DNM1基因变异致早发性婴儿癫痫性脑病31型三例并文献复习

目的探讨DNM1基因变异导致早发性婴儿癫痫性脑病的临床、基因和预后特征。方法三例经基因检测证实为DNM1基因新发变异的患儿,回顾性分析其临床和基因表型以及预后,并在国内外数据库以“Dynamin-1”或“DNM1”检索相应文献,利用单因素方差方法分析临床和癫痫发作表型、抗癫痫药物疗效与基因变异位点结构域相关性。结果女1例,男2例;癫痫发病年龄2~17月龄,癫痫发作表型:2例为癫痫性痉挛发作,1例为局灶性一侧肢体阵挛或继发强直阵挛发作。基因检测结果显示3例患儿DNM1基因存在新发错义变异,2例为NM_004408.4:c.415 G>A(P.Gly 139Arg),1例为NM_004408.4:c.545 C>A(P.Ala 182Asp),随访至2~3岁时,均为肌张力低下、严重智力障碍、无行走能力和主动语言、耐药性癫痫、不能自主进食和不会咀嚼固体食物。经文献检索,至今国内外报道DNM1基因相关脑病36例,包括本组病例共计39例,肌张力低下与基因变异位点区域无关,GTPase酶结构域和中间区域变异存在严重或显著智力发育障碍。对31例诊断癫痫并且临床资料完整患儿进一步分析发现,癫痫性痉挛发作是常见的癫痫发作形式,变异位点位于GTPase酶结构域和中间区域的两组病例,失神发作在GTPase酶结构域更常见(P=0.02),而在性别、起病年龄、其他癫痫发作形式和药物治疗反应上均无统计学差异。结论肌张力低下、严重智力和运动障碍及早发型癫痫是DNM1相关脑病的主要表现,癫痫性痉挛发作是最常见的发作形式,除失神发作外,GTPase酶结构域和中间区域变异的临床和癫痫表型无明显区别,本组病例尚合并进食障碍。     

ASH1L mutation caused seizures and intellectual disability in twin sisters

ASH1L mutations have been identified with variable phenotypes, including intellectual disability, autism spectrum disorder (ASD), and multiple congenital anomalies (MCA). However, the mechanisms underlying this phenotypic variation remain unknown. Here, we present twin sisters exhibiting mild intellectual disability and seizures. Whole-exome sequencing of the family revealed a novel de novo heterozygous sequence variant, NM_018489.2: c.2678dup (p.Lys894*) in exon 3 of ASH1L which was estimated to be pathogenic. Furthermore, we reviewed previously reported ASH1L mutations in order to evaluate genotype-phenotype correlations for ASH1L variants. We found that patients with missense mutations in ASH1L appeared to present with more severe phenotypes and a higher likelihood of ASD than those with truncating mutations. The relationship between phenotype and genotype reported across several patients may help to explain the mechanisms underlying the phenotypic variation commonly observed between ASH1L mutations.     

Exome sequencing identifies a de novo SCN2A mutation in a patient with intractable seizures,severe intellectual disability,optic atrophy,muscular hypotonia,and brain abnormalities

Epilepsy is a phenotypically and genetically highly heterogeneous disorder with >200 genes linked to inherited forms of the disease. To identify the underlying genetic cause in a patient with intractable seizures, optic atrophy, severe intellectual disability (ID), brain abnormalities, and muscular hypotonia, we performed exome sequencing in a 5‐year‐old girl and her unaffected parents. In the patient, we detected a novel, de novo missense mutation in the SCN2A (c.5645G>T; p.R1882L) gene encoding the α_II‐subunit of the voltage‐gated sodium channel Na_v1.2. A literature review revealed 33 different SCN2A mutations in 14 families with benign forms of epilepsy and in 21 cases with severe phenotypes. Although almost all benign mutations were inherited, the majority of severe mutations occurred de novo. Of interest, de novo SCN2A mutations have also been reported in five patients without seizures but with ID (n = 3) and/or autism (n = 3). In the present study, we successfully used exome sequencing to detect a de novo mutation in a genetically heterogeneous disorder with epilepsy and ID. Using this approach, we expand the phenotypic spectrum of SCN2A mutations. Our own and literature data indicate that SCN2A‐linked severe phenotypes are more likely to be caused by de novo mutations. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here .     

