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A poly (3,6-bis(thiophen-2-yl)-2,5-bis(2-decyltetradecyl)-2,5-dihydropyrrolo[3,4-c]pyrrole-1,4-dione-co-(2,3-bis(phenyl)acrylonitrile)) (PDPADPP) copolymer, composed of diketopyrrolopyrrole (DPP) and a cyano (nitrile) group with a vinylene spacer linking two benzene rings, is synthesized via a palladium-catalyzed Suzuki coupling reaction. The electrical performance of PDPADPP in organic field-effect transistors (OFETs) and circuits is investigated. The OFETs based on PDPADPP exhibit typical ambipolar transport characteristics, with the as-cast OFETs demonstrating low field-effect hole and electron mobility values of 0.016 and 0.004 cm2 V-1 s-1 , respectively. However, after thermal annealing at 240 °C, the OFETs exhibit improved transport characteristics with highly balanced ambipolar transport, showing average hole and electron mobility values of 0.065 and 0.116 cm2 V-1 s-1 , respectively. To verify the application of the PDPADPP OFETs in high-voltage logic circuits, compact modeling using the industry-standard small-signal Berkeley short-channel IGFET model (BSIM) is performed, and the logic application characteristics are evaluated. The circuit simulation results demonstrate excellent logic application performance of the PDPADPP-based ambipolar transistor and illustrate that the device annealed at 240 °C exhibits ideal circuit characteristics.
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Acrilonitrila , Simulação por Computador , Eletricidade , Elétrons , Nitrilas , PolímerosRESUMO
Mutations in the SACS gene are associated with autosomal recessive spastic ataxia of Charlevoix-Saguenay disease (ARSACS) or complex clinical phenotypes of Charcot-Marie-Tooth disease (CMT). This study aimed to identify SACS mutations in a Korean CMT cohort with cerebellar ataxia and spasticity by whole exome sequencing (WES). As a result, eight pathogenic SACS mutations in four families were identified as the underlying causes of these complex phenotypes. The prevalence of CMT families with SACS mutations was determined to be 0.3%. All the patients showed sensory, motor, and gait disturbances with increased deep tendon reflexes. Lower limb magnetic resonance imaging (MRI) was performed in four patients and all had fatty replacements. Of note, they all had similar fatty infiltrations between the proximal and distal lower limb muscles, different from the neuromuscular imaging feature in most CMT patients without SACS mutations who had distal dominant fatty involvement. Therefore, these findings were considered a characteristic feature in CMT patients with SACS mutations. Although further studies with more cases are needed, our results highlight lower extremity MRI findings in CMT patients with SACS mutations and broaden the clinical spectrum. We suggest screening for SACS in recessive CMT patients with complex phenotypes of ataxia and spasticity.
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Doença de Charcot-Marie-Tooth , Heterozigoto , Espasticidade Muscular , Mutação , Humanos , Masculino , Doença de Charcot-Marie-Tooth/genética , Feminino , Adulto , República da Coreia/epidemiologia , Espasticidade Muscular/genética , Espasticidade Muscular/diagnóstico por imagem , Estudos de Coortes , Pessoa de Meia-Idade , Imageamento por Ressonância Magnética , Proteínas de Choque Térmico/genética , Linhagem , Sequenciamento do Exoma , Ataxia Cerebelar/genética , Ataxia Cerebelar/diagnóstico por imagem , Fenótipo , Adolescente , Adulto JovemRESUMO
Mutations in INF2 are associated with the complex symptoms of Charcot-Marie-Tooth disease (CMT) and focal segmental glomerulosclerosis (FSGS). To date, more than 100 and 30 genes have been reported to cause these disorders, respectively. This study aimed to identify INF2 mutations in Korean patients with CMT. This study was conducted with 743 Korean families with CMT who were negative for PMP22 duplication. In addition, a family with FSGS was included in this study. INF2 mutations were screened using whole exome sequencing (WES) and filtering processes. As the results, four pathogenic INF2 mutations were identified in families with different clinical phenotypes: p.L78P and p.L132P in families with symptoms of both CMT and FSGS; p.C104Y in a family with CMT; and p.R218Q in a family with FSGS. Moreover, different CMT types were observed in families with CMT symptoms: CMT1 in two families and Int-CMT in another family. Hearing loss was observed in two families with CMT1. Pathogenicity was predicted by in silico analyses, and considerable conformational changes were predicted in the mutant proteins. Two mutations (p.L78P and p.C104Y) were unreported, and three families showed de novo mutations that were putatively occurred from fathers. This study suggests that patients with INF2 mutations show a broad phenotypic spectrum: CMT1, CMT1 + FSGS, CMTDIE + FSGS, and FSGS. Therefore, the genotype-phenotype correlation may be more complex than previously recognized. We believe that this study expands the clinical spectrum of patients with INF2 mutations and will be helpful in the molecular diagnosis of CMT and FSGS.
