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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive degeneration of motor neurons, and it demonstrates high clinical heterogeneity and complex genetic architecture. A variation within TRMT2B (c.1356G>T; p.K452N) was identified to be associated with ALS in a family comprising two patients with juvenile ALS (JALS). Two missense variations and one splicing variation were identified in 10 patients with ALS in a cohort with 910 patients with ALS, and three more variants were identified in a public ALS database including 3317 patients with ALS. A decreased number of mitochondria, swollen mitochondria, lower expression of ND1, decreased mitochondrial complex I activities, lower mitochondrial aerobic respiration, and a high level of ROS were observed functionally in patient-originated lymphoblastoid cell lines and TRMT2B interfering HEK293 cells. Further, TRMT2B variations overexpression cells also displayed decreased ND1. In conclusion, a novel JALS-associated gene called TRMT2B was identified, thus broadening the clinical and genetic spectrum of ALS., (© 2023. Higher Education Press.)

Introduction: Recently, chloride channel CLIC-like 1 (CLCC1) was reported to be a novel ALS-related gene. We aimed to screen CLCC1 variants in our ALS cohort and further explore the genotype-phenotype correlation of CLCC1-related ALS., Methods: We screened rare damaging variants in CLCC1 from our cohorts of 1005 ALS patients and 1224 healthy controls with whole-exome sequencing in Central South China. Fisher's exact test was conducted for association analysis at the entire gene level and single variant level., Results: In total, four heterozygous missense variants in CLCC1 were identified from four unrelated sporadic ALS patients and predicted to be putative pathogenic by in silico tools and protein model prediction, accounting for 0.40% of all patients (4/1005). The four variants were c.A275C (p.Q92P), c.G1139A (p.R380K), c.C1244T (p.T415M), and c.G1328A (p.R443Q), respectively, which had not been reported in ALS patients previously. Three of four variants were located in exon 10. Patients harboring CLCC1 variants seemed to share a group of similar clinical features, including earlier age at onset, rapid progression, spinal onset, and vulnerable cognitive status. Statistically, we did not find CLCC1 to be associated with the risk of ALS at the entire gene level or single variant level., Conclusion: Our findings further expanded the genetic and clinical spectrum of CLCC1-related ALS and provided more genetic evidence for anion channel involvement in the pathogenesis of ALS, but further investigations are needed to verify our findings., (© 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder. An increasing number of researchers have found extra motor features in ALS, which are also called ALS-plus syndromes. Besides, a great majority of ALS patients also have cognitive impairment. However, clinical surveys of the frequency and genetic background of ALS-plus syndromes are rare, especially in China., Methods: We investigated a large cohort of 1015 patients with ALS, classifying them into six groups according to different extramotor symptoms and documenting their clinical manifestations. Meanwhile, based on their cognitive function, we divided these patients into two groups and compared demographic characteristics. Genetic screening for rare damage variants (RDVs) was also performed on 847 patients., Results: As a result, 16.75% of patients were identified with ALS-plus syndrome, and 49.5% of patients suffered cognitive impairment. ALS-plus group had lower ALSFRS-R scores, longer diagnostic delay time, and longer survival times, compared to ALS pure group. RDVs occurred less frequently in ALS-plus patients than in ALS-pure patients (P = 0.042) but showed no difference between ALS-cognitive impairment patients and ALS-cognitive normal patients. Besides, ALS-cognitive impairment group tends to harbour more ALS-plus symptoms than ALS-cognitive normal group (P = 0.001)., Conclusion: In summary, ALS-plus patients in China are not rare and show multiple differences from ALS-pure patients in clinical and genetic features. Besides, ALS-cognitive impairment group tends to harbour more ALS-plus syndrome than ALS-cognitive normal group. Our observations correspond with the theory that ALS involves several diseases with different mechanisms and provide clinical validation., (© 2023. Fondazione Società Italiana di Neurologia.)

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neuromuscular disease. Recently, several gain-of-function mutations in SPTLC1 were associated with juvenile ALS. SPTLC1 encodes for a subunit of the serine-palmitoyltransferase (SPT) - the rate-limiting enzyme in the de novo synthesis of sphingolipids (SL). SPT activity, and thus SL de novo synthesis, is tightly controlled by a homeostatic feedback mechanism mediated by ORMDL proteins. Here we report a novel SPTLC1p.L38R mutation in a young Chinese girl with a signature of juvenile ALS. The patient presented with muscular weakness and atrophy, tongue tremor and fasciculation, breathing problems and positive pyramidal signs. All SPTLC1-ALS mutations including the SPTLC1 p.L38R are located within a single membrane-spanning domain of the protein and impede the interaction with the regulatory ORMDL subunit of SPT. Pertinent to the altered homeostatic control, lipid analysis showed overall increased SL levels in the patient plasma. An increased SPT activity and SL de novo synthesis was confirmed in p.L38R expressing HEK293 cells. Particularily dihydro-sphingolipids (dhSL) were signficantly increased in patient plasma and p.L38R mutant expressing cells. Increased dhSL formation has been previously linked to neurotoxicity and may be involved in the pathomechanism of SPTLC1-ALS mutations., Competing Interests: Declaration of competing interest The authors report no competing interests., (Copyright © 2023. Published by Elsevier B.V.)

