Chinese Sporadic Amyotrophic Lateral Sclerosis Patients Research Articles

No Association between the SORD Gene and Amyotrophic Lateral Sclerosis in a Chinese Cohort.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder. Recently a juvenile ALS patient was reported carrying the c.757delG mutation of the sorbitol dehydrogenase (SORD) gene, which was also a related mutation of Charcot-Marie-Tooth disease (CMT) and distal hereditary motor neuropathy (dHMN). ALS shares pathogenesis and overlapping genes with CMT and dHMN. We used whole-exome sequencing technology to screen the full-length SORD gene in 601 Chinese sporadic ALS patients and 174 controls without a history of neurological diseases. No SORD pathogenic variants were identified in the ALS patients. Our current results did not find an association between SORD and ALS in Chinese patients, and further studies will be required.

Genetic and clinical features of Chinese sporadic amyotrophic lateral sclerosis patients with TARDBP mutations.

ObjectivesTo investigate the genetic and clinical features of Chinese sporadic amyotrophic lateral sclerosis (SALS) patients with TARDBP mutations, we carried out a genetic analysis in a cohort of 391 SALS patients and explored the clinical manifestations of patients with TARDBP variants.Materials and methodsThe coding region of all five coding exons of TARDBP, exons 2–6, were sequenced for mutations in 391 Chinese SALS patients. The clinical features of patients with TARDBP mutations were described and compared with cases in literatures.ResultsTwo missense mutations in TARDBP gene, c.1132A > G (p.N378D) and c.1147A > G (p.I383V), were detected in three cases, showing a low frequency (0.77%, 3/391) of TARDBP missense mutations in Chinese SALS patients. Based on a retrospective analysis of literatures, p.N378D mutation mainly presents a phenotype of early onset, whereas p.I383V mutation presents pure ALS or ALS alongside semantic variant primary progressive aphasia (svPPA), a type of frontotemporal dementia (FTD).ConclusionsOur results demonstrate that TARDBP mutation is a rare cause of Chinese SALS patients and expand the spectrum of phenotype. It is implied that genetic analysis of SALS patients plays a crucial role in uncovering the cause of disease, especially for cases developing early onset or alongside FTD.

GLT8D1 may not be significant in Chinese sporadic amyotrophic lateral sclerosis patients

To detect the mutation frequency of exon 4 of amyotrophic lateral sclerosis (ALS) in a new disease-causing gene, GLT8D1 (NM_018446), in Chinese patients, we used whole-exome sequencing technology to screen the full-length GLT8D1 gene in 539 Chinese sporadic ALS patients and 176 controls without a history of neurological diseases. Then, we sequenced the coding region of exon 4 in the GLT8D1 gene in a cohort consisting of 256 sporadic ALS patients. Our current results did not find an association between GLT8D1 and ALS in Chinese patients, and further studies will be required.

SQSTM1L341V variant that is linked to sporadic ALS exhibits impaired association with MAP1LC3 in cultured cells.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are genetically, pathologically and clinically-related progressive neurodegenerative diseases. Thus far, several SQSTM1 variations have been identified in patients with ALS and FTD. However, it remains unclear how SQSTM1 variations lead to neurodegeneration. To address this issue, we investigated the effects of ectopic expression of SQSTM1 variants, which were originally identified in Japanese and Chinese sporadic ALS patients, on the cellular viability, their intracellular distributions and the autophagic activity in cultured cells. Expression of SQSTM1 variants in PC12 cells exerted no observable effects on viabilities under both normal and oxidative-stressed conditions. Further, although expression of SQSTM1 variants in PC12 cells and Sqstm1-deficient mouse embryonic fibroblasts resulted in the formation of numerous granular SQSTM1-positive structures, called SQSTM1-bodies, their intracellular distributions were indistinguishable from those of wild-type SQSTM1. Nonetheless, quantitative colocalization analysis of SQSTM1-bodies with MAP1LC3 demonstrated that among ALS-linked SQSTM1 variants, L341V variant showed the significantly lower level of colocalization. However, there were no consistent effects on the autophagic activities among the variants examined. These results suggest that although some ALS-linked SQSTM1 variations have a discernible effect on the intracellular distribution of SQSTM1-bodies, the impacts of other variations on the cellular homeostasis are rather limited at least under transiently-expressed conditions.

