SLC35A2基因变异致先天性糖基化障碍Ⅱm型3例并文献复习

目的总结SLC35A2基因变异致先天性糖基化障碍Ⅱm型3例患儿的临床特征、基因变异特点、诊断、治疗及预后。方法总结2018—2020年在中南大学湘雅医院儿科就诊的3例确诊为先天性糖基化障碍Ⅱm型(CDG Ⅱm)患儿的临床资料。以congenital disorders of glycosylation ⅡmSLC35A2先天性糖基化障碍Ⅱm型CDG Ⅱm为关键词, 查阅在线人类孟德尔遗传数据库和PubMed数据库、中国知识基础设施工程(CNKI)数据库、万方数据库建库至2022年1月的相关文献, 总结SLC35A2基因变异患者的临床表现、遗传学、治疗及预后特点。结果 3例患儿均为婴儿期起病, 表现为痉挛发作和全面发育落后, 经多种抗癫痫发作药物治疗有暂时和部分好转, 但不能完全控制;先证者2和先证者3出现丙氨酸氨基转移酶、血小板升高, 眼底检查示双眼视网膜色素上皮发育不良, 接受了D-半乳糖治疗后, 临床或生化指标稍有改善。文献检索SLC35A2变异报道共22篇99例, 共报道75个不同变异位点, 均为杂合变异;临床表型主要包括发育迟缓或智力障碍(89/99)、癫痫发作...     

SCN2A基因突变致癫痫三例

目的探讨SCN2A基因不同位点突变致癫痫的临床特点。方法收集河北省儿童医院神经内科2019年1月-2019年12月收治的SCN2A基因突变阳性致癫痫患儿资料,并进行临床分析。结果共收集3例SCN2A基因突变阳性致癫痫患儿,突变类型均为杂合突变。例1患儿生后2d起病,发作形式为阵挛发作、局灶性发作,诊断为良性家族性新生儿婴儿癫痫;突变基因型c.2426AG(p.K809R),为家族遗传性突变,使用丙戊酸、托吡酯胶囊、苯巴比妥钠后发作控制。例2患儿生后30h起病,发作形式为局灶性发作,痉挛发作,诊断为婴儿游走性部分性癫痫,婴儿痉挛,发育性癫痫性脑病;突变基因型c.4391CT(p.T1464I),为自发突变,使用托吡酯及ACTH治疗后发作逐渐减停。例3患儿1岁3月龄起病,发作形式为强直发作,诊断为全面性癫痫伴热性惊厥附加征;突变基因型c.1711C T(p.R571C),遗传自父亲,未使用抗癫痫药物。结论本组病例提示SCN2A基因应作为婴幼儿期良性癫痫、癫痫性脑病、智力、运动发育落后、孤独症等疾病的候选筛查基因之一。     

先天性糖基化障碍ALG11基因突变致大田原综合征1例报道及文献复习

目的 探讨先天性糖基化障碍(Congenital disorders of glycosylation, CDG)致病基因ALG11(Asparagine-linked glycosylation 11)复合杂合变异致大田原综合征的临床特点、突变致病性分析和治疗手段。方法 回顾分析1例以癫痫发作为首发症状、高通量测序证实CDG致病基因ALG11复合杂合变异致大田原综合征的临床资料、家系基因检测、致病性分析、治疗及随访并作文献复习。结果 患儿,男,5个月23 d,主因“间断抽搐2月余”就诊,癫痫发作早期为部分性发作,后转为痉挛发作、脑电图背景呈爆发-抑制图形,临床诊断大田原综合征; 同时患儿反复感染并存在视听障碍、喂养困难、小头畸形、全面性发育迟缓、四肢肌张力高等; 采用高通量测序法发现患儿携带ALG11基因(OMIM# 613666)c.1403G>A及c.1307G>T复合杂合突变,分别来自其父母并导致p.R468H及p.G436V氨基酸改变,关联疾病为糖基化障碍CDG-1p型; 患儿早期给予苯巴比妥/溴化钠合剂及左乙拉西坦口服,癫痫控制效果不佳,联合生酮饮食治疗后癫痫发作逐渐改善,精神运动发育亦有进步。结论 婴儿早发癫痫性脑病合并神经系统多发异常、重复感染时需考虑到CDG可能,生酮饮食辅助疗法可在一定程度上改善癫痫发作。     

