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Chorea-acanthocytosis (ChAc) is the most common subtype of neuroacanthocytosis syndrome, characterized by the presence of acanthocytes and neurological disorders. It is thought to be caused by VPS13A mutations. Characteristic movement disorders in ChAc is choreiform movements affecting both trunk and extremities and prominent orolingual dyskinesia is pathognomonic. Acanthocytosis in peripheral blood smear, elevated serum creatine kinase and atrophy of heads of caudate nuclei and dilation of the anterior horn of the lateral ventricles in magnetic resonance imaging could assist the diagnosis of ChAc. Botulinum toxin injection is a possible treatment for the typical orofacial dystonia. Deep brain stimulation is a novel surgical treatment modality. Most cases chose globus pallidus internus as target. Patients with dystonia as a major manifestation will benefit more from high-frequency stimulation and those with major findings of chorea and dysarthria are suitable for low-frequency stimulation. More evidence of long-term outcomes is warranted.
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Abetalipoproteinemia/diagnóstico , Abetalipoproteinemia/metabolismo , Toxinas Botulínicas/uso terapéutico , Corea/diagnóstico , Corea/metabolismo , Abetalipoproteinemia/terapia , Animales , Corea/terapia , Estimulación Encefálica Profunda , Globo Pálido/patología , Humanos , Proteínas de Transporte Vesicular/metabolismoRESUMEN
BACKGROUND: The ΔGAG deletion of the TOR1A gene (DYT1) is responsible for DYT1 dystonia. However, no other TOR1A mutation has been reported in the Chinese population. METHODS: Two hundred one dystonia patients without the ΔGAG deletion were screened for other mutations in TOR1A. Gene function changes were analyzed by subcellular distribution and luciferase reporter assay. RESULTS: A novel TOR1A mutation (c.581A>T, p.Asp194Val) was found in a patient with early-onset segmental dystonia harboring a THAP1 mutation (c.539T>C, p.Leu180Ser). Overexpression of mutant TOR1A Asp194Val protein induces inclusion formation in SK-N-AS cell lines, and the repressive activity of the mutant THAP1 Leu180Ser protein on TOR1A gene expression is decreased compared with wild-type THAP1. CONCLUSIONS: This is the first report about a dystonia patient harboring two distinct dystonia gene mutations. Functional analysis indicated a potential additive effect of these two mutations, which might provoke the occurrence of dystonic symptoms in this patient.
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Proteínas Reguladoras de la Apoptosis/genética , Proteínas de Unión al ADN/genética , Trastornos Distónicos/genética , Predisposición Genética a la Enfermedad/genética , Chaperonas Moleculares/genética , Mutación/genética , Proteínas Nucleares/genética , Adulto , Proteínas Reguladoras de la Apoptosis/metabolismo , Pueblo Asiatico , Ácido Aspártico/genética , Línea Celular Tumoral , Estudios de Cohortes , Análisis Mutacional de ADN , Proteínas de Unión al ADN/metabolismo , Femenino , Genotipo , Células HEK293 , Humanos , Masculino , Chaperonas Moleculares/metabolismo , Neuroblastoma/patología , Proteínas Nucleares/metabolismo , Transfección , Valina/genéticaRESUMEN
This review covers the recent progress in the research field of rod-coil block copolymers (BCPs) containing rigid rod-like blocks and flexible coil-like blocks. Their assembly behaviors are fundamentally different from coil-coil BCPs in morphology because of the geometric disparity between the rod and coil segments and anisotropic interactions between rod blocks to form liquid crystalline or crystalline structures. Rod-coil BCPs can self-assemble into diverse nanostructures in selective solvents, such as micelles, cylinders, vesicles, tubules, belts, and rings. This review highlights valuable contributions in the past six years on the self-assembly behavior of rod-coil BCPs controlled by the volume fraction and the composition of the blocks from both the experimental and theoretical perspectives, and their tunable self-assembled nanostructures triggered by external stimuli, such as solvent, pH, temperature, light, and chemical additives. We also briefly introduce emerging applications of rod-coil nanoparticles in the biological field.
