A rare complex structural variant of novel intragenic inversion combined with reciprocal translocation t(X;1)(p21.2;p13.3) in Duchenne muscular dystrophy.

Structural variants (SVs) are infrequently observed in Duchenne muscular dystrophy (DMD), a condition mainly marked by deletions and point mutations in the DMD gene. SVs in DMD remain difficult to reliably detect due to the limited SV-detection capacity of conventionally used short-read sequencing technology. Herein, we present a family, a boy and his mother, with clinical signs of muscular dystrophy, elevated creatinine kinase levels, and intellectual disability. A muscle biopsy from the boy showed dystrophin deficiency. Routine molecular techniques failed to detect abnormalities in the DMD gene, however, dystrophin mRNA transcripts analysis revealed an absence of exons 59 to 79. Subsequent long-read whole-genome sequencing identified a rare complex structural variant, a 77 kb novel intragenic inversion, and a balanced translocation t(X;1)(p21.2;p13.3) rearrangement within the DMD gene, expanding the genetic spectrum of dystrophinopathy. Our findings suggested that SVs should be considered in cases where conventional molecular techniques fail to identify pathogenic variants.

Environmental factors affecting the risk of generalization for ocular-onset myasthenia gravis: a nationwide cohort study.

BACKGROUND: The environmental effects on the prognosis of ocular myasthenia gravis (OMG) remain largely unexplored. AIM: To investigate the association between specific environmental factors and the generalization of OMG. DESIGN: The cohort study was conducted in China based on a nationwide multicenter database. METHODS: Adult patients with OMG at onset, who were followed up for at least 2 years until May 2022, were included. We collected data on demographic and clinical factors, as well as environmental factors, including latitude, socioeconomic status (per capita disposable income [PDI] at provincial level and education) and smoking. The study outcome was the time to the development of generalized myasthenia gravis (GMG). Cox models were employed to examine the association between environmental exposures and generalization. Restricted cubic spline was used to model the association of latitude with generalization risk. RESULTS: A total of 1396 participants were included. During a median follow-up of 5.15 (interquartile range [IQR] 3.37-9.03) years, 735 patients developed GMG within a median of 5.69 (IQR 1.10-15.66) years. Latitude of 20-50°N showed a U-shaped relation with generalization risk, with the lowest risk at around 30°N; both higher and lower latitudes were associated with the increased risk (P for non-linearity <0.001). Living in areas with lower PDI had 1.28-2.11 times higher risk of generalization. No significant association was observed with education or smoking. CONCLUSIONS: Latitude and provincial-level PDI were associated with the generalization of OMG in China. Further studies are warranted to validate our findings and investigate their potential applications in clinical practice and health policy.

Electrooxidation of chlorophene and dichlorophen by reactive electrochemical membrane: Key determining factors of removal efficiency.

This study systematically investigated the variable main electrooxidation mechanism of chlorophene (CP) and dichlorophen (DCP) with the change of reaction conditions at Ti4O7 anode operated in batch and reactive electrochemical membrane (REM) modes. Significant degradation of CP and DCP was observed, that is, CP exhibited greater removal efficiency in batch mode at 0.5-3.5 mA cm-2 and REM operation (0.5 mA cm-2) with a permeate flow rate of 0.85 cm min-1 under the same reaction conditions, while DCP exhibited a faster degradation rate with the increase of current density in REM operation. Density functional theory (DFT) simulation and electrochemical performance tests indicated that the electrooxidation efficiency of CP and DCP in batch mode was primarily affected by the mass transfer rates. And the removal efficiency when anodic potentials were less than 1.7 V vs SHE in REM operation was determined by the activation energy for direct electron transfer (DET) reaction, however, the adsorption function of CP and DCP on the Ti4O7 anode became a dominant factor in determining the degradation efficiency with the further increase of anodic potential due to the disappeared activation barrier. In addition, the degradation pathways of CP and DCP were proposed according to intermediate products identification and frontier electron densities (FEDs) calculation, the acute toxicity of CP and DCP were also effectively decreased during both batch and REM operations.

