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1.
Orphanet J Rare Dis ; 15(1): 248, 2020 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-32928263

RESUMO

OBJECTIVE: This study aimed to explore the efficacy and safety of pantethine in children with pantothenate kinase-associated neurodegeneration (PKAN). METHODS: A single-arm, open-label study was conducted. All subjects received pantethine during the 24-week period of treatment. The primary endpoints were change of the Unified Parkinson's Disease Rating Scale (UPDRS) I-III and Fahn-Marsden (FM) score from baseline to week 24 after treatment. RESULTS: Fifteen children with PKAN were enrolled, and all patients completed the study. After 24 weeks of treatment with pantethine at 60 mg/kg per day, there was no difference in either UPDRS I-III (t = 0.516, P = 0.614) or FM score (t = 0.353, P = 0.729) between the baseline and W24. Whereas the rates of increase in UPDRS I-III (Z = 2.614, p = 0.009) and FM scores (Z = 2.643, p = 0.008) were slowed. Four patients (26.7%) were evaluated as "slightly improved" by doctors through blinded video assessment. Patients with lower baseline UPDRS I-III or FM scores were more likely to be improved. The quality of life of family members improved after pantethine treatment, evaluated by PedsQL TM 2.0 FIM scores, whereas the quality of life of the patients was unchanged at W24, evaluated by PedsQL TM 4.0 and PedsQL TM 3.0 NMM. Serum level of CoA was comparable between baseline and W24. There was no drug related adverse event during the study. CONCLUSIONS: Pantethine could not significantly improve motor function in children with PKAN after 24 weeks treatment, but it may delay the progression of motor dysfunction in our study. Pantethine was well-tolerated at 60 mg/kg per day. TRIAL REGISTRATION: Clinical trial registration number at www.chictr.org.cn :ChiCTR1900021076, Registered 27 January2019, the first participant was enrolled 30 September 2018, and other 14 participants were enrolled after the trial was registered.

2.
Epilepsy Behav ; 112: 107376, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32882627

RESUMO

PURPOSE: The purpose of the study was to describe epileptologists' opinion on the increased use of remote systems implemented during the COVID-19 pandemic across clinics, education, and scientific meetings activities. METHODS: Between April and May 2020, we conducted a cross-sectional, electronic survey on remote systems use before and during the COVID-19 pandemic through the European reference center for rare and complex epilepsies (EpiCARE) network, the International and the French Leagues Against Epilepsy, and the International and the French Child Neurology Associations. After descriptive statistical analysis, we compared the results of France, China, and Italy. RESULTS: One hundred and seventy-two respondents from 35 countries completed the survey. Prior to the COVID-19 pandemic, 63.4% had experienced remote systems for clinical care. During the pandemic, the use of remote clinics, either institutional or personal, significantly increased (p < 10-4). Eighty-three percent used remote systems with video, either institutional (75%) or personal (25%). During the pandemic, 84.6% of respondents involved in academic activities transformed their courses to online teaching. From February to July 2020, few scientific meetings relevant to epileptologists and routinely attended was adapted to virtual meeting (median: 1 [25th-75th percentile: 0-2]). Responders were quite satisfied with remote systems in all three activity domains. Interestingly, before the COVID-19 pandemic, remote systems were significantly more frequently used in China for clinical activity compared with France or Italy. This difference became less marked during the pandemic. CONCLUSION: The COVID-19 pandemic has dramatically altered how academic epileptologists carry out their core missions of clinical care, medical education, and scientific discovery and dissemination. Close attention to the impact of these changes is merited.