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BACKGROUND: Paroxysmal dyskinesias (PDs), a clinically and genetically heterogeneous group of episodic movement disorders, include kinesigenic PD (PKD), exercise-induced PD (PED) and non-kinesigenic PD (PNKD). These disorders are all transmitted as autosomal dominant traits with incomplete penetrance. Several PD-related genetic disorders, including PKD and familial infantile convulsions with paroxysmal choreoathetosis (ICCA), mapped to the same region on chromosome 16. Independent genetic studies have recently revealed that PKD can be caused by loss-of-function mutations in the proline-rich transmembrane protein 2 gene (PRRT2). We tested the hypothesis that other forms of PDs are also due to PRRT2 mutations. METHODS/RESULTS: The whole genomic region of PRRT2 was sequenced in six Han Chinese families and 15 sporadic cases of PD-related phenotypes. The previously reported mutation, c.649dupC (p.R217Pfs*7), was found in two families with PKD, one family with ICCA, one family with PNKD-like phenotype, and two sporadic cases with PED. In an additional ICCA family, a novel frameshift mutation, c.904dupG (p.D302Gfs*38), was identified. A missense mutation, c.913GâA (p.G305R), and a synonymous substitution, c.1011CâT (p.G337G), were also detected in two sporadic PKD cases. CONCLUSION: This study shows that PKD, ICCA and some other PD-related phenotypes are part of the same phenotypic spectrum, caused by mutations in PRRT2. This underscores the complexity of the phenotypic consequences of PRRT2 mutations.
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Corea/genética , Proteínas de la Membrana/genética , Mutación , Proteínas del Tejido Nervioso/genética , Corea/diagnóstico , Diagnóstico Diferencial , Orden Génico , Humanos , FenotipoRESUMEN
OBJECTIVE: We aimed to evaluate the safety and efficacy of subthalamic nucleus deep brain stimulation (STN-DBS) with a new stimulator (Beijing PINS Medical Co., Ltd, PNS 1101) in Parkinson's disease (PD). MATERIALS AND METHODS: Forty patients received a PINS device implantation in the subthalamic nucleus. The effects of stimulation on motor score, activities of daily living, good-quality on-time, and the levodopa-equivalent dose were analyzed for all 40 patients with PD treated with bilateral or unilateral STN-DBS. The scores were collected at baseline in two conditions (on/off medication) and at 3, 6, 9, 12, and 24 months of follow-up with stimulation in the absence or presence of medication. The patients were followed up for two years. RESULTS: At 3, 6, 9, 12, and 24 months of follow-up, our results showed a significant increase from baseline in both activities of daily living and motor scores (p < 0.001) and good-quality on-time (p < 0.001); the daily levodopa-equivalent dose decreased compared with baseline (p < 0.01). No patient died during the study, and none of the adverse effects were classified as severe. All of the adverse events were resolved or improved by the end of the study. CONCLUSIONS: STN-DBS with the PINS device significantly improved the symptoms of PD when compared with baseline in this trial. This new device may be recommended for the treatment of patients with advanced PD; however, a randomized, double-blinding trial will be required.
