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BACKGROUND: Sialidosis type 1 (ST-1) is a rare autosomal recessive disorder caused by mutation in the NEU1 gene. However, limited reports on ST-1 patients in the Chinese mainland are available. METHODS: This study reported the genetic and clinical characteristics of 10 ST-1 patients from southeastern China. A haplotype analysis was performed using 21 single nucleotide polymorphism (SNP) markers of 500 kb flanking the recurrent c.544 A > G in 8 families harboring the mutation. Furthermore, this study summarized and compared previously reported ST-1 patients from Taiwan and mainland China. RESULTS: Five mutations within NEU1 were found, including two novel ones c.557 A > G and c.799 C > T. The c.544 A > G mutation was most frequent and identified in 9 patients, 6 patients were homozygous for c.544 A > G. Haplotype analysis revealed a shared haplotype surrounding c.544 A > G was identified, suggesting a founder effect presenting in southeast Chinese population. Through detailed assessment, 52 ST-1 patients from 45 families from Taiwan and mainland China were included. Homozygous c.544 A > G was the most common genotype and found in 42.2% of the families, followed by the c.544 A > G/c.239 C > T compound genotype, which was observed in 22.2% of the families. ST-1 patients with the homozygous c.544 A > G mutation developed the disease at a later age and had a lower incidence of cherry-red spots significantly. CONCLUSION: The results contribute to gaps in the clinical and genetic features of ST-1 patients in southeastern mainland China and provide a deeper understanding of this disease to reduce misdiagnosis.

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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. SOD1V48A 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.

In our ALS cohort, 44 ALS probands were identified with 25 SOD1 variants, of which p.H47R, p.V48A and p.C112Y variants were the most frequent. The genotype­phenotype relationship of patients with SOD1 p.H47R, p.V48A and p.C112Y patients were summarized.SOD1^V48A fibroblasts showed mutant SOD1 aggregate formation, enhanced intracellular reactive oxygen species level, and decreased mitochondrial membrane potential compared to the control fibroblast.Our study expanded the understanding of the genotype­phenotype correlation of ALS with SOD1 variants and showed the common variants p.H47R or p.V48A did not have a founder effect.

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The CACNA1A gene encodes the alpha-1A subunit of P/Q type voltage-gated calcium channel Cav2.1, which is associated with a broad clinical spectrum and variable symptomatology. While few patients with progressive ataxia caused by CACNA1A missense variants have been reported, here we report three unrelated Chinese patients with progressive ataxia due to de novo missense variants in the CACNA1A gene, including a novel pathogenic variant (c.4999C > G) and a previously reported pathogenic variant (c.4037G > A). Our findings and a systematic literature review show the unique phenotype of progressive ataxia caused by missense variants and enlarge the genetic and clinical spectrum of CACNA1A. This suggests that in addition to routine screening for dynamic mutations, screening for CACNA1A variants is important for clinicians facing patients with progressive ataxia.

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Dysbiosis of the gut microbiota is closely associated with neurodegenerative diseases, including Huntington's disease (HD). Gut microbiome-derived metabolites are key factors in host-microbiome interactions. This study aimed to investigate the crucial gut microbiome and metabolites in HD and their correlations. Fecal and serum samples from 11 to 26 patients with HD, respectively, and 16 and 23 healthy controls, respectively, were collected. The fecal samples were used for shotgun metagenomics while the serum samples for metabolomics analysis. Integrated analysis of the metagenomics and metabolomics data was also conducted. Firmicutes, Bacteroidota, Proteobacteria, Uroviricota, Actinobacteria, and Verrucomicrobia were the dominant phyla. At the genus level, the presence of Bacteroides, Faecalibacterium, Parabacteroides, Alistipes, Dialister, and Christensenella was higher in HD patients, while the abundance of Lachnospira, Roseburia, Clostridium, Ruminococcus, Blautia, Butyricicoccus, Agathobaculum, Phocaeicola, Coprococcus, and Fusicatenibacter decreased. A total of 244 differential metabolites were identified and found to be enriched in the glycerophospholipid, nucleotide, biotin, galactose, and alpha-linolenic acid metabolic pathways. The AUC value from the integrated analysis (1) was higher than that from the analysis of the gut microbiota (0.8632). No significant differences were found in the ACE, Simpson, Shannon, Sobs, and Chao indexes between HD patients and controls. Our study determined crucial functional gut microbiota and potential biomarkers associated with HD pathogenesis, providing new insights into the role of the gut microbiota-brain axis in HD occurrence and development.

