ABSTRACT
Host-guest complex has attracted much attention because of their fantastic capability. Accurate prediction of their binding affinity and enthalpy is essential to the rational design of guest molecules. The attach-pull-release (APR) method proposed by Henriksen et al. (J. Chem. Theory Comput., 2015, 11:4377.) shows good prediction capability of binding affinity especially for host-guest system. In order to further evaluate the performance of APR method in practice, we have conducted the calculations on the macrocycle cucurbit [7]urils (CB7) encapsulated with four structurally similar alkaloids (berberine, coptisine, epiberberine and palmatine) with two force fields (GAFF and GAFF2) and three water models (TIP3P, SPC/E and OPC). Compared to the experimental data, the calculation by the combination of GAFF2 and SPC/E force field presents the best performance, of which the Pearson correlation coefficients (R2) is 0.95, and the root-mean-square-deviation is 3.04 kcal/mol. While the predictions from GAFF force field all overestimated the binding affinity, suggesting a systematic error may be involved. Comparison of calculation also indicates that the accuracy of prediction was susceptible to the combination of force field. Therefore, it would be necessary to repeat the simulation with different combination of force fields in practice.
Subject(s)
Alkaloids , Bridged-Ring Compounds , Molecular Dynamics Simulation , Thermodynamics , Alkaloids/chemistry , Bridged-Ring Compounds/chemistry , Imidazoles/chemistry , Water/chemistry , Heterocyclic Compounds, 2-Ring , Macrocyclic Compounds , ImidazolidinesABSTRACT
This paper focuses on the formation control of multi-robot systems with leader-follower network structure in directed topology to guide a system composed of multiple mobile robot agents to achieve global path navigation with a desired formation. A distributed linear formation control strategy based on the complex Laplacian matrix is employed, which enables the robot agents to converge into a similar formation of the desired formation, and the size and orientation of the formation are determined by the positions of two leaders. Additionally, in order to ensure that all robot agents in the formation move at a common velocity, the distributed control approach also includes a velocity consensus component. Based on the realization of similar formation control of a multi-robot system, the path navigation algorithm is combined with it to realize the global navigation of the system as a whole. Furthermore, a controller enabling the scalability of the formation size is introduced to enhance the overall maneuverability of the system in specific scenarios like narrow corridors. The simulation results demonstrate the feasibility of the proposed approach.
ABSTRACT
When the autonomous vehicle (AV) is under various road friction and speed, emergency collision avoidance is extremely difficult. In this situation, the AV may encounter severe understeering problem, so it is hard to achieve collision avoidance, even under the control of active safety system. To tackle this problem, an adaptive collision avoidance strategy (ACAS) is proposed for AV under various road friction and speed. The adaptive performance of the ACAS is realized via three aspects. (1) An adaptive reference path planning method is proposed to provide desired evasive speed and reference path for the AV according to various road friction and reduces the turning burden of AV. (2) A predictive-based fuzzy controller is designed to realize the speed control, and it improves the tracking accuracy of various desired evasive speed. (3) A novel turning enhanced method built with a direct yaw turning controller and a torque distribution method can enhance the turning capability of AV. Finally, the proposed strategy is verified on AV via simulation experiments. The code can be found online here: https://github.com/wangjinlei-hnu/ACAS.
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BACKGROUND: Clinical and genetic features were analyzed in five pedigrees with Pelizaeus-Merzbacher-like disease (PMLD) to provide bases for genetic counseling and prenatal diagnosis. CONCLUSIONS: Six patients from five pedigrees were diagnosed with PMLD based on their clinical data. Six GJC2 novel mutations were found in this study, expanding the spectrum of GJC2 mutations. This is the second group of GJC2 mutations reported from six Chinese patients with PMLD. METHODS: Clinical data including medical history, physical signs, and auxiliary examinations were collected from six patients and their family numbers in five pedigrees with PMLD. Polymerase chain reaction and sequence analysis were used to amplify GJC2 and PLP1 alterations, while multiplex ligation-dependent probe amplification (MLPA) was performed to detect PLP1 dosage changes. The gene mutations were diagnosed for further analysis of the genetic features. RESULTS: A total of seven GJC2 mutations were identified in these patients, including two novel missense mutations (c.217C>T, p.Pro73Ser; c.1199C>A, p.Ala400Glu), one nonsense mutation (c.735C>A, p.Cys245X), three novel frameshift mutations (c.579delC, p.Gly193fsX17 and c.1296_1297insG, p.Gly433fsX59; c.689delG, p.Gly230AlafsX241), and one known missense mutation (c.814T>G, p.Tyr272Asp). Compound heterozygotes were found for P1-3, while homozygotes were found for P4-6 that were inherited from their parents with normal phenotypes except for P5 and P6, respectively. The c.814T>G (p.Tyr272Asp) mutation in P5 was de novo. A c.1199C>A (p.Ala400Glu) homozygous mutation in GJC2 was identified in P6. A heterozygous variation was found in his father and the wild type was seen in his mother.