CUX2基因变异致发育性癫痫性脑病67型1例并文献复习

目的总结经全外显子组测序确诊的发育性癫痫性脑病67型的临床表型及CUX2 基因的变异特点。方法回顾性收集1例于2021年1月就诊于郑州大学附属儿童医院神经内科并确诊为CUX2基因变异相关发育性癫痫性脑病67型患儿的临床资料, 对其临床特点、基因检测、头颅影像学、脑电图检查结果及治疗方案等进行总结, 每3个月对患儿进行1次随访。同时对CUX2基因变异导致发育性癫痫性脑病的国内外相关文献进行复习。结果先证者为女童, 年龄6岁4个月, 主要临床表现为局灶性起源进展为双侧强直-阵挛发作, 智力、语言、运动发育落后, 伴自闭行为、多动性障碍、不自主拍手动作。视频脑电图背景活动慢;醒-睡各期广泛性棘慢波、多棘慢波发放, 睡眠期双侧前头部棘慢波、尖形慢波发放。头颅磁共振成像(MRI)平扫及T2液体衰减反转恢复序列(T2-FLAIR)薄层扫描结果提示左侧海马较右侧信号增高, 稍肿胀;1个月后复查MRI及T2-FLAIR示左侧海马信号仍稍高, 较前有所减低, 海马体积稍减小。染色体拷贝数分析结果未见异常;全外显子组测序示CUX2基因存在c.1768G>A(p.Glu590Lys)杂合错义变异, 父...     

CHD2基因突变致癫痫患者九例

目的 探讨CHD2基因突变致癫痫患儿临床表型及基因型特点。方法 分析2017年01月-2022年07月河北省儿童医院神经内科收治的CHD2基因突变相关性癫痫患儿。并查阅万方、中国知网(CNKI)、PubMed、Uptodate等数据库,结合相关文献进行总结。结果 本研究共收集9例CHD2基因突变阳性患儿,其中自发突变5例,母源性突变4例。9例患儿局灶性发作起病6例,全面性发作起病3例,1例患儿符合LGS诊断,1例患儿符合眼睑肌阵挛综合征诊断。7例患儿伴有轻到中度的发育障碍。9例患儿共发现8个基因突变位点,其中错义突变5个,移码突变3个,突变多集中在SNF2相关解旋酶/ATP酶结构域;其中7个突变位点尚未报道。7例患儿应用丙戊酸钠治疗有效。结论(1)CHD2基因突变多以局灶性发作起病,丙戊酸治疗有效;(2)自发突变起病更早,均伴有轻到中度的发育障碍;(3)CHD2基因致病性突变多集中在SNF2相关解旋酶/ATP酶结构域。     

SLC6A1突变致儿童癫痫伴肌阵挛-失张力发作1例报告

<正>癫痫伴肌阵挛-失张力发作(epilepsy with myoclonic-atonic seizures, EMAS)既往称为肌阵挛-站立不能性癫痫(myoclonic-astatic epilepsy)或肌阵挛-失张力癫痫(myoclonic-atonic epilepsy, MAE)。EMAS是1970年由德国医生Doose等首次报道,所以也被称为Doose综合征^[1]。     

中国汉族人群SLC6A11基因多态性与耐药性癫痫的相关性研究

目的探索中国汉族人群SLC6A11基因多态性与耐药性癫痫的相关性。方法据入选标准和排除标准收集在湘雅医院门诊的480例癫痫患者,应用Illumina Golden Gate定制芯片对288例药物敏感癫痫患者和192例药物耐药癫痫患者进行SLC6A11基因型鉴定,分析单位点基因型频率和单体型与耐药性癫痫的相关性。结果敏感组与耐药组之间SLC6 A11基因14个SNP位点的基因型频率差异无统计学意义(P0.05);耐药性癫痫患者单倍型5的频率高于敏感组(1%vs.4%;OR=2.56[0.107-0.763];P=0.01),经过Bonferroni多重检验后单倍型5的频率在两组间无显著差异。结论 SLC6A11基因的14个SNP多态性可能与中国汉族人群的癫痫耐药性无关。     