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Doença de Charcot-Marie-Tooth , Forminas , Glomerulosclerose Segmentar e Focal , Humanos , Doença de Charcot-Marie-Tooth/genética , Doença de Charcot-Marie-Tooth/complicações , Forminas/genética , Glomerulosclerose Segmentar e Focal/genética , Proteínas dos Microfilamentos/genética , Mutação/genética , FenótipoRESUMO
Background and Objectives. Swallowing and coughing reflexes are both closely associated with airway protection. Peak cough flow (PCF) is associated with dysphagia in several neurogenic diseases. In this study, we aimed to analyze the relationship between PCF and aspiration in Parkinson's disease (PD) and determine the cut-off value of PCF. Materials and Methods. We retrospectively analyzed the records of patients with PD who underwent a videofluoroscopic swallowing study and checked for PCF. A total of 219 patients were divided into an aspiration group (n = 125) and a non-aspiration group (n = 94). Results. Significantly lower PCF values were observed in the aspiration group compared to the non-aspiration group (132.63 ± 83.62 vs. 181.38 ± 103.92 L/min, p < 0.001). Receiver operating characteristic curve analysis revealed that a PCF cut-off value of 153 L/min (area under the receiver operating characteristic curve, 0.648; sensitivity, 73.06%; specificity, 51.06%) was associated with aspiration in PD. Additionally, a univariate analysis showed that the male sex, lower body mass indexes, higher Hoehn and Yahr scales, and PCF values of ≤153 L/min indicated an increased risk of aspiration. Conclusions. Through a multivariate analysis, we demonstrated that a PCF value ≤153 L/min was associated with an increased risk of aspiration (odds ratio 3.648; 1.797-7.407), highlighting that a low PCF is a risk factor for aspiration in patients with PD.
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Transtornos de Deglutição , Doença de Parkinson , Humanos , Masculino , Transtornos de Deglutição/complicações , Doença de Parkinson/complicações , Estudos Retrospectivos , Projetos Piloto , Tosse/etiologiaRESUMO
Charcot-Marie-Tooth disease (CMT) and related diseases are a genetically and clinically heterogeneous group of peripheral neuropathies. Particularly, mutations in several aminoacyl-tRNA synthetase (ARS) genes have been reported to cause axonal CMT (CMT2) or distal hereditary motor neuropathy (dHMN). However, the common pathogenesis among CMT subtypes by different ARS gene defects is not well understood. This study was performed to investigate ARS gene mutations in a CMT cohort of 710 Korean families. Whole-exome sequencing was applied to 710 CMT patients who were negative for PMP22 duplication. We identified 12 disease-causing variants (from 13 families) in GARS1, AARS1, HARS1, WARS1, and YARS1 genes. Seven variants were determined to be novel. The frequency of overall ARS gene mutations was 1.22% among all independent patients diagnosed with CMT and 1.83% in patients negative for PMP22 duplication. WARS1 mutations have been reported to cause dHMN; however, in our patients with WARS1 variants, CMT was associated with sensory involvement. We analyzed genotype-phenotype correlations and expanded the phenotypic spectrum of patients with CMT possessing ARS gene variants. We also characterized clinical phenotypes according to ARS genes. This study will be useful for performing exact molecular and clinical diagnoses and providing reference data for other population studies.
