Search

Deposition of insoluble SOD1 aggregates in motor neurons is the hallmark of SOD1-associated ALS. Mutant SOD1 protein promotes structural instability that leads to misfolded SOD1 protein aggregates, which can be recapitulated in vitro. Therefore, aggregation propensity in cell lines can be a reliable indicator for the pathogenicity classification of SOD1 variants. Herein, we performed in vitro experiment to classify the pathogenicity of 34 SOD1 variants of uncertain significance (VUS) from 215 variants reported previously. The clinical features of 234 ALS patients with 31 SOD1 likely pathogenic (LP) variants were summarized. 31 VUS variants formed aggregates spontaneously, indicating LP variants. Missense variants were mainly located in the C-terminal of SOD1. Among patients with 31 SOD1 LP variants, 75% of patients had lower limb onset. The onset of familial ALS patients (45.7±14.0 years) is earlier than sporadic ALS patients (50.6±13.1 years). Our results expand the spectrum of SOD1 mutations and highlight the natural history of SOD1-positive ALS patients for further clinical trials in SOD1-related ALS.

Background: The Unified Huntington’s Disease Rating Scale (UHDRS) is a universal scale assessing disease severity of Huntington’s disease (HD). However, the English version cannot be widely used in China, and the reliability and validity of the Chinese UHDRS have not yet been confirmed. Objective: To test the reliability and validity of Chinse UHDRS in patients with HD. Methods: Between August 2013 and August 2021, 159 HD patients, 40 premanifest HD, and 64 healthy controls were consecutively recruited from two medical centers in China and assessed by Chinese UHDRS. Internal consistency and interrater reliability of the scale were examined. Intercorrelation was performed to analyze the convergent and divergent validity of the scale. A receiver operating characteristic analysis was conducted to explore the optimal cutoff point of each cognitive test. Results: High internal consistency was found in Chinese UHDRS, and its Cronbach’s alpha values of the motor, cognitive, behavioral and functional subscales were 0.954, 0.826, 0.804, and 0.954, respectively. The interrater reliability of the total motor score was 0.960. The convergent and divergent validity revealed that motor, cognitive and functional subscales strongly related to each other except for Problem Behavior Assessment. Furthermore, we not only provided the normal level of each cognitive test in controls, but also gave the optimal cutoff points of cognitive tests between controls and HD patients. Conclusion: We demonstrate for the first time that the translated version of UHDRS is reliable for assessing HD patients in China. This can promote the universal use of UHDRS in clinical practice.

Qing-Qing Tao,1 Rong-Rong Lin,1 Zhi-Ying Wu1,2 1Department of Neurology and Research Center of Neurology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, People’s Republic of China; 2MOE Frontier Science Center for Brain Science and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, People’s Republic of ChinaCorrespondence: Zhi-Ying Wu, Department of Neurology and Research Center of Neurology, Second Affiliated Hospital, Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, 310009, People’s Republic of China, Email zhiyingwu@zju.edu.cn

Mutations in proline-rich transmembrane protein 2 (PRRT2) are the major cause of paroxysmal kinesigenic dyskinesia (PKD). We recently reported transmembrane protein 151A (TMEM151A) mutations caused PKD. Herein, we aimed to conduct phenotypic comparisons of patients with PKD carrying PRRT2 variants, carrying TMEM151A variants, and carrying neither the PRRT2 nor TMEM151A variant.Sanger sequencing of PRRT2 and TMEM151A was performed, and phenotypic characteristics were analyzed.In a cohort of 131 PKD probands (108 without PRRT2 variants and 23 newly recruited), five novel TMEM151A variants were identified and one (c.647C A) occurred de novo. Together with our previous studies, PRRT2 and TMEM151A variants accounted for 34.7% (85/245) and 6.9% (17/245) of PKD probands, respectively. Compared with patients carrying PRRT2 variants, those with TMEM151A variants tended to exbibit dystonia with shorter durations, have no history of benign infantile epilepsy, and have residual attacks/aura when treated with carbamazepine/oxcarbazepine.Patients with TMEM151A variants have different features from patients with PRRT2 variants. © 2022 International Parkinson and Movement Disorder Society.