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Estimulación Encefálica Profunda/instrumentación , Estimulación Encefálica Profunda/métodos , Enfermedad de Parkinson/terapia , Núcleo Subtalámico/fisiología , Adulto , Anciano , Electrodos Implantados , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Factores de Tiempo , Resultado del TratamientoRESUMEN
Introduction: The pedunculopontine nucleus (PPTg) is a vital interface between the basal ganglia and cerebellum, participating in modulation of the locomotion and muscle tone. Pathological changes of the PPTg have been reported in patients and animal models of dystonia, while its effect and mechanism on the phenotyping of dystonia is still unknown. Methods: In this study, a series of behavioral tests focusing on the specific deficits of dystonia were conducted for mice with bilateral and unilateral PPTg excitotoxic lesion, including the dystonia-like movements evaluation, different types of sensory-motor integrations, explorative behaviors and gait. In addition, neural dysfunctions including apoptosis, neuroinflammation, neurodegeneration and neural activation of PPTg-related motor areas in the basal ganglia, reticular formations and cerebellum were also explored. Results: Both bilateral and unilateral lesion of the PPTg elicited dystonia-like behaviors featured by the hyperactivity of the hindlimb flexors. Moreover, proprioceptive and auditory sensory-motor integrations were impaired in bilaterally lesioned mice, while no overt alterations were found for the tactile sensory-motor integration, explorative behaviors and gait. Similar but milder behavioral deficits were found in the unilaterally lesioned mice, with an effective compensation was observed for the auditory sensory-motor integration. Histologically, no neural loss, apoptosis, neuroinflammation and neurodegeneration were found in the substantia nigra pars compacta and caudate putamen (CPu) following PPTg lesion, while reduced neural activity was found in the dorsolateral part of the CPu and striatal indirect pathway-related structures including subthalamic nucleus, globus pallidus internus and substantia nigra pars reticular. Moreover, the neural activity was decreased for the reticular formations such as pontine reticular nucleus, parvicellular reticular nucleus and gigantocellular reticular nucleus, while deep cerebellar nuclei were spared. Conclusion: In conclusion, lesion of the PPTg could elicit dystonia-like behaviors through its effect on the balance of the striatal pathways and the reticular formations.
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BACKGROUND: Early diagnosis and classification of infections increase the cure rate while decreasing complications, which is significant for severe infections, especially for war surgery. However, traditional methods rely on laborious operations and bulky devices. On the other hand, point-of-care (POC) methods suffer from limited robustness and accuracy. Therefore, it is of urgent demand to develop POC devices for rapid and accurate diagnosis of infections to fulfill on-site militarized requirements. METHODS: We developed a wave-shaped microfluidic chip (WMC) assisted multiplexed detection platform (WMC-MDP). WMC-MDP reduces detection time and improves repeatability through premixing of the samples and reaction of the reagents. We further combined the detection platform with the streptavidin-biotin (SA-B) amplified system to enhance the sensitivity while using chemiluminescence (CL) intensity as signal readout. We realized simultaneous detection of C-reactive protein (CRP), procalcitonin (PCT), and interleukin-6 (IL-6) on the detection platform and evaluated the sensitivity, linear range, selectivity, and repeatability. Finally, we finished detecting 15 samples from volunteers and compared the results with commercial ELISA kits. RESULTS: Detection of CRP, PCT, and IL-6 exhibited good linear relationships between CL intensities and concentrations in the range of 1.25-40 µg/ml, 0.4-12.8 ng/ml, and 50-1600 pg/ml, respectively. The limit of detection of CRP, PCT, and IL-6 were 0.54 µg/ml, 0.11 ng/ml, and 16.25 pg/ml, respectively. WMC-MDP is capable of good adequate selectivity and repeatability. The whole detection procedure takes only 22 min that meets the requirements of a POC device. Results of 15 samples from volunteers were consistent with the results detected by commercial ELISA kits. CONCLUSIONS: WMC-MDP allows simultaneous, rapid, and sensitive detection of CRP, PCT, and IL-6 with satisfactory selectivity and repeatability, requiring minimal manipulation. However, WMC-MDP takes advantage of being a microfluidic device showing the coefficients of variation less than 10% enabling WMC-MDP to be a type of point-of-care testing (POCT). Therefore, WMC-MDP provides a promising alternative to POCT of multiple biomarkers. We believe the practical application of WMC-MDP in militarized fields will revolutionize infection diagnosis for soldiers.
