Aberrant copper metabolism and hepatic inflammation cause neurological manifestations in a mouse model of Wilson's disease.

Pathogenic germline mutations in the P-type copper-transporting ATPase (ATP7B) gene cause Wilson's disease (WD), a hereditary disorder characterized by disrupted copper metabolism. The Arg778Leu (R778L) mutation in exon 8 is prevalent among individuals with WD in East Asia and is associated with more severe phenotypes. In this study, we generated a WD mouse model harboring R778L mutation (R778L mice) using CRISPR/Cas9. R778L mice exhibit a range of pathological characteristics resembling those of patients with WD and the same point mutations, including aberrant copper metabolism, pathological cellular injury, inflammation, and severe hepatic fibrosis. At 3-5 months of age, these mice started to display neurological deficits in motor coordination and cognitive dysfunction, accompanied by increased expression of inflammatory cytokines in the central nervous system. Microglia in the striatum and cortex exhibit significant activation, shorter processes, and decreased branch points. However, the Cu2+ levels in the brain tissue of R778L mice did not differ significantly from those of wild-type mice. Notably, inhibition of hepatic inflammation with PJ34 or siNfkb markedly alleviated the deficiencies in cognitive performance and improved locomotor activity in R778L mice. Thus, this study establishes a novel murine model to investigate the pathophysiology of WD, highlights the liver-brain crosstalk responsible for neurological manifestations in individuals with WD caused by the R778L point mutation, and demonstrates the potential of modulating liver inflammation as a therapeutic strategy for alleviating the neurological manifestations of WD.

Age and Serum Creatinine Can Differentiate Wilson Disease Patients with Pseudonormal Ceruloplasmin.

Methods: We retrospectively screened individuals with serum Cp ≥ 140 mg/L from 1032 WD patients who were hospitalised for the first time. Logistic regression analyses were performed in a case-control study between the WD cohort and another liver disease cohort to explore the independent risk factors for WD diagnosis and establish a regression model to identify them. The follow-up medical records of the WD cohort were subjected to mixed-effects model analysis in a longitudinal study to discover factors associated with Cp normalisation. Results: Eighty-six WD patients and their 353 medical records and another 98 non-WD liver disease patients were included in the present study. Cp normalisation was significantly associated with the copper burden and liver function indexes, such as urinary copper, γ-glutamyltransferase, and albumin (p ≤ 0.001). Logistic regression analysis showed that age and serum creatinine (p ≤ 0.001) were independent risk factors associated with WD. The AUC value of the regression model in the total cohort was 0.926 (p ≤ 0.001). At a cutoff value of ≥0.617 and ≥-1, the positive and negative predictive values were both 90.8% for WD. Conclusion: Increased serum Cp in WD patients is related to excessive copper burden and hepatic injury, and common tests can effectively distinguish WD patients from other liver injury patients.

Polyglucosan body myopathy 1 may cause cognitive impairment: a case report from China.

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.

Characteristics of neurological Wilson's disease with corpus callosum abnormalities.

BACKGROUND: Wilson's disease (WD) is an autosomal recessive disease of impaired copper metabolism. Previous study demonstrated that WD with corpus callosum abnormalities (WD-CCA) was limited to the posterior part (splenium). This study aimed to compare clinical features between WD-CCA and WD without corpus callosum abnormalities (WD-no-CCA). METHODS: Forty-one WD patients who had markedly neurological dysfunctions were included in this study. We retrospectively reviewed clinical, biochemical characteristics and MRI findings in the 41 WD patients. All patients were assessed using the Unified Wilson's Disease Rating Scale. RESULTS: Nine patients had corpus callosum abnormalities, 4 of 9 patients had abnormal signal in the genu and splenium, 5 of 9 patients had abnormal signal only in the splenium. WD-CCA had longer course (9.9 ± 4.0 years vs. 3.4 ± 3.6 years, p<0.01), more severe neurological dysfunctions (37.6 vs. 65.9, p<0.01) and higher psychiatric symptoms scores (11.2 vs. 22.5, p<0.01) than WD-no-CCA. The MRI findings indicated that WD-CCA had higher ratio than WD-no-CCA in globus pallidus (88.9% vs. 43.8%, p = 0.024) and thalamus (100% vs. 59.4%, p = 0.038). The index of liver function and copper metabolism had no significant in WD-CCA and WD-no-CCA patients. CONCLUSION: Our findings indicate Wilson's disease can involve the posterior as well as the anterior part of CC and patients with CC involvement had more extensive brain lesions, more severe neurological dysfunctions and psychiatric symptoms.