Subject(s)
Connexins , Demyelinating Diseases , Hereditary Central Nervous System Demyelinating Diseases , Pelizaeus-Merzbacher Disease , Humans , East Asian People , Hereditary Central Nervous System Demyelinating Diseases/genetics , Mutation , Mutation, Missense , Pelizaeus-Merzbacher Disease/genetics , Connexins/geneticsABSTRACT
Kinases have become an important class of targets for drug discovery since the milestone approval of imatinib in 2001. Although a great success has been achieved for targeting kinases with over 70 inhibitors approved by the FDA, it is inevitable that drug resistance would emerge during treatment. Thus, assessment of the kinase mutations is an essential issue for the development of the next generation inhibitors. Apoptosis signal-regulating kinase 1 (ASK1) is a crucial regulator of classical mitogen-activated protein kinase cascade that is being explored under several clinical trials as a promising target. Herein, we investigate the catalytic activity in vitro of ASK1 by constructing two mutants: M754T and H729L, from gatekeeper and αC-helix, respectively. Compared to wild type, the mutation of M754T and H729L results in a roughly 3-fold and 2-fold decrease in binding affinity experimentally. In addition, their binding modes with substrate are theoretically predicted and compared by molecular dynamics. Trajectory analyses of simulations indicate that the decrease of binding affinity should be attributed to the loss of H-bond interaction with gatekeeper methionine. Unexpectedly, the conformation of αC-helix in H729L mutant did not alter significantly during the simulations, although the putatively important H-bond with H729 is lost. These simulations showed the regulatory role of H729 in αC-helix is maintained by leucine residue through the interaction with non-polar residues around H729 site.
Subject(s)
MAP Kinase Kinase Kinase 5 , Protein Kinase Inhibitors , Humans , MAP Kinase Kinase Kinase 5/genetics , Molecular Dynamics Simulation , Mutation , Protein Kinase Inhibitors/chemistryABSTRACT
This paper is concerned with the adaptive event-triggered finite-time pinning synchronization control problem for T-S fuzzy discrete complex networks (TSFDCNs) with time-varying delays. In order to accurately describe discrete dynamical behaviors, we build a general model of discrete complex networks via T-S fuzzy rules, which extends a continuous-time model in existing results. Based on an adaptive threshold and measurement errors, a discrete adaptive event-triggered approach (AETA) is introduced to govern signal transmission. With the hope of improving the resource utilization and reducing the update frequency, an event-based fuzzy pinning feedback control strategy is designed to control a small fraction of network nodes. Furthermore, by new Lyapunov-Krasovskii functionals and the finite-time analysis method, sufficient criteria are provided to guarantee the finite-time bounded stability of the closed-loop error system. Under an optimization condition and linear matrix inequality (LMI) constraints, the desired controller parameters with respect to minimum finite time are derived. Finally, several numerical examples are conducted to show the effectiveness of obtained theoretical results. For the same system, the average triggering rate of AETA is significantly lower than existing event-triggered mechanisms and the convergence rate of synchronization errors is also superior to other control strategies.
ABSTRACT
This paper studies a novel adaptive fractional-order non-singular terminal sliding mode (FO-NTSM) control strategy for omnidirectional mobile robot manipulator (OMRM) with unknown parameters and external disturbances. Firstly, we adopt the fuzzy wavelet neural networks (FWNNs) to estimate the dynamic uncertainty of the OMRM because it has superior function approximation capability. Secondly, we design the adaptive NTSM controller to attenuate external disturbances by virtue of adjusting the weights of the FWNNs online. Moreover, we obtain a fractional-order (FO) control criterion, which speed up the convergence of the algorithm. In addition, we prove the globally robust stability of the OMRM control system through a designed Lyapunov function. Finally, simulation and experiment researches indicate the feasible and validity of the presented method.