SLC6A1基因变异导致神经发育障碍的家系分析

目的 探讨SLC6A1基因突变导致的儿童癫痫及其他神经发育障碍的临床特征和基因变异特点。方法 对2021年1月-2022年10月在华中科技大学同济医学院附属同济医院儿科住院及门诊随访的1例SLC6A1基因变异导致的肌阵挛-失张力癫痫患儿的临床表现和基因变异特点进行回顾性分析,并检索文献,总结SLC6A1基因突变患者的临床表型及基因突变特点。结果 患儿,女,1岁8月龄出现频繁腿抖,独站不稳及摔跤,伴有频繁眨眼。于2岁3月龄因仍不能独立行走开始康复训练。不会说话,不愿意理人。视频脑电图提示背景节律慢化;醒睡期见双侧前头部、后头部或广泛性高波幅慢波、棘慢波或节律发放。头部MRI提示双侧额叶斑点状高T₂ Flair信号灶。Gesell发育评估量表发育商64,发育年龄为21月龄,儿童孤独症评定量表提示目前无明显孤独症表现。基因突变分析发现患儿SLC6A1基因存在一处杂合变异c. 889G>A(p. Gly297Arg),突变来自母亲及外婆,其母亲及外婆幼时有抽搐史。总结既往文献,SLC6A1基因突变相关的神经发育障碍的主要临床表型为癫痫(失神、失张力、肌阵挛及肌阵挛-...     

有自杀意念的儿童青少年双相障碍抑郁发作患者SLC6A4 基因甲基化研究

目的 探讨儿童青少年双相障碍（PBD）抑郁发作患者自杀意念与SLC6A4基因甲基化 的关系。方法 选取 2020 年 12 月至 2022 年 12 月于新疆维吾尔自治区人民医院临床心理科住院的 43 例 PBD 抑郁发作患者为研究对象。采用自杀意念自评量表（SIOSS）评估患者的自杀意念，将总分≥ 12 分且掩饰因子得分＜ 4 分的患者纳入有自杀意念组（n=29），将总分＜ 12 分的患者纳入无自杀意念组 （n=14）。采用 Methprimer 软件对SLC6A4基因启动子区进行甲基化岛预测和甲基化引物设计，将提取好 的DNA经亚硫酸盐转化后进行PCR扩增和焦磷酸盐测序，确定甲基化的CpG位点和甲基化率。比较两组 患者SLC6A4基因不同位点甲基化的差异，采用 Spearman 相关分析基因甲基化与自杀意念的相关性。 结果 基因甲基化检测结果显示，两组患者SLC6A4基因甲基化的位点包括 CpG1、CpG2.3、CpG4、 CpG5.6位点。有自杀意念组与无自杀意念组患者CpG1、CpG2.3、CpG4位点的基因甲基化率比较［48.28% （14/29）比 8/14、96.55%（28/29）比 14/14、20.69%（6/29）比 6/14］，差异无统计学意义（χ2 =0.297、0.494、2.306； P＞ 0.05）。有自杀意念组患者的 CpG5.6 位点基因甲基化率高于无自杀意念组［68.97%（20/29）比 5/14］， 差异有统计学意义（χ2 =4.289，P＜ 0.05）。相关分析结果显示，PBD 抑郁发作患者的 SIOSS 得分与 SLC6A4基因甲基化CpG1位点、CpG2.3位点、CpG4位点不存在相关性（r=-0.244、-0.210、-0.281；P＞0.05）； 与甲基化 CpG5.6 位点呈正相关（r=0.312，P＜ 0.05）。结论 PBD 抑郁发作患者的自杀意念与SLC6A4基 因甲基化 CpG5.6 位点有关，为明确其自杀意念的发生原因提供了基础。     

不同类型KCNQ2基因突变所致癫痫五例临床分析

目的探讨KCNQ2基因突变不同基因型与癫痫患儿临床表型之间的关系。方法分析2017年10月-2018年10月河北省儿童医院神经内科收治的5例KCNQ2基因突变相关性癫痫患儿,并查阅万方、中国知网(CNKI)、PubMed、Uptodate等数据库,结合相关文献进行总结。结果本研究共收集5例KCNQ2基因突变阳性患儿,其中自发突变3例:含错义突变2例,截短突变1例;家系遗传2例;错义突变、无义突变各1例。3例自发突变临床表型均为癫痫性脑病,家系遗传中1例为良性家族性新生儿癫痫。家系1同一位点突变呈现3种不同表型。结论①KCNQ2基因突变不仅可以引起良性家族性新生儿癫痫(BFNE),还可引起多种癫痫性脑病;②自发突变更可能导致癫痫性脑病;③同一家系携带同一基因突变位点成员也可能有不同表型。     

Congenital disorder of glycosylation type Ia: a clinicopathological report of a newborn infant with cerebellar pathology