Early onset but long survival and other prognostic factors in Chinese sporadic amyotrophic lateral sclerosis

ObjectivesTo explore the cause of long survival but early onset and other prognostic factors among Chinese sporadic amyotrophic lateral sclerosis (ALS) patients. MethodsPatients with ALS were recruited and followed up from Jan 2013 to Jan 2017. Phenotype and survival were compared among different age-at-onset groups. Candidate prognostic factors were analyzed by Kaplan-Meier method, Cox regression and Royston Parmar (RP) model dealing with breaches of proportional hazard assumption. ResultsIn the cohort of 531 patients, mean age-at-onset was 53.68 years (SD:10.85) and overall estimated median survival time was 59 months (95% CI: 48.29–69.71). Pairwise comparison showed that patients above 65 years at onset were more frequently bulbar onset (adjusted residual: 3.0), less frequently lumbosacral onset (adjusted residual: −3.0), and had shorter survival compared with other age groups (p = 0.002). Cox and RP model demonstrated independent prognostic variables including age at onset, bulbar onset, diagnostic delay, MRC-score at first diagnosis and region of residence. ConclusionsThis clinic-based study suggested that Chinese sporadic ALS patients had relatively long survival probably due to young age and less bulbar onset cases. Short diagnostic delay, low MRC-score and northern residence were also predicative of short survival. Reallocation of resources is needed to optimize quality care and prolong survival time.

Mutation analysis of KIF5A in Chinese amyotrophic lateral sclerosis patients

Amyotrophic lateral sclerosis (ALS) is an age-related fatal neurodegenerative orphan disorder that is characterized by progressive injury of both the upper and lower motor neurons. Recently, loss-of-function mutations predominately disrupting the C-terminal amino acid sequence of KIF5A via aberrant exon 27 splicing have been reported in European ALS cohorts. However, the contributions of KIF5A mutations in Asian patients with ALS remain unclear. KIF5A sequences, including exons 26 and 27, were analyzed in a large Chinese ALS cohort comprising 33 unrelated familial ALS probands, 645 sporadic ALS (SALS) patients, 15 ALS patients presenting with concomitant frontotemporal dementia, 400 in-house controls, and 12,951 East Asian individuals from the Exome Aggregation Consortium and Genome Aggregation Database databases. As a result, the previously reported canonical splicing site mutation c.2993-1G>A was found in 1 SALS patient, while no mutations were detected in familial ALS case or ALS patients presenting with concomitant frontotemporal dementia. The frequency of KIF5A mutations accounts for 0.16% (1/645) of Chinese SALS patients, implying that it is an uncommon genetic determinant of ALS in Chinese patients.

Screening for possible oligogenic pathogenesis in Chinese sporadic ALS patients

We investigated all coding regions of 17 known amyotrophic lateral sclerosis (ALS)-related genes in 311 sporadic ALS patients who were of Chinese ancestry using next-generation sequencing technology. All nonsynonymous variants identified were confirmed by Sanger sequencing. 29 (9.32%) patients harbored at least one pathogenic or likely pathogenic variants. Nine (2.8%) patients harbored two or three variants which frequency <1% in population databases that may be related to oligogenic pathogenesis. A higher allele frequency was observed in East Asian than in European patients for the majority variants identified in this screening, which may indicate that genetic factors are responsible for the different clinical characteristics between Chinese and European ALS patients. Our study reports the results of extensive genetic screening and is the first to investigate the possible oligogenic pathogenesis in Chinese sporadic ALS patients. These findings are useful for exploring ALS pathogenesis and treatment strategies.