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Microfluídica , Pruebas en el Punto de Atención , Biomarcadores , Proteína C-Reactiva/análisis , Humanos , Sistemas de Atención de PuntoRESUMEN
This critical review covers the recent progress in the research of mesogen-jacketed liquid crystalline polymers (MJLCPs), special side-on side-chain liquid crystalline polymers with very short spacers or without spacers. MJLCPs can self-organize into supramolecular columnar phases with the polymer chains aligned parallel to one another or smectic phases with the backbones embedded in the smectic layers. The semi-rigid rod-like MJLCP with a tunable rod shape in both length and diameter provides an excellent building block in designing novel rod-coil liquid crystalline block copolymers which can self-assemble into hierarchical supramolecular nanostructures depending on the competition between liquid crystal formation and microphase separation (229 references).
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Background: Dopa-responsive dystonia (DRD) is a movement disorder that is highly clinically and genetically heterogeneous. Our study summarizes clinical characteristics and long-term outcomes in patients with dopa-responsive dystonia with the aim of obtaining further knowledge on this disorder. Methods: Patients who met DRD genetic diagnostic criteria through whole-exome sequencing and took levodopa for over 3 years were included in our study. Detailed information was collected on these patients, including family history, age at onset, age and dosage at starting levodopa, current medication and dosage, levodopa duration, diurnal fluctuation, and other clinical features. The Burke-Fahn-Marsden Dystonia Rating Scale-Motor (BFMDRS-M) score was used to evaluate patients' dystonia and variation after levodopa. According to the long-term outcomes, patients were further graded as good (dystonia improved by more than 50% after levodopa, and no further motor symptoms appeared) and poor (dystonia improved by <50% after levodopa, or new motor symptoms appeared). Results: A total of 20 DRD patients were included (11 with GCH1 variants, 9 with TH variants). During long-term levodopa treatment, three patients with TH variants (3/20, 15%) developed motor symptoms, including body jerks and paroxysmal symptoms, and responded well to increasing levodopa doses. The patient with homozygous mutation c.1481C>T/p. Thr494Met harbored more serious symptoms and poor response to levodopa and showed decreased cardiac uptake in MIBG. Conclusions: Most DRD patients showed satisfactory treatment outcomes after long-term levodopa, whereas few patients with TH variants presented motor symptoms, which is considered to be related to dopamine insufficiency. For patients with motor symptoms after long-term levodopa, increasing the dose slowly might be helpful to relieve symptoms.
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INTRODUCTION: Dystonia is a movement disorder with high clinical and genetic heterogeneity. Mutations in Anoctamin-3 (ANO3) gene have been reported to cause dystonia 24 (DYT24). This study aims to clarify the spectrum and frequency of ANO3 rare variants in Chinese populations with primary dystonia and understand the clinical and genetic features of DYT24. METHODS: Sanger sequencing was used to screen all exons and exon-intron boundaries of ANO3 for rare variants in 115 primary dystonia patients. The clinical manifestations of patients with ANO3 variants in our study and previously reported literatures were further characterized. RESULTS: Four distinct variants of ANO3 (c.1127A > G, c.1235 T > A, c.1531-3T > C, c.-11G > T) were identified in six unrelated individuals. Combined with our work and literature review, a total of 35 different rare variants distributed in ANO3 were identified in 62 dystonia patients. The predominant phenotype is cranio-cervical dystonia and more than half of patients develop head/limb tremor. Most of patients presented with isolated dystonia whereas few of them showed combined dystonia. The age of onset ranged from 1 to 69 years and peaked in late adulthood, while for generalized dystonia it peaked in a young age. Half of patients with generalized dystonia experienced deep brain stimulation (DBS). And all of them showed improvement of dystonia by DBS. CONCLUSIONS: This study confirms a relatively high frequency of rare ANO3 variants in Chinese patients with dystonia and indicates that the late adulthood-onset, cranio-cervical dystonia seems to be an important feature of the ANO3 phenotype. Further functional studies are warranted to understand the role of ANO3 in dystonia.
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Anoctaminas/genética , Pueblo Asiatico/genética , Trastornos Distónicos/diagnóstico , Trastornos Distónicos/genética , Variación Genética/genética , Anciano , Secuencia de Aminoácidos , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Mutations in VPS16 have been identified to be responsible for generalized dystonia. We screened VPS16 variants in 53 unrelated subjects with isolated dystonia via whole-exome sequencing. A novel pathogenic frameshift mutation p.R643fs* was found in a patient with early-onset multifocal dystonia with prominent oromandibular and bulbar involvement. Our findings expanded the spectrum of VPS16-related dystonia and suggested that mutations in VPS16 should be considered in patients with progressive early-onset dystonia.
