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Objectives: Genetics have been shown to have a substantial impact on amyotrophic lateral sclerosis (ALS). The ALS process involves defects in axonal transport and cytoskeletal dynamics. It has been identified that KIF1A, responsible for encoding a kinesin-3 motor protein that carries synaptic vesicles, is considered a genetic predisposing factor for ALS. Methods: The analysis of whole-exome sequencing data from 1,068 patients was conducted to examine the genetic link between ALS and KIF1A. For patients with KIF1A gene mutations and a family history, we extended the analysis to their families and reanalyzed them using Sanger sequencing for cosegregation analysis. Results: In our cohort, the KIF1A mutation frequency was 1.31% (14/1,068). Thirteen nonsynonymous variants were detected in 14 ALS patients. Consistent with the connection between KIF1A and ALS, the missense mutation p.A1083T (c.3247G>A) was shown to cosegregate with disease. The mutations related to ALS in our study were primarily located in the cargo-binding region at the C-terminal, as opposed to the mutations of motor domain at the N-terminal of KIF1A which were linked to hereditary peripheral neuropathy and spastic paraplegia. We observed high clinical heterogeneity in ALS patients with missense mutations in the KIF1A gene. KIF5A is a more frequent determinant of ALS in the European population, while KIF1A accounts for a similar proportion of ALS in both the European and Chinese populations. Conclusion: Our investigation revealed that mutations in the C-terminus of KIF1A could increase the risk of ALS, support the pathogenic role of KIF1A in ALS and expand the phenotypic and genetic spectrum of KIF1A-related ALS. [ABSTRACT FROM AUTHOR]

Objective: To translate Amyotrophic Lateral Sclerosis-Specific Quality of Life-Short Form (ALSSQOL-SF) and test its reliability and validity, so that explore feasibility in Chinese mainland and make up the gap of specific tools for measuring quality of life of patients with ALS. Methods: This was a cross-sectional design. The Brislin translation model was used to translate ALSSQOL-SF, and the Chinese version of ALSSQOL-SF (C-ALSSQOL-SF) was revised through cultural adaptation and pre-test. The convenience sampling method was used to investigate 138 patients with ALS in Tianjin to test the reliability and validity of the C-ALSSQOL-SF. Results: The C-ALSSQOL-SF included 20 items, covering 6 dimensions: physical symptoms, bulbar function, negative emotion, interaction with people and the environment, religiosity and intimacy. The scale-level content validity index (S-CVI) of C-ALSSQOL-SF was 0.964, and the item-level content validity index (I-CVI) was between 0.857 to 1.000. The results of Confirmatory Factor Analysis (CFA) showed that CMIN/DF = 1.161, RMSEA = 0.034, GFI = 0.892, IFI = 0.976, TLI = 0.969, CFI = 0.975, and the 6-factor model fitted well. The scores of C-ALSSQOL-SF and WHOQOL-BREF were positively correlated (r = 0.745). The Cronbach's α coefficient of the scale was 0.85, the Cronbach's α coefficient of each dimension was between 0.59 to 0.86, and the split-half reliability was 0.78. Conclusion: The Chinese version of ALSSQOL-SF has good reliability and validity, and can be used as a tool to evaluate the quality of life of patients with ALS in Chinese mainland. [ABSTRACT FROM AUTHOR]

Yellowfin seabream (Acanthopagrus latus) is one of the most commercially important marine fish in China. In this study, a new continuous cell line, named ALS cells, was developed from the spleen tissue of A. latus. The cell line was maintained in Dulbecco's modified Eagle medium/Nutrient Mixture F‐12 Ham (DMEM/F‐12) supplemented with 10% fetal bovine serum (FBS) and successfully cultured up to 50 passages. The cell line was authenticated by amplifying and sequencing mitochondrial cytochrome C oxidase subunit‐I (coi‐I) gene. The ALS cell line had the maximum growth rate in DMEM/F‐12 medium containing 20% FBS at 27°C. Chromosome number analysis showed that the ALS cells have a modal diploid chromosome number of 34. The ALS cell line was transfected with the pEGFP‐N1 plasmid, and green fluorescence was observed. The ALS cell line was used for testing Mandarinfish ranavirus (MRV) susceptibility, and the cytopathic effects in the cell line were observed at 4 days post‐infection (dpi). Furthermore, the susceptibility of the ALS cell line to MRV and the levels of MRV mRNA and viral loads were found to be significantly increased at 1–7 dpi. This study revealed that the ALS cell line could be useful for molecular, virological, and biotechnological studies on yellowfin seabream. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Repeat expansions in genes other than C9orf72 and ATXN2 have been recently associated with Amyotrophic Lateral Sclerosis (ALS). Indeed, an abnormal number of GGC repeats in NOTCH2NLC has been recently reported in 0.7% of sporadic ALS patients from mainland China. This finding was not confirmed in an ALS cohort of subjects from Taiwan. As the involvement of expanded NOTCH2NLC alleles in ALS is debated, we addressed this point by evaluating NOTCH2NLC repeat expansions in an Italian cohort of ALS patients. A screening analysis of NOTCH2NLC GGC repeats was performed by repeat-primed polymerase chain reaction (RP-PCR) in a cohort of 385 probable/definite ALS Italian patients. Mean age at onset was 60.5 years (SD 13.7), and 60.9% were males. Sporadic cases were 357 (92.7%), and most patients had a spinal onset (71.8%). None of our patients showed the typical sawtooth tail pattern on RP-PCR, thus excluding abnormal repeat expansion in NOTCH2NLC. Overall, we suggest that NOTCH2NLC expanded alleles might be absent or at least extremely rare in ALS Italian patients. Further investigations in larger cohorts with different ethnic backgrounds are required to support the involvement of NOTCH2NLC in ALS. [ABSTRACT FROM AUTHOR]

Introduction: TP73 was recently identified as a novel causative gene for amyotrophic lateral sclerosis (ALS). We aimed to determine the contribution of variations in TP73 in the Chinese ALS population and to further explore the genotype-phenotype correlations. Methods: We screened rare, putative pathogenic TP73 mutations in a large Chinese ALS cohort and performed association analysis of both rare and common TP73 variations between cases and controls. Results: Of the 985 ALS patients studied, six rare, heterozygous putative pathogenic variants in TP73 were identified among six unrelated sALS patients. Exon 14 of TP73 might be a mutant hotspot in our cohort. Patients with ALS with only rare, putative pathogenic TP73 mutations exhibited a characteristic clinical profile. Patients harboring multiple mutations in TP73 and other ALS-related genes displayed a significantly earlier onset of ALS. Association analysis revealed that rare TP73 variants in the untranslated regions (UTRs) were enriched among ALS patients; meanwhile, two common variants in the exon-intron boundary were discovered to be associated with ALS. Discussion: We demonstrate that TP73 variations also have contributed to ALS in the Asian population and broaden the genotypic and phenotypic spectrum of TP73 variants in the ALS-frontotemporal dementia (FTD) spectrum. Furthermore, our findings first suggest that TP73 is not only a causative gene, but also exerts a disease-modifying effect. These results may contribute to a better understanding of the molecular mechanism of ALS. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease involving upper motor neurons (UMN) and lower motor neurons (LMN), which can be caused by mutations of pathogenic genes such as superoxide dismutase 1 (SOD1), sarcoma fusion (FUS), and TAR-DNA binding protein (TARBDP/TDP-43). Among these pathogenic genes, TARBDP mutation accounts for approximately 1% of sporadic ALS (sALS). The clinical phenotype of ALS is heterogeneous owing to different mutant genes and sites. Here, we report a case of sALS from China, the pathogenic site (c.800A > G) of TARDBP in this patient was identified by whole-exome sequencing. But his clinical symptoms involve only the LMN, presented with progressive limb weakness, and dyspnea, without obvious limb muscle atrophy. We considered this patient as a possible LMN-dominant ALS variant and this report further explores the genotype–phenotype correlations of ALS10. Furthermore, interestingly, the pathogenic site in this person was previously reported in a Parkinson's disease (PD) patient and frontotemporal dementia (FTD) patient. Our findings illustrate the clinical heterogeneity and the types of diseases which carry p.Asn267Ser TDP-43 mutation were broadened furtherly. Meanwhile, considering that the range of neurodegenerative diseases associated with this mutant site may be expanding, the mechanism of different neurodegenerative changes mediated by the same pathogenic site still needs to be further studied. [ABSTRACT FROM AUTHOR]