A novel splice-site mutation in CHMP2B associated with frontotemporal dementia: The first report from China and literature review.

BACKGROUND: Frontotemporal dementia (FTD) has genetic heterogeneity, and the endosomal ESCRTIII-complex subunit CHMP2B variant is a rare cause of FTD. The mutations in CHMP2B were first identified in a large Danish pedigree with autosomal dominant FTD, and have also been found in several individuals from Belgium, France, the United States, and Türkiye. In the Chinese population, cases of CHMP2B variant-associated FTD have never been reported. METHODS: The spectrum of clinical symptoms and the genetic analysis of the presented patient were identified and investigated. Besides this case, we assessed previously reported cases with CHMP2B gene mutations. RESULTS: This study presents a Chinese patient harboring a novel heterozygous A-to-T variant (NM_014043:c.532-2A>T) in CHMP2B with a phenotype compatible with FTD. Although previous reports suggested cases of CHMP2B variant-associated FTD initially presented with personality changes and stereotypical movements at the age of 50, this case was characterized by psychosis involving delusion of persecution, auditory hallucination, and suspiciousness at the earlier onset age of 44. Minigene splicing assay revealed that the splice-site variant could result in the retention of intron 5. CONCLUSION: This is the first case of CHMP2B variant-associated FTD reported in the Chinese population. The novel c.532-2A>T variant in the acceptor splice site of exon 6 retaining intron 5 was predicted to cause truncated protein and protein conformation changes. This discovery may expand the genetic and phenotypic spectrum of CHMP2B variant-associated FTD.

A synonymous codon variant altering splicing of RBCK1 expands the phenotype and genotype spectra of polyglucosan body myopathy 1.

Polyglucosan body myopathy type 1 (PGBM1, OMIM #615895.) is a rare autosomal recessive disorder caused by RBCK1 mutations. The patients displayed polyglucosan accumulation in skeletal and cardiac muscles, giving rise to loss of ambulation and heart failure with or without immune system dysregulation. So far, only 24 patients have been reported, all of whom exhibited symptoms before adulthood. Here, we reported the first case of an adult-onset PGBM1 patient with a novel compound heterozygous RBCK1 gene mutation consisting of a nonsense and synonymous variant affecting splicing.

Case report: Meningoencephalocele and recurrent bacterial meningitis in chronic idiopathic intracranial hypertension.

BACKGROUND: Meningoencephalocele is a rare malformation caused by congenital and acquired lesions. The association between recurrent bacterial meningitis and meningoencephaloceles with cerebrospinal fluid (CSF) leak is reported in the literature. We report a rare case of meningoencephalocele secondary to chronic idiopathic intracranial hypertension as a result of hospitalization repeatedly for meningitis due to the lack of CSF leak. CASE PRESENTATION: This study presents a case of a patient with a decade of recurrent meningitis. With clinical symptoms and imaging examination with chronic idiopathic intracranial hypertension, this patient was diagnosed with meningoencephalocele. With the treatment of acetazolamide to decrease CSF product, the patient had no recurrence of meningitis over the 6-months follow-up period. CONCLUSION: In patients with recurrent intracranial infections but no history of immunodeficiency, cranial trauma, or neurosurgery, the possibility of meningitis should be considered appropriately, even in the absence of CSF otorrhea or rhinorrhea.

Formation of chlorate and perchlorate during electrochemical oxidation by Magnéli phase Ti4O7 anode: inhibitory effects of coexisting constituents.