Aims: To study the brain metabolic signature in Chinese amyotrophic lateral sclerosis (ALS) patients and compare the difference in brain metabolic patterns between ALS with and without genetic variants., Methods: We included 146 patients with ALS and 128 healthy controls (HCs). All patients with ALS underwent genetic testing to screen for ALS related genetic variants and were then divided into genetic (n = 22) and nongenetic ALS (n = 93) subgroups. All participants underwent brain 18 F-FDG-PET scans. Group comparisons were performed using the two-sample t-test model of SPM12., Results: We identified a large of hypometabolic clusters in ALS patients as compared with HCs, especially in the bilateral basal ganglia, midbrain, and cerebellum. Moreover, hypometabolism in the bilateral temporal lobe, precentral gyrus and hypermetabolism in the left anterior cingulate, occipital lobe, and bilateral frontal lobe were also found in ALS patients as compared with HCs. Compared with nongenetic ALS patients, genetic ALS patients showed hypometabolism in the right postcentral gyrus, precuneus, and middle occipital gyrus. The incidence of sensory disturbance in patients with genetic ALS was higher than that in patients with nongenetic ALS (5 of 22 [22.72%] vs. 7 of 93 [7.52%], p = 0.036)., Conclusions: Our investigation provided unprecedented evidence of relative hypometabolism in the midbrain and cerebellum in ALS patients. Genetic ALS patients showed a specific signature of brain metabolism and a higher incidence of sensory disturbance, indicating that genetic factors may be an underlying cause affecting the brain metabolism and increasing the risk of sensory disturbance in ALS., (© 2023 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Background: Amyotrophic lateral sclerosis (ALS) is a devastating progressive neurodegenerative disease that affects neurons in the central nervous system and the spinal cord. As in many other neurodegenerative disorders, the genetic risk factors and pathogenesis of ALS involve dysregulation of cytoskeleton and neuronal transport. Notably, sensory and motor neuron diseases such as hereditary sensory and autonomic neuropathy type 2 (HSAN2) and spastic paraplegia 30 (SPG30) share several causative genes with ALS, as well as having common clinical phenotypes. KIF1A encodes a kinesin 3 motor that transports presynaptic vesicle precursors (SVPs) and dense core vesicles and has been reported as a causative gene for HSAN2 and SPG30., Methods: Here, we analyzed whole-exome sequencing data from 941 patients with ALS to investigate the genetic association of KIF1A with ALS., Results: We identified rare damage variants (RDVs) in the KIF1A gene associated with ALS and delineated the clinical characteristics of ALS patients with KIF1A RDVs. Clinically, these patients tended to exhibit sensory disturbance. Interestingly, the majority of these variants are located at the C-terminal cargo-binding region of the KIF1A protein. Functional examination revealed that the ALS-associated KIF1A variants located in the C-terminal region preferentially enhanced the binding of SVPs containing RAB3A, VAMP2, and synaptophysin. Expression of several disease-related KIF1A mutants in cultured mouse cortical neurons led to enhanced colocalization of RAB3A or VAMP2 with the KIF1A motor., Conclusions: Our study highlighted the importance of KIF1A motor-mediated transport in the pathogenesis of ALS, indicating KIF1A as an important player in the oligogenic scenario of ALS., (© 2022. The Author(s).)