PurposeThis paper aims to propose a two-period model in which an original equipment manufacturer (OEM) decides the remanufacturability level of products in product design and unit patent licensing fee at the first period, and a third-party remanufacturer (3PR) that has been licensed by the OEM enters the remanufacturing market to compete with the OEM at the second period.Design/methodology/approachThis paper analyzes the OEM's optimal decisions of remanufacturability level in the product design and unit patent licensing fee at the first period, as well as the OEM's and the 3PR's optimal decisions of selling prices at the second period, under two scenarios that the remanufacturing is constrained or unconstrained by the collected quantity available at the end of the first period, by making use of game theory.FindingsThe study finds that the OEM will choose high remanufacturability in product design only when the unit cost saving of remanufacturing or unit production cost of new products exceed certain thresholds.Originality/valueThe study is the first attempt to simultaneously integrate product design and patent licensing in remanufacturing. It provides useful insights for OEM managers who face competition from 3PRs and may use their product design strategies to deter 3PRs and may protect patent of products by levying patent licensing fees from 3PRs.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease involving motor, cognitive and psychiatric disturbances. HD patients with psychosis symptoms usually have bad prognosis. It is of great significance to explore the clinical, imaging and biological characteristics of HD patients with psychosis. A total of 118 Han Chinese patients with HD confirmed by Huntingtin genetic testing were recruited during 2013–2020. They were assessed by Unified Huntington's Disease Rating Scale (UHDRS) and followed up in an average of 34 months by telephone or clinical visits. Psychosis was determined by the presence of delusions or hallucinations using UHDRS-Problem Behavior Assessment. Data of magnetic resonance imaging (n = 28) and serum neurofilament light chain (NfL, n = 28) were collected in some patients. Among 118 patients (mean age 46.0 years, SD 12.0; female 53.5%), the frequency of psychosis was 14.4% (n = 17) in the cross-sectional analysis and 17.8% (n = 21) in the longitudinal observation. Probands with psychosis were predominantly female (82.3%). They exhibited worse motor, cognitive, behavioral and functional performances compared with patients without psychosis. Furthermore, the lateral ventricle volume was larger in patients with psychosis compared with patients without psychosis (p = 0.0013) while there was no difference in NfL levels between two groups. NfL levels of patients with psychosis were negatively correlated with caudate volumes (r = −0.54, p = 0.044) and white matter volumes (r = −0.57, p = 0.035). In summary, HD patients with psychosis had distinct clinical, imaging and biological features. These features might help clinicians to identify psychosis in HD patients early and provide protective interventions before adverse outcomes occur.

Background and Purpose: Aceruloplasminemia (ACP) is a rare disorder of iron overload resulting from ceruloplasmin (CP) variants. Because of its rarity and heterogeneity, the diagnosis of ACP is often missed or misdiagnosed. Here, we aim to present a clinical spectrum of ACP and raise more attention to the early diagnosis. Methods: Whole exome sequencing (WES) was performed in a Chinese female patient suspected with ACP and her clinical data were collected in detail. The PubMed databases was searched for published ACP patients within the last decade, and we present a systematic review of their clinical features with data extracted from these researches. Results: A novel pathogenic variant (c.2689delC) and a known pathogenic variant (c.606dupA) within ceruloplasmin gene were identified in our patient and confirmed the diagnosis of ACP. Then we reviewed 50 ACP patients including the case we reported here. A possible timeline of symptoms was discovered, anemia appears first (29.7 years old on average), followed by diabetes (37.3 years old) and finally neurological symptoms (52.2 years old). The delay in diagnosis was significantly shortened in patients without neurological symptoms. Biochemical triad including anemia, low to undetectable serum ceruloplasmin, low serum iron and/or hyperferritinemia, showed better sensitivity in diagnosis than clinical triad including diabetes, neurological symptoms and retinal degeneration. Conclusions: Due to the variable symptom spectrum, patients with ACP often visit different departments, which can lead to misdiagnosis. Clinical attention needs to be paid to symptoms and tests that have a warning effect. Prompt diagnosis in the early stage of the disease can be beneficial.

Introduction Distal myopathies are a group of rare muscle disorders characterized by selective or predominant weakness in the feet and/or hands. In 2019, ACTN2 gene was firstly identified to be a cause of a new adult‐onset distal muscular dystrophy calling actininopathy and another distinctly different myopathy, named multiple structured core disease (MsCD). Thus, the various phenotypes and limited mutations in ACTN2‐related myopathy make the genotype‐phenotype correlation hard to understand. Aims To investigate the clinical features and histological findings in a Chinese family with distal myopathy. Whole exome sequencing and several functional studies were performed to explore the pathogenesis of the disease. Results We firstly identified a novel frameshift variant (c.2504delT, p.Phe835Serfs*66) within ACTN2 in a family including three patients. The patients exhibited adult‐onset distal myopathy with multi‐minicores, which, interestingly, was more like a combination of MsCD and actininopathy. Moreover, functional analysis using muscle samples revealed that the variant significantly increased the expression level of α‐actinin‐2 and resulted in abnormal Z‐line organization of muscle fiber. Vitro studies suggested aggregate formations might be involved in the pathogenesis of the disease. Conclusion Our results expanded the phenotypes of ACTN2‐related myopathy and provided helpful information to clarify the molecular mechanisms., A rare adult‐onset distal myopathy with multi‐minicores caused by a novel ACTN2 mutation. Functional analysis using muscle samples revealed that the variant significantly increased the expression level of α‐actinin‐2 and resulted in abnormal Z‐line organization of muscle fiber. Vitro studies suggested aggregate formations might be involved in the pathogenesis of the disease.