A plethora of environmental risk factors has been persistently implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), including metal/metalloids. This study aimed to examine potential associations between cerebral spinal fluid (CSF) metal/metalloids and ALS risks. CSF concentrations of copper (Cu), nickel (Ni), mercury (Hg), arsenic (As), manganese (Mn), and iron (Fe) in ALS (spinal- and bulbar-onset) patients and controls were measured using inductively coupled plasma mass spectrometry (ICP-MS). Results from this study revealed marked differences between control, spinalonset, and bulbar-onset groups. We report that Cu levels were lower in the ALS and spinal-onset groups compared to the control group. Ni level were higher in the spinal-onset group compared to the control and bulbaronset groups. In addition, associations between CSF metal/metalloid levels with disease severity, sex, and serum triglycerides were also examined to broach the potential relevance of neurotoxic metal/metalloids in ALS disease heterogeneity. [ABSTRACT FROM AUTHOR]

Objective: To provide an overview of the range and characteristics of existing evidence, research gaps, and future research priorities in treating amyotrophic lateral sclerosis (ALS) with acupuncture. Method: Clinical studies on acupuncture treatment for ALS were searched in 9 databases and two websites. Two independent researchers screened the literature according to the inclusion and exclusion criteria; extracted the demographic data, interventions, and significant findings of the studies; and comprehensively analyzed the characteristics and limitations of the included articles. Results: A total of 2,326 studies were retrieved, of which 92 were included. Most of the studies were conducted in China, with the number increasing over time. Study designs included case reports, case series, randomized controlled trials (RCTs), and before-and-after studies, among which case reports were the most frequently used. A total of 1,388 patients were enrolled, of whom 1,031 had ALS, 274 had progressive bulbar palsy (PBP), 60 had progressive muscle atrophy (PMA), and 23 had primary lateral sclerosis (PLS). Acupuncture interventions included body acupuncture, electroacupuncture, acupoint injection, scalp acupuncture, acupoint massage, Sa-am acupuncture, needle-embedding therapy, auricular acupuncture, venom pharmacopuncture therapy, plum blossom needling, acupoint paste, electroacupuncture, and needle warming through moxibustion. The most frequently used acupoints were ST36, LI4, SP6, and LI 11. Acupuncture is often applied in combination with other treatments, such as herbal or Western medicine. The frequency of treatment ranged from once a month to three times a day, and the duration of treatment ranged from 5 days to 3 years. Clinical symptoms, muscle strength, and effective rates were the most frequently used outcomes. Most studies reported significant efficacy, and only a few studies reported adverse events explicitly. Conclusion: Evidence gaps include poor study design, complex interventions, limited significance of the selected outcomes, and limited study reporting. The promotion of acupuncture treatment for ALS still faces several obstacles. Rigorous study design and conduct, standardized intervention and outcome measurements, and normative reporting are needed to investigate the efficacy and safety of acupuncture treatment for ALS. [ABSTRACT FROM AUTHOR]

TANK1-binding kinase 1 (TBK1) is mainly involved in the regulation of various cellular pathways through the autophagic lysosomal system, and the loss of function or hypofunction caused by TBK1 gene mutation mainly leads to frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and ALS-FTLD. Alzheimer's disease (AD) due to TBK1 gene mutation is extremely rare, and only one case has been reported in China so far. In this report, we described a patient with early-onset AD (EOAD) in whom a new probable pathogenic variant c.704A>T (p.Tyr235Phe) in the TBK1 gene was identified by a whole-genome sequencing analysis. It is suggested that FTLD gene mutation may exist in patients with clinical manifestations of AD. [ABSTRACT FROM AUTHOR]

Objective: In the Asian population, SOD1 variants are the most common cause of amyotrophic lateral sclerosis (ALS). To date, more than 200 variants have been reported in SOD1 . This study aimed to summarize the genotype-phenotype correlation and determine whether the patients carrying common variants derive from a common ancestor., Methods: A total of 103 sporadic ALS (SALS) and 11 familial ALS (FALS) probands were included and variants were screened by whole exome sequencing. Functional analyses were performed on fibroblasts derived from patients with SOD1 p.V48A and control. Haplotype analysis was performed in the probands with p.H47R or p.V48A and their familial members., Results: A total of 25 SOD1 variants were identified in 44 probands, in which p.H47R, p.V48A and p.C112Y variants were the most common variants. 94.3% and 60% of patients with p.H47R or p.V48A had lower limb onset with predominant lower motor neurons (LMNs) involvement. Patients with p.H47R had a slow progression and prolonged survival time, while patients with p.V48A exhibited a duration of 2-5 years. Patients with p.C112Y variant showed remarkable phenotypic variation in age at onset and disease course. SOD1 V48A fibroblasts showed mutant SOD1 aggregate formation, enhanced intracellular reactive oxygen species level, and decreased mitochondrial membrane potential compared to the control fibroblast. Haplotype analysis showed that seven families had two different haplotypes. p.H47R and p.V48A variants did not originate from a common founder., Conclusions: Our study expanded the understanding of the genotype-phenotype correlation of ALS with SOD1 variants and revealed that the common p.H47R or p.V48A variant did not have a founder effect.

Variations in the UBQLN2 gene are associated with a group of diseases with X-linked dominant inheritance and clinical phenotypes of amyotrophic lateral sclerosis (ALS) and/or frontal temporal lobe dementia (FTD). Cases with UBQLN2 variations have been rarely reported worldwide. The reported cases exhibit strong clinical heterogeneity. Here, we report two adult-onset cases with UBQLN2 variations in Han Chinese. Whole exome sequencing revealed the hemizygous P506S (c.1516C > T) and the heterozygous P509S variation (c.1525C > T), both of which were located within the hotspot mutation region. The patient with the P506S variation was a 24-year-old male. The clinical feature was spastic paraplegia without lower motor neuron damage. The patient's mother was an asymptomatic heterozygote carrier with skewed X-chromosome inactivation. The patient with the P509S variation was a 63-year-old female. Clinical features included ALS and parkinsonism. 18 F-fluorodopa PET-CT revealed presynaptic dopaminergic deficits in bilateral posterior putamen. These cases further highlight the clinical heterogeneity of UBQLN2 cases., (© 2024. Fondazione Società Italiana di Neurologia.)

Background: The large-scale survey about amyotrophic lateral sclerosis (ALS) based on both population and hospitals in the Chinese mainland has been deficient at present. To this end, we conducted a cross-sectional survey about ALS based on the population and hospitals in seven provinces of the Chinese mainland in 2015-2016. Methods: We surveyed patients with ALS in seven provinces in eastern, middle, and western China. Among them, 13 prefecture-level cities, 13 municipal districts, 13 counties, 26 streets, 52 communities, 39 towns, and 78 administrative villages were selected for the population-based survey. Totally, 13 class-3 general hospitals, 13 class-2 general hospitals, and 26 street health centers or community health service centers in urban districts, and 13 county-level general hospitals, 39 township health centers, and 78 village clinics in rural districts were recruited for the hospital-based survey. Results: Among the Chinese mainland, the total prevalence of ALS was slightly lower than that of the world's other nations or districts. The male patients were more than female patients. The prevalence of rural residents was more than that of urban residents. The prevalence of farmers was higher than that of other professions. The majority of ALS was not accompanied by other chronic diseases. The peak onset age of ALS was higher, familial ALS (fALS) cases were slightly more, and the average survival duration of sporadic ALS (sALS) was slightly lower compared with the previous investigation data. The hospitalization expenses of almost 60% of ALS were not more than 10,000 Chinese Yuan. Conclusion: Hospitalization expenses in our survey objectives were the lowest in the current reported countries and districts. A farmer was a possible higher risk profession for ALS, the majority of ALS were not accompanied by other chronic diseases. Our survey provided more information on the epidemiology of ALS worldwide and supplied the deficiency of epidemiology survey about ALS from the Chinese mainland. [ABSTRACT FROM AUTHOR]