A balanced translocation disrupts SYNGAP1 in a patient with intellectual disability, speech impairment, and epilepsy with myoclonic absences (EMA)

Epilepsy with myoclonic absences (EMA) is a rare form of generalized epilepsy occurring in childhood and is often difficult to treat. The underlying etiology of EMA is unknown in the majority of patients. Herein, we describe a patient with EMA and intellectual disability who carries a de novo balanced translocation: t(6;22)(p21.32;q11.21). We mapped the translocation breakpoints by fluorescence in situ hybridization (FISH), and the breakpoint at 6p21.32 was found to truncate the N-methyl-d-aspartate (NMDA)-receptor associated gene SYNGAP1. The breakpoint at 22q11.21 was within a highly variable region without known protein-coding genes. Mutations of SYNGAP1 are associated with nonsyndromal intellectual disability (NSID). Two-thirds of the patients described so far also have generalized epilepsy. This finding, together with our report, suggests that dysfunction of SYNGAP1 contributes to the development of generalized epilepsy, including EMA.     

Biallelic mutations in SZT2 cause a discernible clinical entity with epilepsy,developmental delay,macrocephaly and a dysmorphic corpus callosum

Mutations in SZT2 were first reported in 2013 as a cause of early-onset epileptic encephalopathy. Because only five reports have been published to date, the clinical features associated with SZT2 remain unclear. We herein report an additional patient with biallelic mutations in SZT2. The proband, a four-year-old girl, showed developmental delay and seizures from two years of age. Her seizures were not intractable and readily controlled by valproate. She showed mildly dysmorphic facies with macrocephaly, high forehead, and hypertelorism, and also had pectus carinatum. An EEG showed epileptic discharges which rarely occurred. A brain MRI revealed a short and thick corpus callosum. Whole-exome sequencing detected compound heterozygous biallelic mutations (c.8596dup (p.Tyr2866Leufs¹42) and c.2930-17_2930-3delinsCTCGTG) in SZT2, both of which were novel and predicted to be truncating. This case suggested a broad phenotypic spectrum arises from SZT2 mutations, forming a continuum from epileptic encephalopathy and severe developmental delay to mild intellectual disability without epilepsy. The characteristic thick and short corpus callosum observed in 7/8 cases with epilepsy, including the proband, but not in three non-syndromic cases, appears to be specific, and thus useful for indicating the possibility of SZT2 mutations. This feature has the potential to make loss of SZT2 a clinically discernible disorder despite a wide clinical spectrum.     

A review of behavioral interventions for the treatment of aggression in individuals with developmental disabilities

Aggression can present as a significant problem behavior in individuals with a diagnosis of developmental disability. Much research has focused on the prevalence of aggression in individuals with varying degrees of severity of intellectual disability (AD), autism spectrum disorders (ASD) and co-morbidity of ID and ASD. Research has also focused on the impact of aggressive behavior on individuals’ development including cognitive, adaptive and social functioning. The literature on Applied Behavior Analysis provides abundant examples of various interventions that are effective in reducing or eliminating aggressive behavior across a range of ages and degrees of developmental disabilities. Many interventions report success using antecedent alterations, reinforcement-based strategies and consequence manipulations. The current review provides a focused, comprehensive examination of aggressive behavior intervention research for individuals with developmental disabilities aged 3-18 years published between 1980 and 2009.     

A systematic review of sensory-based treatments for children with disabilities

Sensory-based therapies are designed to address sensory processing difficulties by helping to organize and control the regulation of environmental sensory inputs. These treatments are increasingly popular, particularly with children with behavioral and developmental disabilities. However, empirical support for sensory-based treatments is limited. The purpose of this review was to conduct a comprehensive and methodologically sound evaluation of the efficacy of sensory-based treatments for children with disabilities. Methods for this review were registered with PROSPERO (CRD42012003243). Thirty studies involving 856 participants met our inclusion criteria and were included in this review. Considerable heterogeneity was noted across studies in implementation, measurement, and study rigor. The research on sensory-based treatments is limited due to insubstantial treatment outcomes, weak experimental designs, or high risk of bias. Although many people use and advocate for the use of sensory-based treatments and there is a substantial empirical literature on sensory-based treatments for children with disabilities, insufficient evidence exists to support their use.     