The study of Wilson disease in pregnancy management.

INTRODUCTION: Pregnancy management in women with Wilson disease (WD) remains an important clinical problem. This research was conducted to investigate how to avoid worsening of WD symptoms during pregnancy and increase pregnancy success in women with WD by identifying the best pregnancy management approaches in these patients. PATIENTS AND METHODS: The clinical data of 117 pregnancies among 75 women with WD were retrospectively analyzed. Related information of the fetus was also recorded and analyzed. At the same time, regression analysis was performed for data of 22 pregnant women without WD, as normal controls. RESULTS: Of a total of 117 pregnancies among the 75 women with WD and 31 pregnancies among the 22 control womenincluded in this study, there were 108 successful pregnancies and 9 spontaneous abortions. Among the 108 successful pregnancies, 97 women a history of copper chelation therapy before pregnancy; all 97 women stopped anti-copper therapy during pregnancy. The nine women with spontaneous abortion had no pre-pregnancy history of copper displacement therapy. The incidence of lower limb edema was higher in the WD group than in normal controls (P = 0.036). Compared with the control group, there was a higher proportion in the WD group of male infants (P = 0.022) and lower average infant birth weight (t = 3.514, P = 0.001). CONCLUSION: It is relatively safe for women with WD patients to become pregnant. The best management method for pregnancy in women with WD may be intensive pre-pregnancy copper chelation therapy and no anti-copper treatment during pregnancy.

Inflammatory cytokines expression in Wilson's disease.

BACKGROUND: Wilson's disease (WD) is an autosomal recessive inherited disorder of copper (Cu) metabolism. Inflammation is a self-defensive reaction aimed at eliminating or neutralizing injurious stimuli, and restoring tissue integrity. Copper deposition may lead to inflammation in the organs and tissues of WD patients. OBJECTIVE: The aim of this study was to compare the plasma levels of inflammatory cytokines in patients with WD and healthy group, and also to assess whether inflammatory cytokines affects the clinical manifestation of WD. METHODS: Ninety-nine patients with WD and 32 controls were recruited for this study. Ray Biotech antibody microarray was used to detect the levels of plasma inflammatory cytokines. RESULTS AND CONCLUSION: Our results showed significant increase in T helper (Th) 1 cells (IL-2, TNF-α, and TNF-ß), Th2 cells (IL-5, IL-10, and IL-13), and Th17 (IL-23) (p < 0.05). Higher plasma Th 1 cells (IL-2, TNF-α, and TNF-ß), Th 2 cells (IL-13), and Th 17 (TGF-ß1, IL-23) levels were found in neurological patients compared with control groups (p < 0.01). Besides, we found Th 1 cells (TNF-α and TNF-ß), Th 3 (TGF-ß1), and Th 17 (IL-23) levels were significantly higher in hepatic and neurological patients (p < 0.05). In addition, the higher Th1 cells (IL-2, TNF-α, and TNF-ß), Th2 cells (IL-13), and Th17 (TGF-ß1, IL-23) and the course of WD were associated with the severity of the neurological symptoms for WD patients. Altogether, our results indicated that dysregulation of cytokines, mainly increased expression of cytokines and chemokines, occurred in WD patients.

The c-Abl inhibitor in Parkinson disease.