3.
Orphanet J Rare Dis ; 15(1): 200, 2020 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-32746869

RESUMO

BACKGROUND: Cobalamin C deficiency (cblC) caused by the MMACHC mutations is the most common type of the disorders of intracellular cobalamin metabolism. While the c.609G > A mutation is most frequent in Chinese cblC patients, its correlation with phenotype has not been delineated. Here we aim to investigate the factors affecting variable phenotypes and outcomes associated with the MMACHC c.609G > A homologous mutation in 149 Chinese cases to have implications for treatment and prevention. METHODS: We assessed 149 cblC patients caused by MMACHC c.609G > A homozygous mutation. The clinical manifestations, complications, treatment, and outcomes were evaluated; 120 patients were followed-up till December 2019. RESULTS: Two patients (1.3%) were prenatally diagnosed, treated after birth and consequently showed normal development. In 15 patients (10.1%) detected by newborn screening, 10 were treated at the age of 2 weeks and showed normal development, while the other 5 were treated after onset and showed neurologic disorders. All 132 clinically diagnosed patients (88.6%) developed symptoms at age from few minutes after birth to 72 months. Among them, 101 (76.5%) had early-onset (before the age of 12 months) and 31 (23.5%) had late-onset (after the age of 12 months). Totally 5 patients died and 24 were lost to follow-up. Of the 132 clinical diagnosed patients, 92 (69.7%) presented with developmental delay, 65 (49.2%) had seizures, 37 (28.0%) had anemia, 24 (18.2%) had feeding difficulty, 23 (17.4%) had ocular problems, and 22 (16.7%) had hydrocephalus. Compared with the non-developmental delay group, the onset age, the age at treatment initiation and the time from onset to treatment initiation were later in the developmental delay group. Seizure group showed significantly higher urinary methylmalonic acid concentration. During long-term follow-up, plasma total homocysteine (tHcy) levels were significantly higher in patients in the uncontrolled group than those in the seizure-free group. CONCLUSIONS: Most cblC patients caused by MMACHC c.609G > A homozygous mutation showed early-onset. The clinically diagnosed patients usually showed the presence of irreversible brain disorders. Patients treated from the pre-symptomatic stage showed favorable outcomes. Therefore, newborn screening, prenatal diagnosis and early treatment are crucial and the c.609G > A mutant allele should be listed in the pre-pregnancy carrier screening panel in China.

4.
Dev Med Child Neurol ; 2020 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-32686847

RESUMO

AIM: To characterize the different phenotypes of GABRB2-related epilepsy and to establish a genotype-phenotype correlation. METHOD: We used next-generation sequencing to identify GABRB2 variants in 15 patients. RESULTS: Eleven GABRB2 variants were novel and 12 were de novo. The age at the onset of seizures ranged from 1 day to 26 months. Nine patients had multiple seizure types, including focal seizures, generalized tonic-clonic seizures, myoclonic seizures, epileptic spasms, and atonic seizures. Seizures were fever-sensitive in 13 out of the 15 patients. Eleven patients displayed developmental delay, while 11 had abnormal video electroencephalography. Abnormalities in the brain images included dysplasia of the frontal and temporal cortex, dysplasia of the corpus callosum, and delayed myelination in four patients. One patient was diagnosed with febrile seizures, three with febrile seizures plus, three with Dravet syndrome, three with West syndrome, one with Ohtahara syndrome, three with developmental delays and epilepsy, and one with non-specific early-onset epileptic encephalopathy. INTERPRETATION: The most common phenotypes of patients with GABRB2 variants include early onset of seizure and fever sensitivity. Febrile seizures and febrile seizures plus are new phenotypes of GABRB2 variants. The phenotypic spectrum of GABRB2 variants ranges from mild febrile seizures to severe epileptic encephalopathy.

5.
Epilepsy Res ; 166: 106426, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32693361

RESUMO

PURPOSE: To investigate the surgical outcome in children with epilepsy after viral encephalitis (VE), we studied the prognostic factors for surgery and summarized the surgical strategies of children with epilepsy secondary to VE. METHODS: We retrospectively analyzed 23 surgically treated children with VE. The subjects were divided into two groups according to their surgical outcome. All presurgical evaluation data were collected and analyzed. RESULTS: Among the 23 operated children, the mean age at surgery was 6.1 years. Surgeries were hemispherotomy (n = 12), temporal-parietal-occipital disconnection (n = 4), whole corpus callosotomy (n = 3), lobectomy (n = 3), and vagus nerve stimulation (n = 1). The mean patient follow-up time was 37.2 months, and 13 children had a good outcome (ILAE classification 1-3). Univariate analyses revealed that the latency from infection to the first unprovoked seizure, MRI laterality, concordance of PET and MRI abnormalities, and acute postoperative seizure (APOS) were prognostic factors of seizure outcomes (P < 0.05). No correlation was found between generalized seizures and poor outcome (P = 0.229). CONCLUSIONS: We concluded that the children who achieve favorable surgical outcomes are those with longer latency, unilateral abnormalities on MRI, consistency of PET and MRI abnormalities, and no APOS. Without invasive studies, epilepsy surgery may be successful for selected children with epilepsy after VE, despite diffuse interictal epileptiform discharges on scalp EEG. In addition, children with generalized seizures were not an absolute contraindication for surgery.