Background: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by predominant impairment of upper and lower motor neurons. Over 50 TARDBP mutations have been reported in both familial (FALS) and sporadic ALS (SALS). Some mutations in TARDBP, e.g. A382T and G294V, have genetic founder effects in certain geographic regions. However, such prevalence and founder effect have not been reported in Chinese. Methods: Whole-exome sequencing (WES) was performed in 16 Chinese FALS patients, followed by Sanger sequencing for the TARDBP p.Gly298Ser mutation (G298S) in 798 SALS patients and 1,325 controls. Haplotype analysis using microsatellites flanking TARDBP was conducted in the G298S-carrying patients and noncarriers. The geographic distribution and phenotypic correlation of the TARDBP mutations reported worldwide were reviewed. Results: WES detected the TARDBP G298S mutation in 8 FALS patients, and Sanger sequencing found additional 8 SALS cases, but no controls, carrying this mutation. All the 16 cases came from Southern China, and 7 of these patients shared the 117-286-257-145-246-270 allele for the D1S2736-D1S1151-D1S2667-D1S489-D1S434-D1S2697 markers, which was not found in the 92 non-carrier patients (0/92) (p < 0.0001) and 65 age-matched and neurologically normal individuals (0/65) (p < 0.0001). The A382T and G298S mutations were prevalent in Europeans and Eastern Asians, respectively. Additionally, carriers for the M337V mutation are dominated by bulbar onset with a long survival, whereas those for G298S are dominated by limb onset with a short survival. Conclusions: Some prevalent TARDBP mutations are distributed in a geographic pattern and related to clinical profiles. TARDBP G298S mutation is a founder mutation in the Southern Chinese ALS population. [ABSTRACT FROM AUTHOR]

Background: This study aims to determine the genetic and clinical features of TARDBP-mutated patients in our cohort of Chinese patients with amyotrophic lateral sclerosis (ALS) combined with data in the literature. Methods: We performed TARDBP mutation screening in 1258 Chinese ALS patients, including 1204 sporadic ALS (sALS) and 54 familial ALS (fALS) patients. A systematic literature review was conducted by searching TARDBP-mutated patients from China in the online databases. Results: In our cohort, the mutant frequency of TARDBP variants was 0.3% (4/1258), with two recurrent variants (p.G294V, p.G298V) and one novel variant (p.S332G) identified. Combining with data in the literature review, the TARDBP-mutant frequency in the Chinese population was 1.4% (83/5998), with 0.8% (46/5470) in sALS and 7.0% (37/528) in fALS. Most patients had limb onset (63.0%), with an average life expectancy of 4.3 years (range 0.5–13). Disease durations significantly differed (p = 0.002), with p.M337V showing the longest duration (80 months) and p.N378D showing the shortest duration (16.7 months). Conclusion: Our study found that TARDBP mutation was not rare in Chinese fALS patients. Different TARDBP mutations were associated with specific features in phenotypes. [ABSTRACT FROM AUTHOR]

Objectives: Pain is considered a common symptom in amyotrophic lateral sclerosis (ALS). However, the results of studies on pain in ALS are limited and inconsistent. The aim of our study was to comprehensively evaluate the potential factors of pain and effects on quality of life (QoL) in patients with ALS from China. Participants and Methods: Patients were eligible if they fulfilled the criteria of probable and definitive ALS according to the revised El Escorial criteria. Pain was assessed by the Brief Pain Inventory (BPI). Disease severity, sleep quality, fatigue, anxiety, depression, and quality of life (QoL) were evaluated in ALS patients by the ALS Functional Rating Scale-revised (ALSFRS-R) and ALS severity scale (ALSSS), Pittsburgh Sleep Quality Index (PSQI), Fatigue Severity Scale (FSS), Hamilton Anxiety Rating Scale (HARS), Hamilton Depression Rating Scale (HDRS) and McGill Quality of Life Questionnaire (MQOL). Then, the clinical characteristics of ALS patients with pain were compared with those without pain. Last, associated factors of pain, as well as impact on QoL in Chinese ALS patients, were assessed. Results: A total of 86 ALS patients were included. ALS patients with pain tended to have higher FSS scores and poorer QoL. The FSS score and ALSSS [lower extremity (LE) C upper extremity (UE)] were associated with pain in ALS patients. The ALS Functional Rating Scale-revised (ALSFRS-R), Pain Severity Index (PSI), HARS and HDRS scores were significantly associated with both the physical and psychological domains of QoL. Conclusion: Our study was the first to comprehensively evaluate factors associated with pain in Chinese ALS patients, finding that fatigue can be a risk factor for pain and ALSSS (LE C UE) score was related with pain intensity. Additionally, we identified the adverse effects of ALSSS (LE C UE), HARS and HDRS scores on QoL in Chinese ALS patients. [ABSTRACT FROM AUTHOR]

Objective: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting motor neurons. The proportion of late‐onset ALS in China were low and may have distinct clinical and genetic manifestations. We aimed to investigate the natural history and remarkable psychiatric state of ALS with age at onset over 60 years in China. Materials and methods: We collected all ALS cases from 2017 to 2020 in our center and focused on late‐onset ALS patients particularly, by analyzing the clinical data, including the ALS onset and disease progression. Anxiety, depression, cognitive function, and sleep quality were assessed to reflect the psychiatric state. Results: A total of 193 late‐onset ALS patients were included in this study. The median age at onset of late‐onset ALS was 65 years with the quartile from 62 to 68 years. When compared with 446 non‐late‐onset ALS, late‐onset ALS showed distinct clinical presentation, with lower ALS Functional Rating Scale‐Revised at diagnosis and faster rate of progression. Remarkably, late‐onset ALS were suffering from worse psychiatric state, including serious anxiety and depression, as well as worse cognitive function with sleep quality. The abnormal psychiatric state was more pronounced in female patients of late‐onset. Conclusions: In the current study, ALS patients with late‐onset showed unique clinical features. Severe psychiatric conditions and faster progression in the early stage of the disease of late‐onset ALS indicated the need for more social and psychiatric support in this population. [ABSTRACT FROM AUTHOR]

To investigate the clinical and genetic factors influencing the survival of amyotrophic lateral sclerosis (ALS) patients in China. Patients were enrolled in the study between December 2013 and December 2018. Clinical variables were recorded upon patient diagnosis. Causative genes related to ALS were screened by whole-exome sequencing and validated by Sanger sequencing. Each patient was followed up every 3–6 months until the endpoint (death or tracheotomy) or the last connection time on 31 December 2020. Propensity score matching analysis was performed to match the genetic and non-genetic ALS patients. The Kaplan–Meier method and multivariable Cox regression were performed for survival analysis. A total of 337 patients, including 32 with genetic ALS and 305 with non-genetic ALS, were enrolled in the study. Before matching, in univariate analysis, age of onset (P < 0.001), site of onset (P = 0.036), diagnostic delay (P < 0.001), ALSFRS-R score at diagnosis (P < 0.001), ΔALSFRS-R (P < 0.001), and causative mutations (P = 0.020) were significant prognostic factors. These factors remained statistically significant after multivariate analysis. After matching, in the multivariate analysis, age of onset (P = 0.003), site of onset (P = 0.014), diagnostic delay (P = 0.007), ALSFRS-R score at diagnosis (P = 0.010), ΔALSFRS-R (P = 0.007), and causative mutations (P = 0.003) were found to be significant prognostic factors. Both clinical factors and genetic factors influenced survival in our ALS cohort. Clarifying of the underlying mechanisms is crucial for the development of future therapies. [ABSTRACT FROM AUTHOR]

