Angelman syndrome

Angelman syndrome (AS) is a rare genetic disorder that affects the nervous system and causes severe intellectual disability, limited or absent speech, movement and balance problems, and a characteristic happy demeanour.天使人综合征（Angelman syndrome，简称 AS）是一种罕见的遗传性疾病，累及神经系统，导致严重智力障碍、语言缺失或极少、运动与平衡障碍，以及特征性的快乐面容。

It results from loss or dysfunction of the maternally inherited UBE3A gene on chromosome 15 and affects approximately one in 12,000 to 20,000 people.该病源于母源第 15 号染色体 UBE3A 基因的缺失或功能障碍，发生率约为 1/12000 至 1/20000。

Terminology and classification

• Angelman syndrome is named after the English paediatrician Harry Angelman, who first reported three affected children in 1965.该综合征以 1965 年首次报告 3 例患病儿童的英国儿科医生 Harry Angelman 命名。^[1]
• Angelman first called the condition "Puppet Children", and it was later also known as happy puppet syndrome before being renamed Angelman syndrome.Angelman 最初称之为「木偶儿童」（Puppet Children），后来也被称为快乐木偶综合征，最终改称天使人综合征。
• ICD-10 assigns the code Q93.5 for Angelman syndrome within the group of chromosome deletions, and ICD-11 places the disease within the developmental anomalies chapter.世界卫生组织 ICD-10 在天使人综合征下编码为 Q93.5，ICD-11 则将其归入发育异常章节。
• Cross-ontology identifiers include MeSH D017204, MONDO:0007113, Orphanet ORPHA:72, Disease Ontology DOID:1932, UMLS C0162635 and NCIt C75462.跨本体标识包括 MeSH D017204、MONDO:0007113、Orphanet ORPHA:72、疾病本体 DOID:1932、UMLS C0162635 与 NCIt C75462。
• Angelman syndrome is a rare disease listed by Orphanet and is distinguished from Prader–Willi syndrome, which involves a different gene cluster in the same 15q11-13 region on the paternal chromosome.天使人综合征被 Orphanet 列为罕见病，并与普瑞德威利综合征相区别，后者涉及同一 15q11-13 区域但位于父源染色体的另一基因簇。

History

• Harry Angelman, a paediatrician in Warrington, England, reported three children with the condition in 1965.英国沃灵顿的儿科医生 Harry Angelman 于 1965 年报告了 3 名患病儿童。
• He chose the title "Puppet Children" after seeing an oil painting called "Boy with a Puppet" in the Castelvecchio Museum in Verona, because his patients had laughing faces and jerky movements.他在维罗纳老城堡博物馆看到一幅名为《手持木偶的男孩》的油画后，选用「木偶儿童」作为标题，因为患儿有着笑意的面容与抽动样动作。
• The name did not please all parents but grouped the patients together, and was later changed to Angelman syndrome.这个名称并未令所有家长满意，却把几位患者归为一类，后来改称天使人综合征。
• The article lay almost forgotten until the early 1980s, when case reports from the United States began to appear, including one in 1982 by Charles Williams and Jaime Frias.该文发表后一度几乎被遗忘，直至 1980 年代初美国开始出现病例报告，其中 1982 年有 Charles Williams 与 Jaime Frias 的报告。
• In 1987 Ellen Magenis discovered a genetic marker of the syndrome, noting that about half of affected children have a small piece of chromosome 15 missing, and the Angelman Syndrome Foundation was created in 1992.1987 年 Ellen Magenis 发现了该病的遗传学标志——约半数患儿第 15 号染色体有小片段缺失；天使综合征基金会于 1992 年成立。
• In 1997 Arthur Beaudet discovered that the cause was mutation of the UBE3A gene.1997 年 Arthur Beaudet 发现其病因为 UBE3A 基因突变。

Epidemiology

• The prevalence of Angelman syndrome is not precisely known, but is estimated at about one in 12,000 to 20,000 individuals.天使人综合征的确切患病率尚不清楚，估计约为 1/12000 至 1/20000。
• The best available data come from studies of school-age children in Sweden and Denmark, which found prevalence of about 1 per 20,000 and at least 1 per 10,000 respectively.目前最好的数据来自瑞典与丹麦对学龄儿童的研究，分别发现患病率约为 1/20000 与至少 1/10000。
• Rates are similar between males and females.男女患病率相近。
• Most individuals are diagnosed in early childhood, often around one year of age.多数患者在幼儿期确诊，常在约 1 岁时。