7.
J Child Neurol ; 35(13): 924-933, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32666891

RESUMO

OBJECTIVE: To evaluate the effect of the COVID-19 pandemic on global access to care and practice patterns for children with epilepsy. METHODS: We conducted a cross-sectional, online survey of pediatric neurologists across the world affiliated with the International Child Neurology Association, the Chinese Child Neurology Society, the Child Neurology Society, and the Pediatric Epilepsy Research Consortium. Results were analyzed in relation to regional burden of COVID-19 disease. RESULTS: From April 10 to 24, 2020, a sample of 212 respondents from 49 countries indicated that the COVID-19 pandemic has dramatically changed many aspects of pediatric epilepsy care, with 91.5% reporting changes to outpatient care, 90.6% with reduced access to electroencephalography (EEG), 37.4% with altered management of infantile spasms, 92.3% with restrictions in ketogenic diet initiation, 93.4% with closed or severely limited epilepsy monitoring units, and 91.3% with canceled or limited epilepsy surgery. Telehealth use had increased, with 24.7% seeing patients exclusively via telehealth. Changes in practice were related both to COVID-19 burden and location. CONCLUSIONS: In response to COVID-19, pediatric epilepsy programs have implemented crisis standards of care that include increased telemedicine, decreased EEG use, changes in treatments of infantile spasms, and cessation of epilepsy surgery. The long-term impact of these abrupt changes merit careful study.


Assuntos
Betacoronavirus , Infecções por Coronavirus/prevenção & controle , Assistência à Saúde/métodos , Epilepsia/terapia , Pesquisas sobre Serviços de Saúde/métodos , Internacionalidade , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Telemedicina/métodos , Criança , Estudos Transversais , Eletroencefalografia/estatística & dados numéricos , Saúde Global , Pesquisas sobre Serviços de Saúde/estatística & dados numéricos , Humanos , Neurologistas , Neurologia/métodos , Pediatras , Pediatria/métodos
8.
J Neurol ; 267(9): 2612-2618, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32388833

RESUMO

BACKGROUND: Epilepsy might be one of the manifestations in children with leukodystrophies, but the incidence of epilepsy in different types of leukodystrophies is unclear yet. METHODS: A retrospective observational cohort study was performed on children diagnosed with leukodystrophies in Peking University First Hospital from January 2004 to June 2019, and the patients were followed for 5.5 years (0.4-14.2 years) after the first visit. RESULTS: A total of 333 patients were included. The overall incidence of epilepsy was 30.6% (102/333). Alexander disease had the highest incidence (77.3%, 51/66), followed by vanishing white matter disease (41.2%, 21/51), Canavan disease (33.3%, 1/3), megalencephalic leukoencephalopathy with subcortical cysts (32.1%, 9/28), X-linked adrenoleukodystrophy (23.1%, 3/13), Krabbe disease (18.8%, 3/16), metachromatic leukodystrophy (14.3%, 6/42), and Pelizaeus-Merzbacher disease (7.0%, 8/114). The incidence of epilepsy in leukodystrophies classified as astrocytopathies was higher than that in myelin disorders (55.9% vs. 11.2%, P < 0.001). Of the 102 patients with epilepsy, seizures were the chief complaint in 61.8% (63/102) and the initial symptom in 22.5% (23/102). The median age at seizure onset was 20.5 months (1 day-176 months). A total of 63.7% (65/102) of children were treated with antiepileptic drugs (AEDs), and the responder rate was 90.8% (59/65) at the last follow-up, including 71.2% (42/59) of children who were seizure free. CONCLUSIONS: Epilepsy was not uncommon in children with leukodystrophies. Children with Alexander disease had the highest incidence; whereas, children with Pelizaeus-Merzbacher disease had the lowest incidence. Children with leukodystrophies classified as astrocytopathies were more prone to have epilepsy than those classified as myelin disorders. Most children with leukodystrophies who presented with epilepsy showed a good response to antiepileptic drugs.

