Background: Infantile spasm is a type of pediatric seizure often associated with a negative prognosis. The aim of this study was to evaluate the role of Magnetic Resonance Imaging (MRI) in categorization and neurodeve...Background: Infantile spasm is a type of pediatric seizure often associated with a negative prognosis. The aim of this study was to evaluate the role of Magnetic Resonance Imaging (MRI) in categorization and neurodevelopmental outcomes in children with infantile spasm. Materials and Methods: A retrospective study of the clinical charts and MRI findings of infants diagnosed with infantile spasm between December 2007 and February 2014. Results: A total of 26 children (16 males;1.6/1) were included: 8 of unknown etiology and 18 with a genetic/structural-metabolic causes. Unknown etiology cases revealed normal brain MRI in 5/8 (62.5%). In the genetic/ structural-metabolic group, only 2/18 (11.1%) had normal imaging. Abnormal imaging findings significantly correlated with genetic/structural-metabolic infantile spasm which had unfavorable neurodevelopmental outcome. Conclusion: Neuroimaging conveys substantial information to the further categorization of children with infantile spasm, providing not only relevant information of the underlying cause but also the prediction of the neurodevelopmental outcome.展开更多
Importance:Infantile spasm(IS)is a kind of refractory epilepsy.The first-line treatments for IS are adrenocorticotropic hormone(ACTH),oral corticosteroids,and vigabatrin.Objective:This study aimed to evaluate the effi...Importance:Infantile spasm(IS)is a kind of refractory epilepsy.The first-line treatments for IS are adrenocorticotropic hormone(ACTH),oral corticosteroids,and vigabatrin.Objective:This study aimed to evaluate the efficacy of magnesium sulfate and ACTH(MgSO_(4)+ACTH)combination therapy in patients with IS who failed first-line treatments.Methods:In this retrospective study,the clinical data of patients with IS who failed first-line treatments were collected in the Chinese PLA General Hospital.Patients received MgSO_(4)+ACTH combination therapy after first-line treatments failed.The course of treatments was 2 weeks.The therapeutic dose of ACTH and MgSO_(4)was 2.5 U·kg^(-1)·d^(-1)and 0.25 g·kg^(-1)·d^(-1),respectively.Results:A total of 229 patients with IS who failed the first-line treatments were collected.At the end of the MgSO_(4)+ACTH combination treatment,the seizure-free rate was 48.5%(111/229),and the resolution of hypsarrhythmia on electroencephalogram(EEG)was 72.1%(165/229).About 21.4%(49/229)of patients showed side effects,including infectious diseases,hypokalemia,and diarrhea.Interpretation:For patients with IS who failed first-line treatments,in terms of the seizure-free rate and resolution of hypsarrhythmia on EEG,MgSO_(4)+ACTH combination therapy can be considered.展开更多
Background:Ketogenic diet(KD)therapy is one of the main treatments for drug-resistant epilepsy.However,the KD therapy has been applied in only a small number of infantile spasm cases.In this large multicenter study,we...Background:Ketogenic diet(KD)therapy is one of the main treatments for drug-resistant epilepsy.However,the KD therapy has been applied in only a small number of infantile spasm cases.In this large multicenter study,we investigated the efficacy of KD therapy in the treatment of infantile spasms.Methods:In this retrospective,multicenter cohort study,clinical data from main epilepsy centers were analyzed.Patients were classified into different groups according to age,type of drug and whether glucocorticoid was used before initiation of KD.Results:From October 2014 to March 2020,481 patients(308 males and 173 females)with infantile spasms were treated with the KD therapy.The age of the patients ranged from 2 months to 20 years,with a mean age of 1 year and 10 months.The number of anti-seizure medications(ASMs)used before KD initiation ranged 0-6,with a median of 3.In different time from initiation(1,3,6,and 12 months),the rates of seizure freedom after KD were 6.9,11.6;16.0 and 16.8%,respectively(x^(2)=27.1772,P<0.0001).There was a significant difference in the rate of seizure freedom between 3 months and 1 month(x^(2)=6.5498,P=0.0105)groups,and 6 months and 3 