Pathogenicity classification of SOD1 variants of uncertain significance by in vitro aggregation propensity.

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.

Clinical and genetic characteristics of Chinese patients with reducing body myopathy.

Reducing body myopathy (RBM) is a rare myopathy characterized by reducing bodies (RBs) in morphological presentation. The clinical manifestations of RBM present a wide clinical spectrum, varying from infantile lethal form through childhood and adult benign forms. FHL1 gene is the causative gene of RBM. To date, only 6 Chinese RBM patients have been reported. Here, we reported the clinical presentations and genetic findings of 3 Chinese RBM patients from two families. Two novel pathogenic variants, c.395G>A and c.401_402insGAC, were identified by whole exome sequencing. Furthermore, by reviewing previous studies, we revealed that most RBM patients manifested with an early onset, symmetric, progressive limb-girdle and axial muscle weakness with joint contractures, rigid spine or scoliosis except familial female patients who exhibited asymmetric benign muscle involvements. Our results provide insightful information to help better diagnose and understand the disease.

Ataxic Severity Is Positively Correlated With Fatigue in Spinocerebellar Ataxia Type 3 Patients.

Background: Spinocerebellar ataxia type 3 (SCA3) is an inherited form of ataxia that leads to progressive neurodegeneration. Fatigue is a common non-motor symptom in SCA3 and other neurodegenerative diseases, such as Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). Although risk factors to fatigue in these diseases have been thoroughly studied, whether or not fatigue can affect clinical phenotypes has yet to be investigated. Methods: Ninety-one molecularly confirmed SCA3 patients and 85 age- and sex-matched controls were recruited for this study. The level of fatigue was measured using the 14-item Fatigue Scale (FS-14), and the risk factors to fatigue and how fatigue correlates with clinical phenotypes were studied using multivariable linear regression models. Results: We found that the severity was significantly higher in the SCA3 group than in the control group (9.30 ± 3.04% vs. 3.94 ± 2.66, P = 0.000). Daytime somnolence (ß = 0.209, P = 0.002), severity of ataxia (ß = 0.081, P = 0.006), and poor sleep quality (ß = 0.187, P = 0.037) were found to have a positive relationship with fatigue. Although fatigue had no relationship with age at onset or ataxic progression, we found that it did have a positive relationship with the severity of ataxia (ß = 7.009, P = 0.014). Conclusions: The high level of fatigue and the impact of fatigue on the clinical manifestation of SCA3 patients suggest that fatigue plays a large role in the pathogenesis of SCA3, thus demonstrating the need for intervention and treatment options in this patient cohort.

Genetic Spectrum and Variability in Chinese Patients with Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disease characterized by selective impairment of upper and lower motor neurons. We aimed to investigate the genetic spectrum and variability in Chinese patients with ALS. A total of 24 familial ALS (FALS) and 21 early-onset sporadic ALS (SALS) of Chinese ancestry were enrolled. Targeted next-generation sequencing (NGS) was performed in the probands, followed by verification by Sanger sequencing and co-segregation analysis. Clinical features of patients with pathogenic or likely pathogenic variants were present. The mutation frequency of ALS-related genes was then analyzed in Chinese population. In this cohort, 17 known mutations (9 SOD1, 5 FUS, 2 TARDBP and one SETX) were identified in 14 FALS and 6 early-onset SALS. Moreover, 7 novel variants (SOD1 c.112G>C, OPTN c.811C>T, ERBB4 c.965T>A, DCTN1 c.1915C>T, NEFH c.2602G>A, NEK1 c.3622G>A, and TAF15 c.1535G>A) were identified. In southeastern Chinese FALS, the mutation frequency of SOD1, FUS, and TARDBP was 52.9%, 8.8%, 8.8% respectively. In early-onset SALS, FUS mutations were the most common (22.6%). In Chinese ALS cases, p.H47R is most frequent SOD1 mutations, while p.R521 is most common FUS mutation and p.M337V is most common TARDBP mutation. Our results revealed that mutations in SOD1, FUS and TARDBP are the most common cause of Chinese FALS, while FUS mutations are the most common cause of early-onset SALS. The genetic spectrum is different between Chinese ALS and Caucasian ALS.

