Child Neurology Section, Department of Pediatrics, University of Arkansas for Medical Sciences, Debopam Samanta 1 Children's Way, Little Rock, AR 72202, USA.
Brain Dev. 2021 Jan;43(1):32-44. doi: 10.1016/j.braindev.2020.08.014. Epub 2020 Sep 4.
Angelman Syndrome (AS) is characterized by severe developmental delays including marked speech impairment, movement abnormalities(ataxia, tremor), and unique behaviors such as frequent laughter and is caused by dysfunctional maternal UBE3A gene (maternal 15q11-13 deletions, maternal specific UBE3A mutation, uniparental disomy, and imprinting defect). Intractable epileptic seizures since early childhood with characteristic EEG abnormalities are present in 80-90% patients with AS. Underlying pathophysiology may involve neocortical and thalamocortical hyperexcitability secondary to severe reduction of GABAergic input, as well as dysfunctional synaptic plasticity, deficient synaptogenesis, and neuronal morphological immaturity. The onset of epilepsy is most prevalent between 1 and 3 years of age; however, approximately 25% of patients developed epilepsy before one year of age. Various types of generalized seizures are most prevalent, with most common types are myoclonic and atypical absence.More than 95% of epilepsy patients may have daily seizures at least for a limited time during early childhood, and two-third patients develop disabling seizures. Fever provoked seizures, and frequent occurrence of nonconvulsive status epilepticus are two unique features. Seizures are frequently pharmacoresistant. Considering underlying prominent GABAergic dysfunction, clinicians had used AEDs that target GABAergic signaling such as valproate, phenobarbital, and clonazepam as first-line therapies for AS. However, due to the unfavorable side effect profile of these AEDs, a recent treatment approach involves priority use of levetiracetam, clobazam, topiramate, lamotrigine, ethosuximide, VNS, and carbohydrate-restricted diets. Besides symptomatic management, there has been recent progress to find a curative treatment with the following approaches: 1. Gene/protein replacement therapy (Adeno and lentiviral vector therapy to deliver a gene or secretory protein); 2. Activation of the intact but silent paternal copy of UBE3A (antisense oligonucleotide therapy and artificial transcription factors); and 3. Downstream therapies (OV101/gaboxadol, ketone supplement, novel compounds/peptides, anti-inflammatory/regenerative therapy).
天使综合征（AS）的特征是严重的发育迟缓，包括明显的言语障碍、运动异常（共济失调、震颤）和独特的行为，如频繁大笑，是由母源性UBE3A 基因功能障碍引起的（母源性 15q11-13 缺失、母源性特异性 UBE3A 突变、单亲二倍体和印记缺陷）。80-90%的 AS 患者自幼儿时期即出现难以控制的癫痫发作，并伴有特征性脑电图异常。潜在的病理生理学可能涉及皮质和丘脑皮质过度兴奋，这是由于 GABA 能传入的严重减少，以及突触可塑性功能障碍、突触生成不足和神经元形态不成熟。癫痫发作的发病高峰在 1 至 3 岁之间，但约 25%的患者在 1 岁之前就出现癫痫发作。各种类型的全身性发作最为常见，最常见的类型是肌阵挛和非典型失神发作。超过 95%的癫痫患者在幼儿时期至少有一段时间每天都会发作，三分之二的患者会出现致残性癫痫发作。热性惊厥和非惊厥性癫痫持续状态的频繁发生是两个独特的特征。癫痫发作通常对抗癫痫药物治疗耐药。考虑到 GABA 能功能障碍突出，临床医生曾使用靶向 GABA 能信号的抗癫痫药物（AEDs）作为 AS 的一线治疗药物，如丙戊酸钠、苯巴比妥和氯硝西泮。然而，由于这些 AEDs 的不良副作用谱，最近的治疗方法涉及优先使用左乙拉西坦、氯巴占、托吡酯、拉莫三嗪、乙琥胺、迷走神经刺激术和碳水化合物限制饮食。除了对症治疗外，最近在寻找有治愈可能的治疗方法方面取得了进展，包括：1. 基因/蛋白替代治疗（腺相关病毒和慢病毒载体治疗以递送基因或分泌蛋白）；2. 激活完整但沉默的父本 UBE3A 拷贝（反义寡核苷酸治疗和人工转录因子）；3. 下游治疗（OV101/gaboxadol、酮补充剂、新型化合物/肽、抗炎/再生治疗）。