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Trastornos Distónicos/genética , Trastornos Distónicos/fisiopatología , Proteínas de Transporte Vesicular/genética , Adulto , Anciano , Femenino , Mutación del Sistema de Lectura , Humanos , Masculino , Persona de Mediana Edad , Secuenciación del ExomaRESUMEN
ATP1A3-related dystonia is a disorder with high heterogeneous spectrum of clinical manifestations caused by mutations in ATP1A3 gene. Here, 2 atypical cases carring 2 de-novo ATP1A3 variants with RDP-CAPOS overlapping phenotype or continuous hemi-dystonia are described.
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Ataxia Cerebelosa/genética , Ataxia Cerebelosa/fisiopatología , Trastornos Distónicos/genética , Trastornos Distónicos/fisiopatología , Deformidades Congénitas del Pie/genética , Deformidades Congénitas del Pie/fisiopatología , Pérdida Auditiva Sensorineural/genética , Pérdida Auditiva Sensorineural/fisiopatología , Atrofia Óptica/genética , Atrofia Óptica/fisiopatología , Reflejo Anormal/genética , ATPasa Intercambiadora de Sodio-Potasio/genética , Adulto , Niño , China , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Linaje , Secuenciación del Exoma , Adulto JovenRESUMEN
BACKGROUND: KMT2B-related dystonia is a recently discovered hereditary dystonia that mostly occurs in childhood. This dystonia usually progresses to generalized dystonia with cervical, cranial, pharynx and larynx involvement. Our study summarizes genotype-phenotype features and deep brain stimulation (DBS) efficacy observed with KMT2B-related dystonia patients in China. METHODS: We identified 20 patients with KMT2B variations from dystonia samples with a gene panel and whole exome sequencing. Genetic, clinical and treatment analyses of these patients with KMT2B mutations were further conducted. RESULTS: We summarized the genotype and phenotypic characteristics of KMT2B-related patients in China, including 16 sporadic patients and 3 pedigrees (including 4 patients). Thirty-five percent (7/20) of patients had been published previously. The age of onset was between 1 month and 24 years (average 6.90 ± 5.72 years). Sixty-five percent (13/20) of patients had onset from lower limbs. Upper limbs or larynx accounted for 15% (3/20) and 20% (4/20) of patients, respectively. In the same family, male patients tended to have more severe symptoms than female patients. Carriers of KMT2B variants may present with nonmotor symptoms without dystonia. Abnormal endocrine metabolism could also be seen in our patients, including advanced bone age that had never been reported previously. Nine of our patients underwent DBS surgery. The mean follow-up time was 4.9 (range 1.3-16) months after DBS, and perceptible improvement of clinical symptoms were observed. CONCLUSIONS: The genotypic and phenotypic spectra of Chinese KMT2B-related dystonia patients were further expanded. DBS surgery might be the preferred option for severe KMT2B-related dystonia patients till now.