Objectives: CYLD was a novel causative gene for frontotemporal dementia (FTD) and amyotrophic lateral sclerosis. Given the clinical and pathological overlap of FTD and Alzheimer's disease (AD), it is necessary to screen CYLD in AD patients and FTD patients in the Chinese population., Methods: In our study, using a targeted sequencing panel, we sequenced the CYLD gene in a large cohort of 2485 participants in the Chinese population, including 1008 AD patients, 105 FTD patients, and 1372 controls., Results: In the present study, the average onset age of AD and FTD patients was 66.84 ± 30.42 years old and 60 ± 10.00 years old, respectively. Our study reported three novel CYLD variants: p.Phe288Leu (patient No. 1, AD), p.Tyr485Phe (patients No. 6-9, all AD) and p.Thr951Ala (patient No. 10, AD), plus a previously reported variant: p.Arg397Ser (patient No. 2-5, AD and No. 11, FTD). These variants were absent in our in-house controls and predicted to be deleterious according to the MutationTaster. The variant carriers were composed of 10 AD patients and one FTD patient, and the average onset age was 61.2 ± 10.9 years. The frequency of CYLD variants in AD was similar to that in FTD, which was 0.99% (10/1008) and 0.95% (1/105), respectively., Interpretation: Our finding extended the genotype and phenotype of the CYLD gene and demonstrated that CYLD rare damaging variants may be implicated in AD and FTD pathogenesis., (© 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background and Purpose: Synaptic loss is well established as the major correlate of characteristic and consistent pathology in amyotrophic lateral sclerosis (ALS). We aimed to assess the possible discriminant diagnostic value of 18 F-SynVesT-1 positron emission tomography (PET) as a marker of ALS pathology and investigate whether specific synaptic density signatures are present in ALS with different subtypes., Methods: Twenty-one patients with ALS and 25 healthy controls (HCs) were recruited. All participants underwent 18 F-SynVesT-1-PET. Synaptic density between ALS and HCs and between different ALS subgroups were compared. Correlation between synaptic density and clinical features in ALS was also analyzed., Results: Low uptake distribution was found in the group comprising 21 ALS patients as compared with HCs in the right temporal lobe and the bilateral inferior frontal gyrus, anterior cingulate, and hippocampus-insula region. We also found low uptake in the bilateral superior temporal gyrus, hippocampus-insula, anterior cingulate, and left inferior frontal gyrus in ALS patients with cognitive impairment compared to HCs. Furthermore, compared to spinal onset ALS, bulbar onset ALS showed low uptake in the bilateral cingulate gyrus and high uptake in the bilateral superior temporal gyrus and left occipital lobe. No significant result was found in correlation analysis., Conclusions: This approach may provide a direct measure of synaptic density, and it therefore might represent a potentially useful biomarker for ALS diagnosis, as well as for estimating the cognitive decline and site of onset in ALS. 18 F-SynVesT-1-PET is presently not justified as a routine investigation to detect evidence of brain dysfunction leading to progression in ALS., (© 2022 European Academy of Neurology.)

Background: Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disorder. Mitochondrial dysfunction is involved in the complex pathophysiology of ALS; however, the role of mitochondrial DNA (mtDNA) variants in ALS is poorly understood. We aimed to elucidate the role of mtDNA variants in the pathogenesis of ALS., Methods: The mitochondrial haplogroups of 585 ALS patients and 371 healthy controls were determined; 38 ALS patients and 42 controls underwent long-range polymerase chain reaction combined with next-generation sequencing technology to analyze whole mitochondrial genome variants., Results: A higher percentage of variants accumulated in ALS patients than in controls. Analysis of coding region variations that were further stratified by mtDNA genes revealed that nonsynonymous variants were more vulnerable in ALS patients than in controls, particularly in the ND4L, ND5, and ATP8 genes. Moreover, pathogenic nonsynonymous variants tended to over-represent in ALS patients. Unsurprisingly, nonsynonymous variants were not related to the phenotype. Haplogroup analysis did not found evidence of association between haplogroups with the risk of ALS, however, patients belonging to haplogroup Y and M7c were prone to develop later onset of ALS., Conclusions: This is the first study to profile mtDNA variants in ALS patients from mainland China. Our results suggest that an increase in the number of nonsynonymous variants is linked to the pathogenesis of ALS. Moreover, haplogroup Y and M7c may modulate the clinical expression of ALS. Our findings provide independent, albeit limited, evidence for the role of mtDNA in the pathogenesis of ALS., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

To analyze the mutational spectrum of known ALS causative genes in China ALS patients. We comprehensively analyzed 51 ALS causative genes by combining different sequencing technologies in 753 unrelated ALS patients from Central South China. The mean age at onset (AAO) was 53.7±11.4 years. The AAO was earlier in the autosomal dominant (AD) ALS patients than in the sporadic ALS (sALS) patients. Bulbar onset was more frequent in females than in males. SOD1 was the most frequently mutated gene in the AD-ALS and the sALS patients, followed by the ATXN2 and FUS genes in the AD-ALS patients and the NEK1 and CACNA1H genes in the sALS patients. Patients with RDVs in the SOD1 or FUS genes had an earlier AAO than the mean AAO of all the patients, while the patients with RDVs in the NEK1 gene showed later onset. SOD1 gene was the most commonly mutated gene in ALS patients in China, followed by ATXN2 and NEK1. The phenotype might be determined synergistically by sex and genetic variants., (Copyright © 2021. Published by Elsevier Inc.)