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Aminoacil-tRNA Sintetases , Doença de Charcot-Marie-Tooth , Aminoacil-tRNA Sintetases/genética , Doença de Charcot-Marie-Tooth/patologia , Estudos de Coortes , Humanos , Mutação/genética , Fenótipo , Proteínas/genética , República da CoreiaRESUMO
The functional native states of globular proteins become unstable at low temperatures, resulting in cold unfolding and impairment of normal biological function. Fundamental understanding of this phenomenon is essential to rationalizing the evolution of freeze-tolerant organisms and developing improved strategies for long-term preservation of biological materials. We present fully atomistic simulations of cold denaturation of an α-helical protein, the widely studied Trp-cage miniprotein. In contrast to the significant destabilization of the folded structure at high temperatures, Trp-cage cold denatures at 210 K into a compact, partially folded state; major elements of the secondary structure, including the α-helix, are conserved, but the salt bridge between aspartic acid and arginine is lost. The stability of Trp-cage's α-helix at low temperatures suggests a possible evolutionary explanation for the prevalence of such structures in antifreeze peptides produced by cold-weather species, such as Arctic char. Although the 310-helix is observed at cold conditions, its position is shifted toward Trp-cage's C-terminus. This shift is accompanied by intrusion of water into Trp-cage's interior and the hydration of buried hydrophobic residues. However, our calculations also show that the dominant contribution to the favorable energetics of low-temperature unfolding of Trp-cage comes from the hydration of hydrophilic residues.
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Peptídeos/química , Desnaturação Proteica , Temperatura Baixa , Dobramento de Proteína , Estabilidade Proteica , Estrutura Secundária de Proteína , TermodinâmicaRESUMO
OBJECTIVE: Distal myopathy is a heterogeneous group of muscle diseases characterized by predominant distal muscle weakness. A study was done to identify the underlying cause of autosomal recessive adolescent onset distal myopathy. METHODS: Four patients from 2 unrelated Korean families were evaluated. To isolate the genetic cause, exome sequencing was performed. In vitro and in vivo assays using myoblast cells and zebrafish models were performed to examine the ADSSL1 mutation causing myopathy pathogenesis. RESULTS: Patients had an adolescent onset distal myopathy phenotype that included distal dominant weakness, facial muscle weakness, rimmed vacuoles, and mild elevation of serum creatine kinase. Exome sequencing identified completely cosegregating compound heterozygous mutations (p.D304N and p.I350fs) in ADSSL1, which encodes a muscle-specific adenylosuccinate synthase in both families. None of the controls had both mutations, and the mutation sites were located in well-conserved regions. Both the D304N and I350fs mutations in ADSSL1 led to decreased enzymatic activity. The knockdown of the Adssl1 gene significantly inhibited the proliferation of mouse myoblast cells, and the addition of human wild-type ADSSL1 reversed the reduced viability. In an adssl1 knockdown zebrafish model, muscle fibers were severely disrupted, which was evaluated by myosin expression and birefringence. In these conditions, supplementing wild-type ADSSL1 protein reversed the muscle defect. INTERPRETATION: We suggest that mutations in ADSSL1 are the novel genetic cause of the autosomal recessive adolescent onset distal myopathy. This study broadens the genetic and clinical spectrum of distal myopathy and will be useful for exact molecular diagnostics.