months(x^(2)=3.8478,P=0.0498)groups,but not between 12 months and 6 months(x^(2)=0.1212,P=0.7278)groups.The rates of effectiveness were 44.7;62.8,49.1 and 32.0%(x^(2)=93.2674,P<0.0001),respectively.The retention rates were 94.0,82.5,55.7 and 33.1%(x^(2)=483.7551,P<0.0001),correspondingly.The rate of effectiveness and the retention rate of KD were significantly different among the 1,3,6 and 12 months.KD treatment was the first choice in 25 patients(5.2%),55 patients(11.4%)started KD after the failure of the first ASM,158 patients(32.8%)started KD after the failure of the second ASM,157 patients(32.6%)started KD after the failure of the third drug,and 86 patients(17.9%)started KD after the failure of the fourth and more.The KD effect was not related to the number of ASMs used before KD startup(P>0.05).Two hundred and eighteen patients(45.3%)failed to respond to corticotropin or glucocorticoid before initiation.There was no significant difference in the effectiveness rate at different time points between the group of KD therapy after glucocorticoid failure and the group after non-hormone failure (x^(2)=0.8613,P=0.8348).The rate of adverse events of KD in 1,3,6,and 12 months after KD initiation were 22.3,21.7,16.8 and 6.9%,respectively.The adverse events mainly occurred during the first 3 months of KD,and the main adverse events were gastrointestinal disturbance and constipation.Conclusions:The efficacy of the KD treatment for infantile spasms was not affected by age,medication,and glucocorticoid use before initiation.KD is one of the effective treatments for infantile spasms.展开更多
Background Even though adrenocorticotropic hormone(ACTH)demonstrated powerful efficacy in the initially successful treatment of infantile spasms(IS),nearly half of patients have experienced a relapse.We sought to inve...Background Even though adrenocorticotropic hormone(ACTH)demonstrated powerful efficacy in the initially successful treatment of infantile spasms(IS),nearly half of patients have experienced a relapse.We sought to investigate whether features of electroencephalogram(EEG)predict relapse in those IS patients without structural brain abnormalities.Methods We retrospectively reviewed data from children with IS who achieved initial response after ACTH treatment,along with EEG recorded within the last two days of treatment.The recurrence of epileptic spasms following treatment was tracked for 12 months.Subjects were categorized as either non-relapse or relapse groups.General clinical and EEG recordings were collected,burden of amplitudes and epileptiform discharges(BASED)score and multiscale entropy(MSE)were carefully explored for cross-group comparisons.Results Forty-one patients were enrolled in the study,of which 26(63.4%)experienced a relapse.The BASED score was significantly higher in the relapse group.MSE in the non-relapse group was significantly lower than the relapse group in theγband but higher in the lower frequency range(δ,θ,α).Sensitivity and specificity were 85.71%and 92.31%,respectively,when combining MSE in theδ/γfrequency of the occipital region,plus BASED score were used to distinguish relapse from non-relapse groups.Conclusions BASED score and MSE of EEG after ACTH treatment could be used to predict relapse for IS patients without brain structural abnormalities.Patients with BASED score≥3,MSE increased in higher frequency,and decreased in lower frequency had a high risk of relapse.展开更多
Background:Infantile spasms(IS)are the most common childhood epileptic encephalopathy.Focal cortical dysplasia(FCD)and gray matter heterotopias(GH)are common structural causes of IS.The recommended first-line treatmen...Background:Infantile spasms(IS)are the most common childhood epileptic encephalopathy.Focal cortical dysplasia(FCD)and gray matter heterotopias(GH)are common structural causes of IS.The recommended first-line treatment for IS patients with structural causes is surgical intervention,according to the International League Against Epilepsy(ILAE)commission guidelines.However,there is currently no consensus on appropriate timings of surgery.Case presentations:Two structural IS cases are presented here:one was caused by FCD,and the other by GH.Both patients exhibited recurrent seizures at the age