Parkinson's disease (PD) is an insidious onset neurodegenerative disease affecting approximately 1% of the population over the age of 65. So far available therapies for PD have only aimed at improving or alleviating symptoms, but not at slowing, preventing, and reversing the course of PD. Recently, some studies have indicated that the levels and activation of Abelson non-receptor tyrosine kinase (c-Abl, Abl1) were up-regulated in the brain tissue of patients with PD and demonstrated that c-Abl inhibitors could improve motor behavior, prevent the loss of dopamine neurons, inhibit phosphorylation of Cdk5, regulate α-synuclein phosphorylation and clearance, inhibit the tyrosine phosphorylation of parkin and decrease parkin substrate, for example, PARIS (zinc finger protein 746), AIMP2 (aminoacyl-tRNA synthetase-interacting multifunctional protein type2), FBP1 (fuse-binding protein 1), and synphilin-1. Therefore, we review the mechanism of the c-Abl inhibitor in PD and conclude that c-Abl inhibitors may be a potential treatment in PD and other neurodegenerative disease.

Renal impairment in different phenotypes of Wilson disease.

Wilson's disease (WD) is a rare autosomal recessive genetic disease resulting in the chronic deposition of copper in both liver and brain. This can lead to hepatic, neurologic, and psychiatric manifestations. Renal impairment can occur in any period of WD, but the mechanism is not yet known. In this study, we analyzed the clinical data of 691 newly diagnosed WD patients to investigate the blood urea nitrogen (BUN), creatinine (Cr), and uric acid (UA) levels in different subtypes of WD. This study included 691 newly diagnosed WD patients, 34 asymptomatic cases, and 127 healthy controls. The entire sample was assessed for serum levels of BUN, Cr, and UA. We found that the levels of BUN and Cr in WD patients who had neurological manifestations were higher (p < 0.001). In contrast, those patients presenting with a combined neurological and hepatic condition showed the lowest serum levels of UA (p = 0.026). There are differences in renal impairment between the endo-phenotypes of WD. Renal impairment can reflect differential copper deposition in organs other than the liver.

Elevated serum brain natriuretic peptide and matrix metalloproteinases 2 and 9 in Wilson's disease.

Wilson's disease (WD) is a disease of copper metabolism characterized by excessive copper deposition in the body. It is reported abnormal copper metabolism has been associated with cardiovascular disease. BNP and MMP2/9 were biomarkers of congestive heart failure (CHF). There is rare study to explore whether serum concentrations of BNP, MMP2, and or MMP9 are altered in patients with WD. In this study we determine whether serum concentrations of brain natriuretic peptide (BNP) and matrix metalloproteinases (MMP) 2 and 9 are increased in patients with WD. Serum BNP, MMP2 and MMP9 were measured by an ELISA in 34 patients with hepatic WD, in 68 patients with neurological WD, and in 33 healthy controls. We found serum BNP levels were higher in patients with neurological WD than in healthy controls (p = 0.033). Serum MMP2 levels were higher in patients with hepatic (p = 0.009) and neurologic (p = 0.0004) WD than in controls. Serum MMP9 levels were higher in patients with neurologic WD than in patients with hepatic WD (p = 0.002) and controls (p = 0.00005), and were higher in patients with hepatic WD than in controls (p = 0.03). Serum BNP levels were negatively correlated with ceruloplasmin (p = 0.017, r = -0.215), while serum (p = 0.019, r = -0.221) and MMP9 (p = 0.011, r = -0.231) in patients with WD were negatively correlated with ceruloplasmin. BNP, MMP2, and MMP9 may reflect the deposition of copper in the heart.

[The Correlation between Blood Uric Acid and Goldstein Grading in Hepatolenticular Degeneration Patients with Different Chinese Medical Syndrome Types].