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Adenilossuccinato Sintase/genética , Miopatias Distais/genética , Adulto , Idade de Início , Animais , Animais Geneticamente Modificados , Modelos Animais de Doenças , Miopatias Distais/enzimologia , Miopatias Distais/fisiopatologia , Feminino , Humanos , Masculino , Camundongos , Mutação , Linhagem , Fenótipo , República da Coreia , Adulto Jovem , Peixe-Zebra , Proteínas de Peixe-ZebraRESUMO
BACKGROUND: Mutations in MPV17 cause the autosomal recessive disorder mitochondrial DNA depletion syndrome 6 (MTDPS6), also called Navajo neurohepatopathy (NNH). Clinical features of MTDPS6 is infantile onset of progressive liver failure with seldom development of progressive neurologic involvement. METHODS: Whole exome sequencing (WES) was performed to isolate the causative gene of two unrelated neuropathy patients (9 and 13 years of age) with onset of the syndrome. Clinical assessments and biochemical analysis were performed. RESULTS: A novel homozygous mutation (p.R41Q) in MPV17 was found by WES in both patients. Both showed axonal sensorimotor polyneuropathy without liver and brain involvement, which is neurophysiologically similar to axonal Charcot-Marie-Tooth disease (CMT). A distal sural nerve biopsy showed an almost complete loss of the large and medium-sized myelinated fibers compatible with axonal neuropathy. An in vitro assay using mouse motor neuronal cells demonstrated that the abrogation of MPV17 significantly affected cell integrity. In addition, the expression of the mutant protein affected cell proliferation. These results imply that both the loss of normal function of MPV17 and the gain of detrimental effects of the mutant protein might affect neuronal function. CONCLUSION: We report a novel homozygous mutation in MPV17 from two unrelated patients harboring axonal sensorimotor polyneuropathy without hepatoencephalopathy. This report expands the clinical spectrum of diseases caused by mutations of MPV17, and we recommend MPV17 gene screening for axonal peripheral neuropathies.
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Homozigoto , Proteínas de Membrana/genética , Proteínas Mitocondriais/genética , Mutação , Polineuropatias/genética , Adulto , Povo Asiático/genética , Feminino , Humanos , Masculino , Linhagem , República da CoreiaRESUMO
Understanding the mechanisms by which proteins fold from disordered amino-acid chains to spatially ordered structures remains an area of active inquiry. Molecular simulations can provide atomistic details of the folding dynamics which complement experimental findings. Conventional order parameters, such as root-mean-square deviation and radius of gyration, provide structural information but fail to capture the underlying dynamics of the protein folding process. It is therefore advantageous to adopt a method that can systematically analyze simulation data to extract relevant structural as well as dynamical information. The nonlinear dimensionality reduction technique known as diffusion maps automatically embeds the high-dimensional folding trajectories in a lower-dimensional space from which one can more easily visualize folding pathways, assuming the data lie approximately on a lower-dimensional manifold. The eigenvectors that parametrize the low-dimensional space, furthermore, are determined systematically, rather than chosen heuristically, as is done with phenomenological order parameters. We demonstrate that diffusion maps can effectively characterize the folding process of a Trp-cage miniprotein. By embedding molecular dynamics simulation trajectories of Trp-cage folding in diffusion maps space, we identify two folding pathways and intermediate structures that are consistent with the previous studies, demonstrating that this technique can be employed as an effective way of analyzing and constructing protein folding pathways from molecular simulations.