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BACKGROUND: LAMA2-related muscular dystrophy including LAMA2-related congenital muscular dystrophy (LAMA2-CMD) and autosomal recessive limb-girdle muscular dystrophy-23 (LGMDR23) is caused by LAMA2 pathogenic variants. We aimed to describe the natural history and establish genotype-phenotype correlations in a large cohort of Chinese patients with LAMA2-related muscular dystrophy. METHODS: Clinical and genetic data of LAMA2-related muscular dystrophy patients enrolled from ten research centers between January 2003 and March 2021 were collected and analyzed. RESULTS: One hundred and thirty patients (116 LAMA2-CMD and 14 LGMDR23) were included. LAMA2-CMD group had earlier onset than LGMDR23 group. Head control, independent sitting and ambulation were achieved in 76.3%, 92.6% and 18.4% of LAMA2-CMD patients at median ages of 6.0 months (range 2.0-36.0 months), 11.0 months (range 6.0-36.0 months), and 27.0 months (range 18.0-84.0 months), respectively. All LGMDR23 patients achieved independent ambulation at median age of 18.0 months (range 13.0-20.0 months). Motor regression in LAMA2-CMD mainly occurred concurrently with rapid progression of contractures during 6-9 years old. Twenty-four LAMA2-related muscular dystrophy patients died, mostly due to severe pneumonia. Seizures occurred in 35.7% of LGMDR23 and 9.5% of LAMA2-CMD patients. Forty-six novel and 97 known LAMA2 disease-causing variants were identified. The top three high-frequency disease-causing variants in Han Chinese patients were c.7147C > T (p.R2383*), exon 4 deletion, and c.5156_5159del (p.K1719Rfs*5). In LAMA2-CMD, splicing variants tended to be associated with a relatively mild phenotype. Nonsense variants were more frequent in LAMA2-CMD (56.9%, 66/116) than in LGMDR23 (21.4%, 3/14), while missense disease-causing variants were more frequent in LGMDR23 (71.4%, 10/14) than in LAMA2-CMD (12.9%, 15/116). Copy number variations were identified in 26.4% of survivors and 50.0% of nonsurvivors, suggesting that copy number variations were associated with lower rate of survival (p = 0.029). CONCLUSIONS: This study provides better understandings of natural history and genotype-phenotype correlations in LAMA2-related muscular dystrophy, and supports therapeutic targets for future researches.
Subject(s)
Muscular Dystrophies, Limb-Girdle , Muscular Dystrophies , Child , Child, Preschool , China , DNA Copy Number Variations , Humans , Infant , Laminin/genetics , Muscular Dystrophies/geneticsABSTRACT
In the hydraulic systems, the non-structural uncertainties such as the nonlinear friction will reduce the tracking accuracy for the hydraulic servo system. In this paper, an incomplete differential-based improved adaptive backstepping integral sliding mode control (ID-BIABISMC) is proposed to realize the position control for the hydraulic servo system based on the friction compensation. The backstepping-based control being integrated the integral sliding mode surface-based sliding mode control with the friction compensation are used to solve the problem of non-structural uncertainty of the hydraulic system. The incomplete differential is introduced to the adaptive update law, by which the low-pass filtering behavior in the incomplete differential is capable of effectively suppressing the interference caused by the pure differential mutation signal. Compared with the traditional adaptive backstepping control (ABC), adaptive sliding mode control (ASMC), the adaptive backstepping sliding mode control (ABSMC) and the proposed adaptive backstepping integral sliding mode control (IABISMC), the experimental results verify the high accuracy tracking performance of the proposed the incomplete differential-based improved adaptive backstepping integral sliding mode control (ID-BIABISMC). For the responses of the sinusoidal signal 40sin(0.2πt+1.5π)+40mm and step signal with 30 mm, the corresponding tracking accuracy for ID-BIABISMC are 0.005 mm and 2.15 mm, respectively.