9.
J Hum Genet ; 65(7): 601-608, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32203252

RESUMO

We analyzed our two new cases of infantile-onset epilepsy with developmental delay with de novo variant in TUBB2A and review the related literatures. Our two probands were both girls with infantile-onset epilepsy and global developmental delay. Case 1 had a novel de novo heterozygous missense variant: c.728C>T [p.Pro243Leu] (NM_001069.2). Her brain magnetic resonance imaging (MRI) showed nonspecific white matter myelination delay and slightly enlarged anterior horn of lateral ventricle. Her epilepsy had been controlled by TPM monotherapy. Case 2 had a reported de novo variant c.743C>T [p.Ala248Val] (NM_001069.2). Her brain MRI showed bilateral microgyria and corpus callosum dysplasia. A total of seven TUBB2A mutations cases had been published previously in five papers, therefore, until now, there were nine patients with TUBB2A mutations. All patients had developmental delay, among them seven cases also with infantile-onset epilepsy, one case with abnormal EEG but without clinical seizures. There are six cases that have different degree of cortical dysplasia, one case with cerebellar vermis atrophy and brainstem sacsinopathy, the rest two cases have no obvious brain structural abnormalities. There was one case with variant c.1249G>A (p.D417N) that had atypical clinical presentation, including prominent progressive spastic ataxia, sensory motor axonal neuropathy, and bilateral optic macular dystrophy, but relatively mild intellectual disability, his MRI showed cerebellar atrophy, thinning of the corpus callosum and pons sacsinopathy, but no cortical malformation. The p.A248V mutation was the most common mutation occurred in three patients (3/9). The clinical phenotypes of these three patients were similar, all of them had global developmental delay with no language and corpus callosum dysplasia, two cases with epilepsy and the other one only have EEG epileptic discharges without clinical seizure, two cases with cortical dysplasia and the other one without obvious brain malformation. In brief, global developmental delay was the most common phenotype of TUBB2A mutation-related disease, most cases also had infantile-onset epilepsy and cortical dysplasia and corpus callosum dysplasia. The region between seventh and eighth alpha-helix of TUBB2A may be a "hot spot" mutation domain.

10.
J Med Genet ; 57(10): 717-724, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32152250

RESUMO

BACKGROUND: Rare variants in hundreds of genes have been implicated in developmental delay (DD), intellectual disability (ID) and neurobehavioural phenotypes. TNRC6B encodes a protein important for RNA silencing. Heterozygous truncating variants have been reported in three patients from large cohorts with autism, but no full phenotypic characterisation was described. METHODS: Clinical and molecular characterisation was performed on 17 patients with TNRC6B variants. Clinical data were obtained by retrospective chart review, parent interviews, direct patient interaction with providers and formal neuropsychological evaluation. RESULTS: Clinical findings included DD/ID (17/17) (speech delay in 94% (16/17), fine motor delay in 82% (14/17) and gross motor delay in 71% (12/17) of subjects), autism or autistic traits (13/17), attention deficit and hyperactivity disorder (ADHD) (11/17), other behavioural problems (7/17) and musculoskeletal findings (12/17). Other congenital malformations or clinical findings were occasionally documented. The majority of patients exhibited some dysmorphic features but no recognisable gestalt was identified. 17 heterozygous TNRC6B variants were identified in 12 male and five female unrelated subjects by exome sequencing (14), a targeted panel (2) and a chromosomal microarray (1). The variants were nonsense (7), frameshift (5), splice site (2), intragenic deletions (2) and missense (1). CONCLUSIONS: Variants in TNRC6B cause a novel genetic disorder characterised by recurrent neurocognitive and behavioural phenotypes featuring DD/ID, autism, ADHD and other behavioural abnormalities. Our data highly suggest that haploinsufficiency is the most likely pathogenic mechanism. TNRC6B should be added to the growing list of genes of the RNA-induced silencing complex associated with ID/DD, autism and ADHD.