Congenital disorders of glycosylation (CDG) represent a newly delineated group of inherited multisystem disorders characterized by defective glycoprotein biosynthesis. In the present study we report and discuss the clinical and neuropathological findings in a newborn with CDG type Ia (CDG-Ia). The patient presented mild dysmorphic facial features, inverted nipples, progressive generalized edema, hypertrophic cardiomyopathy, hepatosplenomegaly, muscular hypotonia and had severe hypoalbuminemia. Deficiency of phosphomannomutase (PMM)-2 activity was detected. Molecular analysis showed V231M/T237R mutations of the PMM2 gene. Muscular biopsy, disclosed myopathic alterations with myofibrillar disarray by electron microscopy. The patient died at 1 month of age of circulatory and respiratory failure. Autopsy showed liver fibrosis and renal abnormalities. Neuropathological abnormalities were mainly confined to the cerebellum. Histological and immunocytochemical examination of cerebellar tissue showed partial atrophy of cerebellar folia with severe loss of Purkinje cells, granular cell depletion and various morphological changes in the remaining Purkinje cells and their dendritic arborization. Autopsy findings confirm the complexity of the CDG-Ia syndrome, and indicate that CDG-Ia is a distinct disease entity, which can be differentiated from other neurological disorders and other types of CDG, not only clinically, but also based on unique pathological findings. The data proved useful in determining the underlying disease process associated with a defective N-glycosylation pathway.     

Congenital disorder of glycosylation type Ic: Report of a Japanese case

Congenital disorders of glycosylation (CDG) are inherited metabolic diseases affecting N-linked glycosylation pathways with variable clinical presentations characterized by psychomotor retardation, seizures, ataxia and hypotonia. CDG-Ic is caused by mutation in the ALG6 gene encoding alpha-1,3-glucosyltransferase. We present a 9-year-old girl diagnosed as having CDG-Ic. She developed severe psychomotor retardation, epileptic seizures, muscle hypotonia, strabismus and some dysmorphic features without inverted nipples or fat pads. She showed a fluctuating serum transaminase level with or without some infection, and a characteristically low level of antithrombin III. MR imaging of the brain at age 2 years demonstrated the lower limit of normal myelination, mild atrophy of the cerebrum, and mild hypoplasia of the brainstem and cerebellum. The patient exhibited a CDG type I pattern of serum transferrin on isoelectric focusing and mass spectrometric profiling. Sequence analysis of the ALG6 gene showed two heterozygous mutations, c.998C>T (A333V) and c.1061C>T (P354L). The patient was diagnosed as having CDG-Ic with a novel mutation, making her the first Japanese case. It was suggested that the severe psychomotor retardation in the patient was due to the existence of multiple mutant ALG6 alleles.     

SLC25A12基因多态性与孤独性障碍的关联

目的：探讨SLC25A12基因单核苷酸多态性（SNP）与孤独性障碍的遗传关联性。方法：采用聚合酶链式反应和DNA芯片杂交技术,在124个汉族孤独性障碍患儿核心家系中,检测了SLC25A12基因的2个SNP位点（rs2056202,rs2292813）,采用传递不平衡检验（TDT）和单倍型的方法进行关联分析。结果：在124个患儿核心家系中,所测得的2个SNP位点的等位基因和基因型的频数分布均符合Hardy-Weinberg平衡检验（χ^2=0.009,P=0.92;χ^2=0.006,P=0.94）。而且这2个SNP处于一个强连锁不平衡区域（D’=0.842,r2=0.566）。对124个核心家系TDT检验,发现带有杂合子基因的父代优先传递给子代的等位基因的传递率和此传递率的置信区间差异无显著性（P〉0.05）;所有样本的2个SNP位点,未发现与孤独性障碍的显著关联。结论：SLC25A12基因可能不是这些汉族家庭儿童孤独性障碍的主要易感基因。     

Congenital disorder of glycosylation type 1T with a novel truncated homozygous mutation in PGM1 gene and literature review