Blood hemoglobin A1c levels and amyotrophic lateral sclerosis survival

BackgroundThere are inconsistences regarding the correlation between diabetes or fasting blood glucose concentrations and the risk and survival of amyotrophic lateral sclerosis (ALS) in the previous studies. Moreover, the association between hemoglobin A1c (HbA1c) levels, which reflect long-term glycemic status, and ALS survival was not examined.MethodsA prospective cohort study including 450 Chinese sporadic ALS patients (254 men and 196 women; mean age: 55.4 y). We identified 223 deaths during average 1.6 years of follow-up. We assessed levels of fasting HbA1c (primary exposure) and glucose (secondary exposure) via ion exchange high-performance liquid chromatography and hexokinase/glucose-6-pgosphate dehydrogenase methods, respectively. Multivariate Cox proportional hazards regression model was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) of ALS mortality across the exposures.ResultsOur results indicated that, higher levels of HbA1c, but not fasting blood glucose concentrations, were significantly associated with higher risks of mortality. The adjusted HR was 1.40 (95% confidence interval (95% CI): 1.02–1.99) for HbA1c of 5.7–6.4%, and 2.06 (95% CI: 1.07–3.96) for HbA1c ≥6.5%, relative to HbA1c <5.7% (P trend =0.01), after adjustment for age, smoking, obesity, disease severity, site of onset, lifestyle, and other potential confounders. The adjusted HR was 1.38 (95% CI: 0.81–2.35, P trend =0.13) for fasting glucose concentrations ≥7.0 mmol/L vs <5.6 mmol/L. We did not observe any significant interactions between HbA1c levels and age, sex, smoking, body mass index, rate of disease progression of ALS, and site of onset (P-interactions >0.05 for all).ConclusionIn this prospective study, we observed that individuals with higher HbA1c levels at the baseline had higher risk of mortality, which is independent of other known risk factors.

MATR3 mutation analysis in a Chinese cohort with sporadic amyotrophic lateral sclerosis

Several recent studies have reported that the MATR3 gene is associated with the risk of amyotrophic lateral sclerosis (ALS). We sequenced the MATR3 gene in 509 unrelated Chinese sporadic ALS patients and 560 control subjects. We identified a novel missense mutation p.Ser610Phe in one patient. We also detected 3 missense variants (p.Ala313Gly, p.Arg147Lys, and p.Gln347Lys) in 3 of the 560 healthy controls. Our results suggest that MATR3 may not be a common genetic factor in Chinese ALS patients.

Large C9orf72 repeat expansions are seen in Chinese patients with sporadic amyotrophic lateral sclerosis

An intronic GGGGCC hexanucleotide repeat expansion in the chromosome 9 open reading frame 72 (C9orf72) gene was considered as the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia in Caucasian populations. Using repeat-primed polymerase chain reaction analysis and Southern blotting methods, we assessed the frequency and size of hexanucleotide repeat expansion in a cohort of 918 sporadic ALS (SALS) patients and 632 control individuals of Han Chinese origin. We identified 8 (0.87%) of the SALS patients and none of control individuals as carriers of C9orf72 expansions with 700–3500 repeats. A comprehensive neuropsychological battery was conducted on 4 expansion-positive ALS patients, where 3 patients were found to have cognitive impairment. All expansion-positive patients were genotyped for the previously reported 20 single-nucleotide polymorphism (SNP) risk haplotypes on chromosome 9p21. Among them, 13 SNP risk haplotypes were shared in all expansion carriers, suggesting a common founder from European ancestry. Further meta-analysis demonstrated that the intermediate expansion size with 24–30 repeats, rare in both patients and controls, were significantly associated with the risk for ALS. To our knowledge, this is the first study to identify a proportion of Chinese SALS patients carrying this pathologic expansion of up to ∼3500 repeats and to completely elaborate the 20-SNP risk haplotypes in Chinese expansion-positive patients, providing indispensable evidence for the origin, geographical range, and population prevalence of the C9orf72-associated ALS.