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KCNA1 is the coding gene for Kv1.1 voltage-gated potassium-channel α subunit. Three variants of KCNA1 have been reported to manifest as paroxysmal kinesigenic dyskinesia (PKD), but the correlation between them remains unclear due to the phenotypic complexity of KCNA1 variants as well as the rarity of PKD cases. Using the whole exome sequencing followed by Sanger sequencing, we screen for potential pathogenic KCNA1 variants in patients clinically diagnosed with paroxysmal movement disorders and identify three previously unreported missense variants of KCNA1 in three unrelated Chinese families. The proband of one family (c.496G>A, p.A166T) manifests as episodic ataxia type 1, and the other two (c.877G>A, p.V293I and c.1112C>A, p.T371A) manifest as PKD. The pathogenicity of these variants is confirmed by functional studies, suggesting that p.A166T and p.T371A cause a loss-of-function of the channel, while p.V293I leads to a gain-of-function with the property of voltage-dependent gating and activation kinetic affected. By reviewing the locations of PKD-manifested KCNA1 variants in Kv1.1 protein, we find that these variants tend to cluster around the pore domain, which is similar to epilepsy. Thus, our study strengthens the correlation between KCNA1 variants and PKD and provides more information on genotype-phenotype correlations of KCNA1 channelopathy.

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The blood brain barrier (BBB) limits the application of most therapeutic drugs for neurological diseases (NDs). Hybrid cell membrane-coated nanoparticles derived from different cell types can mimic the surface properties and functionalities of the source cells, further enhancing their targeting precision and therapeutic efficacy. Neuroinflammation has been increasingly recognized as a critical factor in the pathogenesis of various NDs, especially Alzheimer's disease (AD). In this study, a novel cell membrane coating is designed by hybridizing the membrane from platelets and chemokine (C-C motif) receptor 2 (CCR2) cells are overexpressed to cross the BBB and target neuroinflammatory lesions. Past unsuccessful endeavors in AD drug development underscore the challenge of achieving favorable outcomes when utilizing single-mechanism drugs.Two drugs with different mechanisms of actions into liposomes are successfully loaded to realize multitargeting treatment. In a transgenic mouse model for familial AD (5xFAD), the administration of these drug-loaded hybrid cell membrane liposomes results in a significant reduction in amyloid plaque deposition, neuroinflammation, and cognitive impairments. Collectively, the hybrid cell membrane-coated nanomaterials offer new opportunities for precise drug delivery and disease-specific targeting, which represent a versatile platform for targeted therapy in AD.

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Accurate differential diagnosis among various dementias is crucial for effective treatment of Alzheimer's disease (AD). The study began with searching for novel blood-based neuronal extracellular vesicles (EVs) that are more enriched in the brain regions vulnerable to AD development and progression. With extensive proteomic profiling, GABRD and GPR162 were identified as novel brain regionally enriched plasma EVs markers. The performance of GABRD and GPR162, along with the AD molecule pTau217, was tested using the self-developed and optimized nanoflow cytometry-based technology, which not only detected the positive ratio of EVs but also concurrently presented the corresponding particle size of the EVs, in discovery (n = 310) and validation (n = 213) cohorts. Plasma GABRD+- or GPR162+-carrying pTau217-EVs were significantly reduced in AD compared with healthy control (HC). Additionally, the size distribution of GABRD+- and GPR162+-carrying pTau217-EVs were significantly different between AD and non-AD dementia (NAD). An integrative model, combining age, the number and corresponding size of the distribution of GABRD+- or GPR162+-carrying pTau217-EVs, accurately and sensitively discriminated AD from HC [discovery cohort, area under the curve (AUC) = 0.96; validation cohort, AUC = 0.93] and effectively differentiated AD from NAD (discovery cohort, AUC = 0.91; validation cohort, AUC = 0.90). This study showed that brain regionally enriched neuronal EVs carrying pTau217 in plasma may serve as a robust diagnostic and differential diagnostic tool in both clinical practice and trials for AD.