Background Spinocerebellar ataxia type 1 (SCA1) is the third most common type of spinocerebellar ataxia in China. However, data about Chinese SCA1 patients are limited. This study aims to provide a detailed description of the phenotype and genotype of Chinese SCA1 individuals and guide the clinical practice. Methods A total of 110 SCA1 individuals from 79 pedigrees and 123 unrelated normal controls were recruited. Sanger sequencing, SfaNI restriction and TA cloning were used for the determination of the CAG repeat size and the intrinsic structure. Clinical data including scale scores, magnetic resonance imaging and electromyography were collected. Results Interrupted pathogenic alleles occurred in 5.5% of the SCA1 individuals and caused later disease onset (p

Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a relatively common cerebral small vessel disease. NOTCH3 has been identified as the causative gene of CADASIL. Clinical variability and genetic heterogeneity were observed in CADASIL patients and need to be further clarified.The aim of the study was to clarify genetic spectrum of NOTCH3 and clinical phenotype of CADASIL patients.Suspected CADASIL patients were collected by our center between 2016 and 2021. Whole exome sequencing was performed to screen NOTCH3 mutations of these patients. Genetic and clinical data of CADASIL patients from previous studies were also analyzed. Studies between 1998 and 2021 that reported more than 9 pedigrees with detailed genetic data or clinical data were included. After excluding patients carrying cysteine-sparing mutations, genetic data of 855 Asian pedigrees (433 Chinese; 226 Japanese, and 196 Korean) and 546 Caucasian pedigrees, in a total of 1401 CADASIL pedigrees were involved in mapping mutation spectrum. Clinical data of 901 Asian patients (476 Chinese patients, 217 Japanese patients, and 208 Korean patients) and 720 Caucasian patients, in a total of 1621 patients were analyzed and compared between different populations.Two novel mutations (c.400TC, p.Cys134Arg; c.1511GA, p.Cys504Tyr) and 24 known cysteine-affecting variants were identified in 36 pedigrees. Genetic spectrums of Asians (Chinese, Japanese, and Korean) and Caucasians were clarified, p.R544C and p.R607C were the most common mutations in Asians while p.R1006C and p.R141C in Caucasians. For clinical features, Asians were more likely to develop symptoms of TIA or ischemic stroke (p 0.0001) and cognitive impairment (p 0.0001). Nevertheless, Caucasians had a higher tendency to present migraine (p 0.0001) and psychiatric disturbance (p 0.0001). The involvement of temporal pole was more likely to happen in Caucasians (p 0.0001).The findings help to better understand the clinical variability and genetic heterogeneity of CADASIL.

ObjectiveWe reported the case of a patient with Wilson's disease (WD) with acute-onset visual impairment and summarized previously reported cases to make physicians aware of the complicated clinical expressions of WD and improve diagnosis efficiency.MethodsThe patient was recruited from the Second Affiliated Hospital of Zhejiang University School of Medicine. Clinical data, including cranial images, laboratory tests, and ophthalmic findings were obtained. The PubMed database was searched for published cases of WD with visual impairment.ResultsWe reported a 22-year-old male who presented with hand tremor, personality change, and acute-onset binocular vision blurring. WD was considered to be closely correlated with neuropsychiatric and ocular involvements. After low-copper diet and regular copper-chelation therapy, the related symptoms improved compared to before. Six WD cases of optic neuropathy have been reported, including ours. The patients usually had neurological and/or hepatic symptoms for a period without any treatment. All the reported cases manifested as acute episodes of visual changes, and the ocular manifestations improved after copper-chelation treatment.ConclusionsExcess copper accumulation may be a rare cause of visual impairment in patients with WD. While the etiology behind patients' acute-onset visual impairment remained uncertain, the possibility of WD should be considered through neuropsychiatric and hepatic symptoms, corneal K-F rings, decreased serum ceruloplasmin, and low likelihood or exclusion of other causes. Clinicians need to recognize this rare manifestation and give appropriate treatment to avoid misdiagnosis and unnecessary overtreatment.

