患儿，女，10个月21 d，3月龄开始发育延迟，严重语言发育障碍，刻板动作，喜笑，体格检查可见肤白，枕部扁平，10月龄行视频脑电图提示不典型失神发作，发作间期可见游走性慢波活动。家系三人全外显子组测序提示患儿AP2M1基因存在新发突变c.508C>T(p.R170W)。已报道的国内外AP2M1基因变异相关的常染色体显性智力发育障碍60型伴癫痫发作共6例（包括该研究），主要临床特点包括发育延迟（6例），语言发育障碍（5例），刻板动作（3例），喜欢微笑（1例），临床发作以不典型失神为主（4例），发作间期脑电图可见广泛性棘波、棘慢波发放（5例），游走性慢波活动（1例）。c.508C>T(p.R170W)可能为AP2M1基因突变热点，其临床特点与快乐木偶综合征非常相似。
Abstract
The patient is a 10-month and 21-day-old girl who began to show developmental delays at 3 months of age, with severe language developmental disorders, stereotyped movements, and easily provoked laughter. Physical examination revealed fair skin and a flattened occiput. At 10 months of age, a video electroencephalogram suggested atypical absence seizures, with migrating slow-wave activity observed during the interictal period. Whole exome sequencing of three family members indicated a novel mutation in the AP2M1 gene, c.508C>T (p.R170W), in the patient. A total of six cases of autosomal dominant intellectual developmental disorder 60 with seizures associated with mutations in the AP2M1 gene have been reported both domestically and internationally (including this study). The main clinical features included developmental delays (6 cases), language developmental disorders (5 cases), stereotyped movements (3 cases), a tendency to smile (1 case), and atypical absence seizures (4 cases). Interictal electroencephalograms showed widespread spike waves and spike-slow wave discharges (5 cases), and migrating slow-wave activity (1 case). The c.508C>T (p.R170W) mutation may be a hotspot for mutations in the AP2M1 gene, and its clinical features are similar to those of Angelman syndrome.
关键词
常染色体显性智力发育障碍60型伴癫痫发作 /
快乐木偶综合征 /
AP2M1基因 /
儿童
Key words
Autosomal dominant intellectual developmental disorder 60 with seizures /
Angelman syndrome /
AP2M1 gene /
Child
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参考文献
1 Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology[J]. Genet Med, 2015, 17(5): 405-424. PMID: 25741868. PMCID: PMC4544753. DOI: 10.1038/gim.2015.30.
2 Kelly BT, Graham SC, Liska N, et al. Clathrin adaptors. AP2 controls clathrin polymerization with a membrane-activated switch[J]. Science, 2014, 345(6195): 459-463. PMID: 25061211. PMCID: PMC4333214. DOI: 10.1126/science.1254836.
3 Saheki Y, De Camilli P. Synaptic vesicle endocytosis[J]. Cold Spring Harb Perspect Biol, 2012, 4(9): a005645. PMID: 22763746. PMCID: PMC3428771. DOI: 10.1101/cshperspect.a005645.
4 Dittman J, Ryan TA. Molecular circuitry of endocytosis at nerve terminals[J]. Annu Rev Cell Dev Biol, 2009, 25: 133-160. PMID: 19575674. DOI: 10.1146/annurev.cellbio.042308.113302.
5 Ricotta D, Conner SD, Schmid SL, et al. Phosphorylation of the AP2 mu subunit by AAK1 mediates high affinity binding to membrane protein sorting signals[J]. J Cell Biol, 2002, 156(5): 791-795. PMID: 11877457. PMCID: PMC2173304. DOI: 10.1083/jcb.200111068.
6 Helbig I, Lopez-Hernandez T, Shor O, et al. A recurrent missense variant in AP2M1 impairs clathrin-mediated endocytosis and causes developmental and epileptic encephalopathy[J]. Am J Hum Genet, 2019, 104(6): 1060-1072. PMID: 31104773. PMCID: PMC6556875. DOI: 10.1016/j.ajhg.2019.04.001.
7 Lek M, Karczewski KJ, Minikel EV, et al. Analysis of protein-coding genetic variation in 60,706 humans[J]. Nature, 2016, 536(7616): 285-291. PMID: 27535533. PMCID: PMC5018207. DOI: 10.1038/nature19057.
8 Mitsunari T, Nakatsu F, Shioda N, et al. Clathrin adaptor AP-2 is essential for early embryonal development[J]. Mol Cell Biol, 2005, 25(21): 9318-9323. PMID: 16227583. PMCID: PMC1265839. DOI: 10.1128/MCB.25.21.9318-9323.2005.
9 王丽, 段丽芬, 边成, 等. 1例AP2M1基因突变致智力发育障碍伴癫痫发作的遗传特征与临床表型分析[J]. 中国优生与遗传杂志, 2023, 31(6): 1241-1245. DOI: 10.13404/j.cnki.cjbhh.2023.06.014.
10 杜晓南, 王佶, 王艺. Angelman综合征的诊断与治疗[J]. 中华儿科杂志, 2023, 61(7): 667-669. PMID: 37385816. DOI: 10.3760/cma.j.cn112140-20230322-00198.
基金
河南省医学科技攻关计划（LHGJ20230584）；河南省儿科疾病临床医学研究中心开放课题（YJZX202202）。
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