GGGGCC repeats in a non-coding region of the C9orf72 gene have been identified as a major genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. We previously showed that the GGGGCC expanded repeats alone were sufficient to cause neurodegeneration in Drosophila. Recent evidence indicates that GGGGCC expanded repeats can modify various gene transcriptomes. To determine the role of these genes in GGGGCC-mediated neurotoxicity, we screened an established Drosophila model expressing GGGGCC expanded repeats in this study. Our results showed that knockdown of the DNA topoisomerase II (Top2) gene can specifically modulate GGGGCC-associated neurodegeneration of the eye. Furthermore, chemical inhibition of Top2 or siRNA-induced Top2 downregulation could alleviate the GGGGCC-mediated neurotoxicity in Drosophila assessed by eye neurodegeneration and locomotion impairment. By contrast, upregulated Top2 levels were detected in Drosophila strains, and moreover, TOP2A level was also upregulated in Neuro-2a cells expressing GGGGCC expanded repeats, as well as in the brains of Sod1G93A model mice. This indicated that elevated levels of TOP2A may be involved in a pathway common to the pathophysiology of distinct ALS forms. Moreover, through RNA-sequencing, a total of 67 genes, involved in the pathways of intracellular signaling cascades, peripheral nervous system development, and others, were identified as potential targets of TOP2A to modulate GGGGCC-mediated neurodegeneration., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Recent studies have suggested that rare variants in MFSD8 contribute to risk for frontotemporal dementia (FTD). Considering the common underlying pathogenesis and the shared genetic risk between amyotrophic lateral sclerosis (ALS) and FTD, we screened the coding region of MFSD8 in 551 unrelated patients with ALS (510 unrelated sporadic ALS and 41 familial ALS probands) from mainland China by whole-exome sequencing to assess its mutation frequency in patients with ALS and evaluate its association. Two rare deleterious variants, c.343G>A (p. V115M) and c.695T>C (p.L232P), were identified in this study. The variant c.695T>C (p.L232P) has not been previously reported and the carrier of this variant exhibits a relatively younger age of disease onset. Our studies provide some independent evidence showing that the rare variant p.L232P in MFSD8 might be a candidate risk factor for ALS. However, the relatively small sample size and the lack of patient-derived cells limit the power of the genetic exploration of this study, further robust multicenter studies with larger sizes and biological experiments with patient-derived cells are needed to elucidate the pathogenesis of the rare variant in MFSD8 in ALS., (© 2020 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Low-density lipoprotein receptor-related protein 10 (LRP10) is associated with a series of neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease which share genetic risk factors and pathophysiological processes with amyotrophic lateral sclerosis (ALS). To investigate whether LRP10 variants could cause a predisposition to ALS, we screened rare, pathogenic LRP10 variants among a cohort of 584 patients with ALS from mainland China and performed burden analysis using data from a large external database. A total of 7 rare, pathogenic variants in LRP10, of which one (c.1182A>T, p.R394S) was novel, were identified in 11 unrelated patients. Burden analysis revealed significant associations between ALS and LRP10 at both the gene and single-variant levels (c.1721G>A, p.R574Q; c.1182A>T, p.R394S; and c.1681C>T, p.R561C). Interestingly, patients with sporadic ALS carrying variant c.1721G>A tended to have a bulbar onset, increased phenotype severity, and a worse prognosis. Our findings first provide independent evidence that rare, pathogenic LRP10 variants may be risk factors for ALS and delineate a special phenotype in patients with sporadic ALS carrying variant c.1721G>A., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: To determine whether the GGC repeats in the NOTCH2NLC gene contribute to amyotrophic lateral sclerosis (ALS)., Methods: In this study, 545 patients with ALS and 1,305 healthy controls from mainland China were recruited. Several pathogenic mutations in known ALS-causative genes (including C9ORF72 and ATXN2 ) and polynucleotide repeat expansions in NOP56 and AR genes were excluded. Repeat-primed PCR and GC-rich PCR were performed to determine the GGC repeat size in NOTCH2NLC . Systematic and targeted clinical evaluations and investigations, including skin biopsy and dynamic electrophysiologic studies, were conducted in the genetically affected patients., Results: GGC repeat expansion was observed in 4 patients (numbers of repeats 44, 54, 96, and 143), accounting for ≈0.73% (4 of 545) of all patients with ALS. A comparison with 1,305 healthy controls revealed that GGC repeat expansion in NOTCH2NLC was associated with ALS (Fisher exact test, 4 of 545 vs 0 of 1,305, p = 0.007). Compared to patients with the neuronal intranuclear inclusion disease (NIID) muscle weakness-dominant subtype, patients with ALS phenotype carrying the abnormal repeat expansion tended to have a severe phenotype and rapid deterioration., Conclusion: Our results suggest that ALS is a specific phenotype of NIID or that GGC expansion in NOTCH2NLC is a factor that modifies ALS. These findings may help clarify the pathogenic mechanism of ALS and may expand the known clinical spectrum of NIID., (© 2020 American Academy of Neurology.)