Wilson disease (WD) is a hereditary disorder of copper metabolism, resulting from mutations within ATP7B. Early diagnosis is essential for affected individuals. However, there are still patients with clinically suspected WD who do not have detectable pathogenic variants, which makes diagnosis difficult and delays treatment. This study included such patients from the authors' center and screened for the full-length sequence of ATP7B by next-generation sequencing. Newly identified synonymous and intronic variants were then analyzed with in silico tools. A minigene system was constructed to determine the pathogenicity of these variants in terms of splicing and blood RNA extraction, and RT-PCR experiments were performed on several patients to verify the splicing alterations. The phenotypes of the patients were also analyzed. Fourteen suspected pathogenic variants, including nine synonymous and five intronic variants, were detected in 12 patients with clinically suspected WD. Among them, four synonymous variants (c.1050GA, c.1122CG, c.3243GA, and c.4014TA) and four intronic variants (c.1543 +40GA, c.1707+6_1707+16del, c.1870-49AG, and c.2731-67AG) resulted in splicing changes in ATP7B. After the above analysis, the diagnosis of WD could be confirmed in eight clinically suspected patients with WD who showed a late age of onset.

A 37‐year old man presented a slight delay in early developmental milestones, cognitive decline, difficulty walking, cerebellar signs and extrapyramidal signs. Brain magnetic resonance imaging (MRI) showed a thin corpus callosum, cerebral atrophy, non‐specific white‐matter hyperintensity, and cerebellar atrophy. The genetic test revealed a putative homozygous deletion in SPG21 from exon 3 through exon 7, which was further validated by long‐range primer‐walking PCR. This is the first report of Chinese patient with Mast syndrome carrying a large homozygous SPG21 deletion.

Eomesodermin (Eomes), a transcription factor, could suppress the Th17 cell differentiation and proliferation through directly binding to the promoter zone of the Rorc and Il17a gene, meanwhile the expression of Eomes is suppressed when c-Jun directly binds to its promoter zone. Ginkgolide K (1,10-dihydroxy-3,14-didehydroginkgolide, GK) is a diterpene lactone isolated from the leaves of Ginkgo biloba. A previous study indicated that GK could decrease the level of phospho JNK (c-Jun N-terminal kinase). Here, we reported the therapeutic potential of Ginkgolide K (GK) treatment to ameliorate experimental autoimmune encephalomyelitis (EAE) disease progression. Methods: EAE was induced in both wildtype and CD4-Eomes conditional knockout mice. GK was injected intraperitoneally. Disease severity, inflammation, and tissue damage were assessed by clinical evaluation, flow cytometry of mononuclear cells (MNCs), and histopathological evaluation. Dual-luciferase reporter assays were performed to measure Eomes transcription activity in vitro. The potency of GK (IC50) was determined using JNK1 Kinase Enzyme System. Results: We revealed that GK could ameliorate EAE disease progression by the inhibition of the Th17 cells. Further mechanism studies demonstrated that the level of phospho JNK was decreased and the level of Eomes in CD4+T cells was dramatically increased. This therapeutic effect of GK was almost completely interrupted in CD4-Eomes conditional knockout mice. Conclusions: These results provided the therapeutic potential of GK treatment in EAE, and further suggested that Eomes expression in CD4+T cells might be essential in this process.

Background and purpose Spinocerebellar ataxia type 2 (SCA2) is the second most common type of spinocerebellar ataxia in China. However, data on the clinical and genetic features of Chinese SCA2 patients are scarce. This study aims to provide a comprehensive description of in the Chinese SCA2 cohort. Methods A total of 135 patients with SCA2 from 92 families and 104 unrelated normal controls were recruited from three medical centers between 2008 and 2020. Sanger sequencing and TA cloning were used to determine the CAG repeat length and intrinsic structure. The clinical data of patients with SCA2, including electromyography, magnetic resonance imaging, positron-emission tomography, and clinical scale scores, were recorded. Results The mean ± SD age at onset of SCA2 patients was 32.6 ± 11.9 years and the corresponding CAG repeat length was 42.1 ± 3.6. CAG repeat length accounted for 64% of the age-at-onset variance. We observed that patients had a significantly lower proportion of (CAG)8 CAA(CAG)4 CAA(CAG)8 within normal alleles than normal controls (48.8% vs. 64.9%; p = 0.003), while the distribution of the proportion of (CAG)13 CAA (CAG)8 was the opposite. Peripheral neuropathy was frequent, occurring in 75.9% of the patients. Parkinsonism was relatively common, with a frequency of 11.8%. Two patients with parkinsonism had a significantly more severe reduction in dopamine transporter levels in the bilateral striatum than the one patient with pure ataxia. An infant-onset case of SCA2 with more than 180 CAG repeats was characterized by global development delay, hypotonia and hearing impairment. Conclusions This study describes the genetic profile and clinical characteristics of the largest SCA2 cohort to date in the Chinese population and analyzes inter-population differences. Many aspects of this study population were different from other populations with SCA2.