SLC35A2基因新生变异致先天性糖基化障碍1例

先天性糖基化障碍(CDG)是一组累及多器官系统的遗传代谢性疾病,相对罕见。我院收治1例SLC35A2基因相关CDG患者,临床表现为成串痉挛发作、发育迟缓、多发畸形等。家系3人全外显子基因组测序发现SLC35A2基因新生杂合错义变异:c.844G>A(p.Gly282Arg),根据美国医学遗传学与基因组学学会指南预测为可能致病性突变。此位点国内尚未见报道。     

Neurodevelopmental disorder associated with de novo SCN3A pathogenic variants: two new cases and review of the literature

SCN3A was recently recognized as a gene associated with neurodevelopmental disorder and epilepsy. We present two additional patients with a novel de novo SCN3A pathogenic variant, and a review of all published cases of de novo variants. In one of our patients brain magnetic resonance imaging (MRI) disclosed a severe polymicrogyria and in the other it was normal. The clinical phenotype was characterized by a severe developmental delay and refractory epilepsy in the patient with polymicrogyria and intellectual disability with autistic features and pharmacoresponsive epilepsy in the subject with normal MRI. Polymicrogyria, a disorder of progenitor cells proliferation and migration, is an unanticipated finding for an ion channel dysfunction.     

Mild phenotype in a patient with developmental and epileptic encephalopathy carrying a novel de novo KCNB1 variant

Neurological Sciences -     

Maternal stress predicted by characteristics of children with autism spectrum disorder and intellectual disability

To determine maternal stress and child variables predicting maternal stress, 104 mothers of children with autism spectrum disorder (ASD) and intellectual disability (ID) completed the Dutch version of the Parental Stress Index (PSI; De Brock, Vermulst, Gerris, & Abidin, 1992) every six months over a period of two years. The level of maternal stress remained stable over time. Child characteristics predicting maternal stress are behavioral inflexibility toward objects and initiating social interactions. However, these factors do not predict maternal stress when analyzed in combination with children's emotional and behavioral problems measured on the Child Behavior Checklist (CBCL; Achenbach & Rescorla, 2000). The subscales emotionally reactive behavior, withdrawn behavior and attention problems explain a third of the variance in maternal stress. This study revealed no relation between maternal stress and children's developmental age and IQ, receptive and expressive language, adaptive behavior, severity and subtype of ASD, behavioral flexibility toward the environment and persons, initiating and responding to joint attention, initiating and responding to behavioral requests, responding to social interactions and the other subscales of the CBCL. Findings are discussed in relation to the clinical and non-clinical norm groups of the PSI, the limitations of the study and clinical practice.     

De novo POLR2A p.(Ile457Thr) variant associated with early-onset encephalopathy and cerebellar atrophy: expanding the phenotypic spectrum

BackgroundHeterozygous POLR2A variants have been recently reported in patients with a neurodevelopmental syndrome characterized by profound infantile-onset hypotonia. POLR2A encodes the highly conserved RBP1 protein, an essential subunit of the DNA-dependent RNA polymerase II.Case presentationWe investigated a 12-year-old girl presenting with an early-onset encephalopathy characterized by psychomotor delay, facial dysmorphism, refractory epilepsy with variable seizure types, behavioural abnormalities, and sleep disorder. Brain MRI showed a slowly progressive cerebellar atrophy. Trio-exome sequencing (Trio-ES) revealed the de novo germline variant NM_000937.5:c.1370T>C; p.(Ile457Thr) in POLR2A. This variant was previously reported in a subject with profound generalized hypotonia and muscular atrophy by Haijes et al. Our patient displayed instead a severe epileptic phenotype with refractory hypotonic seizures with impaired consciousness, myoclonic jerks, and drop attacks.ConclusionThis case expands the clinical spectrum of POLR2A-related syndrome, highlighting its phenotypic variability and supporting the relevance of epilepsy as a core feature of this emerging condition.     

Sleep, anxiety and challenging behaviour in children with intellectual disability and/or autism spectrum disorder

Children with an intellectual disability (ID) and/or autism spectrum disorder (ASD) are known to suffer from significantly more sleep problems, anxiety and challenging behaviour (CB) than typically developing children (TD), yet little is known about the relationship between these factors in the child ID/ASD population. The study aim was to examine these relationships. We hypothesised that there would be significant positive correlations between the three factors and that sleep problems and anxiety would predict a significant amount of the variance in levels of CB. Parental measures of sleep problems, anxiety and CB were completed by 187 parents of children with ID and/or ASD. Significant positive associations were found between the three factors. A hierarchical multiple regression showed that medication, sleep problems and anxiety accounted for 42% of the variance in CB, with a large effect size. These findings suggest that these relationships should be considered during clinical practice, particularly in the case of CB interventions where sleep problems and/or anxiety are also present.     