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Peptídeos/química , Dobramento de Proteína , Difusão , Simulação de Dinâmica MolecularRESUMO
OBJECTIVE: To investigate the relation between voluntary cough and swallowing functions according to the type of lesion in patients with acute stroke. DESIGN: Cross-sectional study. SETTING: University rehabilitation hospital. PARTICIPANTS: Acute stroke patients with dysphagia symptoms (N=397). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: A peak cough flow meter was used to measure voluntary coughing ability. Swallowing function was evaluated using the functional dysphagia scale and the penetration-aspiration scale based on the results of a videofluoroscopic swallowing study. Stroke lesions were divided into one of the following 3 categories: cortical, subcortical, and brainstem. These evaluations were performed within 2 weeks after stroke onset. RESULTS: Of the enrolled 397 patients, 207 patients were classified as cortical stroke, 106 patients were classified as subcortical stroke, and 84 patients were classified as brainstem stroke. Among the subscores of the functional dysphagia scale, the amount of pharyngeal residue negatively correlated with peak cough flow meter results across all stroke lesion types. In the brainstem lesion, peak cough flow and penetration-aspiration scale scores were high compared with other lesions, but these 2 functions did not show a correlation. CONCLUSIONS: This study revealed that large amounts of pharyngeal residue correlated with weak voluntary cough ability in all stroke lesion groups. We also showed a discrepancy between 2 functions in the brainstem lesion group. Our results suggest that voluntary coughing exercises could be a helpful therapeutic option for dysphagia to prevent pulmonary complications in some types of patients with stroke.
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Tosse/fisiopatologia , Transtornos de Deglutição/fisiopatologia , Acidente Vascular Cerebral/fisiopatologia , Idoso , Estudos Transversais , Transtornos de Deglutição/etiologia , Transtornos de Deglutição/reabilitação , Feminino , Fluoroscopia , Humanos , Masculino , Pessoa de Meia-Idade , Acidente Vascular Cerebral/complicações , Reabilitação do Acidente Vascular CerebralRESUMO
The drip and ship paradigm for stroke patients enhances the rate of using intravenous tissue plasminogen activator (IVT) in community hospitals. The safety and outcomes of patients treated with IVT for acute ischemic stroke (AIS) under the drip and ship paradigm were compared with patients directly treated at a comprehensive stroke center in the Busan metropolitan area of Korea. This was a retrospective study of patients with AIS treated with IVT between January 2009 and January 2012. Information on patients' baseline characteristics, neuroimaging, symptomatic intracerebral hemorrhage (sICH), and outcome 90 days after using IVT was obtained from our stroke registry. We surveyed stroke neurologists regarding their pattern of post-thrombolysis care. During the observation periods, we selected 317 patients using IVT. Among these, 239 patients received IVT at our stroke center, and 78 were treated at 21 community hospitals under the drip and ship paradigm. Initial neurologic deficits and the size of ischemic lesions on magnetic resonance imaging were much more severe in patients treated with IVT under the drip and ship paradigm compared with patients treated at our comprehensive stroke center. The prevalence of a poor outcome (modified Rankin Scale score 3-6) 90 days after IVT was much higher in patients treated with the drip and ship paradigm than in those treated at our comprehensive stroke center. Regarding the occurrence of sICH, there was no significant difference between the 2 groups. The clinical characteristics and outcomes after using IVT under the drip and ship paradigm may differ greatly among stroke care systems.
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Fibrinolíticos/uso terapêutico , Acidente Vascular Cerebral/terapia , Ativador de Plasminogênio Tecidual/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Feminino , Hospitais/estatística & dados numéricos , Humanos , Injeções Intravenosas , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Transferência de Pacientes/estatística & dados numéricos , Prevalência , República da Coreia/epidemiologia , Estudos Retrospectivos , Acidente Vascular Cerebral/epidemiologia , Terapia Trombolítica/estatística & dados numéricos , Resultado do TratamentoRESUMO
After severe brain injuries, a tracheostomy tube is usually inserted for respiratory support. This study aimed to clarify the prognostic factors for tracheostomy early decannulation in patients with acquired brain injuries. We retrospectively reviewed the medical records of inpatients with acquired brain injuries who underwent successful tracheostomy decannulation between March 2021 and June 2022. Fifty-six patients were included; median age was 68 (59-72) years; 28 (50%) were men; 28 (50%) underwent tracheostomy due to stroke. The median time to decannulation was 47 days. The patients were divided into the early and the late decannulation groups based on the median time, and compared. In univariate analysis, the early decannulation group had a higher BMI, peak cough flow, and acquired brain injuries due to trauma, and a lower penetration-aspiration scale score, duration of antibiotic use, and duration of oxygen use. Multivariate Cox regression analysis revealed that a higher initial peak cough flow [hazard ratio (HR) 1.142; 95% confidence interval (CI) 0.912-0.954; P â <â 0.001] and lower duration of oxygen use (HR 0.930; 95% CI 0.502-0.864; P â =â 0.016) were independent factors for early tracheostomy decannulation, with each unit increase in peak cough flow corresponding to a 14.2% increase and each additional day of duration of oxygen use corresponding to a 7.0% decrease in the likelihood of early decannulation. In conclusion, key prognostic factors for early tracheostomy decannulation were identified as the initial cough strength and duration of oxygen use. These results could play important role in decannulation plans for patients with tracheostomy tube.