Objective To identify and characterize the pathogenicity of novel variants in Chinese patients with Charcot–Marie–Tooth disease. Methods Multiplex ligation‐dependent probe amplification (MLPA) and whole‐exome sequencing (WES) were performed in 30 unrelated CMT patients. Minigene assay was used to verify the effect of a novel splicing variant (c.694+1G>A) on pre‐mRNA. Primary fibroblast cell lines were established from skin biopsies to characterize the biological effects of the novel variants p.L26R and p.S169fs. The mitochondrial structure was observed by an electron microscope. The expression level of protein was analyzed by Western Blotting. Mitochondrial dynamics and mitochondrial membrane potential (MMP, Δψm) were analyzed via immunofluorescence study. Mitochondrial ATP levels were analyzed via bioluminescence assay. The rate of oxygen consumption was measured with a Seahorse Bioscience XF‐96 extracellular flux analyzer. Results We identified 10 pathogenic variants in three known CMT related genes, including three novel variants (p.L26R, p.S169fs, c.694+1G>A) and one known pathogenic variant (p.R120W) in GDAP1. Further, we described the clinical features of patients carrying pathogenic variants in GDAP1 and found that almost all Chinese CMT patients with GDAP1 variants present axonal type. The effect of c.694+1G>A on pre‐mRNA was verified via minigene splice assay. Cellular biological effects showed ultrastructure damage of mitochondrial, reduced protein levels, different patterns of mitochondrial dynamics, decreased mitochondrial membrane potential (Δψm), ATP content, and defects in respiratory capacity in the patient carrying p.L26R and p.S169fs in GDAP1. Interpretation Our results broaden the genetic spectrum of GDAP1 and provided functional evidence for mitochondrial pathways in the pathogenesis of GDAP1 variants.

Objective Early-onset dementia (EOD) is a relatively uncommon form of dementia that afflicts people before age 65. Only a few studies analyzing the genetics of EOD have been performed in the Chinese Han population. Diagnosing EOD remains a challenge due to the diverse genetic and clinical heterogeneity of these diseases. The aim of this study was to investigate the genetic spectrum and clinical features of Chinese patients with EOD. Materials and methods A total of 49 EOD patients were recruited. Targeted next-generation (NGS) analyses were performed to screen for all of the known genes associated with dementia. Possible pathogenic variants were confirmed by performing Sanger sequencing. The genetic spectrum and clinical features of the EOD patients were analyzed. Results Seven previously reported pathogenic variants (p.I213T and p.W165C in PSEN1; p.D678N in APP; c.1349_1352del in TBK1; p.P301L and p.R406W in MAPT; p.R110C in NOTCH3) and two novel variants of uncertain significance (p.P436L in PSEN2; c.239-11G>A in TARDBP) were identified. Conclusion Our study demonstrated the genetic spectrum and clinical features of EOD patients, and it reveals that genetic testing of known causal genes in EOD patients can help to make a precise diagnosis.

Introduction Due to diverse symptoms of spinocerebellar ataxia type 3 (SCA3) and the high prevalence of SCA3 in China, a more in-depth study of Chinese SCA3 patients in a large cohort is well merited. Methods During the last 10 years, 730 patients and 133 premanifest individuals from 667 SCA3 families genetically confirmed to have SCA3 were enrolled from three leading academic hospitals in China. The clinical profile and genotype-phenotype correlation were analyzed. Results A quadratic equation best explained the relationship between the logarithmically transformed age at onset (AAO) and expanded CAG repeats (expCAGs) (r2 = 0.634, p 10 years. Intriguingly, onset after parturition happened in 10 female patients with the AAO of 26.7 ± 4.3 years and the expCAG of 77.4 ± 1.4 repeats. Five out of 12 patients with subtype V and larger expCAGs (78.8 ± 4.8 repeats) suffered from spastic gait initially, and 10 out of 12 showed no limb ataxia. Nystagmus happened most frequently (10.5%) in premanifest individuals. Conclusion We demonstrated the genotype-phenotype correlation in the largest cohort of SCA3 individuals to date, and interestingly found some new phenomena in Chinese SCA3 individuals.

