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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.)

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.)

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]