of 2 months,had poor responses to various antiepileptic drugs(AEDs)and displayed severe mental and motor developmental retardation.Seizure types included focal seizures and spasms.Brain magnetic resonance imaging showed abnormal gray signal or suspicious FCD lesions that coincided with the origin of the focal seizures.The patients underwent lesion resection before the age of 6 months.Follow-up observation showed that seizures of both patients were completely controlled several days after the surgery.All AEDs were gradually reduced in dosage within 1 year,and the mental and motor development almost returned to normal.Conclusion:Early resection of lesions in structural IS patients has benefits of effectively controlling convulsions and improving developmental retardation.Infants at several months of age can well tolerate craniotomy,and their cognitive development is more likely to return to normal after early surgery.展开更多
Background Infantile spasms is a severe epileptic encephalopathy, which is refractory to conventional antiepileptic drugs. Adrenocorticotropic hormone (ACTH) has been the major therapy for infantile spasms; however,...Background Infantile spasms is a severe epileptic encephalopathy, which is refractory to conventional antiepileptic drugs. Adrenocorticotropic hormone (ACTH) has been the major therapy for infantile spasms; however, ACTH therapy is ineffective for some patients. The variations in the receptor genes can contribute to antiepileptic drug resistance. This study was to elucidate the possible associations between the variations of the MC2R gene and ACTH responsiveness in patients with infantile spasms. Methods We screened for variations in the promoter and coding region of the MC2R gene in 91 Chinese patients with infantile spasms and 94 controls, using PCR and a direct sequencing method. The frequencies of the genotypes, alleles and reconstructed haplotypes were analyzed in the cases and controls. The association between ACTH responsiveness and genetic variations of the MC2R gene was also assessed. Results Four single nucleotide polymorphisms (SNPs) were identified in the MC2R promoter, one of which was a novel specimen at position-2 from the transcription start site ATT, -2T〉C. Three SNPs (rs1893220, rs2186944 and -2T〉C) showed a significant difference between the cases and controls (P 〈0.05 for all). The frequency of the common TCCT haplotype carrying four-SNP major alleles was significantly lower in the cases (39%) than in the controls (60%) (P=-0.00003). The homozygous carriers of the TCCT haplotype had a much lower relative risk than the non-carriers (RR=O.42, 95%C/ 0.26-0.70, P=-0.0001). ACTH responsiveness was strongly associated with the TCCT haplotype (P=-0.000082). Compared with non-carriers of the TCCT haplotype, the homozygous and heterozygous carriers were more responsive to ACTH therapy (P=0.0002; P=-0.0003, respectively). Conclusions Our results indicated that the TCCT haplotype in the MC2R promoter is strongly associated with the responsiveness of the ACTH therapy performed on patients with infantile spasms. The polymorphisms of the MC2R promoter might be one important factor that influences the efficacy of ACTH therapy on infantile spasms.展开更多
Background Sandhoff disease(SD)i s an autosomal recessive lysosomal disease with clinical manifestations such as epilepsy,psychomotor retardation and developmental delay.However,infantile SD with onset of infantile ep...Background Sandhoff disease(SD)i s an autosomal recessive lysosomal disease with clinical manifestations such as epilepsy,psychomotor retardation and developmental delay.However,infantile SD with onset of infantile epilepsy spasm syndrome(IESS)is extremely rare.Case presentation The case presented here was a 22-month-old boy,who presented with IESS and psychomotor retardation/regression at 6 months of age.The patient showed progressive aggravation of seizures and excessive startle responses.The whole exome sequencing data,which initially revealed negative results,were reanalyzed and indicated a homozygous mutation at the c.1613+4del splice site of the HEXB gene.The activities ofβ-hexosaminidase A and total hexosaminidase were significantly decreased.The fundus examination showed cherry red spots at the macula.Conclusions IESS can be an epileptic phenotype of infantile SD.Clinical phenotypes should be adequately collected in genetic testing.In the case of negative sequencing results,gene variant reanalysis can be performed when the patients show clinically suspicious indications.展开更多