ABSTRACT
BACKGROUND: LMNA-related muscular dystrophy is caused by mutations in LMNA gene. We aimed to identify genetic variations and clinical features in a large cohort of Chinese patients with LMNA mutations in an attempt to establish genotype-phenotype correlation. METHODS: The clinical presentations of patients with LMNA-related muscular dystrophy were recorded using retrospective and prospective cohort study. LMNA mutation analysis was performed by Sanger sequencing or next-generation sequencing. Mosaicism was detected by personal genome machine amplicon deep sequencing for mosaicism. RESULTS: Eighty-four patients were identified to harbour LMNA mutations. Forty-one of those were diagnosed with LMNA-related congenital muscular dystrophy (L-CMD), 32 with Emery-Dreifuss muscular dystrophy (EDMD) and 11 with limb-girdle muscular dystrophy type 1B (LGMD1B). We identified 21 novel and 29 known LMNA mutations. Two frequent mutations were identified: c.745C>T and c.1357C>T. A correlation between the location of mutation and the clinical phenotype was observed: mutations affecting the head and coil 2A domains mainly occurred in L-CMD, while the coil 2B and Ig-like domains mainly related to EDMD and LGMD1B. We found somatic mosaicism in one parent of four probands. Muscle biopsies revealed 11 of 20 biopsied L-CMD exhibited inflammatory changes, and muscle cell ultrastructure showed abnormal nuclear morphology. CONCLUSIONS: Our detailed clinical and genetic analysis of 84 patients with LMNA-related muscular dystrophy expands clinical spectrum and broadens genetic variations caused by LMNA mutations. We identified 21 novel and 29 known LMNA mutations and found two frequent mutations. A correlation between the location of mutation and the clinical severity was observed. Preliminary data suggested that low-dose corticosteroid treatment may be effective.
Subject(s)
Lamin Type A/genetics , Laminopathies/genetics , Muscular Dystrophies/genetics , Adolescent , Adrenal Cortex Hormones/therapeutic use , Adult , Asian People , Child , Child, Preschool , Cohort Studies , Female , Genetic Association Studies , Humans , Infant , Laminopathies/drug therapy , Laminopathies/pathology , Male , Muscular Dystrophies/drug therapy , Muscular Dystrophies/pathology , Young AdultABSTRACT
LMNA-related muscular dystrophies are caused by mutations of the LMNA gene. Inflammatory changes and cellular apoptosis are significant pathological findings in the muscle cells of these patients. We aimed to investigate the roles of nuclear factor-κB (NF-κB) mediated inflammation as a molecular mechanism for the pathogenesis of LMNA-related muscular dystrophies. Muscle specimen of a patient with LMNA gene mutation (c.1117A>G, p.I373V, reported in our previous work) showed significant inflammatory changes. The ultrastructure of muscle cells showed severe nuclear abnormalities compared with the control. Therefore, we used this mutation to establish mutant cell line for in vitro studies. Transfected human embryonic kidney 293 (HEK293) cells containing a mutant construct from this patient showed irregular nuclear morphology. Mass spectrometry analysis suggested genomic instability and augmented expression of apoptosis-related genes. We detected activation of NF-κB pathway in LMNA mutant cells which promoted the expression of downstream inflammatory factors. The LMNA mutation also activated the molecular pathway of apoptosis in LMNA mutant cells. These are important molecular mechanisms underlying the pathogenesis of LMNA-related muscular dystrophies. Our research provides crucial evidence for future pathogenetic studies and possible treatment strategies for LMNA-related muscular dystrophies.
Subject(s)
Lamin Type A/metabolism , Laminopathies/metabolism , Muscular Dystrophies/metabolism , Mutation, Missense , NF-kappa B/metabolism , Signal Transduction , Amino Acid Substitution , HEK293 Cells , Humans , Lamin Type A/genetics , Laminopathies/genetics , Laminopathies/pathology , Muscular Dystrophies/genetics , NF-kappa B/geneticsABSTRACT
The dysfunction of methyl-CpG-binding protein 2 (MeCP2) is associated with several neurological disorders, of which Rett syndrome (RTT) is the most prominent. This study focused on a Chinese patient cohort with MECP2 mutations, and analyzed the characteristics of these mutations and their clinical manifestations. In total, 666 patients were identified with 126 different MECP2 mutations, including 22 novel mutations. Over 80% of patients carried an MECP2 mutation on exon 4. Nonsense and missense mutations were the most commonly reported types. Missense mutations were mainly located on methyl-CpG-binding domain (MBD), and nonsense mutations predominantly occurred on transcription repression domain (TRD) and inter domain. The predilection site of large deletion was exon 3 and/or exon 4. Patients with p.R133C, p.R294*, p.R306C, and C-terminal domain (CTD) deletions were less severely affected. Significant differences were found in ambulation ability, hand function, and language among different mutation groups. Three female patients with MECP2 mutations (1 with p.R306P and 2 with p.R309W) only presented with intellectual disability/developmental delay (ID/DD), and no obvious RTT symptoms were reported. Eight male individuals with MECP2 mutations were also identified in this study, including 2 diagnosed with typical RTT, 3 with atypical RTT and 3 with ID/DD.