Objective To compare the differences between the gray matter structures of amyotrophic lateral sclerosis (ALS) patients with limb-onset and bulbar-onset. Methods A total of 35 ALS patients with normal cognitive function were enrolled in Peking Union Medical College Hospital ALS Registry Platform from September 2013 to March 2018, and 20 healthy controls with matched age and education were included in the study. ALS patients were divided into limb-onset group (ALS-L group, n = 20) and bulbar-onset group (ALS-B group, n = 15) according to their clinical onset sites. Three-dimensional T1 -fast spoiled gradient-recalled (3D-T1 -FSPGR) of all subjects was collected. Gray matter volume of each group were compared using voxel-based morphometry (VBM). Within the compound region of interest (ROI) consisting of bilateral primary motor cortex, premotor cortex and supplementary motor area, the atrophy patterns of the motor cortex were compared between ALS-L group and ALS-B group. Results Compared with the control group, the ALS-L group had decreased gray matter volume in the left superior temporal gyrus-temporal pole (t = 3.932, uncorrected P < 0.001), left middle temporal gyrus (t = 3.836, uncorrected P < 0.001), right insula (t = 3.992, uncorrected P < 0.001). Compared with the ALS-B group, the ALS-L group had decreased gray matter volume in the right superior frontal gyrus (t = -3.158, uncorrected P < 0.001), left cingulate gyrus (t = -3.002, uncorrected P < 0.001). In the analysis of the motor cortex as ROI, the gray matter volume of the segments representing hand (t = 2.237, uncorrected P < 0.001) and lower limb (t = 2.728, uncorrected P < 0.001) of the left motor cortex in the ALS-L group was reduced significantly than that of ALS-B group. Conclusions ALS-L has more significant gray matter atrophy than ALS-B, and the local atrophy pattern of motor cortex in ALS patients corresponds to its functional disability. [ABSTRACT FROM AUTHOR]

Background: Limited data exists on the clinical features of patients with amyotrophic lateral sclerosis (ALS) during reproductive ages. Objective: Our study characterized the clinical features of ALS and the effects of pregnancy on disease progression in patients with ALS. Methods: We performed a retrospective study of female patients with ALS in three ALS research centers in southern China from 2009 to 2021. Data regarding fertility status, and clinical and genetic features, were collected. Age-matched male patients with ALS served as controls. The patients were divided into the following two subgroups: patients with symptom onset within 1 year of pregnancy and patients with symptom onset over 1 year group after pregnancy. Results: A total of 52 female and 52 matched male patients were enrolled. There were no differences in female and male patients in the mean age of symptom onset, the mean baseline ALSFRS-R score, or median reduction of ALSFRS-R score (p > 0.05). The mean age of first pregnancy was 25.57 ± 4.40) years. The mean age of first pregnancy in the over 1 year group was lower than that in the within 1 year group (p = 0.01). There was no difference in the median reduction of ALSFRS-R between the two subgroups. In the univariate analysis, diagnostic delay was highly correlated with the disease progression, with short delay representing rapid progress. No multicollinearity was found among every variable. In addition, 40.38% patients carried ALS-related gene variants. The proportion with gene mutations in the within 1 year group was higher than that in the over 1 year group (p < 0.01). Furthermore, SETX was the most frequently mutated gene in this cohort (16.67%) including 4 uncertain mutation. Conclusion: Pregnancy and fertility were not associated with disease progression. Diagnostic delay was correlated with disease progression in this cohort. In addition, SETX might be a gene of concern for ALS patients of childbearing age. [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]

ERBB4 is related to amyotrophic lateral sclerosis (ALS) in patients with a family history and is thought to cause ALS-19. We screened 448 ALS patients, including 364 sporadic ALS (sALS) and 84 familial ALS (fALS) patients with ERBB4 variants, in a Chinese cohort. In total, 12 missense variants were identified in this study. Of these, 3 (p.Arg106His, p.Gln164Pro, and p.Val212Leu) were absent from the in-house healthy control cohort and population databases and predicted to be likely pathogenic. Genetic burden analysis did not reveal an increase in damaging variants of the ERBB4 gene. We considered that most of the missense variants in ERBB4 were not pathogenic, but certain variants, such as p.Arg106His, p.Gln164Pro, and p.Val212Leu, were likely pathogenic. The phenotype of these three patients carrying ERBB4 variants revealed the typical clinical manifestations of ALS without cognitive dysfunction. We concluded that ERBB4 likely pathogenic variants account for ~0.67% of ALS patients in China. It is necessary to interpret the relationship between the disease and variants carefully for ALS patients with ERBB4 gene variants. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the clinical features of sporadic Paget's disease of bone (PDB) in China and further explore the underlying genetic abnormalities of the disease. Methods: Clinical characteristics, biochemical indices, bone turnover markers and radiographic examinations of the patients were collected. Genomic DNA was extracted from peripheral blood and whole-exome sequencing was carried out to identify the potential pathogenic genes. The pathogenicity of the variants was thereafter investigated by bioinformatics analysis. Results: A total of 50 patients (57.20 ± 15.52 years, male/female: 1.63: 1) with PDB were included and the mean onset age was 48.34 years (48.34 ± 17.24 years). 94.0% of the patients exhibited symptomatic patterns described as bone pain (86.0%), elevated skin temperature at the lesion site (26.0%), bone deformity (22.0%) and local swelling (18.0%). The most frequently involved lesion sites were pelvis (52.0%), femur (42.0%), tibia (28.0%), skull (28.0%) and spine (18.0%), respectively. Additionally, 40.0% of them accompanied with osteoarthritis, 14.0% with pathological fractures, and the misdiagnosis rate of PDB was as high as 36.0%. Serum level of alkaline phosphatase was significantly increased, with the mean value of 284.00 U/L (quartiles, 177.00-595.00 U/L). Two heterozygous missense mutations of SQSTM1 gene (c.1211T>C, M404T) and one novel heterozygous missense mutation in HNRNPA2B1 gene (c.989C>T, p. P330L) were identified in our study. Moreover, several potential disease-causing genes were detected and markedly enriched in the pathways of neurodegeneration (including WNT16 , RYR3 and RYR1 genes) and amyotrophic lateral sclerosis (ALS, including NUP205 , CAPN2 , and NUP214 genes). Conclusion: In contrast to Western patients, Chinese patients have an earlier onset age, more severe symptoms, and lower frequency of SQSTM1 gene mutation (4.0%). Moreover, a novel heterozygous missense mutation in HNRNPA2B1 gene was identified in one male patient with isolated bone phenotype. As for other genetic factors, it was indicated that WNT16 , RYR3 , RYR1 , NUP205 , CAPN2 and NUP214 genes may be potential pathogenic genes, pathways of neurodegeneration and ALS may play a vital role in the pathogenesis of PDB. [ABSTRACT FROM AUTHOR]