Inflammation is an established etiopathogenesis factor of infantile spasms(IS), a therapy-resistant epileptic syndrome of infancy. We investigated the IS-associated transcriptomic alterations of neurotransmission in...Inflammation is an established etiopathogenesis factor of infantile spasms(IS), a therapy-resistant epileptic syndrome of infancy. We investigated the IS-associated transcriptomic alterations of neurotransmission in rat hypothalamic arcuate nucleus, how they are corrected by antiinflamatory treatments and whether there are sex differences. IS was triggered by repeated intraperitoneal administration of N-methyl-D-aspartic acid following anti-inflammatory treatment(adreno-cortico-tropic-hormone(ACTH) or PMX53)or normal saline vehicle to prenatally exposed to betamethasone young rats. We found that treatments with both ACTH and PMX53 resulted in substantial recovery of the genomic fabrics of all types of synaptic transmission altered by IS. While ACTH represents the first line of treatment for IS, the even higher efficiency of PMX53(an antagonist of the complement C5 a receptor) in restoring the normal transcriptome was not expected. In addition to the childhood epilepsy, the recovery of the neurotransmission genomic fabrics by PMX53 also gives hope for the autism spectrum disorders that share a high comorbidity with IS. Our results revealed significant sex dichotomy in both IS-associated transcriptomic alterations(males more affected) and in the efficiency of PMX53 anti-inflammatory treatment(better for males). Our data further suggest that anti-inflammatory treatments correcting alterations in the inflammatory transcriptome may become successful therapies for refractory epilepsies.展开更多
Background NR2F1 mutations are associated with Bosch-Boonstra-Schaaf optic atrophy syndrome(BBSOAS).Although~46.7%of BBSOAS patients present with epilepsy,which is always drug-resistant and associated with higher rate...Background NR2F1 mutations are associated with Bosch-Boonstra-Schaaf optic atrophy syndrome(BBSOAS).Although~46.7%of BBSOAS patients present with epilepsy,which is always drug-resistant and associated with higher rates of behavioral and cognitive problems,the treatment and outcomes of NR2F1-related epilepsy have rarely been described.Here,we present new cases of BBSOAS-related epilepsy and summarize all previously reported cases to explore the effective treatment for this type of epilepsy.Methods We identified six new Chinese cases of BBSOAS with epilepsy.Five different de novo heterozygous NR2F1 mutations were identified in these cases,including two novel mutations c.365G>T,p.Cys122Phe and c.449G>T,p.Gly150Val.By combining the six cases and 14 previously reported cases,we analyzed the characteristics and treatment outcomes of NR2F1-related epilepsy.Results Twelve of the 20 patients(60%)had infantile epileptic spasms,while the other patients had generalized tonic/tonic-clonic,focal,myoclonic,absence,or unclassified seizures.Several anti-seizure medications,steroids,and a ketogenic diet were administered in these cases.However,seizures were controlled in only 50%of previously reported cases,while all of the six new cases became seizure-free after perampanel as an add-on treatment.The average time from the addition of perampanel to seizure control was 7.33±4.59 months(range,1–12 months).The median time to seizure freedom was 14 months(1–32 months,>19 months in 3 cases).The average dosage of perampanel needed for epilepsy control was 0.22±0.17 mg/kg per day.Conclusions In this paper,we comprehensively summarized the clinical characteristics,treatments and outcomes of NR2F1-related epilepsy for the first time.Perampanel exhibits dramatic efficacy for NR2F1-related epilepsy.This will help optimize the treatment of this type of epilepsy and provide clues for its pathogenic mechanisms.The two novel mutations expand the genotype spectrum of this disease.展开更多