Association analysis of PON polymorphisms in sporadic ALS in a Chinese population

Single nucleotide polymorphisms (SNPs) of the paraoxonase gene family (ordered PON1, PON2, and PON3) have been associated with the risk of developing sporadic amyotrophic lateral sclerosis (SALS) in Caucasian populations. However, this association has yet to be confirmed in Chinese SALS patients. Nine SNPs across the PON gene cluster (i.e., rs662, rs705381, rs705382, rs854548, rs854560, rs7493, rs11981433, rs757158, and rs10487132) were analyzed in a large cohort consisting of 373 SALS patients and 248 controls from Southwest China. The data from the present study suggest that these SNPs of the PON gene cluster do not contribute to the risk for developing SALS in a Chinese population.

No association of five candidate genetic variants with amyotrophic lateral sclerosis in a Chinese population

Recently, 5 single nucleotide polymorphisms (SNPs), rs2306677 in the inositol 1,4,5-triphosphate receptor 2 gene (ITPR2), rs1541160 in the kinesin-association protein 3 gene (KIFAP3), rs6690993 and rs6700125 in the FLJ10986 gene, and rs10260404 in the dipeptidyl-peptidase 6 gene (DPP6) have been reported to be associated with the risk of developing sporadic amyotrophic lateral sclerosis (SALS) in Caucasian populations. However, this association is not consistent among different studies and yet to be tested in Chinese SALS patients. We examined the above SNPs in a large cohort consisting of 395 SALS patients and 288 controls from Southwest China. Our results suggest that these SNPs are unlikely to be a common cause of SALS in Chinese populations.

Ataxin-2 intermediate-length polyglutamine: a possible risk factor for Chinese patients with amyotrophic lateral sclerosis

Intermediate-length polyglutamine (polyQ) expansions in the ataxin-2 (ATXN2) gene have recently been identified as a risk factor for sporadic amyotrophic lateral sclerosis (SALS). Our study aims to analyze cytosine, adenine, guanine (CAG)n expansions in the ATXN2 gene among Chinese patients with SALS. All patients diagnosed with adult-onset sporadic amyotrophic lateral sclerosis (ALS) were consecutively followed up, and their clinical characteristics were collected. To measure the repeat length of ATXN2 polyQ, fluorescence-polymerase chain reaction products were analyzed on a 3100-Avant Genetic Analyzer Applied Biosystem (Foster City, CA, USA) using the ROC-500 size standard. Three hundred forty-five patients with SALS were studied. The mean age of onset was 51.38 ± 12.45 years. ATXN2 polyQ with a repeat length greater than 27 was found to be weakly associated with amyotrophic lateral sclerosis in our study. There was no significant difference in mean age of onset, gender, and onset site between the group of SALS patients with and without ATXN2 polyQ expansion greater than 27. Our finding provides evidence that the ATXN2 polyQ expansion greater than 27 might be a risk factor for Chinese SALS patients.

TARDBP gene mutations among Chinese patients with sporadic amyotrophic lateral sclerosis

Recently, several TARDBP mutations have been identified in sporadic amyotrophic lateral sclerosis (SALS) patients among different ethnicities. Our study aims to analyze the clinical features and mutations in the TARDBP gene among Chinese patients with SALS. One hundred sixty-five patients were studied. The mean age of onset was 50.8±12.0 years. The mean diagnostic delay was 18.8±17.1 months. A novel missense mutation (p.N378S) and a novel silent change (p.A321A) were detected in 2 male patients, respectively. A new variant of c.1098C>G in exon 6 and 2 reported variants, g.IVS1+85C>T in intron 1 and c.57A>G in exon 2, were found. The frequency of the “G” variant of c.57A>G in exon 2 and the “G” variant of c.1098C>G in exon 6 were significantly lower in the patient group than in the control (p=0.001 and p=0.024, respectively). Our findings provide first evidence that the frequency of TARDBP gene mutations is rare among Chinese SALS patients (0.61%). Several polymorphisms may influence susceptibility to amyotrophic lateral sclerosis.