Variants in exon 4 of gene encoding GLT8D1 (glycosyltransferase 8 domain containing 1) gene have recently been suggested as a novel cause of amyotrophic lateral sclerosis (ALS). In addition, there is a synergism between GLT8D1 and ARPP21 (cAMP Regulated Phosphoprotein 21) variants for ALS. However, this observation has not been validated in other ALS cohorts. In this study, we analyzed the rare pathogenic variants in GLT8D1 and ARPP21 genes in a cohort of 512 ALS patients and 3210 healthy controls from mainland China. A total of 25 rare variants in ARPP21 were identified in the patients and controls, but we did not find rare variants in exon 4 of GLT8D1 in the patients. By using Fisher's exact test, we did not find significant association between ALS and GLT8D1 or ARPP21. Therefore, GLT8D1 and ARPP21 are not likely the causative genes for ALS in mainland China., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Recently, the coiled‑coil‑helix‑coiled‑coil‑helix domain 2 (CHCHD2) gene was identified as a possible causative gene for Parkinson's disease (PD). Three other neurodegenerative diseases, Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), share significant overlaps with PD in clinical phenotypes, pathological features and genetic heredities, and it is still unclear whether CHCHD2 variants could explain these three diseases. The present study screened all exons of the CHCHD2 gene in a total of 780 patients (511 AD, 181 ALS and 88 FTD) and 500 healthy controls from the Chinese Han population. Two missense variants, 5C>T (Pro2Leu) and 238A>G (Ile80Val), were identified in five unrelated patients with AD while no mutations were observed in patients with ALS or FTD. These mutations have been reported as low‑frequency variants in the ExAC database with frequencies of 0.0075 and 0.000025. Pro2 Leu, however, was also detected in controls and was confirmed to have no significant association with the risk for AD; Ile80Val was not detected in any normal controls, suggesting that the CHCHD2 gene may be associated with AD in the Chinese Han population.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons in the brain and spinal cord. Frontotemporal dementia (FTD) is a group of dementia syndromes characterized by the progressive deterioration of behaviors, executive dysfunction, and verbal impairment. Increasing evidence indicates that these 2 diseases share a common genetic etiology and pathophysiological mechanism. Recently, rare mutations in the low-complexity domain of the RNA-binding protein T-cell-restricted intracellular antigen-1 (TIA1) gene were identified in Caucasian ALS and ALS-FTD patients. However, no comprehensive mutation analysis of the TIA1 gene has been performed in Chinese patients with ALS and FTD. In this study, we screened the low-complexity domain of TIA1 in a cohort of 241 ALS and 51 FTD patients in mainland China. As a result, 2 novel missense mutations (p.P352L and p.I300T) were identified in 2 sporadic patients with ALS, while no mutation was found in FTD cases. To the best of our knowledge, this report presented the first mutation analysis of the TIA1 gene in patients with ALS and FTD in Chinese population. Our findings broaden the known mutational spectrum in patients with ALS and further confirm TIA1 as a novel causative gene of ALS., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: Mutations of the cyclin F (CCNF) gene were recently identified to be associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in Western and Japanese populations. The rare protein-altering variants frequency is 0.6 to 3.3% in ALS and FTD from these diverse geographic populations while no systematic analysis of CCNF variants were conducted in the Chinese population., Methods: We screened all exons of CCNF in a cohort of 269 cases (including 181 ALS and 88 FTD) from Mainland China using Sanger sequencing., Results: A rare heterozygous variant (c.481G > A, p.G161R) was detected in a sporadic ALS case with a frequency of 0.6%, while no mutation was identified in patients with FTD. The same variant was also found in a sporadic ALS patient from America., Conclusions: Our result indicates that the mutation of CCNF is rare in patients with ALS and FTD from Mainland China.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting motor neurons of the brain, brainstem and spinal cord. To date, mutations in more than 30 genes have been linked to the pathogenesis of ALS. Among them, SOD1, FUS and TARDBP are ranked as the three most common genes associated with ALS. However, no mutation analysis has been reported in central-southern China. In this study, we sequenced SOD1, FUS and TARDBP in a central-southern Chinese cohort of 173 patients with ALS (15 familial ALS and 158 sporadic ALS) to detect mutations. As a result, five missense mutations in SOD1, namely, p.D101N, p.D101G, p.C111Y, p.N86S and p.V87A, were identified in three unrelated familial probands and three sporadic cases; two mutations in FUS were found in two unrelated familial probands, including an insertion mutation (p.P525_Y526insY) and a missense mutation (p.R521H); no variants of TARDBP were observed in patients. Therefore, SOD1 mutations were present in 20.0% of familial ALS patients and 1.9% of sporadic ALS patients, while FUS mutations were responsible for 13.3% of familial ALS cases, and TARDBP mutations were rare in either familial or sporadic ALS cases. This study broadens the known mutational spectrum in patients with ALS and further demonstrates the necessity for genetic screening in ALS patients from central-southern China.

