD patients and 762 control individuals were included. The minor allele frequency was significantly different at SNP rs1564282 between the cases and the controls (OR = 1.59, 95% CI = 1.09, 1.69, P = 0.007) in the overall PD population. Subjects with CT + TT genotypes have an increased risk (OR = 1.34, 95% CI = 1.05, 1.72, P = 0.017) compared to those with CC genotype. A meta-analysis revealed that the frequency of carrier's genotypes was significantly higher in PD than in control subjects (OR = 1.31, 95% CI = 1.19, 1.44, P < 0.00001). The gender, age of onset, Hoehn-Yahr stage and UPDRS scores and clinical features were similar between carriers and non-carriers. In conclusion, we demonstrated that the rs1564282 variant in GAK (PARK17) increases the risk of PD in Han Chinese patients from mainland China and the meta-analysis with European populations revealed a similar finding. However, carriers cannot be distinguished from non-carriers based on their clinical features or motor severity. Functional studies of GAK to unravel its role in the pathophysiologic pathway of PD will be useful.

Association of GWAS loci with PD in China.

Genome-wide association studies (GWAS) have identified numerous single-nucleotide polymorphisms (SNPs) at four loci (SNCA, PARK16, LRRK2, BST1) that can modulate the risk of Parkinson's disease (PD). The strength of these associations has yet to be clarified in Mainland China. Ethnic specific effect is an important consideration in GWAS analysis. Using a case-control methodology, we genotyped multiple SNPs at these four loci to investigate their association with risk of PD in Mainland China. A total of 1,146 study subjects comprising 636 patients with PD and 510 unrelated healthy controls were recruited. The minor alleles at SNPs rs894278, rs1994090, rs2046932, rs4698412, and rs7304279 were found to be significantly higher in cases than in controls, while the minor alleles were found to significantly reduce the risk of developing PD at SNPs rs823128, rs823156, rs6532194, rs1191532, and rs16856139. These associations remained after taking into considerations the effects of age and gender. We showed that multiple SNPs at LRRK2 and SNCA increase risk of PD, while PARK16 SNPs are associated with a lower risk of PD in China. Our study findings will contribute to further research using GWAS-linked data and research on ethnic specific effect of common variants.

Functional parkin promoter polymorphism in Parkinson's disease: new data and meta-analysis.

BACKGROUND: A functional SNP (rs9347683) in the promoter region of the parkin gene had been implicated as a risk factor in older Parkinson's disease (PD) patients. METHODS: Using a case-control methodology, we genotyped the SNP in the promoter region of the parkin gene to investigate their association with risk of PD and conducted a pooled analysis of published papers in the English literature. RESULTS: A total of 1087 study subjects comprising 595 patients with PD and 492 unrelated healthy controls were recruited. The frequency of "GG" genotype in the elderly sub-group (≥ 65 years) was higher in PD compared to controls (OR=1.11) though we did not observe any difference in allele or genotype frequencies between the cases and the controls (P>0.05) in the overall PD population. Those with genotype "GG" were associated with a higher Hoehn-Yahr stage compared with PD patients carrying "GT"+"TT" (P=0.040). A pooled analysis involving more than >3000 subjects revealed that the frequency of genotypes in PD patients did not differ from the controls (OR=0.98, 95% CI: 0.86-1.12). However, in the group ≥ 65 years of age, the "GG" genotype was higher in PD (OR=1.51, 95% CI: 1.06-2.13, P=0.020) among the ethnic Chinese. CONCLUSIONS: While we did not demonstrate a significant association of the parkin promoter polymorphism with PD in our sample, the pooled data suggest that the variant may increase the risk of PD in the more elderly population among the ethnic Chinese, suggesting possible ethnicity-specific effect. Further in vitro and in vivo studies to evaluate this functional parkin variant are warranted.

Multiple LRRK2 variants modulate risk of Parkinson disease: a Chinese multicenter study.

We and others found two polymorphic LRRK2 (leucine-rich repeat kinase 2) variants (rs34778348:G>A; p.G2385R and rs33949390:G>C; p.R1628P) associated with Parkinson disease (PD) among Chinese patients, but the common worldwide rs34637584:G>A; p.G2019S mutation, was absent. Focusing exclusively on Han Chinese, we first sequenced the coding regions in young onset and familial PD patients and identified 59 variants. We then examined these variants in 250 patients and 250 control subjects. Among the 17 polymorphic variants, five demonstrated different frequency in cases versus controls and were considered in a larger sample of 1,363 patients and 1,251 control subjects. The relative risk of an individual with both p.G2385R and p.R1628P is about 1.9, and this is reduced to 1.5-1.6 if the individual also carries rs7133914:G>C; p.R1398H or rs7308720:C>A: p.N551K. The risk of a carrier with p.R1628P is largely negated if the individual also carries p.R1398H or p.N551K. In dopaminergic neuronal lines, p.R1398H had significantly lower kinase activity, whereas p.G2385R and p.R1628P showed higher kinase activity than wild type. We provided the first evidence that multiple LRRK2 variants exert an individual effect and together modulate the risk of PD among Chinese.

[Regional difference of land use/cover change in farming-pasturing zone of Naiman Banner in Inner Mongolia].

Based on the four TM images of Naiman Banner in Inner Mongolia in 1975, 1985, 1995 and 2005, the extent and relative rate of land use change were used as the indices to analyze the regional difference of land use/cover change in the farming-pasturing zone of Naiman Banner, and the indices abundance and importance value were adopted to analyze the spatial distribution features of land use/cover change in the study area. The results showed that from 1975 to 2005, the types of land use/cover became diversified. The annual change rate was high, and the regional difference was significant. In the northern alluvial plain sub-area, woodland area increased rapidly and largely, while sandy land area decreased obviously. The changing speed of the areas of meadow and sandy land was the fastest, while that of residential area was the slowest. The main forms of land conversion were the conversion from sandy land to cropland and woodland. In the middle sandy land sub-area, sandy land had a wide distribution. The changes of other land use types were comparatively small, and the main form of land conversion was the inter-conversion between cropland and sandy land. In southern loess sub-area, cropland was the dominant land use type and had the smallest change, meadow and sandy land changed most quickly, and the conversion from meadow to cropland and woodland was the most important land conversion form. Natural factors determined the principal characteristics of land use structure in each sub-area of the study area, and artificial factors determined the changing trends of each land use type in each sub-area.