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Lesões Encefálicas , Traqueostomia , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Estudos Retrospectivos , Prognóstico , Lesões Encefálicas/reabilitação , Remoção de Dispositivo , Fatores de TempoRESUMO
Osmotic demyelination syndrome (ODS) is an acute demyelinating disorder characterized by the loss of myelin in the center of the basis pons, defined as central pontine myelinolysis (CPM), and demyelination in locations outside the pons, defined as extrapontine myelinolysis (EPM). ODS including CPM and EPM is mainly caused by rapid correction of hyponatremia. However, there are several reports of ODS in medical conditions such as malnutrition; alcoholism; liver transplantation; malignancy; sepsis; and electrolyte imbalance including hypernatremia, hypokalemia, hypophosphatemia, and chronic illness. ODS caused by rapid correction of hyperammonemia or continuous hyperbilirubinemia without sodium fluctuations has rarely been reported. Because ODS may be irreversible, prevention is crucial. Herein, we report a case of ODS secondary to rapid correction of hyperammonemia and continuous hyperbilirubinemia.
RESUMO
High-power terahertz radiation was observed to be emitted from a gas jet irradiated by 100-terawatt-class laser pulses in the laser-wakefield acceleration of electrons. The emitted terahertz radiation was characterized in terms of its spectrum, polarization, and energy dependence on the accompanying electron bunch energy and charge under various gas target conditions. With a nitrogen target, more than 4 mJ of energy was produced at <10 THz with a laser-to-terahertz conversion efficiency of ~0.15%. Such strong terahertz radiation is hypothesized to be produced from plasma electrons accelerated by the ponderomotive force of the laser and the plasma wakefields on the time scale of the laser pulse duration and plasma period. This model is examined with analytic calculations and particle-in-cell simulations to better understand the generation mechanism of high-energy terahertz radiation in laser-wakefield acceleration.
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Neuropatias do Plexo Braquial/diagnóstico , Bursite/diagnóstico por imagem , Condução Nervosa , Neuralgia/diagnóstico , Dor de Ombro/diagnóstico , Potenciais de Ação , Idoso , Neuropatias do Plexo Braquial/etiologia , Neuropatias do Plexo Braquial/fisiopatologia , Bursite/complicações , Bursite/fisiopatologia , Eletromiografia , Feminino , Humanos , Imageamento por Ressonância Magnética , Neuralgia/etiologia , Neuralgia/fisiopatologia , Dor de Ombro/etiologia , Dor de Ombro/fisiopatologiaRESUMO
Extracorporeal shock wave therapy (ESWT) can reduce breast cancer-related lymphedema (BCRL). However, evidence of the long-term effectiveness of ESWT on BCRL is sparse. The aim of the study was to investigate whether ESWT has long-term effects on BCRL. We enrolled patients with stage 2 lymphedema. The 28 female patients were randomly divided into the ESWT group (n = 14) and the control group (n = 14). ESWT was applied thrice a week for a total of 3 weeks with an intensity of 0.056 to 0.068 mJ/mm2 and a frequency of 4 Hz. Complex decongestive therapy (CDT) was applied in both groups. The arm circumference, fluid volume, ratio of water content, and skin thickness were measured. Patients were evaluated at before treatment, 3 weeks after ESWT completion, and 3 months post-ESWT completion. The ESWT group, the circumference of the whole arm, volume, ratio of water content, QuickDASH score, and skin thickness showed statistically significant improvement at 3 weeks and 3 months post-treatment. When comparing the changes in measurement between the two groups at 3 weeks and 3 months post-treatment, ESWT group showed statistically significant improvement in circumference (cm) below the elbow, ratio of water content and skin thickness at 3 weeks and 3 months post treatment. Overall, ESWT improved lymphedema in patients with stage 2 BCRL, and the effects persisted for at least 3 months. Therefore, ESWT may be an additional treatment method for patients with lymphedema.