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Wilson's disease (WD) is a genetic disorder that primarily leads to the pathological accumulation of copper (Cu) in the liver, causing an abnormal increase in reactive oxygen species (ROS). The prevailing clinical therapy for WD involves lifelong use of Cu chelation drugs to facilitate Cu excretion in patients. However, most available drugs exert severely side-effects due to their non-specific excretion of Cu, unsuitable for long-term use. In this study, we construct a prochelator that enables precise and controlled delivery of Cu chelator drugs to the liver in WD model, circumventing toxic side effects on other organs and normal tissues. This innovative prochelator rapidly releases the chelator and the fluorescent molecule methylene blue (MB) upon activation by ROS highly expressed in the liver of WD. The released chelator coordinates with Cu, efficiently aiding in Cu removal from the body and effectively inhibiting the pathological progression of WD.

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Amyloid-ß, tau pathology, and biomarkers of neurodegeneration make up the core diagnostic biomarkers of Alzheimer disease (AD). However, these proteins represent only a fraction of the complex biological processes underlying AD, and individuals with other brain diseases in which AD pathology is a comorbidity also test positive for these diagnostic biomarkers. More AD-specific early diagnostic and disease staging biomarkers are needed. In this study, we performed tandem mass tag proteomic analysis of paired cerebrospinal fluid (CSF) and serum samples in a discovery cohort comprising 98 participants. Candidate biomarkers were validated by parallel reaction monitoring-based targeted proteomic assays in an independent multicenter cohort comprising 288 participants. We quantified 3,238 CSF and 1,702 serum proteins in the discovery cohort, identifying 171 and 860 CSF proteins and 37 and 323 serum proteins as potential early diagnostic and staging biomarkers, respectively. In the validation cohort, 58 and 21 CSF proteins, as well as 12 and 18 serum proteins, were verified as early diagnostic and staging biomarkers, respectively. Separate 19-protein CSF and an 8-protein serum biomarker panels were built by machine learning to accurately classify mild cognitive impairment (MCI) due to AD from normal cognition with areas under the curve of 0.984 and 0.881, respectively. The 19-protein CSF biomarker panel also effectively discriminated patients with MCI due to AD from patients with other neurodegenerative diseases. Moreover, we identified 21 CSF and 18 serum stage-associated proteins reflecting AD stages. Our findings provide a foundation for developing blood-based tests for AD screening and staging in clinical practice.

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Monogenic disorders refer to a group of human diseases caused by mutations in single genes. While disease-modifying therapies have offered some relief from symptoms and delayed progression for some monogenic diseases, most of these diseases still lack effective treatments. In recent decades, gene therapy has emerged as a promising therapeutic strategy for genetic disorders. Researchers have developed various gene manipulation tools and gene delivery systems to treat monogenic diseases. Despite this progress, concerns about inefficient delivery, persistent expression, immunogenicity, toxicity, capacity limitation, genomic integration, and limited tissue specificity still need to be addressed. This review gives an overview of commonly used gene therapy and delivery tools, along with the challenges they face and potential strategies to counter them.

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INTRODUCTION: Hereditary spastic paraplegias (HSPs) comprise a group of neurodegenerative disorders characterized by progressive degeneration of upper motor neurons. Homozygous or compound heterozygous variants in COQ4 have been reported to cause primary CoQ10 deficiency-7 (COQ10D7), which is a mitochondrial disease. AIMS: We aimed to screened COQ4 variants in a cohort of HSP patients. METHODS: A total of 87 genetically unidentified HSP index patients and their available family members were recruited. Whole exome sequencing (WES) was performed in all probands. Functional studies were performed to identify the pathogenicity of those uncertain significance variants. RESULTS: In this study, five different COQ4 variants were identified in three Chinese HSP pedigrees and two variants were novel, c.87dupT (p.Arg30*), c.304C>T (p.Arg102Cys). More importantly, we firstly described two early-onset pure HSP caused by COQ4 variants. Functional studies in patient-derived fibroblast lines revealed a reduction cellular CoQ10 levels and the abnormal mitochondrial structure. CONCLUSIONS: Our findings revealed that bilateral variants in the COQ4 gene caused HSP predominant phenotype, expanding the phenotypic spectrum of the COQ4-related disorders.