Formation of chlorate (ClO3-) and perchlorate (ClO4-) as by-products in electrooxidation process has raised concern. In the present study, the formation of ClO3- and ClO4- in the presence of 1.0 mM Cl- on boron doped diamond (BDD) and Magneli phase titanium suboxide (Ti4O7) anodes were evaluated. The Cl- was transformed to ClO3- (temporal maximum 276.2 µM) in the first 0.5 h on BDD anodes with a constant current density of 10 mA cm2, while approximately 1000 µM ClO4- was formed after 4.0 h. The formation of ClO3- on the Ti4O7 anode was slower, reaching a temporary maximum of approximately 350.6 µM in 4.0 h, and the formation of ClO4- was also slower on the Ti4O7 anode, taking 8.0 h to reach 780.0 µM. Compared with the BDD anode, the rate of ClO3- and ClO4- formation on the Ti4O7 anode were always slower, regardless of the supporting electrolytes used in the experiments, including Na2SO4, NaNO3, Na2B4O7, and Na2HPO4. It is interesting that the formation of ClO4- during electrooxidation was largely mitigated or even eliminated, when methanol, KI, and H2O2 were included in the reaction solutions. The mechanism of the inhibition on Cl- transformation by electrooxidation was explored.

Electrooxidation of per- and polyfluoroalkyl substances in chloride-containing water on surface-fluorinated Ti4O7 anodes: Mitigation and elimination of chlorate and perchlorate formation.

Electrooxidation (EO) has been shown effective in degrading per- and polyfluoroalkyl substances (PFASs) in water, but concurrent formation of chlorate and perchlorate in the presence of chloride is of concern due to their toxicity. This study examined EO treatment of three representative PFASs, perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA) and 6:2 fluorotelomer sulfonate (6:2 FTS), in chloride-containing solutions on pristine and surface-fluorinated Ti4O7 anodes having different percentage of surface fluorination. The experiment results indicate that surface fluorination of Ti4O7 anodes slightly inhibited PFAS degradation, while significantly decreased the formation of chlorate and perchlorate. Further studies with spectroscopic and electrochemical characterizations and density functional theory (DFT) computation reveal the mechanisms of the impact on EO performance by anode fluorination. In particular, chlorate and perchlorate formation were fully inhibited when fluorinated Ti4O7 anode was used in reactive electrochemical membrane (REM) under a proper anodic potential range (<3.0 V vs Standard Hydrogen Electrode), resulting from slower intermediate reaction steps and short residence time of the REM system. The results of this study provide a basis for design and optimization of modified Ti4O7 anodes for efficient EO treatment of PFAS while limiting chlorate and perchlorate formation.

Case Report: A Novel Splice-Site Mutation in DNAJB6 Associated With Juvenile-Onset Proximal-Distal Myopathy in a Chinese Patient.

DNAJB6 was identified as the causative gene of limb-girdle muscular dystrophy type 1D. In recent years, the phenotypic and molecular spectrum of DNAJB6-myopathy has been expanded, and several mutations of DNAJB6 have been identified in Europe, North America, and Asia. Interestingly, almost all identified mutations in previous reports were point mutations, and most of them were clustered in exon 5, which encodes the G/F domain of DNAJB6. The so-far unique splice site mutation eliminating the entire G/F domain was reported to cause a severe, early-onset phenotype. Here, we report a juvenile-onset Chinese patient who presented with proximal-distal myopathy as well as esotropia and facial weakness. Muscle pathology showed rimmed vacuolation and myofibrillar disarrangement. A novel splice-site mutation NM_058246:c.236-1_240delGGTGGA of the DNAJB6 gene was identified by targeted exome sequencing, which results in a severe defect of the G/F domain. This rare mutation type expands the molecular spectrum of DNAJB6-myopathy and further underlines the importance of the G/F region.