Background Developmental and epileptic encephalopathy(DEE)is a group of rare inherited disorders characterized by intellectual disability,delayed development,epileptic seizures,and other related symptoms.DEE44 is caus...Background Developmental and epileptic encephalopathy(DEE)is a group of rare inherited disorders characterized by intellectual disability,delayed development,epileptic seizures,and other related symptoms.DEE44 is caused by mutations in the UBA5 gene,which encodes a ubiquitin-like protein involved in protein degradation and cell signaling.However,there is limited information on the genotype–phenotype correlation of DEE44,and its clinical features remain to be fully characterized.Case presentation We report a 12-month-old infant who presented with epileptic spastic seizures beginning at 4 months of age,accompanied by overall developmental delay,short stature,microcephaly,inability to hold his head upright,chasing vision,and high muscle tone in the extremities.Genetic findings showed compound heterozygous mutations of the UBA5 gene:NM_024818 c.562C>T(p.R188X)from the mother and NM_024818 c.214C>T(p.R72C)from the father.Conclusions This case report expands the clinical spectrum of DEE44 and highlights the importance of considering DEE44 in the differential diagnosis of developmental delay and epilepsy,even in the absence of classical symptoms suggestive of the condition.We hope that this case report will advance the understanding of DEE44 and improve the expertise of clinicians and early diagnose of this disease.展开更多
文摘Background: Infantile spasm is a type of pediatric seizure often associated with a negative prognosis. The aim of this study was to evaluate the role of Magnetic Resonance Imaging (MRI) in categorization and neurodevelopmental outcomes in children with infantile spasm. Materials and Methods: A retrospective study of the clinical charts and MRI findings of infants diagnosed with infantile spasm between December 2007 and February 2014. Results: A total of 26 children (16 males;1.6/1) were included: 8 of unknown etiology and 18 with a genetic/structural-metabolic causes. Unknown etiology cases revealed normal brain MRI in 5/8 (62.5%). In the genetic/ structural-metabolic group, only 2/18 (11.1%) had normal imaging. Abnormal imaging findings significantly correlated with genetic/structural-metabolic infantile spasm which had unfavorable neurodevelopmental outcome. Conclusion: Neuroimaging conveys substantial information to the further categorization of children with infantile spasm, providing not only relevant information of the underlying cause but also the prediction of the neurodevelopmental outcome.
基金The National Key Research and Development Program of China(2016YFC1000707)
文摘Importance:Infantile spasm(IS)is a kind of refractory epilepsy.The first-line treatments for IS are adrenocorticotropic hormone(ACTH),oral corticosteroids,and vigabatrin.Objective:This study aimed to evaluate the efficacy of magnesium sulfate and ACTH(MgSO_(4)+ACTH)combination therapy in patients with IS who failed first-line treatments.Methods:In this retrospective study,the clinical data of patients with IS who failed first-line treatments were collected in the Chinese PLA General Hospital.Patients received MgSO_(4)+ACTH combination therapy after first-line treatments failed.The course of treatments was 2 weeks.The therapeutic dose of ACTH and MgSO_(4)was 2.5 U·kg^(-1)·d^(-1)and 0.25 g·kg^(-1)·d^(-1),respectively.Results:A total of 229 patients with IS who failed the first-line treatments were collected.At the end of the MgSO_(4)+ACTH combination treatment,the seizure-free rate was 48.5%(111/229),and the resolution of hypsarrhythmia on electroencephalogram(EEG)was 72.1%(165/229).About 21.4%(49/229)of patients showed side effects,including infectious diseases,hypokalemia,and diarrhea.Interpretation:For patients with IS who failed first-line treatments,in terms of the seizure-free rate and resolution of hypsarrhythmia on EEG,MgSO_(4)+ACTH combination therapy can be considered.
基金This study was supported by the Sanming Project of Medicine in Shenzhen(SZSM201812005)Shenzhen Key Medical Discipline Construction Fund(No.SZXK033)Shenzhen Fund for Guangdong Provincial High Level Clinical Key Specialties(No.SZGSPO12).