The GGGGCC repeat expansion in the C9orf72 gene was recently identified as a major cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in white populations. To estimate the frequency of hexanucleotide repeats in patients with ALS and FTD from mainland China, we screened for C9orf72 in a cohort of 128 patients and 150 control subjects using the repeat-primed polymerase chain reaction method. We observed pathogenic repeat expansions in a family with ALS-FTD and in a patient with sporadic FTD. In the family with ALS-FTD, the proband and the 2 asymptomatic siblings exhibited C9orf72 repeat expansions, and the clinical feature of the proband was characterized by pure motor syndrome with no cognitive impairment. The patient with sporadic FTD presented primarily with deteriorating behavior and mental status. Genotype analysis revealed that the proband shared the previously reported 20-single nucleotide polymorphism risk haplotype, whereas the patient with sporadic FTD carried all single nucleotide polymorphisms except rs2814707-A. To our knowledge, this study is the first to report 2 C9orf72 mutation patients in mainland China, and they shared the similar risk haplotype identified in white populations, suggesting that ALS and FTD associated with C9orf72 mutation was probably derived from a single founder., (Copyright © 2014 Elsevier Inc. All rights reserved.)

To identify susceptibility genes for amyotrophic lateral sclerosis (ALS), we conducted a genome-wide association study (GWAS) in 506 individuals with sporadic ALS and 1,859 controls of Han Chinese ancestry. Ninety top SNPs suggested by the current GWAS and 6 SNPs identified by previous GWAS were analyzed in an independent cohort of 706 individuals with ALS and 1,777 controls of Han Chinese ancestry. We discovered two new susceptibility loci for ALS at 1q32 (CAMK1G, rs6703183, Pcombined = 2.92 × 10(-8), odds ratio (OR) = 1.31) and 22p11 (CABIN1 and SUSD2, rs8141797, Pcombined = 2.35 × 10(-9), OR = 1.52). These two loci explain 12.48% of the overall variance in disease risk in the Han Chinese population. We found no association evidence for the previously reported loci in the Han Chinese population, suggesting genetic heterogeneity of disease susceptibility for ALS between ancestry groups. Our study identifies two new susceptibility loci and suggests new pathogenic mechanisms of ALS.

Background and purpose: Synaptic loss is well established as the major correlate of characteristic and consistent pathology in amyotrophic lateral sclerosis (ALS). We aimed to assess the possible discriminant diagnostic value of 18F‐SynVesT‐1 positron emission tomography (PET) as a marker of ALS pathology and investigate whether specific synaptic density signatures are present in ALS with different subtypes. Methods: Twenty‐one patients with ALS and 25 healthy controls (HCs) were recruited. All participants underwent 18F‐SynVesT‐1‐PET. Synaptic density between ALS and HCs and between different ALS subgroups were compared. Correlation between synaptic density and clinical features in ALS was also analyzed. Results: Low uptake distribution was found in the group comprising 21 ALS patients as compared with HCs in the right temporal lobe and the bilateral inferior frontal gyrus, anterior cingulate, and hippocampus–insula region. We also found low uptake in the bilateral superior temporal gyrus, hippocampus–insula, anterior cingulate, and left inferior frontal gyrus in ALS patients with cognitive impairment compared to HCs. Furthermore, compared to spinal onset ALS, bulbar onset ALS showed low uptake in the bilateral cingulate gyrus and high uptake in the bilateral superior temporal gyrus and left occipital lobe. No significant result was found in correlation analysis. Conclusions: This approach may provide a direct measure of synaptic density, and it therefore might represent a potentially useful biomarker for ALS diagnosis, as well as for estimating the cognitive decline and site of onset in ALS. 18F‐SynVesT‐1‐PET is presently not justified as a routine investigation to detect evidence of brain dysfunction leading to progression in ALS. [ABSTRACT FROM AUTHOR]