OBJECTIVE: To observe blood uric acid levels and Goldstein grading, as well as their correlation in Wilson's disease (WD) patients with different Chinese medical syndrome types. METHODS: Totally 906 WD patients in line with inclusive criteria were assigned to 6 groups, i.e., the heart spirit confused by phlegm group (HSCP, 26 cases), the phlegm-fire disturbing heart group (PFDH, 90 cases), the retention of damp-heat group (RDH, 113 cases), deficiency of qi and blood group (DQB, 168 cases), the deficiency of Gan-yin and Shen-yin group (DGYSY, 327 cases), the deficiency of Gan and Shen group (DGS, 182 cases) due to different Chinese medical syndrome types. Recruited were another 160 healthy subjects having similar ages and diet structures, who came for medical examinations, as the healthy control group. Venous blood was collected from the medial cubital vein of each-patient on an empty stomach in early mornings to detect blood uric acid levels. Results Blood uric acid levels were lower in each syndrome type group than in the healthy control group (146.08 +/- 67.24 micromol/L in the HSCP group; 157.08 +/- 69.77 micromol/L in the PFDH group; 162.58 +/- 97.72 micromol/L in the RDH group; 156.20 +/- 62.63 micromol/L in the DQB group; 161.83 +/- 111.23 micromol/L in the DGYSY group; 194.41 +/- 90.01 micromol/L in the DGS group; 242.39 +/- 87.55 micromol/L in the healthy control group, P < 0.01). Blood uric acid levels were higher in the DGYSY group than in the other 5 syndrome groups (P < 0.01). Correlation analyses between Goldstein grading and blood uric acid showed that, along with increased Goldstein grade (that was aggravating disease conditions), WD patients' blood uric acid levels decreased (P < 0.01). CONCLUSIONS: WD patient's blood uric acid levels decreased more. Blood uric acid levels and Goldstein grading were different in various Chinese medical syndrome types. Blood uric acid levels had certain value in assessing the severity of WD.

Wilson disease in the South chinese han population.

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.

Outcomes of pregnancy in Wilson's disease: a population-based study from multiple centres of the Han population in China.

Objectives: Wilson's disease is an autosomal recessive disorder related to copper metabolism which mostly patients occurs in adolescents, fertility has become a problem that WD needs to face. Methods: A 21 years retrospective follow up study was conducted and a total of 220 female patients were included to identify patients with outcomes of pregnancy. Results: Untreated female patients with WD had a spontaneous abortion rate of 44%. During the study period, 146 female patients with WD from multicenter, 75 patients (51.4%) had successful outcomes of pregnancy. Notably, urinary copper levels below 616 µg/24 h were strongly associated with successful pregnancy. The nomogram built on these variables were age, urinary copper, haemoglobin and Child-Pugh classification, internally validated and showed good performance. Conclusion: The spontaneous abortion rate was 44% in untreated females with WD and developed a four-variable risk prediction model to accurately predict the likelihood of a successful pregnancy.

[Clinical and genetic study of Wilson's disease in affected twins and siblings].

OBJECTIVE: To study the clinical and genetic characteristics of twins and siblings affected with Wilson's disease (WD). METHODS: Clinical data and blood samples were collected from the subjects after informed consent was obtained. Genomic DNA was extracted and potential mutations in the exons in ATP7B gene were detected with PCR-DNA sequencing. Short tandem repeat (STR) genotyping was performed to determine the zygosity of the twins. RESULTS: The 5 pairs of twins have all met the diagnostic criteria for WD. STR genotyping has confirmed that 4 pairs were monozygotic twins. 3 pairs of twins had an onset with liver symptoms, the other 2 had an onset with brain symptoms. ATP7B gene mutations were detected in 4 pairs of twins, which have all located in exons 8 and 13. A heterozygous p.R778W mutation in exon 8 and homozygous p.P992L mutation in exon 13 were detected in all patients from one family, whose parents have carried a heterozygous p.R778W mutation and p.P992L heterozygous mutation, respectively, which suggested loss of heterozygosity (LOH). In one family, no mutation was detected in all exons of the ATP7B gene in the patients and their parents. For a triplet, one female was with definite WD and brain symptoms at the onset, one male had subclinical type with WD, whilst another female was completely normal. The triplets and their mother have all carried a p.P992L heterozygous mutation . CONCLUSION: Above results have confirmed an important role for genetic factors in the pathogenesis of WD. In addition to point mutations, LOH is also involved in the pathogenesis for WD.

[Research on the correlation between Chinese medical syndrome types and objective indices of Wilson's disease].