Subject(s)
Genetic Predisposition to Disease , Intellectual Disability/genetics , Methyl-CpG-Binding Protein 2/genetics , Rett Syndrome/genetics , Child, Preschool , China/epidemiology , Codon, Nonsense/genetics , Developmental Disabilities/genetics , Developmental Disabilities/pathology , Female , Humans , Infant , Intellectual Disability/pathology , Male , Mutation, Missense/genetics , Protein Domains/genetics , Rett Syndrome/pathologyABSTRACT
The predicted synonymous mutation c.1251G>A of ISPD (NM_001101426.3) is a hot spot causing exon 9 skipping in five patients.
Subject(s)
Genetic Predisposition to Disease , Muscular Dystrophies/genetics , Nucleotidyltransferases/genetics , Exons/genetics , Female , Humans , Male , Muscular Dystrophies/pathology , Mutation/genetics , Protein Isoforms/geneticsABSTRACT
The aim of this report was to refine the genotypes and phenotypes of chromodomain helicase DNA-binding protein 2 (CHD2)-related epilepsy. Seventeen patients with CHD2 mutations were enrolled. CHD2 mutations were identified by application of next-generation sequencing of epilepsy or whole exome sequencing. Sixteen mutations were identified, among which 15 have not yet been reported. Thirteen mutations were de novo. Age at seizure onset ranged from 3 months to 10 years 5 months. Seizures observed were generalized tonic-clonic, myoclonic, atonic, atypical absence, focal, and myoclonic-atonic. Epileptic spasms occurred in two patients. Developmental disability was present in 14 patients. Autism features were observed in seven patients. Video electroencephalogram was abnormal in 15 patients. Five patients were diagnosed with non-specific epileptic encephalopathy, two with epilepsy with myoclonic-atonic seizures, two with Lennox-Gastaut syndrome, two with febrile seizures plus, and one with West syndrome. Seizures were controlled in nine patients. Q1392TfsX17 may be a hot-spot mutation of CHD2. West syndrome was observed as a new phenotype of CHD2 mutation. The severity of the phenotypes of CHD2 mutations ranged from mild febrile seizures to severe epileptic encephalopathy. WHAT THIS PAPER ADDS: Q1392TfsX17 maybe the hot-spot mutation of CHD2. West syndrome could be a new phenotype of CHD2 mutation.
Subject(s)
DNA-Binding Proteins/genetics , Epilepsy/genetics , Brain/physiopathology , Child , Child, Preschool , Developmental Disabilities/complications , Developmental Disabilities/genetics , Epilepsy/complications , Epilepsy/physiopathology , Female , Genotype , Humans , Infant , Male , Mutation , Pedigree , Phenotype , Spasms, Infantile/complications , Spasms, Infantile/geneticsABSTRACT
BACKGROUND: This study aimed to investigate the new genetic etiologies of Rett syndrome (RTT) or Rett-like phenotypes. METHODS: Targeted next-generation sequencing (NGS) was performed on 44 Chinese patients with RTT or Rett-like phenotypes, in whom genetic analysis of MECP2, CDKL5, and FOXG1 was negative. RESULTS: The detection rate was 31.8% (14/44). A de novo pathogenic variant (c.275_276ins AA, p. Cys92*) of KIF1A was identified in a girl with all core features of typical RTT. A patient with atypical RTT was detected having de novo GRIN1 pathogenic variant (c.2337C > A, p. Val793Phe). Additionally, compound heterozygous pathogenic variants of PPT1 gene were detected in a girl, who initially displayed typical RTT features, but progressed into neuronal ceroid lipofuscinoses (NCL) afterwards. Pathogenic variants in KCNQ2, MEF2C, WDR45, TCF4, IQSEC2, and SDHA were also found in our cohort. CONCLUSIONS: It is the first time that pathogenic variants of GRIN1 and KIF1A were linked to RTT and Rett-like profiles. Our findings expanded the genetic heterogeneity of Chinese RTT or Rett-like patients, and also suggest that some patients with genetic metabolic disease such as NCL, might displayed Rett features initially, and clinical follow-up is essential for the diagnosis.