Characterization of 31 Patients with Riboflavin-Responsive Multiple acyl-CoA Dehydrogenase Deficiency

Aims: To evaluate the clinical, pathological, and genetic features of patients with riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency (RR-MADD). Methods: Thirty-one patients with RR-MADD admitted to our hospital from January 2005 to November 2020 were enrolled, and their clinical data were collected. Pathological characteristics of the muscle tissue and possible pathogenic gene mutations were analyzed. Results: The most common clinical features in all patients were symmetrical proximal muscle weakness. Laboratory examination revealed elevated levels of creatine kinase, homocysteine, and uric acid, acylcarnitines, and organic acid. The muscle biopsy revealed typical pathological changes like lipid deposition. Genetic analysis identified ETFDH mutations in 29 patients, among which one had homozygotes, 19 had compound heterozygotes, 7 had heterozygous mutations, and 2 had heterozygous mutations of both ETFDH and ETFA. Two patients had no pathogenic gene mutations. All patients were treated with riboflavin, and their symptoms improved, which was consistent with the diagnosis of RR-MADD. Conclusion: The clinical manifestations and genetic test results of patients with RR-MADD are heterogeneous. Therefore, a comprehensive analysis of clinical, pathological, and genetic testing is essential for the early diagnosis of RR-MADD.

Electrochemical oxidation combined with UV irradiation for synergistic removal of perfluorooctane sulfonate (PFOS) in water.

The effect of electrochemical degradation on Magnéli phase Ti4O7 anode combined with UV irradiation on the removal of PFOS was systematically evaluated in the present study. A synergistic effect of electrolysis and UV irradiation rather than a simple additive effect for PFOS degradation was demonstrated experimentally and theoretically. The short wavelength irradiation within 400 nm is the main contribution to enhance the electrochemical degradation of PFOS, while the initial pH of the solution has little effect on the PFOS degradation. The increase of current density accelerates the removal of PFOS either by electrolysis treatment or the joint process. The time-dependent density functional theory (TD-DFT) calculation indicates that the synergistic effect of the electrolysis and UV irradiation is most likely due to the involvement of the excited PFOS induced under UV irradiation in the electrochemical reaction. This study provides the first mechanistic explanation for the electrochemical degradation of PFOS enhanced by UV irradiation.

A novel compound heterozygous SPG7 variant is associated with progressive spastic ataxia and persecutory delusions found in Chinese patients: two case reports.

BACKGROUND: Hereditary spastic paraplegia 7 (SPG7) is one of the subtypes of autosomal-recessive hereditary spastic paraplegia, which is a clinically heterogeneous neurodegenerative disorder. SPG7 often displays a complicated phenotype, including optic atrophy, ophthalmoparesis, and impaired emotional communication. In the Chinese population, sporadic cases of SPG7 variant-associated spastic ataxia are rarely reported. CASE PRESENTATION: We carefully analysed the clinical features, imaging and genetic tests of two sporadic patients with SPG7, both from the Hebei region of China. One patient presented with progressive bilateral lower limb weakness, spastic-ataxia and no cognitive impairment. Brain MRI revealed mild cerebellar atrophy. Genetic analysis revealed c.1150_1151insCTAC (p.G384Afs*13) frameshift variant and exon1-3 heterozygous deletion. The other patient presented with progressive bilateral lower limb weakness, ataxia, dysarthria and a mild psychosis associated with persecutory delusions, which drew almost no attention, in addition to mild cognitive impairments characterized by a decrease in verbal memory and executive function. Genetic analysis identified two heterozygous variants in the SPG7 gene: c.1150_1151insCTAC (p.G384Afs*13) and c.1496delC (p.Q500Sfs*13). CONCLUSIONS: The c.1496delC (p.Q500Sfs*13) variant in exon 11 has not been reported before. The c.1150_1151insCTAC variant is speculated to be a hotspot variant in the Chinese population. Patients with SPG7 may have cognitive impairments and psychosis, displaying specific characteristics, which should be of concern.

Identification of Hub Genes and Biological Pathways in Inclusion Body Myositis Using Bioinformatics Analysis.

