Wilson’s disease (WD) is an inherited disorder characterized by excessive accumulation of copper in the body, particularly in the liver and brain. In the central nervous system (CNS), extracellular copper accumulation triggers pathological microglial activation and subsequent neurotoxicity. Growing evidence suggests that levels of inflammatory cytokines are elevated in the brain of murine WD models. However, the mechanisms associated with copper deposition to neuroinflammation have not been completely elucidated. In this study, we investigated how the activation of NLR family pyrin domain containing 3 (NLRP3) inflammasome contributes to copper-mediated neuroinflammation in an animal model of WD. Elevated levels of interleukin-1β, interleukin-18, interleukin-6, and tumor necrosis factor-α were observed in the sera of WD patients and toxic milk (TX) mice. The protein levels of inflammasome adaptor molecule apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC), cleaved caspase-1, and interleukin-1β were upregulated in the brain regions of the TX mice. The NLRP3 inflammasome was activated in the TX mice brains. Furthermore, the activation of NLRP3 inflammasome was noted in primary microglia treated with CuCl2, accompanied by the increased levels of cleaved caspase-1, ASC, and interleukin-1β. Blocking NLRP3 inflammasome activation with siNlrp3 or MCC950 reduced interleukin-1β and interleukin-18 production, thereby effectively mitigating cognitive decline, locomotor behavior impairment, and neurodegeneration in TX mice. Overall, our study demonstrates the contribution of copper overload-mediated activation of NLRP3 inflammasome to progressive neuropathology in the CNS of a murine model of WD. Therefore, blockade of the NLRP3 inflammasome activation could be a potential therapeutic strategy for WD.

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

Wilson disease (Wd), also known as hepatolenticular degeneration (hld), is an autosomal recessive genetic disorder involving disruption of copper metabolism. Wilson disease is caused by mutations in the ATP7B gene on chromosome 13q14.3 encoding a p-type copper transporting adenosine triphosphate (atp) enzyme. the mutations of ATP7B gene leads to obstacles in bile excretion of copper in the liver and to obstacles in combination of copper with ceruloplasmin. it also causes the emergence of characteristic biochemical changes, including decreased ceruloplasmin (Cp) levels in the serum, increased copper content in the liver, and increased 24-hour urinary copper level. due to excessive deposition of copper in the liver, brain, kidney, cornea, and other tissues and organs, the main clinical ABSTRACT: Purpose: to prospectively investigate the incidence and prevalence of Wilson disease (Wd) in Chinese han population in anhui province, to analyze the genetic mutations in individuals with Wd, and to provide basic epidemiological data regarding Wd in this Chinese han population. Methods: between november 2008 and June 2010, individuals aged from 7 to 75 years were screened for the cornea K-f ring in both eyes using slit lamp examination and random sampling methods based on age stratification and cluster level 1. the participants were from anhui province's hanshan County, Jinzhai County, and lixin County. the clinical manifestations of the brain, liver, kidney, skin, and other organs in each individual were also determined. individuals with positive K-f rings and clinical manifestations indicative of Wd underwent copper biochemistry evaluations, abdominal ultrasound testing, and ATP7B gene mutation screening to confirm or exclude the diagnosis of Wd. Results: of 153,370 individuals investigated in this study, nine were diagnosed with Wd. in these Wd individuals, three cases had neurological symptoms, one has hepatic symptoms, one was hepatic and neurological combined, and the other four cases were presymptomatic. of the eight individuals in whom genetic mutations were detected, seven individuals had mutations in the ATP7B gene. the other individual had no ATP7B gene mutations but her copper biochemical test results met the diagnostic criteria for Wd. the incidence and prevalence of Wd in this population were approximately 1.96/100,000 and 5.87/100,000 respectively. Conclusion: the Chinese han population had a higher average prevalence of Wd than the populations of the united States or europe. Chez ces individus atteints de la MW, trois présentaient des manifestations neurologiques, un présentait des manifestations hépatiques, un présentait des manifestations hépatiques et neurologiques et les quatre autres étaient présymptomatiques. parmi les 8 individus chez qui des mutations génétiques ont été détectées, 7 avaient des mutations du gène atp7b. l'autre individu n'avait pas de mutation du gène atp7b mais ses résultats biochimiques pour le dosage du cuivre rencontraient les critères diagnostiques de la MW. l'incidence et la pr...