Subject(s)
Kinesins/genetics , Mutation , Nerve Tissue Proteins/genetics , Receptors, N-Methyl-D-Aspartate/genetics , Rett Syndrome/genetics , Rett Syndrome/pathology , Child , Child, Preschool , Female , Genetic Testing , High-Throughput Nucleotide Sequencing , Humans , Infant , Male , Phenotype , Rett Syndrome/classificationABSTRACT
Objective: To evaluate the efficacy and safety of ketogenic diet (KD) in patients with Dravet syndrome (DS). Methods: 60 DS patients receiving treatment of KD for more than 12 weeks from 2009 to 2018 were analyzed retrospectively. Modified Johns Hopkins protocol was used to initiate KD. Seizure frequency, electroencephalogram (EEG), cognition, language, and motor function of the patients were assessed. Side effects were monitored and adjusted accordingly. SPSS 23.0 software was used for all statistical analysis. Results: In total, 60 DS patients (34 boys, 26 girls) received treatment of KD for more than 12 weeks, and among them 41 (68.3%) patients remained on the diet for more than 24 weeks, 22 (36.7%) patients for more than 48 weeks. Seizures in 35 patients (58.3%) were reduced by over 50% at 12 weeks, and the KD effect was observed within 2 weeks in most of them. At 24 weeks, 61.1% (25/41) of the patients had a >50% seizure reduction. At 48 weeks, 77.3% (17/22) had an over 50% reduction in their seizure frequency. With the treatment of KD in the 60 DS patients, 10 patients had ever been seizure free for 12 months to 24 months (The median duration was 20 months). In 10 KD-effective patients, the background rhythm of their EEG showed obvious improvement, and interictal epileptic discharges decreased significantly. Cognitive function of 22 patients was improved. Language progressed in 14 patients. Motor function was improved in 13 patients. The efficacy of KD in DS patients did not correlate with the seizure onset age, the starting age of KD treatment, the SCN1A mutation and the numbers of antiepileptic drugs combined with KD treatment. The main adverse reactions of KD in the treatment process were gastrointestinal symptoms and metabolic disorders. Conclusions: KD treatment in DS patients has many advantages, including working rapidly, being effective in more than half of the DS patients and tolerable adverse reactions. Pharmoco-resistant DS patients are suggested to receive KD treatment.
ABSTRACT
PURPOSE: To summarize the clinical features and neuroimaging changes of epilepsy associated with TBC1D24 mutations. METHODS: Genetic testing was conducted in all epilepsy patients without acquired risk factors for epilepsy. Epilepsy patients identified with TBC1D24 compound heterozygous mutations by next-generation sequencing (NGS) epilepsy panel or whole exome sequencing (WES) were enrolled. The enrolled patients were followed up to summarize the clinical features. RESULTS: Nineteen patients were identified with TBC1D24 compound heterozygous mutations. Nine patients carried the same pathogenic variant c.241_252del. The seizure onset age ranged from 1 day to 8 months of age (median age 75 days). The most prominent features were multifocal myoclonus and epilepsia partialis continua (EPC). Myoclonus could be triggered by fever or infection in 15 patients, and could be terminated by sleep or sedation drugs. Psychomotor developmental delay was presented in 11 patients. Six patients exhibited hearing loss. Brain MRIs were abnormal in eight patients. Twelve patients were diagnosed with epilepsy syndromes including one patient who was diagnosed with Dravet syndrome. Two patients died due to status epilepticus at 4 months and 19 months of age, respectively. CONCLUSION: TBC1D24 mutation related epilepsy was drug-resistant. Multifocal myoclonus, EPC, and fever-induced seizures were common clinical features. Most patients presented psychomotor developmental delay. The neuroimaging abnormality and hearing loss could exacerbate during follow-up.