BACKGROUND: Inclusion body myositis (IBM) is a unique idiopathic inflammatory myopathy with unclear pathogenesis and poor prognosis. Although previous publications have identified some molecular biomarkers, the value of these biomarkers is unknown. OBJECTIVE: To identify hub genes and signaling pathways related to IBM for understanding the IBM-related mechanisms and providing guidance for therapy development. METHODS: Two microarray datasets (GSE3112 and GSE128470) were downloaded from the Gene Expression Omnibus (GEO) database. GEO2R was used to detect differentially expressed genes (DEGs) between IBM and normal muscle tissues. The hub genes were determined using protein-protein interaction (PPI) network in Cytoscape. The specific signaling pathways and biological functions of IBM were identified using GO, KEGG, and GSEA enrichment analyses. Moreover, CIBERSORT was applied to estimate the expression level of 22 immune cell types in IBM and normal muscle tissue. The relationship between the immune cell types and hub genes was then explored. RESULTS: A total of 219 DEGs and 10 hub genes were identified. Enrichment analyses revealed that the chemokine signaling pathway, cellular response to interferon-gamma, and P53 pathway have crucial roles in IBM. Immune infiltration analyses showed that IBM was associated with high level of CD8 T cells, Tregs, and macrophages. Finally, five potential drugs were predicted for IBM patients through CMap (connectivity map) database. CONCLUSION: In this study, the underlying molecular mechanisms and immunological landscape of IBM were investigated, and thus may provide new directions for future research on IBM pathogenesis.

An electrocoagulation and electrooxidation treatment train to remove and degrade per- and polyfluoroalkyl substances in aqueous solution.

This study examined the feasibility of a novel treatment train that combines electrocoagulation (EC) with electrooxidation (EO) treatment to remove and degrade per- and polyfluoroalkyl substances (PFASs) from water. Electrocoagulation with a zinc anode could effectively remove PFASs from water, and long-chain PFASs (C7-C10) tended to have a higher removal rate. Foam was generated when a relatively high current density (>1 mA cm-2) was applied to a relatively high PFAS concentration (each PFAS > 0.1 µM) during EC, which promoted the separation of PFASs from the bulk solution, especially for long-chain PFASs. Isotherm-like adsorption results indicated that competitive adsorption on floc occurred between PFASs when no foam was produced in a solution containing 10 different PFASs. Acid dissolution methods could recover and concentrate 10 PFASs in controlled volumes from both the floc and the foam, and it was also successfully applied in groundwater collected from a contaminated site. The concentrated PFASs in the acid solutions were efficiently destructed using EO treatment with a Ti4O7 anode at 10 mA cm-2, and no supplement of electrolyte was needed for the floc dissolved solution. This electrochemical-based process can economically separate, concentrate and destroy PFASs in groundwater and wastewater.

A case of reversible splenial lesion syndrome secondary to Fanconi syndrome with white matter swelling as the main manifestation.

Reversible splenial lesion syndrome (RESLES) is a rare clinical imaging syndrome that is characterized by magnetic resonance imaging (MRI) findings of reversible abnormal signals in the splenium of the corpus callosum (SCC). There are a variety of pathogenic causes, including infection, metabolic disturbances, and antiepileptic drug use. Moreover, the disease is clinically rare and easily misdiagnosed. Here, we report a unique case of a 32-year-old man with Fanconi syndrome who had an intensified signal in the SCC and diffuse white matter swelling on MRI. We believe this to be the first adult case of RESLES as a manifestation of Fanconi syndrome, which further expands the disease spectrum leading to RESLES. The imaging features of this case included extensive lesions, symmetrical diffuse restricted signals, and reversibility. The identification of these features improves our understanding of the imaging characteristics of RESLES, thus enabling clinicians to better understand this disease, correctly establish its diagnosis, and improve its prognosis in this kind of patient.

A family with riboflavin-reactive lipid deposition myopathy caused by a novel compound heterozygous mutation in the electron transfer flavoprotein dehydrogenase gene.