The congenital disorders of glycosylation are a group of clinically and biochemically heterogeneous diseases characterized by multisystem involvement due to glycosylation defect of protein and lipid. Here we report a 49-year-old man with exercise-induced fatigue and pain of muscle, tachypnea, cleft palate and bifid uvula. Exercise induced elevation of serum creatine kinase (CK), ammonia and lactic acid was recorded. The abnormal levels of myoglobin, CK-MB and LDH as well as S-T elevation in electrocardiogram were observed in repeated hospitalization recordings. Electromyography showed myopathic damage. Repetitive nerve stimulation test of low rates showed decrement in the left deltoid muscle. He was identified with a novel homozygous frameshift variant in Phosphoglucomutase type 1 gene (c.405delT p.N135Kfs*9) by whole exome sequencing. Muscle biopsy exhibited minimal variation in fiber size without abnormal glycogen accumulation. Compared with controls’, the patient's sample showed no signal at ～61?kDa using N- or C-terminus antibody of Phosphoglucomutase type 1 in western blotting. A signal at ～20?kDa was detected in patient using N-terminus antibody. Immunofluorescence revealed trace expression of C-terminus and a much lower expression of N-terminus on the sarcolemma than normal. Our findings indicate that c.405delT encodes a truncated protein with abnormal distribution and expression in skeletal muscle. In conclusion, genes associated with congenital disorders of glycosylation should be analyzed in patients with maxillofacial dysplasia, exertional weakness, cardiac involvement and exercise-induced-ammoniemia, without glycogen storage in skeletal muscle.     

Mild epileptic phenotype associates with de novo eef1a2 mutation: Case report and review

BackgroundMutations in the elongation factor 1 alpha 2 (EEF1A2) gene have been recently shown to cause epileptic encephalopathy (MIM # 616409 EIEE33) associated with neurodevelopmental disorders such as intellectual disability, autistic spectrum disorder, hypotonia and dysmorphic facial features. EEF1A2 protein is involved in protein synthesis, suppression of apoptosis, regulation of actin function and cytoskeletal structure. To date, only sixteen patients with EEF1A2 mutations have been reported.Case reportWe described a new case, a boy with severe intellectual disability with absent speech, autistic spectrum disorder, mild dysmorphic facial features, failure to thrive and epilepsy associated to a de novo heterozygous missense mutation in EEF1A2 (c.364G>A; p.Glu122Lys) identified by next generation sequencing; it was already reported in other studies. Most clinical features are shared by all individuals with EEF1A2 mutation, but unlike others reports our patient showed a mild epileptic phenotype: epilepsy developed in late infancy and was well-controlled with antiepileptic drugs. Moreover, at the onset of epilepsy, interictal wake/sleep electroencephalograms showed typical pattern that disappeared with age.ConclusionThis report focused that EEF1A2 mutations should be considered not only in patients with epileptic encephalopathy, but also in those with less severe epilepsy. A typical EEG pattern may be a biomarker for EEF1A2 mutation, but further investigations and longitudinal clinical observations are required.     

Clinical and pathological heterogeneity of a congenital disorder of glycosylation manifesting as a myasthenic/myopathic syndrome

Congenital disorders of glycosylation are often associated with muscle weakness in apparent isolation or as part of a multi-systemic disorder. We report here the clinical and pathological features resulting from a homozygous mutation of ALG2 in an extended family. Phenotypic heterogeneity is observed among the small cohort of patients reported to date and is highlighted by our study. Linkage analysis, homozygozity mapping and whole exome sequencing followed clinical and pathological characterization of patients who presented with a congenital limb girdle pattern of weakness with no ocular or bulbar involvement. Nerve stimulation studies were consistent with a congenital myasthenic syndrome. Severity and progression of disease was variable. Muscle biopsies showed myopathic features, ragged red fibers and a sub-sarcolemmal accumulation of structurally normal mitochondria. Whole exome sequencing revealed an indel mutation c.214_224delGGGGACTGGCTdelinsAGTCCCCG, p.72_75delGDWLinsSPR in exon 1 of ALG2. Mutation of ALG2 manifested as a limb girdle pattern of muscle weakness with defects at both the neuromuscular junction and sarcomere. In addition the accumulation and distribution of mitochondria in the diseased muscle and the presence of ragged red fibers were supportive of a mitochondrial myopathy. ALG2 mutation results in a heterogeneous phenotype and care should be taken in categorization and treatment of these patients.     

Anticipation in a family with primary familial brain calcification caused by an SLC20A2 variant

Aim of the study

To describe a family with primary familial brain calcification (PFBC) due to SLC20A2 variant showing possible genetic anticipation.

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.     

Paramyotonia congenita due to a de novo mutation: a case report

A Japanese man with a negative family history of paramyotonia congenita (PMC) was evaluated for symptoms of cold-induced weakness and stiffness. Exercise testing revealed findings characteristic of PMC, and a genetic analysis was therefore performed. A well-known sodium channel mutation for PMC (T1313M) was identified in the patient, but was absent in his biological parents. These data demonstrate the occurrence of a de novo mutation, suggesting that evaluation for PMC should be performed in patients with typical symptoms even if the family history is negative.