Background: Repeat expansions, including those in C9orf72 and ATXN2 , have been implicated in amyotrophic lateral sclerosis (ALS). However, there have been few studies on the association of AR and NOP56 repeat expansion with ALS, especially in China. Accordingly, we aimed to evaluate the frequency of C9orf72 and ATXN2 repeat mutations and investigate whether NOP56 and AR repeat expansion are risk factors for ALS. Methods: In this study, 736 ALS patients and several hundred healthy controls were recruited. Polymerase chain reaction (PCR) and repeat-primed PCR (RP-PCR) were performed to determine the repeat lengths in C9orf72, ATXN2, AR , and NOP56. Results: GGGGCC repeats in C9orf72 were observed in six ALS patients (0.8%, 6/736) but not in any of the controls (0/365). The patients with pathogenic GGGGCC repeats showed shorter median survival times than those with a normal genotype (p = 0.006). Regarding ATXN2 CAG repeats, we identified that intermediate repeat lengths (29–34 copies) were associated with ALS (p = 0.033), and there was no difference in clinical characteristics between the groups with and without intermediate repeats (p > 0.05). Meanwhile, we observed that there was no association between the repeat size in AR and NOP56 and ALS (p > 0.05). Conclusions: Our results demonstrated that pathogenetic repeats in C9orf72 are rare in China, while intermediate CAG repeats in ATXN2 are more frequent but have no effect on disease phenotypes; the repeat size in AR and NOP56 may not be a risk factor for ALS. [ABSTRACT FROM AUTHOR]

Accumulating evidence has revealed that immunity plays an important role in amyotrophic lateral sclerosis (ALS) progression. However, the results regarding the serum levels of immunoglobulin and complement are inconsistent in patients with ALS. Although immune dysfunctions have also been reported in patients with other neurodegenerative diseases, few studies have explored whether immune dysfunction in ALS is similar to that in other neurodegenerative diseases. Therefore, we performed this study to address these gaps. In the present study, serum levels of immunoglobulin and complement were measured in 245 patients with ALS, 65 patients with multiple system atrophy (MSA), 60 patients with Parkinson's disease (PD), and 82 healthy controls (HCs). Multiple comparisons revealed that no significant differences existed between patients with ALS and other neurodegenerative diseases in immunoglobulin and complement levels. Meta-analysis based on data from our cohort and eight published articles was performed to evaluate the serum immunoglobulin and complement between patients with ALS and HCs. The pooled results showed that patients with ALS had higher C4 levels than HCs. In addition, we found that the IgG levels were lower in early-onset ALS patients than in late-onset ALS patients and HCs, and the correlations between age at onset of ALS and IgG or IgA levels were significant positive. In conclusion, our data supplement existing literature on understanding the role of peripheral immunity in ALS. [ABSTRACT FROM AUTHOR]

Functional Analysis Based on the Prioritized Genes Further data mining based on the prioritized genes was performed to schematize the functional relevance of MND-related genes, and genes with a total score of at least 4 were considered prioritized genes. For example, using GO analysis, we revealed that most MND-related genes are involved in the immune response, which is consistent with previous studies (Mantovani et al., [16]; Hooten et al., [11]; Brown and Al-Chalabi, [3]), suggesting that immunomodulation plays important roles in the pathogenesis of MND. Keywords: amyotrophic lateral sclerosis; motor neuron disease; one-stop online database; gene ontology analysis; immunomodulation; gene EN amyotrophic lateral sclerosis motor neuron disease one-stop online database gene ontology analysis immunomodulation gene N.PAG N.PAG 6 04/26/21 20210401 NES 210401 Introduction Motor neuron diseases (MND) refer to a wide and heterogeneous expanding group of neurodegenerative disorders involving the upper and lower motor neurons, which are characterized by rapidly progressive weakness leading to paralysis and eventually death from respiratory failure. In this study, we developed a one-stop database of MND-related genes and variants, Gene4MND, to facilitate analysis of genes and variants related to MND. [Extracted from the article]