11.
Orphanet J Rare Dis ; 15(1): 78, 2020 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-32220244

RESUMO

OBJECTIVE: To summarize and extend the phenotypic characterization of Multiple Congenital Anomalies-Hypotonia-Seizures Syndrome, and to discuss genotype-phenotype correlations. METHODS: Collecting clinical information of 17 patients with pathogenic variants in PIGN, PIGA, and PIGT. Genetic studies were performed on all patients. RESULTS: There were 7 patients with 15 PIGN mutations (one patient carrying 3 mutations), 8 patients with 8 PIGA mutations, and 2 patients with 5 PIGT mutations (one patient carrying 3 mutations). All patients had epilepsy and developmental delay, with 71% of them showed hypotonia. And among these patients' various seizure types, the focal seizure was the most common one. Eighty-two percent patients showed a significant relationship between seizures and fever. Serum ALP was elevated in one patient with PIGN mutations and in two patients with PIGA mutations. Brain MRI showed enlarged subarachnoid space in 56% of patients. Some other different characteristics had also been found in our patients: First, atypical absence seizures presented in three patients with PIGN mutations; Second, diffuse slow waves mixed with focal or multifocal discharges of interictal EEG in 88% cases with PIGA-deficient; Third, phenotypes of seven out of eight patients with PIGA mutations were difficult to be classified as severe or less severe group; Last, mild neurological symptoms and developmental status rather than severe conditions occurred in one patient with PIGT mutations. CONCLUSION: With epilepsy, developmental delay, and/or hypotonia as common features, the knowledge of MCAHS in terms of phenotype and genotype has been expanded. In cases with PIGN-deficient, we expanded the types of atypical absence seizures, and described one patient with elevated serum ALP. Focal seizures with diffuse slow waves mixed with focal or multifocal discharges on EEG rather than infantile spasms with hypsarrhythmia, which as previously reported were often seen in our patients with PIGA mutations. The classifications of phenotypes caused by PIGA mutations should be more continuous than discrete. The mild phenotype of one patient with PIGT mutations expanded the clinical presentation of MCAHS3.

12.
Epilepsia ; 61(4): 667-678, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32216069

RESUMO

OBJECTIVE: Focal cortical dysplasia type II (FCDII) is a malformation of cortex development commonly found in children with drug-resistant epilepsy. FCDII has been associated with somatic mutations in mammalian target of rapamycin (mTOR)-related pathway genes and an upregulation of mTOR. Somatic mutations were found in 10%-63% of FCDII samples; the frequency of the mutant allele was 0.93%-33.5%. This study aimed to find new candidate genes involved in FCDII. METHODS: We collected resected FCD lesions, perilesional brain tissues, and peripheral blood from 17 children with pathologically confirmed FCDII. We performed whole exome sequencing and followed a set of screening and analysis strategies to identify potentially deleterious somatic variants (PDSVs) in brain-expressed genes. We performed site-specific amplicon sequencing to validate the results. We also performed an in vitro functional study on an IRS1 variant. RESULTS: In six of 17 samples, we identified seven PDSVs in seven genes, including two frameshift variants and five missense variants. The frequencies of the variant allele were 1.29%-5.50%. The genes were MTOR, TSC2, IRS1, RAB6B, RALA, HTR6, and ZNF337. PDSVs in IRS1, RAB6B, ZNF337, RALA, and HTR6 had not been previously associated with FCD. In one lesion, two PDSVs were found in two genes. In a transfected cell line, we demonstrated that the c.1791dupG (identified in FCDII from Patient 1) led to a truncated IRS1 and significant mTOR hyperactivation compared to cells that carried wild-type IRS1. mTOR was also activated in FCDII tissue from Patient 1. SIGNIFICANCE: Seven PDSVs were identified in FCDII lesions in six of 17 children. Five variant genes had not been previously associated with cortical malformations. We demonstrated that the IRS1 variant led to mTOR hyperactivation in vitro. Although functional experiments are needed, the results provide evidence for novel candidate genes in the pathogenesis of FCDII.


Assuntos
Epilepsia/genética , Predisposição Genética para Doença/genética , Malformações do Desenvolvimento Cortical do Grupo I/genética , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Mutação
13.
CNS Neurosci Ther ; 26(7): 754-761, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32043823