文摘Background:Ketogenic diet(KD)therapy is one of the main treatments for drug-resistant epilepsy.However,the KD therapy has been applied in only a small number of infantile spasm cases.In this large multicenter study,we investigated the efficacy of KD therapy in the treatment of infantile spasms.Methods:In this retrospective,multicenter cohort study,clinical data from main epilepsy centers were analyzed.Patients were classified into different groups according to age,type of drug and whether glucocorticoid was used before initiation of KD.Results:From October 2014 to March 2020,481 patients(308 males and 173 females)with infantile spasms were treated with the KD therapy.The age of the patients ranged from 2 months to 20 years,with a mean age of 1 year and 10 months.The number of anti-seizure medications(ASMs)used before KD initiation ranged 0-6,with a median of 3.In different time from initiation(1,3,6,and 12 months),the rates of seizure freedom after KD were 6.9,11.6;16.0 and 16.8%,respectively(x^(2)=27.1772,P<0.0001).There was a significant difference in the rate of seizure freedom between 3 months and 1 month(x^(2)=6.5498,P=0.0105)groups,and 6 months and 3 months(x^(2)=3.8478,P=0.0498)groups,but not between 12 months and 6 months(x^(2)=0.1212,P=0.7278)groups.The rates of effectiveness were 44.7;62.8,49.1 and 32.0%(x^(2)=93.2674,P<0.0001),respectively.The retention rates were 94.0,82.5,55.7 and 33.1%(x^(2)=483.7551,P<0.0001),correspondingly.The rate of effectiveness and the retention rate of KD were significantly different among the 1,3,6 and 12 months.KD treatment was the first choice in 25 patients(5.2%),55 patients(11.4%)started KD after the failure of the first ASM,158 patients(32.8%)started KD after the failure of the second ASM,157 patients(32.6%)started KD after the failure of the third drug,and 86 patients(17.9%)started KD after the failure of the fourth and more.The KD effect was not related to the number of ASMs used before KD startup(P>0.05).Two hundred and eighteen patients(45.3%)failed to respond to corticotropin or glucocorticoid before initiation.There was no significant difference in the effectiveness rate at different time points between the group of KD therapy after glucocorticoid failure and the group after non-hormone failure (x^(2)=0.8613,P=0.8348).The rate of adverse events of KD in 1,3,6,and 12 months after KD initiation were 22.3,21.7,16.8 and 6.9%,respectively.The adverse events mainly occurred during the first 3 months of KD,and the main adverse events were gastrointestinal disturbance and constipation.Conclusions:The efficacy of the KD treatment for infantile spasms was not affected by age,medication,and glucocorticoid use before initiation.KD is one of the effective treatments for infantile spasms.
基金This research was partially supported by National Natural Science Foundation of China(Nos.62171028,62001026)the Natural Science Foundation of Beijing,China(No.7222187)+2 种基金the Medical Big Data and Artificial Intelligence Research and Development Project of the Chinese PLA General Hospital(No.2019MBD-004)the Epilepsy Research Fund of China Association Against Epilepsy(No.CU-B-2021-11)the Nutrition and Care of Maternal&Child Research Fund Project of Guangzhou Biostime Institute of Nutrition&Care(No.2021BINCMCF030).
文摘Background Even though adrenocorticotropic hormone(ACTH)demonstrated powerful efficacy in the initially successful treatment of infantile spasms(IS),nearly half of patients have experienced a relapse.We sought to investigate whether features of electroencephalogram(EEG)predict relapse in those IS patients without structural brain abnormalities.Methods We retrospectively reviewed data from children with IS who achieved initial response after ACTH treatment,along with EEG recorded within the last two days of treatment.The recurrence of epileptic spasms following treatment was tracked for 12 months.Subjects were categorized as either non-relapse or relapse groups.General clinical and EEG recordings were collected,burden of amplitudes and epileptiform discharges(BASED)score and multiscale entropy(MSE)were carefully explored for cross-group comparisons.Results Forty-one patients were enrolled in the study,of which 26(63.4%)experienced a relapse.The BASED score was significantly higher in the relapse group.MSE in the non-relapse group was significantly lower than the relapse group in theγband but higher in the lower frequency range(δ,θ,α).Sensitivity and specificity were 85.71%and 92.31%,respectively,when combining MSE in theδ/γfrequency of the occipital region,plus BASED score were used to distinguish relapse from non-relapse groups.Conclusions BASED score and MSE of EEG after ACTH treatment could be used to predict relapse for IS patients without brain structural abnormalities.Patients with BASED score≥3,MSE increased in higher frequency,and decreased in lower frequency had a high risk of relapse.
基金the National Natural ScienceFoundation of China(No.81671297).
文摘Background:Infantile spasms(IS)are the most common childhood epileptic encephalopathy.Focal cortical dysplasia(FCD)and gray matter heterotopias(GH)are common structural causes of IS.The recommended first-line treatment for IS patients with structural causes is surgical intervention,according to the International League Against Epilepsy(ILAE)commission guidelines.However,there is currently no consensus on appropriate timings of surgery.Case presentations:Two structural IS cases are presented here:one was caused by FCD,and the other by GH.Both patients exhibited recurrent seizures at the age of 2 months,had poor responses to various antiepileptic drugs(AEDs)and displayed severe mental and motor developmental retardation.Seizure types included focal seizures and spasms.Brain magnetic resonance imaging showed abnormal gray signal or suspicious FCD lesions that coincided with the origin of the focal seizures.The patients underwent lesion resection before the age of 6 months.Follow-up observation showed that seizures of both patients were completely controlled several days after the surgery.All AEDs were gradually reduced in dosage within 1 year,and the mental and motor development almost returned to normal.Conclusion:Early resection of lesions in structural IS patients has benefits of effectively controlling convulsions and improving developmental retardation.Infants at several months of age can well tolerate craniotomy,and their cognitive development is more likely to return to normal after early surgery.