Additional observation of a de novo pathogenic variant in KCNT2 leading to epileptic encephalopathy with clinical features of frontal lobe epilepsy

IntroductionKCNT2 was recently recognized as a gene associated with neurodevelopmental disorder and epilepsy.Case reportWe present an additional observation of a 16-year-old male patient with a novel de novo KCNT2 likely pathogenic variant and review the five previously reported cases of de novo variants in this gene.DiscussionWhole exome sequencing identified the missense variant c.725C > A p.(Thr242Asn), which was confirmed by Sanger sequencing. Our patient has a refractory stereotyped and monomorphic type of hyperkinetic focal motor seizure, similar to what is seen in frontal lobe epilepsy, occurring only during sleep. This type of seizure is not usually seen in epileptic encephalopathies.     

Daily living skills in children with autism spectrum disorder and intellectual disability: A comparative study from Turkey

BackgroundBetter daily living skills (DLS) are associated with increased independence and positive functional outcomes in Autism Spectrum Disorder (ASD).MethodThe present study aimed to investigate daily living skills (DLS) and the associated factors in 51 children with ASD and intellectual disability (ASD group) and 51 age- and gender-matched controls with intellectual disability (ID group). The severity of the autistic symptoms was measured with the clinician-rated Childhood Autism Rating Scale and the parent-reported Autism Behavior Checklist (ABC) in all children. The mothers also completed the Pediatric Quality of Life Inventory and the Basic DLS Questionnaire.ResultsThe ASD group scored lower than the comparison group in the total DLS score, personal hygiene, dressing, safety and interpersonal skills, despite being comparable in the parent-reported quality of life. Regression analysis of the whole sample demonstrated that the child’s age, intellectual level, speech level, autism symptom severity and the monthly household income were independent correlates of the total DLS. Exploratory analyses for each group revealed differential effects of these variables: in the ASD group; a higher speech level and monthly income, while in the ID group; an older age, a higher intellectual level and monthly income and a lower ABC score emerged as significant predictors of higher DLS.ConclusionsDeficient DLS in Turkish children with ASD, given their IQ, suggest that lower level of adaptive skills is inherent in ASD, rather than culture-specific to US and Western Europe.     

Neuropsychological and neuroimaging phenotype induced by a CAMTA1 mutation

Background/Aims: CAMTA1 mutations have recently been reported in families with intellectual disability and/or non-progressive congenital ataxias. The objective of this study was to describe the neuropsychological and neuroimaging phenotype of CAMTA1 mutation. Methods: We performed neuropsychological examinations, MRI and FDG-PET imaging in three patients with autosomal dominant mild intellectual disabilities and ataxia induced by a CAMTA1 intragenic deletion at 1p36.31p36.23. Results: Neuropsychological tests showed similar findings in two patients, with low information processing speed, slow memory consolidation, phonological disorders, working memory deficits, but mainly preserved executive function. Bilateral parietal and medial temporal abnormalities were found on brain MRI. Diffuse parieto-occipital and local left temporo-parietal decrease of FDG uptake was observed on PET images. Conclusion: These results suggest that CAMTA1 mutation may induce an unusual neuropsychological profile and parieto-temporal developmental abnormalities. We recommend screening for CAMTA1 mutations in patients with autosomal dominant mild intellectual disability presenting with similar a phenotype.     

Effectiveness of low intensity behavioral treatment for children with autism spectrum disorder and intellectual disability

To determine the effectiveness of low intensity behavioral treatment (LIBT) supplementing regular treatment in young children with autism spectrum disorder (ASD) and intellectual disability (ID) standardized tests of cognition, adaptive behavior, interpersonal relations, play, language, characteristics of autism, emotional and behavioral problems, behavioral flexibility, early social communication, and maternal stress were administered in a treatment group (n = 20), receiving 4–10 h LIBT per week and a control group (n = 20) receiving treatment as usual. At baseline, no differences were found between groups (mean chronological age: 5.3 years; mean developmental age: 1.11 years) on several key variables, but after two years of intervention the treatment group outperformed the control group on IQ, developmental age, adaptive behavior, interpersonal relations, play and receptive language, and less autistic symptoms were seen in treatment group. Following intervention, no differences between groups were found on expressive language, behavioral flexibility and maternal stress. Progress in developmental age, adaptive behavior, interpersonal relations, play and receptive and expressive language was clinically and reliably significant for the majority of the LIBT group.