RESUMO

AIMS: To investigate the natural history and genotype-phenotype correlation of pantothenate kinase-associated neurodegeneration. METHODS: We collected data of patients with PKAN by searching from available publications in English and Chinese. Patients diagnosed in our center (Peking University First Hospital) were also included. The difference in natural history and genotype between early-onset (<10 year of age at onset) and late-onset patients (≥10 year of age at onset) with PKAN was compared. RESULTS: A total of 248 patients were included. The median age at onset was 3.0 years in the early-onset group and 18.0 years in the late-onset group. Dystonia in lower limbs was the most common initial symptom in both groups. In the early-onset group, the median interval between the disease onset and occurrence of oromandibular dystonia, generalized dystonia, loss of independent ambulance was 6.0 years, 5.0 years, and 5.0 years. The corresponding values in late-onset group were 1.0 year, 4.0 years, and 6.0 years. About 20.0% died at median age of 12.5 years and 9.5 years after the onset in early-onset group. About 2.0% of the late-onset patients died during the follow-up. A total of 176 mutations were identified. Patients carrying two null alleles in PANK2 showed significantly earlier age of disease onset and progressed more rapidly to loss of independent ambulance. CONCLUSIONS: This study provided a comprehensive review on the natural history and genotype of 248 patients with PKAN. The results will serve as a historical control data for future clinical trial on PKAN.

14.
CNS Neurosci Ther ; 26(2): 270-277, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31368639

RESUMO

AIMS: To investigate clinical characteristics and surgery outcomes of young children with focal cortical dysplasia (FCD) type II. METHODS: Young children (onset age ≤6 years) with FCDII who underwent epileptic surgery in Children Epilepsy Center of Peking University First Hospital in 2014-2018 were followed up for at least 6 months after surgery. RESULTS: One hundred and twelve children with FCDII were included, with median age of onset 0.9 years (0.01-5.9), who underwent surgery at 4.1 years old (0.8-16.2). Focal seizures were most frequent (90.2%) and epileptic spasms presented in 23 (20.5%) cases. Epileptic encephalopathy was not uncommon (12.5%), associated with earlier epilepsy onset and higher rate of bilateral onset on ictal EEG (OR = 0.213, 9.059; P = .041, .004). At the last follow-up, 88.4% achieved seizure-free. Before surgery, 49.1% showed moderate/severe developmental delay, associated with earlier seizure onset and higher rate of history of epileptic encephalopathy (OR = 0.740, 5.160, P = .023, .042). For 48 children with preoperatively moderate/severe developmental delay, DQ rank at 6 months postsurgery was improved in only four cases. CONCLUSION: For young children with FCDII, they tend to present with epileptic encephalopathies and show moderate/severe developmental delay before surgery. The seizure outcome was favorable after surgery. For children with preoperatively moderate/severe developmental delay, developmental outcome at 6 months after surgery was not satisfactory.

15.
Dev Med Child Neurol ; 62(3): 315-321, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31737911

RESUMO

AIM: To characterize the clinical and genetic characteristics of a large cohort of patients with pyridoxine-dependent epilepsy (PDE). METHOD: We retrospectively collected clinical and genetic information of 33 (15 males, 18 females; mean [SD] age 4y 11mo [2y 5mo]; 1y 3mo-10y 4mo) patients with PDE from 31 unrelated families at a single centre. RESULTS: There were many types of seizures, with focal seizures in 32 cases. Dravet syndrome was suspected clinically in two patients. Electroencephalogram (EEG) was normal in seven patients at the initial stage and then in 17 patients during pyridoxine maintenance therapy. Genetic studies revealed 26 kinds of variants in ALDH7A1 and four in PLPBP with 18 variants unreported previously, and 48 ALDH7A1 variants were located in exon 11, 12, 14, and 17 or intron 9 and 11. In addition, three patients carried different exons deletion. Among these, seizures could be controlled for several years in one patient by levetiracetam monotherapy. Another patient remained seizure free for up to 7 months without therapy. All patients received oral pyridoxine treatment, with only one case (with exon 8-13 deletion) showing poor control. INTERPRETATION: This study illustrates the range of clinical presentations and genetic causes in PDE, as well as responsiveness to antiepileptic drugs. A relationship between EEG and pyridoxine therapy could be seen in many cases. Seizure control was seen in all with pyridoxine monotherapy except for one patient. WHAT THIS PAPER ADDS: There is a parallel relationship between electroencephalogram and pyridoxine therapy in many patients. Patients with pyridoxine-dependent epilepsy may respond well to low-dose pyridoxine.