We report a family with riboflavin-reactive multiple acyl-CoA dehydrogenase deficiency (RR-MADD) partially caused by a novel mutation in the electron transfer flavoprotein dehydrogenase gene (ETFDH). The RR-MADD family was identified by physical examination, electromyography, and muscle biopsy of the proband. Laboratory examination and electromyography suggested a muscle disease of the lipid storage myopathies. This was confirmed by a muscle biopsy that revealed lipid deposition in the muscle fibers. The proband's sister previously had a similar disease, so the family underwent genetic testing. This revealed complex heterozygous ETFDH mutations c.389A > T (p. D130V) and c.1123C > A (p. P375T) in the proband and her sister, of which c.1123C > A (p. P375T) is a novel pathogenic mutation. The proband was treated with riboflavin and changes in physical symptoms and laboratory tests were evaluated before and after treatment. The discovery of a novel locus further expands the ETFDH mutation spectrum and suggests that genotyping is vital for early detection of RR-MADD as it can greatly improve the prognosis.

Neutral lipid storage disease with myopathy presenting asymmetrical muscle weakness: a case report.

NLSDM is a rare metabolic myopathy caused by mutations in the patatin-like phosphatase domain protein 2 (PAPLA2) genes. In the present study, we describe the clinical and genetic findings in our Chinese patient with NLSDM. Sequence analysis of PNPLA2 gene was performed. Gene analysis for PNPLA2 revealed an identical homozygous mutation c.757+1G>T in our patient. The clinical symptoms of our patient are related to the type of mutation in the PNPLA2 gene and environmental effects.

Degradation kinetics of target compounds and correlations with spectral indices during UV/H2O2 post-treatment of biologically treated acrylonitrile wastewater.

In this study, the post-treatment of biologically treated acrylonitrile wastewater was investigated during UV/H2O2 process. Five contaminants in the effluent were selected as target compounds, including Furmaronitrile (FMN), 3-Pyridinecarbonitrile (3PCN), 1,3-Dicyanobenzene (1,3-DCB), 5-Methyl-1H-benzotriazole (5MBT), and 7-Azaindole (7AID). Under optimal reaction conditions, the UV/H2O2 post-treatment exhibited good performances in destruction of organic compounds and toxicity. The photo-chemical parameters of the target compounds were measured and it was found that 5MBT and 3PCN had fast degradation rate constants under direct UV photolysis. The second-order rate constants of the target compounds with hydroxyl radicals were determined to be in the range of (1.0-5.0) × 109 M-1 s-1 at pH 3.0 and 25 °C. A simplified pseudo-first-order steady state (Sim-PSS) model, which considered direct UV photolysis and radical oxidation simultaneously, agreed well with the experimental data from the post-treatment of a biologically treated effluent. High-performance size exclusion chromatography (HPSEC) coupled with diode-array detector (DAD) and fluorescence detector (FLD) analysis revealed that humic-like sub-peak signals from different molecular weights of fluorescent organic matter decreased consistently during the oxidation process, which made humic-like fluorescence exhibit higher correlation with the target compounds' degradation than the spectral indices of UV absorbance at 254 nm (UVA254) and protein-like fluorescence.

Effects of chloride on electrochemical degradation of perfluorooctanesulfonate by Magnéli phase Ti4O7 and boron doped diamond anodes.

This study examined the degradation of perfluorooctanesulfonate (PFOS) in an electrochemical system using Magnéli phase titanium suboxide (Ti4O7) as the anode. In particular, the influence of chloride on the treatment process was examined. Tests were also conducted with boron doped diamond (BDD) electrodes for comparison. Experimental data demonstrated that PFOS was effectively degraded by electrochemical oxidation on both BDD and Magnéli phase Ti4O7 anodes. It appeared that PFOS degradation occurred via direct electron transfer (DET) in combination with attack by hydroxyl radicals adsorbed on the anode surface (HO•ads) that were formed by anodic oxidation of water. The presence of Cl- inhibited the degradation of the PFOS on Ti4O7 electrode by suppressing the oxidation of water, but accelerated PFOS degradation on BDD electrode, where the oxidation of Cl- via DET occurred. Formation of chlorate and perchlorate was slower on Ti4O7 than on the BDD anode. The mechanisms governing the behavior of PFOS and chloride reactions on BDD and Ti4O7 anodes were explored by experiments in combination with density functional theory (DFT) computations.