The proline-rich coiled-coil 2A (PRRC2A) gene has been reported to underlie risk of various autoimmune diseases. However, no data reveal the risk susceptibility of PRRC2A to neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS) so far. To explore the association between PRRC2A variants and NMOSD and MS susceptibility in Han Chinese population. Totally, 207 NMOSD (98 AQP4+ and 109 AQP4−) patients, 141 MS and 196 healthy controls (HC) were enrolled. Candidate tagging single nucleotide polymorphisms (tag-SNPs) were selected from the 1000G database based on the Chinese data. SNP genotyping was performed using MassArray and Sanger sequencing. PRRC2A variants rs2736171, rs2736157, rs2844470 alter susceptibility to AQP4+ NMOSD, while rs2242659 to MS. Genotype AT of rs2844470 and AG of rs2242659 increased risk susceptibility for AQP4+ NMOSD and MS, respectively. AQP4+ NMOSD exhibited a higher frequency of genotype AG of rs2736157 compared with AQP4− NMOSD. Haplotype TCAAGGTAG was conferred risk susceptibility to AQP4+ NMOSD and haplotype TTAGAGTAG had a protective effect on both AQP4+ and AQP4− NMOSD. Further, we identified various gene expression levels in disease-related regions that are significantly modulated by three cis-eQTL SNPs rs2736157, rs2736171 and rs2242659 (p

Spinocerebellar ataxia type 3 (SCA3) is caused by unstable expanded CAG repeats (expCAGs) in ATXN3. Factors associated with intergenerational instability (delta-expCAG) and genetic anticipation in SCA3 have never been reported in Chinese mainland. Here, we demonstrated that unstable transmissions occurred more often in sons than in daughters (91% vs 72%, Fisher’s exact test, p = 0.012). The extended delta-expCAG of father-son transmissions was greater than that of mother-son transmissions (3.8 ± 2.3 repeats vs 1.6 ± 1.0 repeats, Mann-Whitney U, p = 0.001). Genetic anticipation was frequently observed between generations but not affected by the delta-expCAG.

Primary age-related tauopathy (PART) is characterized by the presence of tau neurofibrillary tangles (NFTs) which are typically observed in alzheimer’;s disease (AD) brains, with few or without β-amyloid (Aβ) plaques. The diagnosis of PART can be categorized into “definite” or “possible” depending on the amount of Aβ plaques. Definite PART is diagnosed when NFTs are observed and the Braak stage is ≤IV, with Thal Aβ Phase 0 (Crary et al., 2014). According to the neuropathological diagnostic criteria, we reported that PART was frequently observed in the Chinese population according to our findings from specimens in our brain bank, with 47% of brain bank subjects meeting the criteria for PART. There is no consensus on the nature of PART. It remains to be elucidated whether PART is an early form of AD or a novel tauopathy (Duyckaerts et al., 2015; Jellinger et al., 2015).

PLA2G6-associated neurodegeneration (PLAN) is a rare autosomal recessive disorder caused by PLA2G6 mutations. This study aimed to investigate the clinical characteristics and mutation spectrum of PLAN and to investigate the founder effects in Chinese PLAN patients. Six Chinese PLAN families were clinically examined in detail and whole-exome sequencing was performed in the probands. Haplotype analysis was performed in five families with the PLA2G6 c.991G > T mutation using 23 single nucleotide polymorphism markers. Furthermore, all previously reported PLA2G6 mutations and patients in China were reviewed to summarize the genetic and clinical features of PLAN. Interestingly, we found that one patient had hereditary spastic paraplegia and showed various atypical clinical characteristics of PLAN, and five patients had a phenotype of parkinsonism. All probands were compound heterozygotes for PLA2G6 variants, including four novel pathogenic/likely pathogenic mutations (c.967G > A, c.1450G > T, c.1631T > C, and c.1915delG) and five known pathogenic mutations. Haplotype analyses revealed that patients carrying PLA2G6 c.991G > T mutations shared a haplotype of 717 kb. The frequencies of psychiatric features, cognitive decline, and myoclonus in Chinese patients with PLA2G6-related parkinsonism were significantly different from those in European patients. Thus, our study expands the clinical and genetic spectrum of PLAN and provides an insightful view of the founder effect to better diagnose and understand the disease.