In this study, we analyzed the difference of intestinal flora polymorphisms between Wilson's disease (WD) patients and healthy people by high-throughput sequencing technology, and explored the correlation between WD and intestinal flora polymorphism.A total of 22 cases of WD patients and 22 healthy persons as control were recruited. The total DNA was extracted from the fecal specimens of all the subjects, V4 high variable region of 16S rRNA gene was amplified and sequenced by high-throughput sequencing. The sequencing results were analyzed by α diversity and β diversity. The unweighted UniFrac distance matrices were calculated and trees were built by unweighted-pair group method with arithmetic mean (UPGMA).A total of 2,548,262 sequences were obtained after the data are optimized, the average sequences in the WD group was 36,836 ± 4104 and it was 35,051 ± 3075 in the normal control group, there was no significant difference in the average sequence number between the 2 groups. OTU analysis showed that 2663 OTU were obtained in WD group, and 3271 OTU were obtained in the control group, of which 941 were common OTU. Colony diversity analysis showed that the intestinal flora of WD group and control group belonged to 5 phyla, they were Bacteroidetes, Firmicutes, Proteobacteria, Fusobacteria, and Tenericutes, respectively. In WD group, the abundance of Bacteroidetes was significantly lower than that of the control group (67.19% vs 76.75%, P < .001), and the abundance of Firmicutes (26.18% vs 19.83%, P < .001), Proteobacteria (4.31% vs 3.09%, P < .05), Fusobacteria (1.88% vs 0.04%, P < .001) were significantly higher than that of control group. Compared with the control group at the level of the genus, the abundance of Bacteroides (4.85% vs 4.6%, P < .05), Faecalibacterium (2.92% vs 2.13%, P < .05), Megamonas (0.84% vs 0.22%, P < .001), Lachnospira (0.16% vs 0.09%, P < .001) significantly increased in WD group, while the abundance of Prevotella (1.63% vs 2.48%, P < .001), Roseburia (0.75% vs 1.39%, P < .001) and Phascolarctobacterium (1.72% vs 2.45%, P < .001) significantly decreased in WD group. PCoA and UPGMA tree analysis showed that there were significant differences of gut microbial compositions between the 2 groups.The diversity and composition of intestinal flora in the WD patients were significantly lower than those in the healthy controls, and the diversity of intestinal flora may be associated with the presence of WD.

Background Polyglucosan body myopathy 1 (PGBM1) is a type of glycogen storage disease that can cause skeletal muscle myopathy and cardiomyopathy with or without immunodeficiency due to a pathogenic mutation in the RBCK1 gene. PGBM1 has been reported in only 14 European and American families, and no cognitive impairment phenotype was reported. Its prevalence in Asia is unknown. Case presentation: We report a Chinese boy with teenage onset of skeletal muscle myopathy and mild cognitive impairment. Whole-exome sequencing analysis identified a homozygous missense mutation in RBCK1 (c.1411G > A:p.Glu471Lys). A muscle biopsy indicated the accumulation of periodic acid-Schiff-positive material, which could be ubiquitinated by immunohistochemistry with an anti-ubiquitin antibody. In skeletal muscle tissue, HOIL-1 and HOIP protein levels were lower than those in the control, confirming the phenotype of an RBCK1 mutation. MRI revealed abnormal cerebral white matter signals. Immune system and cardiac examination found no abnormalities. The patient was diagnosed with PGBM1 with no effective treatment. Conclusions This case from China with a novel homozygous missense mutation in RBCK1 extends the phenotypic spectrum and geographical distribution of PGBM 1, which may cause cerebral white matter changes and cognitive impairment.