Pathophysiology

• Angelman syndrome is caused by mutations or loss of the UBE3A gene, located within the chromosome 15 region 15q11-q13.天使人综合征由位于第 15 号染色体 15q11-q13 区域的 UBE3A 基因突变或缺失引起。
• UBE3A codes for a highly selective E6-AP ubiquitin ligase that tags proteins such as MAPK1, PRMT5 and beta-catenin for degradation by the proteasome.UBE3A 编码一种高度选择性的 E6-AP 泛素连接酶，可将 MAPK1、PRMT5 与 β-连环蛋白等标记以经蛋白酶体降解。
• In certain areas of the developing brain the paternal copy of UBE3A is inactivated by imprinting, so the fetus relies solely on the maternal copy.在发育中脑的某些区域，父源 UBE3A 拷贝因印记而失活，故胎儿完全依赖母源拷贝。
• About 70% of cases involve a 5- to 7-Mb maternal deletion in 15q11.2-q13, 11% a maternal UBE3A mutation, 6% an imprinting-centre defect, and 3% paternal uniparental disomy.约 70% 的病例为 15q11.2-q13 区域 5 至 7 Mb 的母源缺失，11% 为母源 UBE3A 突变，6% 为印记中心缺陷，3% 为父源单亲二体。
• The genotype predicts severity, with deletion-positive cases tending to have more severe symptoms such as microcephaly, seizures and hypopigmentation, while paternal uniparental disomy tends to be milder.基因型可预测严重程度：缺失型往往症状更重，如小头畸形、癫痫与色素减退，而父源单亲二体者相对较轻。
• The paternal copy is silenced in the hippocampus, cortex, thalamus, olfactory bulb and cerebellum, and dysfunction in these regions underlies learning, memory, motor and sleep deficits.父源拷贝在海马、皮质、丘脑、嗅球与小脑中沉默，这些区域的功能障碍是该病学习、记忆、运动与睡眠缺陷的基础。
• Impaired cortical activity, altered hippocampal synaptic plasticity with ARC accumulation, and cerebellar granule-cell dysfunction each contribute to seizures, cognitive deficits and ataxia.皮质活动异常、伴 ARC 蓄积的海马突触可塑性改变以及小脑颗粒细胞功能障碍，分别导致癫痫、认知缺陷与共济失调。

Clinical features

• All diagnosed individuals have severe developmental delay, speech impairment with no or minimal words, and a movement or balance disorder such as ataxia.所有确诊者均有严重发育迟缓、无或极少用词的言语障碍，以及共济失调等运动或平衡障碍。
• Behavioural features include frequent laughter or smiling, an atypically happy demeanour, an easily excitable personality with hand flapping, hypermotoric behaviour and a short attention span.行为特征包括频繁发笑或微笑、异常快乐的举止、易兴奋并伴拍手动作、活动过度与注意广度缩短。
• About 80% have microcephaly by age 2, seizures beginning usually before age 3, and a characteristic EEG pattern of large-amplitude slow spike waves.约 80% 在 2 岁前出现小头畸形、通常 3 岁前起病癫痫，以及大振幅慢棘波的典型脑电图模式。
• Associated features occurring in 20% to 80% include strabismus, hypopigmentation of skin and eyes, tongue thrusting, feeding problems, frequent drooling and gastro-oesophageal reflux disease.见于 20% 至 80% 的相关表现包括斜视、皮肤与眼部色素减退、伸舌、喂养困难、频繁流涎与胃食管反流病。
• Other frequent features are hyperactive tendon reflexes, uplifted flexed arms while walking, a prominent mandible, increased sensitivity to heat, wide-spaced teeth and constipation.其他常见表现有腱反射活跃、行走时双臂上举屈曲、下颌突出、对热敏感、牙间隙增宽与便秘。
• Sleep disturbance with reduced total sleep time due to night-time waking is common, as are mouthing behaviours and an attraction to water.睡眠障碍常见，因夜间觉醒而致总睡眠时间减少；口部探索行为与对水的迷恋亦常见。
• Individuals have higher receptive than expressive language, understand speech in typical auditory brain regions but show atypical memory responses, and process speech more slowly.患者的接受性语言强于表达性语言，其听觉脑区对言语的反应典型而记忆反应异常，且言语加工速度较慢。
• As adulthood approaches, hyperactivity and poor sleep improve, seizures decrease or cease, and many adults look youthful, though obesity and worsening scoliosis can occur.接近成年时，多动与睡眠问题改善，癫痫减少甚至停止；许多成人显得年轻，但可能出现肥胖与脊柱侧弯加重。