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Duplication and deletion of the peripheral myelin protein 22 (PMP22) gene cause Charcot-Marie-Tooth disease type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP), respectively, while point mutations or small insertions and deletions (indels) usually cause CMT type 1E (CMT1E) or HNPP. This study was performed to identify PMP22 mutations and to analyze the genotype−phenotype correlation in Korean CMT families. By the application of whole-exome sequencing (WES) and targeted gene panel sequencing (TS), we identified 14 pathogenic or likely pathogenic PMP22 mutations in 21 families out of 850 CMT families who were negative for 17p12 (PMP22) duplication. Most mutations were located in the well-conserved transmembrane domains. Of these, eight mutations were not reported in other populations. High frequencies of de novo mutations were observed, and the mutation sites of c.68C>G and c.215C>T were suggested as the mutational hotspots. Affected individuals showed an early onset-severe phenotype and late onset-mild phenotype, and more than 40% of the CMT1E patients showed hearing loss. Physical and electrophysiological symptoms of the CMT1E patients were more severely damaged than those of CMT1A while similar to CMT1B caused by MPZ mutations. Our results will be useful for the reference data of Korean CMT1E and the molecular diagnosis of CMT1 with or without hearing loss.
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Doença de Charcot-Marie-Tooth , Proteínas da Mielina/genética , Artrogripose , Doença de Charcot-Marie-Tooth/genética , Surdez , Neuropatia Hereditária Motora e Sensorial , Humanos , MutaçãoRESUMO
Charcot-Marie-Tooth disease (CMT) is the most common hereditary peripheral neuropathy. Mutations in the neurofilament light polypeptide (NEFL) gene produce diverse clinical phenotypes, including demyelinating (CMT1F), axonal (CMT2E), and intermediate (CMTDIG) neuropathies. From 2005 to 2020, 1,143 Korean CMT families underwent gene sequencing, and we investigated the clinical, genetic, and neuroimaging spectra of NEFL-related CMT patients. Ten NEFL mutations in 17 families (1.49%) were identified, of which three (p.L312P, p.Y443N, and p.K467N) were novel. Eight de novo cases were identified at a rate of 0.47 based on a cosegregation analysis. The age of onset was ≤3 years in five cases (13.5%). The patients revealed additional features including delayed walking, ataxia, dysphagia, dysarthria, dementia, ptosis, waddling gait, tremor, hearing loss, and abnormal visual evoked potential. Signs of ataxia were found in 26 patients (70.3%). In leg MRI analyses, various degrees of intramuscular fat infiltration were found. All compartments were evenly affected in CMT1F patients. The anterior and anterolateral compartments were affected in CMT2E, and the posterior compartment was affected in CMTDIG. Thus, NEFL-related CMT patients showed phenotypic heterogeneities. This study's clinical, genetic, and neuroimaging results could be helpful in the evaluation of novel NEFL variants and differential diagnosis against other CMT subtypes.