Wilson's disease (WD) currently lacks a promising indicator that could reflect neurological impairment and monitor treatment outcome. We aimed to investigate whether serum neurofilament light chain (sNfL) functions as a candidate for disease assessment and treatment monitoring of WD.We assessed preclinical and manifested WD patients' sNfL levels compared to controls and analyzed the differences between patients with various clinical symptoms. We then explored the correlation between clinical scales and sNfL levels. And repeated measurements were performed in 34 patients before and after treatment.WD patients with neurological involvement had significantly higher sNfL levels than both hepatic patients and controls. Positive correlations were found between Unified Wilson's Disease Rating Scale scores and sNfL and between semiquantitative magnetic resonance imaging scales and sNfL levels in WD patients. However, in the treatment follow-up analysis, the trend of sNfL before and after treatment disaccorded with clinical response.These findings suggest that sNfL levels can be an ideal indicator for the severity of neurological involvement but fail to evaluate change in disease condition after treatment. © 2022 International Parkinson and Movement Disorder Society.

Purpose: The endocrine manifestations of Wilson’s disease (WD) tended to be ignored, especially as initial clinical aspects. Currently there was a paucity of studies for endocrine involvement in WD patients. We aim to explore the explicit impact of WD on the endocrine system, to reduce the misdiagnosis.Methods: A retrospective study was performed in 37 female patients with WD. They were recruited from the Second Affiliated Hospital of Zhejiang University School of Medicine from October 2018 to October 2020. Each patient was diagnosed with WD according to clinical evaluation and genetic test. Their menstrual, pregnancy and childbirth history, and sex hormone levels were collected and analyzed.Results: The average age of menarche was 13.7 ± 2.0 years. The proportion of delayed menarche was 37.8%. The patients with irregular menstruation after menarche accounted for 50%. Among 65 conceptions of 37 WD patients, the spontaneous abortion, induced abortion, preterm birth, and full-term delivery rate was 46.2%, 27.7%, 12.3% and 13.8% respectively. The abnormal hormone levels of the 35 cases mainly consisted of 14 cases (40%) with increased PRL, 10 cases with decreased P (28.6%), 8 cases (22.9%) with increased SHBG and 6 cases (17.1%) with increased T.Conclusion: The endocrinologic manifestations among WD patients could be not uncommon. WD patients could manifest as irregular menstruation, recurrent abortion, and even infertility. These minor aspects as a presenting feature of WD are prone to be neglected. Therefore, WD should be encountered in the differential diagnosis of endocrine system dysfunction.

Alzheimer's disease (AD) is the most common form of neurodegenerative disease. The predominant characteristics of AD are the accumulation of amyloid-β (Aβ) and hyperphosphorylated tau in the brain. Blood brain barrier (BBB) dysfunction as one of the causative factors of cognitive impairment is increasingly recognized in the last decades. However, the role of BBB dysfunction in AD pathogenesis is still not fully understood. It remains elusive whether BBB dysfunction is a consequence or causative fact of Aβ pathology, tau pathology, neuroinflammation, or other conditions. In this review, we summarized the major findings of BBB dysfunction in AD and the reciprocal relationships between BBB dysfunction, Aβ pathology, tau pathology, and neuroinflammation. In addition, the implications of BBB dysfunction in AD for delivering therapeutic drugs were presented. Finally, we discussed how to better determine the underlying mechanisms between BBB dysfunction and AD, as well as how to explore new therapies for BBB regulation to treat AD in the future.

The cerebellum is conceptualized as a processor of complex movements and is also endowed with roles in cognitive and emotional behaviors. Although the axons of deep cerebellar nuclei are known to project to primary thalamic nuclei, macroscopic investigation of the characteristics of these projections, such as the spatial distribution of recipient zones, is lacking. Here, we studied the output of the cerebellar interposed nucleus (IpN) to the ventrolateral (VL) and centrolateral (CL) thalamic nuclei using electrophysiological recording in vivo and trans-synaptic viral tracing. We found that IpN stimulation induced mono-synaptic evoked potentials (EPs) in the VL but not the CL region. Furthermore, both the EPs induced by the IpN and the innervation of IpN projections displayed substantial heterogeneity across the VL region in three-dimensional space. These findings indicate that the recipient zones of IpN inputs vary between and within thalamic nuclei and may differentially control thalamo-cortical networks. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12264-021-00780-y.