Diagnosis

• Diagnosis requires the consistent clinical features of Angelman syndrome, supported by genetic testing.诊断需具备天使人综合征的一致性临床特征，并辅以基因检测。
• Methylation studies show methylation of the maternal UBE3A copy in about 80% of patients, supporting the diagnosis.甲基化检测显示约 80% 的患者存在母源 UBE3A 拷贝甲基化，可支持诊断。
• Fluorescence in situ hybridisation is performed after methylation studies to detect a maternal deletion of UBE3A on chromosome 15.荧光原位杂交（FISH）在甲基化检测后进行，用以发现第 15 号染色体上的母源 UBE3A 缺失。
• DNA marker analysis and sequencing are used to detect imprinting defects or UBE3A mutations, which methylation studies may miss.DNA 标志物分析与测序用于检出甲基化检测可能遗漏的印记缺陷或 UBE3A 突变。
• Electroencephalography reveals characteristic patterns of brain activity and epileptic activity, and three interictal patterns are recognised.脑电图可显示特征性脑活动模式与癫痫活动，并已识别出三种发作间期模式。
• The most common EEG pattern is a very large-amplitude 2 to 3 Hz rhythm, most prominent in prefrontal leads.最常见的脑电图模式是振幅极大的 2 至 3 Hz 节律，以前额导联最为显著。
• The main differential diagnoses include autism spectrum disorder, cerebral palsy, Rett syndrome, Mowat–Wilson syndrome, Pitt–Hopkins syndrome and Prader–Willi syndrome.主要鉴别诊断包括孤独症谱系障碍、脑性瘫痪、Rett 综合征、Mowat-Wilson 综合征、Pitt-Hopkins 综合征与普瑞德威利综合征。

Management

• There is no approved cure, and treatment is symptomatic and supportive.目前尚无获批的治愈方法，治疗为对症与支持性。
• Epilepsy can be controlled with one or more anticonvulsant medications, though determining optimal levels is difficult because patients often have multiple seizure types.癫痫可用一种或多种抗癫痫药控制，但因患者常有多种发作类型，确定最佳剂量较为困难。
• Melatonin is widely used to promote sleep, mild laxatives are used for constipation, and ranitidine was the most frequently prescribed medication for reflux in one cohort.褪黑素被广泛用于促进睡眠，温和泻药用于便秘；在一项队列中，雷尼替丁是治疗反流最常处方的药物。
• Early physiotherapy encourages joint mobility and prevents stiffening.早期物理治疗可促进关节活动并防止僵硬。
• Occupational therapy develops non-verbal communication skills such as finger isolation, motor planning, hand-eye coordination, spatial awareness and gesture refinement.作业治疗可培养手指分离、运动计划、手眼协调、空间感知与手势精细等非言语沟通能力。
• Because expressive speech is limited, most communicate non-verbally through deictic gesturing, physically guiding others, or non-speech vocalisations, and some use signing.由于表达性言语受限，多数患者通过指示性手势、身体引导他人或非言语发声进行交流，部分能使用手语。
• Speech communication should account for the delay in processing speed, and some patients use augmentative and alternative communication devices.言语交流应考虑到加工速度延迟；部分患者使用辅助与替代沟通设备。
• Participation in physical, occupational and communication therapies is believed to improve cognition and communication outcomes.参与物理、作业与沟通治疗被认为可改善认知与沟通方面的结局。

Research and controversies

• Alogabat, an experimental small molecule in clinical development, acts as a positive allosteric modulator of the GABA-A alpha-5 receptor and aims to improve learning, sleep and seizure control without targeting UBE3A.处于临床开发阶段的实验性小分子阿洛加巴特（alogabat）是 GABA-A α5 受体的正向别构调节剂，旨在不经 UBE3A 途径改善学习、睡眠与癫痫控制。
• Antisense oligonucleotides such as RO7248824, GTX-102 and ION582 are being tested in phase 1 to 3 trials to unsilence the paternal UBE3A allele or increase UBE3A production.RO7248824、GTX-102 与 ION582 等反义寡核苷酸正在 1 至 3 期试验中测试，以解除父源 UBE3A 等位基因的沉默或增加 UBE3A 生成。
• Activating the normally silenced paternal UBE3A allele in neurons has been achieved in mice with the topoisomerase inhibitor topotecan, and Neuren's NNZ-2591 is being studied in phase 2 trials.在小鼠中已用拓扑异构酶抑制剂拓扑替康激活神经元内通常沉默的父源 UBE3A 等位基因；Neuren 公司的 NNZ-2591 正在 2 期试验中研究。
• Because rodent models have limitations, a porcine model has been developed with a UBE3A gene more similar to humans and an ataxic wide-stance gait that closely matches human disease.鉴于啮齿动物模型的局限，研究者开发了猪模型——其 UBE3A 基因与人类更相似，且宽基共济失调步态与人类疾病高度相符。
• Angelman syndrome is not degenerative, and most affected people have good overall health and a reduced but near-normal life expectancy, dying on average 10 to 15 years earlier than the general population.天使人综合征并非退行性疾病，多数患者总体健康良好，预期寿命虽缩短但接近正常，平均比一般人群早 10 至 15 年死亡。