Subject(s)
Epilepsy/genetics , GTPase-Activating Proteins/genetics , Mutation , Myoclonus/genetics , Brain/diagnostic imaging , Brain/physiopathology , Developmental Disabilities/diagnostic imaging , Developmental Disabilities/genetics , Developmental Disabilities/physiopathology , Developmental Disabilities/therapy , Epilepsia Partialis Continua/diagnostic imaging , Epilepsia Partialis Continua/genetics , Epilepsia Partialis Continua/physiopathology , Epilepsia Partialis Continua/therapy , Epilepsy/diagnostic imaging , Epilepsy/physiopathology , Epilepsy/therapy , Female , Follow-Up Studies , Genetic Predisposition to Disease , Hearing Loss/diagnostic imaging , Hearing Loss/genetics , Hearing Loss/physiopathology , Hearing Loss/therapy , Humans , Infant , Infant, Newborn , Male , Myoclonus/diagnostic imaging , Myoclonus/physiopathology , Myoclonus/therapy , Seizures, Febrile/diagnostic imaging , Seizures, Febrile/genetics , Seizures, Febrile/physiopathology , Seizures, Febrile/therapyABSTRACT
This study aimed to identify monogenic mutations from Chinese patients with childhood absence epilepsy (CAE) and summarize their characteristics. A total of 100 patients with CAE were recruited in Peking University First Hospital from 2005 to 2016 and underwent telephone and outpatient follow-up review. We used targeted disease-specific gene capture sequencing (involving 300 genes) to identify pathogenic variations for these patients. We identified three de novo epilepsy-related gene mutations, including missense mutations of SCN1A (c. 5399 T > A; p. Val1800Asp), SCN8A (c. 2371 G > T; p. Val791Phe), and CLCN2 (c. 481 G > A; p. Gly161Ser), from three patients, separately. All recruited patients presented typical CAE features and good prognosis. To date, CAE has been considered a complex disease caused by multiple susceptibility genes. In this study, we observed that 3% of typical CAE patients had a de novo mutation of a known monogenic epilepsy-related gene. Our study suggests that a significant proportion of typical CAE cases may be monogenic forms of epilepsy. For genetic generalized epilepsies, such as CAE, further studies are needed to clarify the contributions of de novo or inherited rare monogenic coding, noncoding and copy number variants.
Subject(s)
Chloride Channels/genetics , Epilepsy, Absence/diagnosis , Epilepsy, Absence/genetics , Mutation, Missense/genetics , NAV1.1 Voltage-Gated Sodium Channel/genetics , NAV1.6 Voltage-Gated Sodium Channel/genetics , CLC-2 Chloride Channels , Child , Child, Preschool , China/epidemiology , Chloride Channels/chemistry , Cohort Studies , Epilepsy, Absence/epidemiology , Female , Genetic Variation/genetics , Humans , Male , NAV1.1 Voltage-Gated Sodium Channel/chemistry , NAV1.6 Voltage-Gated Sodium Channel/chemistry , Protein Structure, SecondaryABSTRACT
Congenital muscular dystrophies (CMDs) are clinically and genetically heterogeneous conditions. We launched a nationwide study to determine the frequency of CMD in the Chinese population and assess the status of diagnosis and disease management for CMD in China. Cases were chosen from databases in 34 tertiary academic hospitals from 29 first-level administrative divisions (provinces, municipalities, autonomous regions, and special administrative regions), and medical records were reviewed to confirm the diagnoses. The study included 409 patients, of those patients who consented to genetic testing (n = 340), mutations were identified in 286 of them. The most common forms identified were LAMA2-related CMD (36.4%), followed by COL6-related CMD (23.2%) and α-dystroglycanopathy (21.0%). The forms of CMD related to mutations in LMNA and SEPN1 were less frequent (12.5% and 2.4%, respectively). We also recorded a significant difference in the diagnostic capabilities and disease management of CMD, with this being relatively backward in research centers from less developed regions. We provide, for the first time, comprehensive epidemiologic information of CMD in a large cohort of Chinese people. To our knowledge, this is the largest sample size of its kind so far highlighting the prevalence of CMD in China.