Background Although many causative genes have been uncovered in recent years, genetic diagnosis is still missing for approximately 50% of autosomal recessive cerebellar ataxia (ARCA) patients. Few studies have been performed to determine the genetic spectrum and clinical profile of ARCA patients in the Chinese population. Methods Fifty-four Chinese index patients with unexplained autosomal recessive or sporadic ataxia were investigated by whole-exome sequencing (WES) and copy number variation (CNV) calling with ExomeDepth. Likely causal CNV predictions were validated by CNVseq. Results Thirty-eight mutations including 29 novel ones were identified in 25 out of the 54 patients, providing a 46.3% positive molecular diagnostic rate. Ten different genes were involved, of which four most common genes were SACS, SYNE1, ADCK3 and SETX, which accounted for 76.0% (19/25) of the positive cases. The de novo microdeletion in SACS was reported for the first time in China and the uniparental disomy of ADCK3 was reported for the first time worldwide. Clinical features of the patients carrying SACS, SYNE1 and ADCK3 mutations were summarized. Conclusions Our results expand the genetic spectrum and clinical profiles of ARCA patients, demonstrate the high efficiency and reliability of WES combined with CNV analysis in the diagnosis of suspected ARCA, and emphasize the importance of complete bioinformatics analysis of WES data for accurate diagnosis.

Background Charcot-Marie-Tooth (CMT) disease is a group of inherited peripheral neuropathies, which are subdivided into demyelinating and axonal forms. Biallelic mutations in POLR3B are the well-established cause of hypomyelinating leukodystrophy, which is characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism. To date, only one study has reported the demyelinating peripheral neuropathy phenotype caused by heterozygous POLR3B variants. Case presentation A 19-year-old male patient was referred to our hospital for progressive muscle weakness of the lower extremities. Physical examination showed muscle atrophy, sensory loss and deformities of the extremities. Nerve conduction studies and electromyography tests revealed sensorimotor demyelinating polyneuropathy with secondary axonal loss. Trio whole-exome sequencing revealed a de novo variant in POLR3B (c.3137G > A). Conclusions In this study, we report the case of a Chinese patient with a de novo variant in POLR3B (c.3137G > A), who manifested demyelinating CMT phenotype without additional neurological or extra-neurological involvement. This work is the second report on POLR3B-related CMT.

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease involving motor, cognitive and psychiatric disturbances. HD patients with psychosis symptoms usually have bad prognosis. Exploring clinical, imaging and biological features of psychosis in patients with HD is of importance. A total of 118 Han Chinese patients with HD confirmed by Huntingtin genetic testing were recruited during 2013 to 2020. They were assessed by Unified Huntington’s Disease Rating Scale (UHDRS) and followed up in an average of 34 months by telephone. Psychosis was determined by the presence of delusions or hallucinations using UHDRS-Problem Behavior Assessment. Data of magnetic resonance imaging (n=28), serum neurofilament light chain (NfL, n=15) and Positive and Negative Syndrome Scale (PANSS, n=7) were collected in some patients. Of 118 patients (mean age 46.0 years, SD 12.0; female 53.5%), frequency of psychosis was 14.4% (n=17) in the cross-sectional analysis and 17.8% (n=21) in the longitudinal observation. Probands with psychosis were predominantly female (82.3%). They exhibited worse motor, cognitive, behavioral and functional performances compared with patients without psychosis. Furthermore, patients with psychosis had larger lateral ventricles compared with those without psychosis (p=0.0013). In addition, PANSS score showed negative correlations with caudate, putamen volumes (r=-0.85, p=0.014; r=-0.89, p=0.006), positive correlations with lateral ventricle volumes (r=0.60, p=0.010), but no association with NfL concentration. In summary, patients with psychosis had distinct clinical, imaging and biological features. These features might help clinicians to identify psychosis in HD patients early and provide protective interventions for bad outcomes caused by psychosis.

Aim Leukodystrophies are a group of inherited white matter disorders with clinical, genetic, and imaging heterogeneity, which usually pose a diagnostic challenge for physicians. We aimed to identify new clinical characteristics and novel pathogenic variants of hereditary leukodystrophies in this study. Methods Whole exome sequencing (WES) was performed in 28 unrelated patients clinically suspected with leukodystrophies. Leukocytes enzyme activity test, electroencephalogram (EEG), electromyography (EMG), and brain MRI were conducted. Functional analysis was performed, and the pathogenicity of variants was classified according to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines. Results We made definite diagnosis in 8 probands with 12 pathogenic variants and reported new clinical characteristics and imaging features of these patients. Three novel pathogenic variants were identified, including a microdeletion variant c.2654_2654+3del within CSF1R, a nonsense variant c.1321C>T, and a missense variant c.166G>C within GALC. Conclusion Our results have deepened the understanding of clinical, genetic, and imaging heterogeneity of hereditary leukodystrophies, and expanded the spectrum of pathogenic variants and clinical features.