基金This study was supported by the grants from the National Natural Science Foundation of China (No. 30770747), the Beijing Municipal Natural Science Foundation (No. 7081002, No. 7042024) and the Capital Development Foundation of Beijing (No. 2003-2007).
文摘Background Infantile spasms is a severe epileptic encephalopathy, which is refractory to conventional antiepileptic drugs. Adrenocorticotropic hormone (ACTH) has been the major therapy for infantile spasms; however, ACTH therapy is ineffective for some patients. The variations in the receptor genes can contribute to antiepileptic drug resistance. This study was to elucidate the possible associations between the variations of the MC2R gene and ACTH responsiveness in patients with infantile spasms. Methods We screened for variations in the promoter and coding region of the MC2R gene in 91 Chinese patients with infantile spasms and 94 controls, using PCR and a direct sequencing method. The frequencies of the genotypes, alleles and reconstructed haplotypes were analyzed in the cases and controls. The association between ACTH responsiveness and genetic variations of the MC2R gene was also assessed. Results Four single nucleotide polymorphisms (SNPs) were identified in the MC2R promoter, one of which was a novel specimen at position-2 from the transcription start site ATT, -2T〉C. Three SNPs (rs1893220, rs2186944 and -2T〉C) showed a significant difference between the cases and controls (P 〈0.05 for all). The frequency of the common TCCT haplotype carrying four-SNP major alleles was significantly lower in the cases (39%) than in the controls (60%) (P=-0.00003). The homozygous carriers of the TCCT haplotype had a much lower relative risk than the non-carriers (RR=O.42, 95%C/ 0.26-0.70, P=-0.0001). ACTH responsiveness was strongly associated with the TCCT haplotype (P=-0.000082). Compared with non-carriers of the TCCT haplotype, the homozygous and heterozygous carriers were more responsive to ACTH therapy (P=0.0002; P=-0.0003, respectively). Conclusions Our results indicated that the TCCT haplotype in the MC2R promoter is strongly associated with the responsiveness of the ACTH therapy performed on patients with infantile spasms. The polymorphisms of the MC2R promoter might be one important factor that influences the efficacy of ACTH therapy on infantile spasms.
基金funded by the Capital’s Funds for Health Improvement and Research(No.2022-1-5081).
文摘Background Sandhoff disease(SD)i s an autosomal recessive lysosomal disease with clinical manifestations such as epilepsy,psychomotor retardation and developmental delay.However,infantile SD with onset of infantile epilepsy spasm syndrome(IESS)is extremely rare.Case presentation The case presented here was a 22-month-old boy,who presented with IESS and psychomotor retardation/regression at 6 months of age.The patient showed progressive aggravation of seizures and excessive startle responses.The whole exome sequencing data,which initially revealed negative results,were reanalyzed and indicated a homozygous mutation at the c.1613+4del splice site of the HEXB gene.The activities ofβ-hexosaminidase A and total hexosaminidase were significantly decreased.The fundus examination showed cherry red spots at the macula.Conclusions IESS can be an epileptic phenotype of infantile SD.Clinical phenotypes should be adequately collected in genetic testing.In the case of negative sequencing results,gene variant reanalysis can be performed when the patients show clinically suspicious indications.