Objectives: The beneficial effects of many substances have been discovered because of regular dietary consumption. This is also the case with curcumin, whose effects have been known for more than 4,000 years in Eastern countries such as China and India. A curcumin-rich diet has been known to counteract many human diseases, including cancer and diabetes, and has been shown to reduce inflammation. The effect of a curcumin treatment for neurological diseases, such as spinal muscular atrophy; Alzheimer's disease; Parkinson's disease; amyotrophic lateral sclerosis; multiple sclerosis; and others, has only recently been brought to the attention of researchers and the wider population. Methods: In this paper, we summarise the studies on this natural product, from its isolation two centuries ago to its characterisation a century later. Results: We describe its role in the treatment of neurological diseases, including its cellular and common molecular mechanisms, and we report on the clinical trials of curcumin with healthy people and patients. Discussion: Commenting on the different approaches adopted by the efforts made to increase its bioavailability. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Introduction: Alterations in the visual pathway involving the retina have been reported in amyotrophic lateral sclerosis (ALS) but they lack consistency and subgroup analysis. We aimed to assess the retinal nerve fiber layer (RNFL) and retinal ganglion cells (RGCs) alterations in different stages of ALS patients and their association with ALS progression parameters. Methods: The study population consisted of 70 clinically diagnosed ALS patients and 55 age, sex matched controls. All of them underwent ophthalmic assessments and optical coherence tomography imaging. Four quadrants of the peripapillary RNFL and ganglion cell/inner plexiform complex (GCIP) were observed and automatically measured. Early-stage distal motor neuron axon dysfunction in ALS was detected by compound muscle action potential (CMAP) of the distal limbs within 12 months. The ALS disease parameters included the ALSFRS-R score and the disease progression rate (ΔFS). Results: Generally compared with controls, the nasal (p = 0.016) quadrant of the RNFL was thicker in ALS patients. When controlling for age and ΔFS, the RNFL(r = 0.37, p = 0.034) and GCIP(r = 0.40, p = 0.021) were significantly thickened as disease progressed within 12 months, while the RNFL declined with time after one year (r = −0.41, p = 0.037). ALS patients was subclassified into thickened RNFL (T-RNFL, >95th percentile of normal), impaired RNFL (I-RNFL, <5th percentile of normal) and normal RNFL. There were significant differences in the GCIP among the three groups (p < 0.001). In the T-RNFL group (n = 18), the RNFL was negatively correlated with the abductor pollicis brevis-CMAP amplitude within 12 months (r = −0.56, p = 0.01). Patients within 12 months in this group progressed faster than others (p = 0.039). In the normal RNFL group (n = 22), 13 patients were diagnosed beyond 12 months, whose ΔFS was remarkably lower (p = 0.007). In I-RNFL group (n = 30), the early stage patients (<12 months) had significant higher ΔFS (p = 0.006). One patient was with SOD1 pathogenic variant (p.A5V). Conclusion: Alterations of retinal nerve were not consistent in ALS patients with diverse phenotypes and progression rates. Generally speaking, the RNFL thickened during the first year and then gradually declined, which is related to but preceding the thickness change of the RGCs. Patients with a significant RNFL thinning in the early stage may have a faster progression rate. The inverse U-shaped curve transformation might be in accordance with early-stage motor neuron axonopathy. [ABSTRACT FROM AUTHOR]

Background: Aberrant DNA methylation alterations are implicated in amyotrophic lateral sclerosis (ALS). Nevertheless, the influence of genetic variants in genes regulating DNA methylation on ALS patients is not well understood. Therefore, we aim to provide a comprehensive variant profile of genes related to DNA methylation (DNMT1, DNMT3A, DNMT3B, DNMT3L) and demethylation (TET1, TET2, TET3, TDG) and to investigate the association of these variants with ALS., Methods: Variants were screened in a cohort of 2240 ALS patients from Southwest China, using controls from the Genome Aggregation Database (n = 9976) and the China Metabolic Analytics Project (n = 10,588). The over-representation of rare variants and their association with ALS risk were evaluated using Fisher's exact test with Bonferroni correction at both allele and gene levels. Kaplan-Meier analysis and Cox regression analysis were employed to explore the relationship between variants and survival., Results: A total of 210 variants meeting the criteria were identified. Gene-based burden analysis identified a significant increase in ALS risk associated with rare variants in the TET2 gene (OR = 1.95, 95% CI = 1.29-2.88, P = 0.001). Survival analysis demonstrated that patients carrying variants in demethylation-related genes had a higher risk of death compared to those with methylation-related gene variants (HR = 1.29, 95% CI = 1.03-1.86, P = 0.039)., Conclusions: This study provides a genetic variant profile of genes involved in DNA methylation and demethylation regulation, along with the clinical characteristics of ALS patients carrying these variants. The findings offer genetic evidence implicating disrupted DNA methylation dynamics in ALS., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. In recent years, continuous discoveries of new ALS-causing genes have enhanced the understanding of the genotype-phenotype relationship in ALS, aiding in disease progression prediction and providing a more comprehensive basis for genetic diagnosis., Methods: A total of 1672 ALS patients who visited the Neurology Department of Peking Union Medical College Hospital between January 2014 and December 2022 and met the revised El Escorial diagnostic criteria were included. Clinical data were collected, whole exome sequencing and dynamic mutation screening of the C9ORF72 gene were performed, and the clinical phenotypes and genotypes of the patients were analyzed., Results: The average age of onset for the 1672 ALS patients was 52.6 ± 11.2 years (range 17-85 years), with a median disease duration of 14 months at the time of visit (interquartile range 9-24 months, range 2-204 months). The male to female ratio was 833:839. The patients included 297 (17.8%) with bulbar onset, 198 (11.8%) with flail arm/leg syndrome, 89 (5.3%) with familial ALS, and 52 (3.1%) with concomitant frontotemporal dementia (FTD). Pathogenic variants associated with ALS were detected in 175 patients (10.5% of the cohort), with the most common mutations being SOD1, FUS, and ANXA11. Among patients with familial ALS, 56.2% (50/89) had genetic mutations, compared to 7.9% (125/1583) in sporadic ALS cases. From the perspective of phenotype-genotype correlation, (1) In ALS-FTD patients, the most common genetic mutations were ANXA11 and C9ORF72 repeat expansions. Patients with flail arm/leg syndrome more frequently carried mutations in SOD1, ANXA11, and hnRNPA1; (2) Despite genetic heterogeneity, it was observed that mutations in FUS and NEK1 were more common in males, and patients with FUS mutations had a younger age of onset; mutations in SOD1 and SQSTM1 were more likely to present with lower limb onset., Conclusion: This study provides comprehensive data on the genetic characteristics of ALS patients in China through large-scale clinical data and genetic analysis of 1672 cases. Differences in age of onset, onset site, and clinical phenotype among ALS patients with different genotypes can help clinicians better predict disease progression and provide a basis for precise diagnosis and individualized treatment., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

• Analysis 51 ALS causative genes in a large ALS cohort from central-south of China. • Site of onset of ALS was influenced by rare damage variants and sex. • SOD1 gene was the most common mutated gene in China, followed by ATXN2 and NEK1. • Mutation spectrum of AD-ALS patients differed from that of sporadic ALS patients. 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. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that predominately involves the motor neurons in the brain and spinal cord. The TARDBP gene, encoding TAR DNA-binding protein 43 (TDP-43) protein, has been identified as a major causative gene in ALS. In this study, we screened 275 SALS patients and 20 unrelated FALS probands for TARDBP mutations. We identified three TARDBP mutations in three SALS patients and two TARDBP mutations in two FALS probands, including a previously unreported mutation, p.K176I, in FALS patients consistent with frontotemporal dementia (FTD) and parkinsonism. The p.K176I mutation is the first mutation outside exon 6 of the TARDBP gene manifesting parkinsonism and the first TARDBP mutation manifesting parkinsonism identified in the Chinese population. Our results support that TARDBP mutations are one of the most common changes in both FALS and SALS in China. Patients with TARDBP mutations may have a broad phenotype spectrum of ALS, FTD, and parkinsonism. The TARDBP gene should be included in genetic screening for ALS with FTD, and/or parkinsonism. • A novel TARDBP mutation p.K176I found in a FALS pedigree with FTD and parkinsonism • p.K176I is the first mutation outside exon 6 of TARDBP manifesting parkinsonism • p.K176I is the first TARDBP mutation manifesting parkinsonism in Chinese [ABSTRACT FROM AUTHOR]