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Paroxysmal kinesigenic dyskinesia (PKD), the most common type of paroxysmal movement disorder, is characterized by sudden and brief attacks of choreoathetosis or dystonia triggered by sudden voluntary movements. PKD is mainly caused by mutations in the PRRT2 or TMEM151A gene. The exact pathophysiological mechanisms of PKD remain unclear, although the function of PRRT2 protein has been well characterized in the last decade. Based on abnormal ion channels and disturbed synaptic transmission in the absence of PRRT2, PKD may be channelopathy or synaptopathy, or both. In addition, the cerebellum is regarded as the key pathogenic area. Spreading depolarization in the cerebellum is tightly associated with dyskinetic episodes. Whereas, in PKD, other than the cerebellum, the role of the cerebrum including the cortex and thalamus needs to be further investigated.

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Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common hereditary cerebral small vessel disease in adults. Many CADASIL cases were reported after NOTCH3 was identified as the causative gene of CADASIL. However, there is still no specific and effective therapies for CADASIL. In this review, we summarize recent research progress on disease models, symptomatic treatments and potential therapies for CADASIL, thereby providing a reference for follow-up CADASIL treatment research.

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Spinocerebellar ataxia type 1 (SCA1) is the third most common type of spinocerebellar ataxias in China. CAT interruptions in the pathogenic alleles of SCA1 patients had only been reported by limited documents and there was a lack of data based on the Chinese population. In this study, we detected CAT interrupted pathogenic alleles in SCA1 patients from 4 out of 79 (5.1%) Chinese families. Their total CAG repeats were larger (median 58 vs. 47, p < 0.001) but ages at onset were later (median 46 vs. 38, p = 0.020). The longest uninterrupted CAG repeats could explain 65.4% of the AAO variance, making an increase of 28.0% compared to the total CAG repeats. The interruption pattern was greatly different between Chinese cohort and Caucasian cohort, indicating the effect of race.

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INTRODUCTION: Depression is considered a prodromal state of Alzheimer's disease (AD), yet the underlying mechanism(s) by which depression increases the risk of AD are not known. METHODS: Single-nucleotide polymorphism (SNP) analysis was used to determine the CALHM2 variants in AD patients. Cellular and molecular experiments were conducted to investigate the function of CALHM2 V136G mutation. We generated a new genetically engineered Calhm2 V136G mouse model and performed behavioral tests with these mice. RESULTS: CALHM2 V136G mutation (rs232660) is significantly associated with AD. V136G mutation resulted in loss of the CALHM2 ATP-release function in astrocytes and impaired synaptic plasticity. Mice homozygous for the Calhm2 V136G allele displayed depressive-like behaviors that were rescued by administration of exogenous ATP. Moreover, Calhm2 V136G mutation predisposed mice to cognitive decline in old age. DISCUSSION: CALHM2 dysfunction is a biologically relevant mechanism that may contribute to the observed clinical correlation between depression and AD.

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Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by CAG expansions in huntingtin (HTT) gene, involving motor, cognitive, and neuropsychiatric symptoms. However, genetic modifiers and CAG repeat instability may lead to variations of clinical manifestations, making diagnosis of HD difficult. In this study, we recruited 229 HD individuals from 164 families carrying expanded CAG repeats of HTT, and analyzed loss of CAA interruption (LOI) on the expanded allele and CAG instability during germline transmission. Sanger sequencing and TA cloning were used to determine CAG repeat length and identify LOI variants. Detailed clinical features and genetic testing results were collected. We identified 6 individuals with LOI variants from 3 families, and all probands presented with earlier motor onset age than predicted onset age. In addition, we also presented 2 families with extreme CAG instability during germline transmission. One family showed an expansion from 35 to 66 CAG repeats, while the other family showed both CAG expansion and contraction in lineal three generations. In conclusion, we present the first document of Asian HD population with LOI variant, and we suggest that for symptomatic individuals with intermediate or reduced penetrance allele or negative family history, HTT gene sequencing should be considered in the clinical practice. KEY MESSAGES : We screened the loss of CAA interruption (LOI) variant in a Chinese HD cohort and presented the first document of Asian patients with Huntington's disease carrying LOI variant. We identified 6 individuals with LOI variants from 3 families, and all probands presented with earlier motor onset age than predicted onset age. We presented 2 families with extreme CAG instability during germline transmission. One family showed an expansion from 35 to 66 CAG repeats, while the other family showed both CAG expansion and contraction in lineal three generations. We suggest that for symptomatic individuals with intermediate or reduced penetrance allele or negative family history, HTT gene sequencing should be considered in the clinical practice.

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