OBJECTIVE: To explore the correlation between Chinese medical syndrome types of Wilson's disease (WD) and clinical materials as well as physical and chemical indices. METHODS: Totally 116 WD patients were typed by Chinese medical syndrome. The correlation between Chinese medical syndrome types and clinical materials as well as physical and chemical indices were analyzed using binary stepwise Logistic regression by SPSS 19.0 Software, taking the common Chinese medical syndrome types as the dependent variable and clinical materials as well as physical and chemical indices as the independent variables. RESULTS: Gan-Galibladder dampness-heat syndrome (GGDHS, 35.3%). Gan-stagnation and Pi-deficiency syndrome (GSPDS, 13.8%), Gan-Shen yin deficiency syndrome (GSYDS, 13.8%), and phlegm-dampness retention syndrome (PDRS, 12.1%) were most often seen. GGDHS was positively correlated with grade of K-F ring, total bilirubin (TBIL), alanine transaminase (ALT), laminin (LN) (P < 0.01). GSYDS was positively correlated with TBIL (P < 0.01). PDRS was positively correlated with clinical types, ceruloplasmin (CP), aspartate aminotransferase (AST), and total protein (TP) (P < 0.01, P < 0.05). Qi blood deficiency syndrome was positively correlated with disease course, blood ammonia, blood urea nitrogen (BUN), and LN (P < 0.01, P < 0.05). CONCLUSIONS: Chinese medical syndrome types were correlated with clinical materials, physical and chemical indices in WD patients, which could provide experimental reference for Chinese medical syndrome typing. GGDHS, GSPDS, GSYDS, and PDRS were most often seen.

Identification of Lncrna-Mrna Networks in Hepg2 Cells upon ATP7B Knockout and Copper Accumulation.

Background: Hepatolenticular degeneration (HLD) is an inherited disorder caused by the mutation in the adenosine triphosphatase copper transporting ß gene (ATP7B). W aimed to explore the genetic changes in HLD using bioinformatics analysis. Methods: The study was conducted in Nepal, in 2019. The GSE107323 dataset was downloaded and the differentially expressed lncRNAs (DElncRNAs) as well as differentially expressed genes (DEGs) induced by ATP7B knockout (KO) and copper toxicity were clustered using Mfuzz clustering analysis. LncRNAs and genes with high coexpression (correlation coefficient > 0.9) and pathways involving the DEGs were used to construct the lncRNA-gene-pathway network. Results: ATP7B KO and ATP7B KO + copper induced 51 overlapping DEGs and 687 overlapping DElncRNAs, respectively. Mfuzz analysis identified four clusters, including two clusters of consistently upregulated and downregulated DEGs/DElncRNAs. The lncRNA-gene-pathway network consisted of 13 DElncRNAs, 10 DEGs, and two pathways, including "hsa04630: Jak-STAT signaling pathway" and "hsa04920: Adipocytokine signaling pathway". Eight downregulated genes, including erythropoietin (EPO), insulin receptor substrate 1 (IRS1), and PPARG coactivator 1 alpha (PPARGC1A), and two upregulated genes (cardiotrophin-like cytokine factor 1 and cyclin D3) were involved in the two pathways. These genes were targeted by multiple lncRNAs, including PCAT6 and MALAT1. Conclusion: Collectively, the differentially expressed lncRNA-mRNA axes play crucial roles in HLD pathogenesis through mediating cell proliferation and inflammation. Moreover, the EPO, IRS1, or PPARGC1A genes were potent therapeutic targets for HLD.

Sexual dysfunction in Wilson disease: Prevalence and influencing factors.

Wilson disease is a rare neurogenetic disorder that receives significant attention due to its manifestations, such as jaundice, cirrhosis, tremor, dystonia, and others. However, the impact of Wilson disease on sexual function has been overlooked. In this study, we aimed to investigate current status of sexual dysfunction in Wilson disease. In this study, we investigated the sexual function status and possible influencing factors of 245 Wilson disease patients by questionnaire. Our study identified sexual dysfunction as a prevalent issue in Wilson disease patients, with an overall prevalence of 49.0 %, of which 33.9 % in males and 63.7 % in females, both higher than the prevalence of sexual dysfunction in the normal Chinese population. Compared with non-sexual dysfunction patients, sexual dysfunction was more common in the older age group, females, less educated, rural residence, no occupation, lower income, taking sedatives/antipsychotics, and high SIS scores (P < 0.05). Our binary logistic regression analysis revealed that older age (OR: 1.103, 95 %CI: 1.058-1.151, P < 0.001), being female (OR: 5.900,95 %CI: 2.966-11.736, P < 0.001), and the use of antipsychotics or sedatives (OR: 3.277,95 %CI: 1.065-10.077, P < 0.05) were all positively linked with an increased risk of sexual dysfunction. Despite the well-known symptoms of Wilson disease, sexual dysfunction is also a frequent issue in Wilson disease patients, necessitating further attention.