Background: Mutations in superoxide dismutase 1 gene (SOD1) are the most frequent high penetrant genetic cause for amyotrophic lateral sclerosis (ALS) in the Chinese population. A detailed natural history of SOD1 -mutated ALS patients will provide key information for ongoing genetic clinical trials. Methods: We screened for SOD1 mutations using whole exome sequencing (WES) in Chinese ALS cases from 2017 to 2021. Functional studies were then performed to confirm the pathogenicity of novel variants. In addition, we enrolled previously reported SOD1 mutations in our centers from 2007 to 2017. The SOD1 mutation spectrum, age at onset (AAO), diagnostic delay, and survival duration were analyzed. Results: We found two novel SOD1 variants (p.G17H and p.E134*) that exerted both gain-of-function and loss-of-function effects in vitro. Combined with our previous SOD1 -mutated patients, 32 probands with 21 SOD1 mutations were included with the four most frequently occurring mutations of p.V48A, p.H47R, p.C112Y, and p.G148D. SOD1 mutations account for 58.9% of familial ALS (FALS) cases. The mean (SD) AAO was 46 ± 11.4 years with a significant difference between patients carrying mutations in exon 1 [ n = 5, 34.6 (12.4) years] and exon 2 [ n = 8, 51.4 (8.2) years] (p = 0.038). The mean of the diagnostic delay of FALS patients is significantly earlier than the sporadic ALS (SALS) patients [9.5 (4.8) vs. 20.3 (9.3) years, p = 0.0026]. In addition, male patients survived longer than female patients (40 vs. 16 months, p = 0.05). Conclusion: Our results expanded the spectrum of SOD1 mutations, highlighted the mutation distribution, and summarized the natural history of SOD1 -mutated patients in southeastern China. Male patients were found to have better survival, and FALS patients received an earlier diagnosis. Our findings assist in providing a detailed clinical picture, which is important for ongoing genetic clinical trials. [ABSTRACT FROM AUTHOR]

Background and purpose: The aim was to determine the transitional patterns in the clinical characteristics, treatments and comorbidities in amyotrophic lateral sclerosis (ALS) patients over the past 14 years using data from a large clinical cohort in mainland China. Methods: Sporadic ALS patients who visited the Peking University Third Hospital from January 2005 to December 2018 were included in this study. The 14 years were divided into three periods, and changes in the baseline characteristics of the participants were analyzed at 5‐year intervals. Results: In total, 3410 patients with sporadic ALS were recruited: 2181 were men and 1229 were women. The proportion of patients with bulbar‐onset ALS increased from 13.0% in 2005–2009 to 19.5% in 2015–2018 (p < 0.001). The mean (standard deviation) age at onset increased from 49.5 (11.4) years in 2005–2009 to 53.0 (11.0) years in 2015–2018 (p < 0.001). ALS patients with diabetes or hypertension showed a delay in ALS onset, and the delay was even more apparent when the patients had both comorbidities. The proportion of riluzole users in 2015–2018 was approximately 2.5‐fold of that in 2005–2009 (p < 0.001). Conclusions: In the context of a lack of clinical data on ALS in mainland China, this study evaluated a large cohort of patients diagnosed over a 14‐year period. The age at onset and percentage of patients who used riluzole both increased over the study period. Additionally, it was found that patients with comorbidities such as diabetes and hypertension had a delayed age of ALS onset. [ABSTRACT FROM AUTHOR]

The pathogenesis of sporadic amyotrophic lateral sclerosis (sALS) remains unknown; however, recent research suggests that genetic factors may play an important role. This study aimed at investigating possible genetic risk factors for the pathogenesis of sALS. In our previous study, we conducted a genome-wide association study (GWAS) in 250 sALS patients and 250 control participants of Han ancestry from mainland China (HACM) and retrospectively analyzed the previously reported candidate loci related with sALS including our GWAS investigated results. In this study, twenty-seven candidate loci that were most likely associated with sALS were selected for further analysis in an independent case/control population of 239 sALS patients and 261 control subjects of HACM ethnicity using sequenom massARRAY methodology and DNA sequencing. We discovered that the polymorphism rs2619566 located within the contactin-4 (CNTN4) gene, rs10260404 in the dipeptidyl-peptidase 6 (DPP6) gene, and rs79609816 in the inositol polyphosphate-5-phosphatase B (INPP5B) gene were strongly associated with sALS in subjects of HACM ethnicity. Subjects harboring the minor C allele of rs2619566 and the minor T allele of rs79609816 exhibited an increased risk for sALS development, while carriers of the minor C allele of rs10260404 showed a decreased risk of sALS development compared to the subjects of other genotypes. The polymorphisms of rs2619566, rs10260404, and rs79609816 may change or affect the splicing, transcription, and translation of CNTN4 , DPP6 , and INPP5B genes and may play roles in the pathogenesis of sALS roles in the pathogenesis of sALS. [ABSTRACT FROM AUTHOR]

Backgbround: Frontotemporal dementia (FTD) is the second most common presenile dementia, characterized by prominent behavioral, language, and cognitive impairment, which has a strong genetic component contributing to its pathogenesis. Due to geographical and ethnic variability, the prevalence of the causative genes of FTD may be different. Methods: To explore the genetics of FTD in the Chinese population, we reviewed 97 closely related studies that were searched in PubMed and Web of Science. In this review, we summarized the characteristics of each FTD gene. We also reassessed their pathogenicity and revised some mutations from pathogenic to uncertain significance according to the American College of Medical Genetics and Genomics (ACMG). Results: Thirty-two rare variants in genes of MAPT, GRN, C9orf72, CHCHD10, VCP, and TBK1 were identified in Chinese FTD populations, including 25 pathogenic mutations and seven variants of uncertain significance (VUS). Among them, the frequency of rare variants in the CHCHD10 gene was the highest. Surprisingly, twelve variants reported as pathogenic mutations were revised as VUS by ACMG. The correlations between genes and clinical manifestations were MAPT and frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), GRN and frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD-TDP), C9orf72/CHCHD10/TBK1 and amyotrophic lateral sclerosis (ALS)-FTD spectrum, and VCP corresponds inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD). Conclusions: It is necessary to strictly interpret the contributions of genes to diseases by ACMG. MAPT is the most common pathogenic gene for FTD in China. [ABSTRACT FROM AUTHOR]

Background. Pain was considered a common and neglected symptom in amyotrophic lateral sclerosis (ALS) and had a substantial impact on the quality of life of ALS patients and their caregivers. However, pain in ALS was mainly evaluated from the perspective of nociceptive pain; only three studies referred to neuropathic pain in ALS, and there has been yet no study considering the neuropathic pain characteristics in ALS patients from China. Therefore, the purpose of our study was to determine characteristics of pain (nociceptive pain and neuropathic pain) by three different types of questionnaires. The correlation between pain and clinical parameters in ALS patients was also evaluated. Methods. Patients were eligible if they fulfilled the criteria of probable and definitive ALS according to the revised El Escorial criteria. Healthy normal controls, matched to ALS patients by age and gender, were recruited. Pain was evaluated by numerical pain rating scale (NRS), Brief Pain Inventory (BPI), and Douleur Neuropathique-4 (DN4) in ALS patients and controls. Physical status of ALS patients was evaluated with ALS Functional Rating Scale-revised (ALSFRS-R). Results. 65 patients with sporadic ALS and 100 healthy normal controls in Southwestern China were included. Pain in the preceding week was more frequently reported by patients with ALS (30, 46.2%) than controls (36, 36%) (p = 0.193). DN4 score ⩾ 4 was found in three ALS patients and one control (p = 0.480). Ten ALS patients (33.3%) and twenty-eight controls (77.8%) (p < 0.001) received therapy for pain. ALS patients with a DN4 score ≥ 4 had a longer disease duration and a higher PSI and PII score than ALS cases reporting nociceptive pain (p = 0.041 , 0.048, and 0.027, respectively). Pain mainly interfered with ALS patients' mood, enjoyment of life, and the Pain Interference Index (PII) score. Conclusions. Our findings indicated that pain in our ALS cohorts was insufficiently treated and interfered with patients' mood and enjoyment of life. Most notably, we found that ALS patients with a DN4 score ⩾ 4 may have a longer disease duration and a higher PSI and PII score than ALS patients reporting nociceptive pain, which has never been reported, strongly deserving further validation. [ABSTRACT FROM AUTHOR]