Variants in the DNAJC7 gene have been shown to be novel causes of amyotrophic lateral sclerosis (ALS). However, the contributions of DNAJC7 mutations in Asian ALS patients remain unclear. In this study, we screened rare pathogenic variants in the DNAJC7 gene in a cohort of 578 ALS patients from Mainland China. A novel, rare, putative pathogenic variant c.712A>G (p.R238G) was identified in one sporadic ALS patient. The carrier with this variant exhibited symptom onset at a relatively younger age and experienced rapid disease progression. Our results expand the pathogenic variant spectrum of DNAJC7 and indicate that variants in the DNAJC7 gene may also contribute to ALS in the Chinese population. [ABSTRACT FROM AUTHOR]

To date, conflicting results about the role of vitamins in amyotrophic lateral sclerosis (ALS) have been reported along with a lack of systematic studies on all types of serum vitamins in patients with ALS. Moreover, extensive studies have been conducted on vitamins in other neurodegenerative diseases; however, whether serum vitamin alterations in ALS are similar to those in other neurodegenerative diseases remains unclear. Therefore, we performed a study involving a large Chinese cohort of patients with ALS to address this gap. In this study, 202 patients with ALS, 214 with a neurodegenerative disease that mimicked ALS (mimics), and 208 healthy controls were enrolled. Serum vitamins of all subjects were examined under fasting state in Clinical Laboratory. As a result, we found that higher vitamin A and E levels and lower vitamin B2, B9, and C levels were in patients with ALS compared to healthy controls, and that high vitamin A and E levels, and low vitamin B2, B9, and C levels were associated with an increased risk for ALS. In addition, serum vitamin C was lower in early-onset ALS patients compared to those in late-onset ALS patients; however, there was no significant correlation between serum vitamins and age at onset, sites at onset, disease duration, or disease severity of ALS. We also found that patients with ALS showed similar vitamin alterations to mimics, with the exception of vitamin E. In summary, our study adds information to the literature on the role of vitamins in ALS and provides support for clinical guidance regarding dietary changes and vitamin supplements in patients with ALS. [ABSTRACT FROM AUTHOR]

Objective: Mutations of the cyclin F (CCNF) gene were recently identified to be associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in Western and Japanese populations. The rare protein-altering variants frequency is 0.6 to 3.3% in ALS and FTD from these diverse geographic populations while no systematic analysis of CCNF variants were conducted in the Chinese population. Methods: We screened all exons of CCNF in a cohort of 269 cases (including 181 ALS and 88 FTD) from Mainland China using Sanger sequencing. Results: A rare heterozygous variant (c.481G > A, p.G161R) was detected in a sporadic ALS case with a frequency of 0.6%, while no mutation was identified in patients with FTD. The same variant was also found in a sporadic ALS patient from America. Conclusions: Our result indicates that the mutation of CCNF is rare in patients with ALS and FTD from Mainland China. [ABSTRACT FROM AUTHOR]

Background: The TANK-Binding Kinase 1 (TBK1) gene has recently been identified as the third or fourth most frequent cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). The aim of this study was to assess the genetic contribution of TBK1 in a Chinese cohort. Methods: A total of 270 cases with ALS, FTD, or their combination were recruited into this study. All the coding exons of TBK1 and intron-exon boundaries were sequenced using Sanger sequencing. The frequency of TBK1 variants and the correlation with clinical phenotypes were analyzed. Results: A novel mutation (c.1959_1960insGT, p.E653fs) was identified in a sporadic case with semantic dementia, secondarily developing ALS. Another novel variant (c.2063_2064delTT, p.L688Rfs*14) was found in an ALS-FTD family. Totally, the TBK1 variants could only account for 0.7% of cases. Conclusions: This study enlarges the genetic and phenotypic spectrum of TBK1 mutation in a Chinese cohort. Our data indicates that TBK1 mutation is not a common cause for ALS and FTD in Chinese patients. [ABSTRACT FROM AUTHOR]

Background Recently, a hexanucleotide repeat expansion in the C9orf72 gene has been identified to cause frontotemporal dementia, amyotrophic lateral sclerosis families and many other neurodegenerative diseases. Owing to the overlapping phenotypes among HSP, frontotemporal dementia and amyotrophic lateral sclerosis we hypothesized that C9orf72 expansions might be a genetic risk factor or modifier of HSP. Objectives The aim of this study was to find out whether C9orf72 expansions also confer risk to spastic paraplegia (SPG). Methods We recruited 112 genetically unidentified SPG patients, 68 SPG4 patients and 313 controls in mainland China to determine if hexanucleotide repeat of C9orf72 plays a role in spastic paraplegia. Results No large expansion was detected in all subjects. C9orf72 repeat expansions were not associated with onset of HSP. Conclusion Our results support the notion that repeat expansions in C9orf72 may not be associated with HSP in China. [ABSTRACT FROM AUTHOR]