Assuntos
Aldeído Desidrogenase/genética , Epilepsia/diagnóstico , Proteínas/genética , Encéfalo/fisiopatologia , Criança , Pré-Escolar , China , Análise Mutacional de DNA , Eletroencefalografia , Epilepsia/genética , Epilepsia/fisiopatologia , Feminino , Humanos , Lactente , Masculino , Mutação , Estudos Retrospectivos
16.
Epilepsy Res ; 159: 106246, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31837575

RESUMO

This study aimed to evaluate the efficacy, adverse events and expense burden of outpatient versus remote programming for vagus nerve stimulation (VNS) in children with epilepsy. A total of 46 children with drug-resistant epilepsy, who underwent VNS at the Pediatric Epilepsy Center, Peking University First Hospital between March 2017 and June 2018, were enrolled into the study. Participants were assigned (non-randomized) into an outpatient programming group or remote programming group (where VNS parameters were adjusted through the internet) by parental choice. The responder rate, expenditure for VNS programming and adverse events were compared between the two groups. The median age at VNS implantation was 5.17 years (3.83-6.71), with the median epileptic course being 3.79 years (2.65-4.90). Twenty-four patients were assigned to the outpatient programming group and 22 were assigned to the remote programming group. Baseline data were comparable between the two groups, with the exception of the remote group having a longer distance between their place of residence and the hospital. The median time from VNS implantation to last follow-up was 1.33 years (1.25-1.75) and 1.46 years (1.17-1.58) in the outpatient and remote groups, respectively. In the outpatient programming group, 15 patients (62.5 %,) were VNS responders and four patients (16.6 %) became seizure-free. In the remote programming group, 16 patients (72.7 %) were VNS responders and four (17.4 %) became seizure-free. Cough and hoarseness were common adverse events in both the outpatient and remote groups (33.3 % vs. 18.2 %). There were no significant differences between the two groups in terms of adverse events. The median cost of each follow-up visit per patient in the outpatient group was 192.4 US dollars ($120.0-$376.5), of which travelling expenses were the major component, followed by accommodation fees, outpatient service fees and indirect costs. Whereas, patients in the remote programming group only needed to pay for the remote programming expense, which totaled 75.8 US dollars per person each time. The efficacy and adverse events were both comparable between the outpatient and remote programming patients. Remote programming was found to be a more cost-effective treatment, especially for patients living further away from centers specializing in epilepsy.

17.
Sci Rep ; 9(1): 17909, 2019 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-31784560

RESUMO

CSNK2B, which encodes the beta subunit of casein kinase II (CK2), plays an important role in neuron morphology and synaptic transmission. Variants in CSNK2B associated with epilepsy and/or intellectual disability (ID)/developmental delay (DD) have been reported in five cases only. Among the 816 probands suspected hereditary epilepsy whose initial report of trio-based whole exome sequencing (WES) were negative, 10 de novo pathogenic or likely pathogenic variants of CSNK2B in nine probands were identified after reanalysis of their raw Trio-WES data. Six of the nine epileptic patients had ID/DD. The age of seizure onset of these nine patients with CSNK2B variants ranged from 2-12 months. Eight patients had age of seizure onset of less than 6 months. The epilepsy of most probands (8/9) was generalized tonic-clonic seizure and clustered (6/9). Most patients had normal electroencephalogram (5/9) and brain magnetic resonance image (7/9) results. Most patients (7/9) had easy-to-control seizures. Levetiracetam was the most commonly used drug in seizure-free patients (5/7). The variants detected in five patients (5/9, 55.6%) were located in the zinc-binding domain. In summary, our research provided evidence that variants in CSNK2B are associated with epilepsy with or without ID/DD. CSNK2B-related epilepsy is relatively easy to be controlled. The zinc-binding domain appears to be the hotspot region for mutation.

18.
Am J Hum Genet ; 105(5): 996-1004, 2019 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-31587869

RESUMO

Mechanically activated (MA) ion channels convert physical forces into electrical signals. Despite the importance of this function, the involvement of mechanosensitive ion channels in human disease is poorly understood. Here we report heterozygous missense mutations in the gene encoding the MA ion channel TMEM63A that result in an infantile disorder resembling a hypomyelinating leukodystrophy. Four unrelated individuals presented with congenital nystagmus, motor delay, and deficient myelination on serial scans in infancy, prompting the diagnosis of Pelizaeus-Merzbacher (like) disease. Genomic sequencing revealed that all four individuals carry heterozygous missense variants in the pore-forming domain of TMEM63A. These variants were confirmed to have arisen de novo in three of the four individuals. While the physiological role of TMEM63A is incompletely understood, it is highly expressed in oligodendrocytes and it has recently been shown to be a MA ion channel. Using patch clamp electrophysiology, we demonstrated that each of the modeled variants result in strongly attenuated stretch-activated currents when expressed in naive cells. Unexpectedly, the clinical evolution of all four individuals has been surprisingly favorable, with substantial improvements in neurological signs and developmental progression. In the three individuals with follow-up scans after 4 years of age, the myelin deficit had almost completely resolved. Our results suggest a previously unappreciated role for mechanosensitive ion channels in myelin development.