Clinical and genetic characteristics of Chinese patients with cerebrotendinous xanthomatosis.

BACKGROUND: Cerebrotendinous xanthomatosis (CTX) is a rare inborn lipid-storage disease caused by mutations in the sterol 27-hydroxylase (CYP27A1) gene with an autosomal recessive pattern of inheritance. To date, only 19 CTX patients from 16 families have been reported in the Chinese population. RESULTS: Three novel likely pathogenic mutations (c.368_374delCCAGTAC, c.389 T > A and c.571C > T) and 7 previously reported pathogenic mutations (c.379C > T, c.435G > T, c.1016C > T, c.1214G > A, c.1263 + 1G > A, c.1420C > T and c.1435C > T) were identified. In addition, we summarized the genotypes and phenotypes of reported Chinese CTX patients. The most predominant mutations in CYP27A1 were c.410G > A and c.379C > T, and the most common clinical manifestations were pyramidal signs, xanthomatosis, cerebellar ataxia, and cognitive impairment. CONCLUSION: Our study broadens the genetic and clinical spectrum of CTX and provides insightful information to help better diagnose and understand the disease.

Identification and functional analysis of novel mutations in the SOD1 gene in Chinese patients with amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by selective involvement of motor neurons in the central nervous system (CNS). The most common causative gene of ALS in the Chinese population is the Cu/Zn superoxide dismutase 1 (SOD1) gene, which accounts for 20-42.9% of familial ALS (FALS) and 1-2% of sporadic ALS (SALS) cases. In this study, we identify three novel SOD1 mutations, Gly17Cys, Pro75Ser, and His121Gln, in four ALS pedigrees. A functional analysis was performed, and the results showed that all three mutations could lead to the formation of misfolded proteins. In addition, genotype-phenotype correlations in these patients are also described. Our study helps to characterize the genotype and phenotype of ALS with SOD1 mutations.

Diagnostic Value of Contrast-Enhanced Spectral Mammography for Screening Breast Cancer: Systematic Review and Meta-analysis.

BACKGROUND: Contrast-enhanced spectral mammography (CESM) is a new image examination technology that has developed over the past few years. As CESM technology keeps improving, a current meta-analysis review is needed to systematically evaluate the potential diagnostic value of CESM. METHODS: A total of 18 studies were included in the review. Sensitivity, specificity, and other important parameters of CESM accuracy for breast cancer diagnosis were pooled and analyzed using random-effects models. Summary receiver operating characteristic curves were calculated for overall accuracy estimation. RESULTS: The summary estimates for CESM in the diagnosis of breast cancer were as follows: the pooled sensitivity and specificity were 0.89 (95% confidence interval [CI], 0.88-0.91) and 0.84 (95% CI, 0.82-0.85), respectively. Positive likelihood ratio was 3.73 (95% CI, 2.68-5.20), negative likelihood ratio was 0.10 (95% CI, 0.06-0.15), and diagnostic odds ratio was 71.36 (95% CI, 36.28-140.39). The area under the curve was 0.96 (standard error = 0.011). CONCLUSION: CESM has a high diagnostic accuracy for evaluating breast cancer and can be considered as a useful test for initial assessment of breast lesions.

Homozygote of spinocerebellar Ataxia type 3 correlating with severe phenotype based on analyses of clinical features.