Aims and objectives: This study aims to gain a comprehensive understanding of the illness experience of amyotrophic lateral sclerosis (ALS) patients in China and the meaning they attach to those experiences. Background: ALS is a progressive and fatal neurodegenerative disorder that significantly impacts individuals and families. There is a large number of patients with ALS in China. However, little is known about how they live with ALS. Design: Phenomenological qualitative research was performed among twenty people with ALS from the neurology department of a tertiary hospital in China. Colaizzi's method was used to analyse the participants' data. The Consolidated Criteria for Reporting Qualitative Research (COREQ) was used as a guideline to secure accurate and complete reporting of the study. Results: We proposed three themes and eight subthemes on the illness experience of participants: (1) life countdown: 'my body was frozen' (body out of control and inward suffering); (2) family self‐help: 'we kept an eye on each other' (family warmth and hardship, and supporting the supporter); and (3) reconstruction of life: 'what was the meaning of my life' (learning to accept, rebuilding self‐worth, resetting the priority list and living in the moment). Conclusions: In the family self‐help model, patients are prompted to turn from negative mentalities to search for meaning in life actively. Healthcare providers need to attach importance to the family self‐help model to alleviate the pressure on medical resources. Relevance to clinical practice: Healthcare providers should encourage patients to play a supportive role in the family and provide more care support and professional care knowledge guidance to caregivers, to promote the formation of the family self‐help model which might help to improve the experience of patients and families. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS), also known as a major type of motor neuron disease, is a disease characterized by the degeneration of both upper and lower motor neurons. Astragaloside IV (AST) is one of the most effective compounds isolated from Astragalus membranaceus. Echinacoside (ECH) is also an active constituent in Cistanche tubulosa. These two herbs had been used in treating disease described like ALS in ancient China under the guidance of traditional Chinese medicine theory and now they are still being used extensively for ALS in current Chinese medicine practice, but whether AST or ECH has effect on ALS disease condition is still unclear. Survivals of primary cultured neuron and astrocyte were determined by the MTS assay. Proteins including GLT1 and GFAP, from SOD1 G93A Tg (transgenic) astrocyte lysate were determined by Western blot. Synaptic markers, PSD95 and VGLUT1, were stained by immunofluorescence and observed by a confocal microscope. Proper dilution of AST and ECH was confirmed to be not harmful to both astrocytes and neurons. AST and ECH enhanced neuronal synaptic markers density or intensity/area in different aspects. Both AST and ECH could significantly rescue SOD1 astrocyte conditional medium–treated neuronal survival and synapse loss. Ten micromolars ECH could significantly rescue the suppressed GLT1 level expressed by SOD1 Tg astrocyte. This present research proved that AST and ECH could benefit neuronal properties and rescue certain dysfunction, such as GLT1 low expression, loss of neuron-supporting function, of astrocytes under SOD1 condition. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Young-onset amyotrophic lateral sclerosis (ALS) refers to ALS patients with initial symptoms earlier than 45 years, representing a novel disease pattern. We aim to summarize the clinical and genetic features of 102 young-onset ALS patients in China. Methods: Clinical information and blood samples were collected from all registered patients, and we performed next generation sequencing techniques in an ALS customized panel to detect ALS-related genes. Results: A total of 95 sporadic ALS and seven familial ALS were involved in this study. Young-onset ALS showed male prevalence and had more spinal onset. With 44 patients carrying one or more variants, mutations in SPG11, ALS2, and SETX were the most frequent, followed by FUS variants. Other prevalent genes like SOD1, TARDBP, and C9ORF72 were relatively rare in young-onset patients. Conclusions: Our study highlighted distinct clinical manifestation and genetic background in young-onset ALS patients in China. These features should be verified in further investigations in other populations. [ABSTRACT FROM AUTHOR]

Background and Aim: Traditional Chinese medicine (TCM) is widely used by patients with amyotrophic lateral sclerosis (ALS). However, their reasons and experience in using TCM have received insufficient attention. Therefore, we conducted a mixed method study to gain insights into this issue., Materials and Methods: This study was conducted on the basis of the China Amyotrophic Lateral Sclerosis Registry of Patients with Traditional Chinese Medicine (CARE-TCM). Data were collected from Dongzhimen Hospital through a mixed method approach, including a questionnaire and a semi-structured interview. Patients with ALS who were using TCM when they were initially registered with CARE-TCM and who had been followed-up for over six months were recruited. The questionnaires' outcomes were statistically outlined, and the interview transcripts were thematically analysed to identify themes and sub-themes., Results: Fifty-two and sixteen patients were included in the questionnaire and semi-structured interview groups, respectively. Patients used TCM with the hope of regulating their body holistically to improve nonmotor symptoms and quality of life (QOL). Those who recognised TCM as ineffective tended to discontinue it after a three-month trial period. Although quality was a major concern, herbal medicine (HM) was the most frequently used modality among all participants (n = 52), with the majority (n = 44, 84.6%) continuing to use it. Patients emphasised in-person consultations as a crucial part of TCM treatment. However, the disability caused by disease often made this interaction unattainable., Conclusion: Nonmotor symptoms and QOL hold substantial importance for patients with ALS using TCM. HM is a more suitable modality than other TCM treatment modalities, but patients are facing challenges in seeking HM treatment. It is necessary to promote the implementation of hierarchical diagnosis and treatment, thus making TCM more accessible., Trial Registration: ClinicalTrials.gov identifier: NCT04885374 (registered on May 13, 2021)., (© 2024. The Author(s).)

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by progressive damage to both upper and lower motor neurons. Genetic factors are known to play a crucial role in ALS, as genetic studies not only advance our comprehension of disease mechanisms but also help unravel the complex phenotypes exhibited by patients. To gain further insights into the genetic landscape of ALS in the Chinese population and explore genotype-phenotype correlations among individuals, we conducted whole-genome sequencing to screen genes in 34 Chinese familial ALS (FALS) probands lacking the most common ALS-associated genes. Within this cohort, we identified a rare heterozygous missense mutation in the N-terminal domain of KIF5A (c.86A>G) in one of the probands. This finding is significant as mutations in the KIF5A gene have been implicated in ALS in European cohorts since 2018, predominantly characterized by C-terminal mutations. Analysis of the clinical phenotype within this familial lineage revealed a delayed onset of symptoms, an extended survival duration, and initial manifestations in both upper limbs. These observations underscore the clinical heterogeneity observed in ALS patients harboring KIF5A mutations. In conclusion, our study contributes to the growing body of evidence linking KIF5A to ALS and enhances our understanding of the intricate genetic landscape of this disease.

DnaJ heat shock protein family member C7 gene (DNAJC7) has been identified as a genetic risk factor for amyotrophic lateral sclerosis (ALS). In our study, we aimed to screen for rare variants in DNAJC7 in a large cohort of Chinese ALS patients, and investigate the genotype-phenotype correlation of DNAJC7 in ALS. Four (0.19%) variants of DNAJC7 with minor allele frequency (MAF) < 0.1% among 2124 patients were identified, including 1 protein-truncating variant and 3 missense variants, all of which were predicted to be damaging. The patients carrying variants of DNAJC7 in our cohort tented to have a limb onset and a relatively slow disease progression. However, burden analysis did not show an enrichment of rare damaging variants in ALS patients compared to controls. Further analysis involving diverse regions and larger sample size is necessary to elucidate the role of DNAJC7 in the pathogenicity of ALS., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Neurofilament light chain (NFL) was believed to be a promising biomarker for the diagnosis of Amyotrophic lateral sclerosis (ALS) and disease burden evaluation. Objective: To determine the serum NFL level and its clinical relevance, including its association with disease severity [evaluated by the ALS Functional Rating Scale–revised (ALSFRS-r) score and King's College staging system] and progression (evaluated by the disease progression rate (DPR) and diagnostic delay), in ALS patients in China. Method: Serum NFL levels were detected using the Single Molecule Array (Simoa) technology in 30 ALS patients and 20 healthy controls (HCs). Results: There were significantly elevated levels of serum NFL in patients with ALS than in the HCs (P < 0.001). The serum NFL levels were significantly higher in rapidly progressive ALS and patients in Stage 3 than in slowly progressive ALS and patients in Stage 2 (P DPR < 0.001, P Diagnosticdelay = 0.019; P stage = 0.033). Furthermore, the serum NFL levels negatively correlated with the diagnostic delay (R 2 = 0.23, P = 0.016), the ALSFRS-r score (R 2 = 0.15, P = 0.047) and disease duration (R 2 = 0.15, P = 0.034), and positively correlated with the DPR (R 2 = 0.42, P < 0.001). Conclusions: The present study preliminarily investigated the diagnostic value of serum NFL and its clinical relevance in the Chinese ALS population using the ultrasensitive Simoa technology. The results demonstrated that the level of serum NFL may become a potential biomarker for ALS diagnosis and indicate disease severity and progression. [ABSTRACT FROM AUTHOR]