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Distonía/genética , Distonía/terapia , N-Metiltransferasa de Histona-Lisina/genética , Mutación/genética , Resultado del Tratamiento , Adolescente , Adulto , Pueblo Asiatico , Niño , Estimulación Encefálica Profunda/métodos , Distonía/diagnóstico , Femenino , Genotipo , Humanos , Masculino , Linaje , Fenotipo , Adulto JovenRESUMEN
BACKGROUND: Dystonia is a movement disorder with high clinical and genetic heterogeneity. Molecular diagnosis is important for an accurate diagnosis of dystonia. Targeted gene capture sequencing has been an effective method for screening multiple candidate genes simultaneously. This method, however, has been rarely reported to be used with dystonia patients. OBJECTIVES AND METHODS: To assess the effectiveness of the targeted gene capture sequencing in dystonia, we performed custom target gene capture followed by next-generation sequencing in dystonia patients from China. Sanger sequencing was utilized to substantiate the findings. The effects of identified variants were classified according to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines. RESULTS: A total of 65 patients (34 female and 31 male) were recruited in this study. The mean age at onset was 22.7⯱â¯13.3â¯years ranging from 2 to 59â¯years. According to ACMG standards and guidelines, of 65 patients, 12 were identified with pathogenic variants (12/65, 18.5%) in gene TOR1A, PANK2 or ATP1A3, and another four were identified with likely-pathogenic variants (4/65, 6.2%) in gene PRRT2, GCH1 or THAP1. In total, 24.6% of patients in this cohort were detected to have a genetic cause of dystonia. Another four patients (4/65, 6.2%) were identified with variants which were considered to be VUS (Variants of Uncertain Significance) in gene SGCE, TH, ANO3 and ATP1A3 respectively. The most common detected gene was TOR1A, known to be causative for DYT1 (8/65, 12.3%). CONCLUSIONS: The study demonstrates that targeted gene capture sequencing is an effective tool for identifying the genetic cause of heterogeneous dystonia patients.
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Trastornos Distónicos/diagnóstico , Trastornos Distónicos/genética , Análisis de Secuencia/métodos , Adolescente , Adulto , Niño , Preescolar , Femenino , Variación Genética , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
A microalgal strain, Chlorella sp. GD, cultivated in aquaculture wastewater (AW) aerated with boiler flue gas, was investigated. When AW from a grouper fish farm was supplemented with additional nutrients, the microalgal biomass productivity after 7days of culture was 0.794gL-1d-1. CO2 fixation efficiencies of the microalgal strains aerated with 0.05, 0.1, 0.2, and 0.3vvm of boiler flue gas (containing approximately 8% CO2) were 53, 51, 38, and 30%, respectively. When the microalgal strain was cultured with boiler flue gas in nutrient-added AW, biomass productivity increased to 0.892gL-1d-1. In semi-continuous cultures, average biomass productivities of the microalgal strain in 2-day, 3-day, and 4-day replacement cultures were 1.296, 0.985, and 0.944gL-1d-1, respectively. These results demonstrate the potential of using Chlorella sp. GD cultivations in AW aerated with boiler flue gas for reusing water resources, reducing CO2 emission, and producing microalgal biomass.
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Acuicultura/métodos , Dióxido de Carbono/metabolismo , Chlorella/metabolismo , Microalgas/metabolismo , Aguas Residuales , Biomasa , Chlorella/crecimiento & desarrollo , Microalgas/crecimiento & desarrollo , Eliminación de Residuos Líquidos/métodosRESUMEN
OBJECTIVE: [corrected] To evaluate efficacy and safety of botulinum toxin type B (BTX-B) in treatment of movement disorders including blepharospasm, oromandibular dystonia, hemifacial spasm, tremor, tics, and hypersecretory disorders such as sialorrhea and hyperhidrosis. METHODS: A retrospective study of BTX-B injections in treatment of 58 patients with various neurological disorders was performed. The mean follow-up time was 0.9 +/- 0.8 years. Results of the first and last treatment of patients with at least 3 injection sessions were compared. RESULTS: The response of 58 patients to a total of 157 BTX-B treatment sessions was analyzed. Of the 157 treatment sessions, 120 sessions (76.4%) resulted in moderate or marked improvement while 17 sessions (10.8%) had no response. The clinical benefits after BTX-B treatment lasted an average of 14 weeks. Of the 41 patients with at least 3 injection sessions (mean 10 +/- 8.6), most patients needed increased dosage upon the last session compared to the first session. Nineteen patients (32.8%) with 27 sessions (17.2%) reported adverse effects with BTX-B treatment. CONCLUSIONS: Though most patients require increased dosage to maintain effective response after repeated injections, BTX-B is an effective and safe treatment drug for a variety of movement disorders, as well as drooling and hyperhidrosis.