BACKGROUND: Spinocerebellar ataxia type 3 (SCA3) is the most common subtype of SCAs worldwide. SCA3 homozygote is defined as expanded CAG repeats in both alleles that might exhibit severe phenotype due to gene dosage effect. However, a study on the systematic comparison of clinical phenotypes between homozygotes and heterozygotes to indicate these verity of phenotypes of homozygotes is still lacking. METHODS: A total of 14 SCA3 homozygotes (3 Chinese participants and 11 participants from various ethnicity in different published studies) and 143 Chinese heterozygotes of SCA3 were recruited for this study. The 95% confidence intervals (CIs) of age at onset and disease severity expected from heterozygous patients were analyzed to detect the phenotypic differences between homozygotes and heterozygotes. RESULTS: Almost all the homozygotes (13 of 14) were found to present a significant earlier age at onset compared with heterozygotes, because age at onset of most homozygotes was lower than the 95% CIs of age at onset of heterozygotes. Also, the clinical severity in most of the homozygotes (3 of 4) with identified clinical phenotypes was higher than the 95% CIs of severity in heterozygotes, indicating more severe clinical phenotypes in SCA3 homozygotes. CONCLUSIONS: The homozygosity for SCA3 could lead to an earlier age of onset and putative severe clinical features. The findings of the present study suggested an influence of gene dosage on SCA3 phenotypes.

Bidirectional Connections between Depression and Ataxia Severity in Spinocerebellar Ataxia Type 3 Patients.

BACKGROUND: Spinocerebellar ataxia type 3 (SCA3), which is the most common subtype of SCA worldwide, exhibits common neuropsychological symptoms such as depression. However, the contribution of depression to the severity of SCA3 has not yet been thoroughly investigated. METHODS: The present study investigated the prevalence of depression using Beck depression inventory in 104 molecularly confirmed SCA3 patients from China. The putative risk factors for depression and whether the depression could affect the severity of ataxia were established by multivariable linear regression models. RESULTS: The frequency of depression in the study subjects was 57.69% (60/104), which was higher than that in SCA3 patients from a subset of other populations. The gender (p = 0.03) and severity (p < 0.01) of ataxia were those risk factors that could affect depression. Conversely, depression (p < 0.01) together with the duration (p < 0.01) of SCA3 could also play a positive role in the severity of ataxia. CONCLUSIONS: The extremely common depression results from motor disability caused by ataxia; it also affects the disease severity of SCA3. These findings suggested that depression was a part of neurodegeneration in SCA3 and necessitated intensive focus and interventions while caring for SCA3 patients.

Association Between Body Mass Index and Disease Severity in Chinese Spinocerebellar Ataxia Type 3 Patients.

Spinocerebellar ataxia type 3 (SCA3), the most common subtype of SCA worldwide, is caused by mutation of CAG repeats expansion in ATXN3. Body mass index (BMI) is an important modulatory factor in the progression of neurodegenerative disorders such as Huntington disease and amyotrophic lateral sclerosis. However, its relevance in SCA3 is not well understood. In this study, BMI was investigated in 134 molecularly confirmed SCA3 patients and 136 healthy controls from China. The multivariable linear regression models were performed to establish the putative risk factors for BMI, and whether BMI could affect the severity of ataxia. We found that BMI was significantly lower in the case group than that in the control group. The age at onset (positive correlation) and severity of ataxia (negative correlation) were the risk factors affecting BMI. Conversely, BMI along with the disease duration, the age at onset, and the numbers of CAG repeats could also have influence on the severity of ataxia. In conclusion, SCA3 patients had lower BMI than matched controls and BMI is a predictor of disease progression in SCA3. Nutritional intervention to promote weight gain could be a promising strategy to impede SCA3 progression.

Structural Features of Alkaline Extracted Polysaccharide from the Seeds of Plantago asiatica L. and Its Rheological Properties.

Polysaccharide from the seeds of Plantago asiatica L. has many bioactivities, but few papers report on the structural and rheological characteristics of the alkaline extract. The alkaline extracted polysaccharide was prepared from seeds of P. asiatica L. and named herein as alkaline extracted polysaccharide from seeds of P. asiatica L. (PLAP). Its structural and rheological properties were characterized by monosaccharide composition, methylation, GC-MS and rheometry. PLAP, as an acidic arabinoxylan, was mainly composed of 1,2,4-linked Xylp and 1,3,4-linked Xylp residues. PLAP solution showed pseudoplastic behavior, and weak gelling properties at high concentration. Sodium and especially calcium ions played a significant role in increasing the apparent viscosity and gel strength.