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Ataxia Cerebelar , Doença de Charcot-Marie-Tooth , Ataxia Cerebelar/genética , Doença de Charcot-Marie-Tooth/genética , Potenciais Evocados Visuais , Humanos , FenótipoRESUMO
BACKGROUND: Charcot-Marie-Tooth disease type 1C (CMT1C) is a rare subtype associated with LITAF gene mutations. Until now, only a few studies have reported the clinical features of CMT1C. OBJECTIVE: This study was performed to find CMT1C patients with mutation of LITAF in a Korean CMT cohort and to characterize their clinical features. METHODS: In total, 1,143 unrelated Korean families with CMT were enrolled in a cohort. We performed whole exome sequencing to identify LITAF mutations, and examined clinical phenotypes including electrophysiological and MRI features for the identified CMT1C patients. RESULTS: We identified 10 CMT1C patients from three unrelated families with p.G112S mutation in LITAF. The frequency of CMT1C among CMT1 patients was 0.59%, which is similar to reports from Western populations. CMT1C patients showed milder symptoms than CMT1A patients. The mean CMT neuropathy score version 2 was 7.7, and the mean functional disability scale was 1.0. Electrophysiological findings showed a conduction block in 22% of affected individuals. Lower extremity MRIs showed that the superficial posterior and anterolateral compartments of the calf were predominantly affected. CONCLUSIONS: We found a conduction block in Korean CMT1C patients with p.G112S mutation and first described the characteristic MRI findings of the lower extremities in patients with LITAF mutation. These findings will be helpful for genotype-phenotype correlation and will widen understanding about the clinical spectrum of CMT1C.
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Doença de Charcot-Marie-Tooth , Doença de Charcot-Marie-Tooth/diagnóstico por imagem , Doença de Charcot-Marie-Tooth/genética , Humanos , Mutação , Proteínas Nucleares/genética , Fatores de Transcrição/genéticaRESUMO
BACKGROUND AND OBJECTIVE: To investigate the clinical relevance of CSF myelin oligodendrocyte glycoprotein-immunoglobulin G (MOG-IgG) testing in a large multicenter cohort. METHODS: In this multicenter cohort study, paired serum-CSF samples from 474 patients with suspected inflammatory demyelinating disease (IDD) from 11 referral hospitals were included. After serum screening, patients were grouped into seropositive myelin oligodendrocyte glycoprotein antibody associated disease (MOGAD, 31), aquaporin-4-IgG-positive neuromyelitis optica spectrum disorder (AQP4-IgG + NMOSD, 60), other IDDs (217), multiple sclerosis (MS, 45), and non-IDDs (121). We then screened CSF for MOG-IgG and compared the clinical and serologic characteristics of patients uniquely positive for MOG-IgG in the CSF to seropositive patients with MOGAD. RESULTS: Nineteen patients with seropositive MOGAD (61.3%), 9 with other IDDs (CSF MOG + IDD, 4.1%), 4 with MS (8.9%), but none with AQP4-IgG + NMOSD nor with non-IDDs tested positive in the CSF for MOG-IgG. The clinical, pathologic, and prognostic features of patients uniquely positive for CSF MOG-IgG, with a non-MS phenotype, were comparable with those of seropositive MOGAD. Intrathecal MOG-IgG synthesis, observed from the onset of disease, was shown in 12 patients: 4 of 28 who were seropositive and 8 who were uniquely CSF positive, all of whom had involvement of either brain or spinal cord. Both CSF MOG-IgG titer and corrected CSF/serum MOG-IgG index, but not serum MOG-IgG titer, were associated with disability, CSF pleocytosis, and level of CSF proteins. DISCUSSION: CSF MOG-IgG is found in IDD other than MS and also in MS. In IDD other than MS, the CSF MOG-IgG positivity can support the diagnosis of MOGAD. The synthesis of MOG-IgG in the CNS of patients with MOGAD can be detected from the onset of the disease and is associated with the severity of the disease. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that the presence of CSF MOG-IgG can improve the diagnosis of MOGAD in the absence of an MS phenotype, and intrathecal synthesis of MOG-IgG was associated with increased disability.