Cognitive and gait in Wilson's disease: a cognitive and motor dual-task study.

Background: Cognitive and motor dual-tasks play important roles in daily life. Dual-task interference impacting gait performance has been observed not only in healthy subjects but also in subjects with neurological disorders. Approximately 44-75% of Wilson's disease (WD) patients have gait disturbance. According to our earlier research, 59.7% of WD patients have cognitive impairment. However, there are few studies on how cognition affects the gait in WD. Therefore, this study aims to explore the influence of cognitive impairment on gait and its neural mechanism in WD patients and to provide evidence for the clinical intervention of gait disturbance. Methods: We recruited 63 patients who were divided into two groups based on their scores on the Addenbrooke's cognitive examination III (ACE-III) scale: a non-cognitive impairment group and a cognitive impairment group. In addition to performing the timed up and go (TUG) single task and the cognitive and motor dual-task digital calculation and animal naming tests, the Tinetti Balance and Gait Assessment (POMA), Berg Balance Scale (BBS), and brain MRI severity scale of WD (bMRIsc-WD) were evaluated. The dual-task cost (DTC) was also computed. Between the two groups, the results of the enhanced POMA, BBS, and bMRIsc-WD scales, as well as gait performance measures such as TUG step size, pace speed, pace frequency, and DTC value, were compared. Results: (1) Among the 63 patients with WD, 30 (47.6%) patients had gait disturbance, and the single task TUG time was more than 10 s. A total of 43 patients had cognitive impairment, the incidence rate is 44.4%. Furthermore, 28 (44.4%) patients had cognitive impairment, 39 (61.9%) patients had abnormal brain MRI. (2) The Tinetti gait balance scale and Berg balance scale scores of patients with cognitive impairment were lower than those of patients without cognitive impairment (p < 0.05), and the pace, step size, and pace frequency in the single task TUG were slower than those of patients without cognitive impairment (p < 0.05). There was no change in the pace frequency between the dual-task TUG and the non-cognitive impairment group, but the pace speed and step size in the dual-task TUG were smaller than non-cognitive impairment group (p < 0.05). There was no difference in DTC values between cognitive impairment group and non-cognitive impairment group when performing dt-TUG number calculation and animal naming respectively (p > 0.05). However, regardless of cognitive impairment or not, the DTC2 values of number calculation tasks is higher than DTC1 of animal naming tasks in dt-TUG (p < 0.05). (3) Pace speed and step size were related to the total cognitive score, memory, language fluency, language understanding, and visual space factor score of the ACE-III (p < 0.05), and step frequency was correlated with memory and language comprehension factors (p < 0.05). There was no correlation between the attention factor scores of the ACE-III and TUG gait parameters of different tasks (p > 0.05). Brain atrophy, the thalamus, caudate nucleus, and cerebellum were correlated with cognitive impairment (p < 0.05), the lenticular nucleus was related to the step size, brain atrophy was related to the pace speed, and the thalamus, caudate nucleus, and midbrain were involved in step frequency in WD patients (p < 0.05). Conclusion: WD patients had a high incidence of cognitive impairment and gait disorder, the pace speed and step size can reflect the cognitive impairment of WD patients, cognitive impairment affects the gait disorder of WD patients, and the different cognitive and motor dual-tasks were involved in affecting gait parameters. The joint participation of cognitive impairment and lesion brain area may be the principal neural mechanism of gait abnormality in WD patients.

Case report: A Chinese patient with spinocerebellar ataxia finally confirmed as Gerstmann-Sträussler-Scheinker syndrome with P102L mutation.