Assuntos
Canais Iônicos/genética , Proteínas de Membrana/genética , Bainha de Mielina/genética , Doença de Pelizaeus-Merzbacher/genética , Adolescente , Adulto , Pré-Escolar , Feminino , Heterozigoto , Humanos , Masculino , Mutação de Sentido Incorreto/genética , Oligodendroglia/metabolismo , Adulto Jovem
19.
Front Neurol ; 10: 880, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31474931

RESUMO

Object: To explore the post-hemispherotomy seizure outcome and its prognostic predictors in children with refractory epilepsy. Methods: We reviewed 83 consecutive child patients with refractory epilepsy who underwent a hemispherectomy from June 2014 to January 2017 at our Pediatric Epilepsy Center. Demographic, clinical, EEG, neuroimaging, and surgical data were collected. Seizure outcome data were collected via outpatient clinics as well as telephone visits and were graded according to Engel criteria. Logistic regression model and Cox proportional hazard regression model were, respectively, applied to explore the related factors predicting the seizure outcomes of children after a hemispherotomy. Results: Of the 83 patients, 55 (63.2%) were male. The mean seizure onset age was 1.9 years (0-8.7 years), and the mean surgery age was 5 years (0.8-14 years). At a mean follow-up of 3 years, 69 children (83.1%) were seizure free, and 14 (16.9%) exhibited seizure recurrence. In a univariate analysis, whether or not considering follow-up time, a non-lateralized interictal EEG pattern, bilateral PET abnormalities and acute postoperative seizures (APOS) could all predict poor seizure outcomes post-hemispherotomy. Bilateral PET abnormalities were independently correlated with unfavorable seizure outcomes in the multivariate Logistic regression analysis (Odds ratio(OR) = 13.05, 95%CI = 1.52-112.29, P = 0.019) and in the multivariate Cox proportional hazard analysis(OR = 13.99, 95%CI = 2.75-71.17, P = 0.001). Conclusions: Child epileptic patients with bilateral PET abnormalities may have poor seizure outcomes after a hemispherotomy procedure. This study will facilitate better candidate selection for hemispherotomies and early identification of unfavorable seizure outcomes.

20.
Brain ; 142(10): 3009-3027, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31504254

RESUMO

N-methyl d-aspartate receptors are ligand-gated ionotropic receptors mediating a slow, calcium-permeable component of excitatory synaptic transmission in the CNS. Variants in genes encoding NMDAR subunits have been associated with a spectrum of neurodevelopmental disorders. Here we report six novel GRIN2D variants and one previously-described disease-associated GRIN2D variant in two patients with developmental and epileptic encephalopathy. GRIN2D encodes for the GluN2D subunit protein; the GluN2D amino acids affected by the variants in this report are located in the pre-M1 helix, transmembrane domain M3, and the intracellular carboxyl terminal domain. Functional analysis in vitro reveals that all six variants decreased receptor surface expression, which may underline some shared clinical symptoms. In addition the GluN2D(Leu670Phe), (Ala675Thr) and (Ala678Asp) substitutions confer significantly enhanced agonist potency, and/or increased channel open probability, while the GluN2D(Ser573Phe), (Ser1271Phe) and (Arg1313Trp) substitutions result in a mild increase of agonist potency, reduced sensitivity to endogenous protons, and decreased channel open probability. The GluN2D(Ser573Phe), (Ala675Thr), and (Ala678Asp) substitutions significantly decrease current amplitude, consistent with reduced surface expression. The GluN2D(Leu670Phe) variant slows current response deactivation time course and increased charge transfer. GluN2D(Ala678Asp) transfection significantly decreased cell viability of rat cultured cortical neurons. In addition, we evaluated a set of FDA-approved NMDAR channel blockers to rescue functional changes of mutant receptors. This work suggests the complexity of the pathological mechanisms of GRIN2D-mediated developmental and epileptic encephalopathy, as well as the potential benefit of precision medicine.

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