基金supported by Citizens United for Research in Epilepsy (CURE) Infantile Spasms Research Initiative(to LV and DAI)NIH grant NS-072966(to LV)
文摘Inflammation is an established etiopathogenesis factor of infantile spasms(IS), a therapy-resistant epileptic syndrome of infancy. We investigated the IS-associated transcriptomic alterations of neurotransmission in rat hypothalamic arcuate nucleus, how they are corrected by antiinflamatory treatments and whether there are sex differences. IS was triggered by repeated intraperitoneal administration of N-methyl-D-aspartic acid following anti-inflammatory treatment(adreno-cortico-tropic-hormone(ACTH) or PMX53)or normal saline vehicle to prenatally exposed to betamethasone young rats. We found that treatments with both ACTH and PMX53 resulted in substantial recovery of the genomic fabrics of all types of synaptic transmission altered by IS. While ACTH represents the first line of treatment for IS, the even higher efficiency of PMX53(an antagonist of the complement C5 a receptor) in restoring the normal transcriptome was not expected. In addition to the childhood epilepsy, the recovery of the neurotransmission genomic fabrics by PMX53 also gives hope for the autism spectrum disorders that share a high comorbidity with IS. Our results revealed significant sex dichotomy in both IS-associated transcriptomic alterations(males more affected) and in the efficiency of PMX53 anti-inflammatory treatment(better for males). Our data further suggest that anti-inflammatory treatments correcting alterations in the inflammatory transcriptome may become successful therapies for refractory epilepsies.
文摘Background NR2F1 mutations are associated with Bosch-Boonstra-Schaaf optic atrophy syndrome(BBSOAS).Although~46.7%of BBSOAS patients present with epilepsy,which is always drug-resistant and associated with higher rates of behavioral and cognitive problems,the treatment and outcomes of NR2F1-related epilepsy have rarely been described.Here,we present new cases of BBSOAS-related epilepsy and summarize all previously reported cases to explore the effective treatment for this type of epilepsy.Methods We identified six new Chinese cases of BBSOAS with epilepsy.Five different de novo heterozygous NR2F1 mutations were identified in these cases,including two novel mutations c.365G>T,p.Cys122Phe and c.449G>T,p.Gly150Val.By combining the six cases and 14 previously reported cases,we analyzed the characteristics and treatment outcomes of NR2F1-related epilepsy.Results Twelve of the 20 patients(60%)had infantile epileptic spasms,while the other patients had generalized tonic/tonic-clonic,focal,myoclonic,absence,or unclassified seizures.Several anti-seizure medications,steroids,and a ketogenic diet were administered in these cases.However,seizures were controlled in only 50%of previously reported cases,while all of the six new cases became seizure-free after perampanel as an add-on treatment.The average time from the addition of perampanel to seizure control was 7.33±4.59 months(range,1–12 months).The median time to seizure freedom was 14 months(1–32 months,>19 months in 3 cases).The average dosage of perampanel needed for epilepsy control was 0.22±0.17 mg/kg per day.Conclusions In this paper,we comprehensively summarized the clinical characteristics,treatments and outcomes of NR2F1-related epilepsy for the first time.Perampanel exhibits dramatic efficacy for NR2F1-related epilepsy.This will help optimize the treatment of this type of epilepsy and provide clues for its pathogenic mechanisms.The two novel mutations expand the genotype spectrum of this disease.
基金supported by Natural Science Foundation of Hainan Province of China(821RC1133).
文摘Background Developmental and epileptic encephalopathy(DEE)is a group of rare inherited disorders characterized by intellectual disability,delayed development,epileptic seizures,and other related symptoms.DEE44 is caused by mutations in the UBA5 gene,which encodes a ubiquitin-like protein involved in protein degradation and cell signaling.However,there is limited information on the genotype–phenotype correlation of DEE44,and its clinical features remain to be fully characterized.Case presentation We report a 12-month-old infant who presented with epileptic spastic seizures beginning at 4 months of age,accompanied by overall developmental delay,short stature,microcephaly,inability to hold his head upright,chasing vision,and high muscle tone in the extremities.Genetic findings showed compound heterozygous mutations of the UBA5 gene:NM_024818 c.562C>T(p.R188X)from the mother and NM_024818 c.214C>T(p.R72C)from the father.Conclusions This case report expands the clinical spectrum of DEE44 and highlights the importance of considering DEE44 in the differential diagnosis of developmental delay and epilepsy,even in the absence of classical symptoms suggestive of the condition.We hope that this case report will advance the understanding of DEE44 and improve the expertise of clinicians and early diagnose of this disease.