Gerstmann-Sträussler-Scheinker syndrome (GSS) is a rare genetic prion disease caused by a mutation in the prion protein (PRNP) gene. It is typically characterized by progressive cerebellar ataxia and slowly progressive dementia. We present a case study of the GSS from China in which a 45-year-old male with a progressive gait and balance disorder developed cerebellar ataxia onset but was misdiagnosed as spinocerebellar ataxia (SCA) for 2 years. The patient's clinical, electrophysiological, and radiological data were retrospectively analyzed. Examination revealed ataxia, dysarthria, muscle weakness, areflexia in lower limbs, including a pyramidal sign, whereas cognitive decline was insignificant. His late mother had a similar unsteady gait. An electroencephalogram (EEG) showed normal findings, and 14-3-3 protein was negative. A brain MRI was performed for global brain atrophy and ventricular enlargement. Positron emission tomography-computed tomography (PET-CT) (18F-fluoro-2-deoxy-d-glucose, FDG) images showed mild to moderate decreased glucose metabolism in the left superior parietal lobe and left middle temporal lobe. According to genetic testing, his younger brother also had the P102L variant in the PRNP gene. This single case adds to the clinical and genetic phenotypes of GSS.

A weighted cranial diffusion-weighted imaging scale for Wilson's disease.

Objectives: Cranial magnetic resonance imaging (MRI) could be a crucial tool for the assessment for neurological symptoms in patients with Wilson's disease (WD). Diffusion-weighted imaging (DWI) hyperintensity reflects the acute brain injuries, which mainly occur in specific brain regions. Therefore, this study aimed to develop a weighted cranial DWI scale for patients with WD, with special focus on specific brain regions. Materials and methods: In total, 123 patients with WD were enrolled, 118 of whom underwent 1.5 T-MRI on admission. The imaging score was calculated as described previously and depended on the following sequences: one point was acquired when abnormal intensity occurred in the T1, T2, and fluid-attenuation inversion recovery sequences, and two points were acquired when DWI hyperintensity were found. Consensus weighting was conducted based on the symptoms and response to treatment. Results: Intra-rater agreement were good (r = 0.855 [0.798-0.897], p < 0.0001). DWI hyperintensity in the putamen was a high-risk factor for deterioration during de-copper therapy (OR = 8.656, p < 0.05). The high-risk factors for readmission for intravenous de-copper therapies were DWI hyperintensity in the midbrain (OR = 3.818, p < 0.05) and the corpus callosum (OR = 2.654, p < 0.05). Both scoring systems had positive correlation with UWDRS scale (original semi-quantitative scoring system, r = 0.35, p < 0.001; consensus semi-quantitative scoring system, r = 0.351, p < 0.001.). Compared to the original scoring system, the consensus scoring system had higher correlations with the occurrence of deterioration (OR = 1.052, 95%CI [1.003, 1.0103], p < 0.05) and readmission for intravenous de-copper therapy (OR = 1.043, 95%CI [1.001, 1.086], p < 0.05). Conclusion: The predictive performance of the consensus semi-quantitative scoring system for cranial MRI was improved to guide medication, healthcare management, and prognosis prediction in patients with WD. For every point increase in the neuroimaging score, the risk of exacerbations during treatment increased by 5.2%, and the risk of readmission to the hospital within 6 months increased by 4.3%.

[Wilson's disease in decision-making functions of Iowa gambling task].

OBJECTIVE: To explore the presence of impaired decision-making functions of Wilson's disease patients in Iowa gambling task (IGT) and its association with basal ganglia damage. METHODS: Thirty-two IGT patients with WD (WD group) and 29 healthy people (control group) were recruited from the same period. And two options of high and low rewards were selected. Before the start of experiment, a basal figure of 2000 yuan was shown on computer display and they were prompted to win more money as much as possible. The general trend was observed with or without social learning effects. RESULTS: With the increased number of cards selected, the number of favorable and unfavorable selections shifted from negative to positive and gradually rose in the control group. However, such a pattern was absent in the WD group. The WD patients in the IGT group in Trial4 and Trial5 were significantly lower than the controls (P = 0.009 and P = 0.020). CONCLUSION: The WD IGT patients have significant impairments of policy-making functions due to the damage of basal ganglia. And the effects of copper metabolism on cerebral cortex should be further studied in WD patients.