To determine the practical diagnostic utility of split-hand index (SI) values calculated from F-wave persistence (SIFP) and the F/M amplitude ratio (SIF/M) for differentiating patients with amyotrophic lateral sclerosis (ALS) from other conditions. Methods: This prospective study recruited consecutive patients from Peking Union Medical College Hospital, China, between June 2019 and December 2019. Patients 18-80 years old who had clinical neuromuscular symptoms affecting the upper limbs and required electrophysiological examinations to aid diagnosis were eligible. Compound muscle action potentials (CMAPs) and F-waves recorded from the abductor pollicis brevis (APB), first dorsal interosseous muscle (FDI), and abductor digiti minimi (ADM) were examined. SIFP and SIF/M were calculated as: SI = (APB × FDI)/ADM. The sensitivity and specificity of SIFP and SIF/M in differentiating ALS from non-ALS conditions were derived using receiver operating characteristic (ROC) curves. Results: A total of 309 participants, comprising 91 (29.4%) with ALS and 218 (70.6%) with other neuromuscular disorders, were enrolled after 54 were excluded. SIFP was significantly reduced and SIF/M increased in the ALS group compared with the non-ALS group (p < 0.001). By ROC curve analysis, an SIFP cutoff of 73.3 showed 85.7% sensitivity and 80.7% specificity for differentiating ALS from non-ALS. SIF/M and SICMAP showed lower sensitivity (67% and 75.8%, respectively, p < 0.001) than SIFP for ALS diagnosis. SIFP and SIF/M combined did not outperform SIFP alone. Conclusion: SIFP could be a sensitive, noninvasive neurophysiological diagnostic marker for ALS patients with affected upper limbs. In particular, an SIFP value of 73.3 might be the optimal cutoff for diagnosing ALS. [ABSTRACT FROM AUTHOR]

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]

Background and purpose: Amyotrophic lateral sclerosis (ALS)‐related genes and mutations have been increasingly discovered recently and an improved understanding of genotype–phenotype relationships may help to predict the disease course and refine genetic diagnosis. Methods: We collected clinical data and blood samples from 268 patients and used next‐generation sequencing to comprehensively assay genetic variations in a panel of known ALS genes from 2015 to 2019. Results: Among these patients, the mean age of onset was 52.30 ± 10.42 years with a mean diagnosis delay of 15.90 ± 11.88 months. Patients with SOD1, TARDBP and FUS variants were more likely to suffer from familial ALS. Additionally, carriers of FUS variants displayed the earliest onset, followed by those with SOD1 variants. Patients with NEFH variants showed a closer link to pesticide exposure. Patients with SETX variants were prone to bulbar onset with moderate anxiety problems. No genotype–phenotype relations were found in SPG11 and ERBB4 mutants. Conclusion: Our findings uncovered some genotype–phenotype relationships and may help to predict the disease course of patients with ALS in southern China. [ABSTRACT FROM AUTHOR]

Objective: To assess the role of premorbid type 2 diabetes in patients with amyotrophic lateral sclerosis (ALS) in China. Methods: We compared data from ALS patients with premorbid type 2 diabetes (T2D) and ALS patients without T2D with regard to the age of onset of ALS. In addition, survival was compared between these two groups of patients using propensity score matching (PSM). Results: Among 1331 consecutive sporadic ALS patients, 100 (7.5%) were labeled as ALS-T2D and 1231 were labeled as ALS-control according to the presence or absence of premorbid T2D. The mean age of onset in patients in the ALS-T2D group was 57.0 years, with a 4.4-year delay compared to that in the ALS-control group [57.0 (SD, 9.6) years vs 52.6 (SD, 10.3) years, respectively; p = 0.000]. This 4.4-year delay was significant after adjusting for sex and the site of onset in a multiple linear regression model. Additionally, after comparison with matched pairs, a nonsignificant increase in survival was observed among the ALS patients with premorbid T2D. Conclusions: The results support the protective role of diabetes in ALS. It is possible to infer that these beneficial effects occur mainly in the preclinical and early stages of the disease course. [ABSTRACT FROM AUTHOR]

Objective: Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease and information on disease burden of ALS in mainland China was limited. We aimed to estimate the prevalence and incidence of ALS in China.Methods: We used 2012-2016 data from China's Urban Employee Basic Medical Insurance and Urban Residence Basic Medical Insurance, covering approximately 0.43 billion individuals. ALS cases were identified by the primary diagnosis (International Classification of Diseases code or text of diagnosis) in the insurance database.Results: The crude prevalence and incidence in 2016 were 2.91 per 100 000 person-years (95% CI 2.31 to 3.58) and 1.65 (95% CI 1.33 to 2.01), respectively. The standardised prevalence and incidence based on 2010 Chinese census data were 2.97 (95% CI 2.91 to 3.03) and 1.62 (95% CI 1.58 to 1.67), respectively. The annual prevalence between 2013 and 2016 remained relatively constant, ranging from 2.91 (95% CI 2.31 to 3.58) in 2016 to 3.29 (95% CI 2.51 to 4.17) in 2014 (linear regression: β=-0.129, p=0.104). Both rates peaked in the group aged 75-79 years.Conclusions: The prevalence and incidence of ALS in mainland China were lower than those in developed countries, and maintained a relatively stable trend. The age at onset and age at diagnosis for ALS patients were younger than those in developed countries. Further research is expected to clarify the potential pathophysiological mechanism of ALS. [ABSTRACT FROM AUTHOR]

Objective: ALS2-related disorder involves retrograde degeneration of the upper motor neurons of the pyramidal tracts, among which autosomal recessive Infantile-onset ascending hereditary spastic paralysis (IAHSP) is a rare phenotype. In this study, we gathered clinical data from two Chinese siblings who were affected by IAHSP. Our aim was to assess the potential pathogenicity of the identified variants and analyze their clinical and genetic characteristics., Method: Here, Whole-exome sequencing (WES) was performed on proband to identify the candidate variants. Subsequently, Sanger sequencing was used to verify identified candidate variants and to assess co-segregation among available family members. Utilizing both silico prediction and 3D protein modeling, an analysis was conducted to evaluate the potential functional implications of the variants on the encoded protein, and minigene assays were performed to unravel the effect of the variants on the cleavage of pre-mRNA., Results: Both patients were characterized by slurred speech, astasia, inability to walk, scoliosis, lower limb hypertonia, ankle clonus, contracture of joint, foot pronation and no psychomotor retardation was found. Genetic analysis revealed a novel homozygous variant of ALS2, c.1815G > T(p.Lys605Asn) in two Chinese siblings. To our knowledge, it is the first confirmed case of a likely pathogenic variant leading to IAHSP in a Chinese patient., Conclusion: This study broadens the range of ALS2 variants and has practical implications for prenatal and postnatal screening of IAHSR. Symptom-based diagnosis of IAHSP is frequently difficult for medical practitioners. WES can be a beneficial resource to identify a particular disorder when the diagnosis cannot be determined from the symptoms alone., (© 2024. The Author(s).)