Angelman syndrome …

Ryan W Y Lee MD

Neurobehavioral & Cognitive Disorders

Updated 04.28.2024
Released 06.25.2004
Expires For CME 04.28.2027

Angelman syndrome

Author: Ryan W Y Lee MD

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Editor: Ann Tilton MD

Angelman syndrome

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Introduction

Overview

Angelman syndrome is a neurodevelopmental disorder characterized by intellectual disability, epilepsy, ataxia, and a unique behavioral phenotype. In this article, the author discusses the diagnosis, prognosis, genetic counseling, and health surveillance of patients with Angelman syndrome. Also discussed are studies using models of Angelman syndrome, which provide insight into the pathoetiology and potential treatment of Angelman syndrome.

Key points

	• Diagnosing Angelman syndrome has important implications for prognosis, genetic counseling, health surveillance, and, in some instances, specific symptomatic therapies.
	• The number of genetic mechanisms that lead to Angelman syndrome and the paradigm for diagnostic testing has evolved as cytogenic and molecular technologies have been introduced.
	• Molecular and genetic models have produced an increasingly comprehensive view of the mechanisms responsible for altered experience-dependent hippocampal and neocortical plasticity in this disorder.
	• Understanding the genetic factors involved in the imprinting process has allowed researchers to target therapeutics that may show promise for treatment of this disorder.

Historical note and terminology

In 1965, Dr. Harry Angelman described three unrelated children who had in common severe intellectual disability, fits of laughter, ataxia, epilepsy, and similar physical features. Because of the quality of their movement, their particular facies, and the characteristic bouts of laughter, he felt they resembled “puppet children” (03), and further case reports referred to the condition as the “happy puppet syndrome.” In 1982, Williams and Frias suggested the eponymous “Angelman syndrome” as a less derisive-sounding alternative (116).

Clinical manifestations

Presentation and course

Children with Angelman syndrome share many physical, cognitive, behavioral, and motoric characteristics; the vast majority also have epilepsy. Criteria for the clinical diagnosis of Angelman syndrome were put forth in 1995 and were updated a decade later in light of subsequent research (114; 115). They are arranged by their prevalence in children with Angelman syndrome. There is no scoring system or diagnostic threshold, though these features can guide the clinical diagnosis of Angelman syndrome in children who have unrevealing genetic testing.

Table 1. Clinical Features of Angelman Syndrome

Consistent (100%):
	• Developmental delay, functionally severe
	• Movement or balance disorder, usually ataxia of gait, or tremulous movement of limbs. Movement disorder can be mild and may not appear as frank ataxia but can be forward lurching, unsteadiness, clumsiness, or quick, jerky motions.
	• Speech impairment, none or minimal use of words; receptive and nonverbal communication skills higher than verbal ones
	• Behavioral uniqueness: any combination of frequent laughter/smiling; apparent happy demeanor; easily excitable personality, often with uplifted hand-flapping or waving movements; hypermotoric behavior.
Frequent (more than 80%):
	• Delayed, disproportionate growth in head circumference, usually resulting in microcephaly (2 or less standard deviation of normal occipital-frontal circumference) by 2 years of age. Microcephaly is more pronounced in those with 15q11.2-q13 deletions. Microcephaly may be less common in Chinese and Japanese populations than in Caucasian populations (04).
	• Seizures, onset usually before 3 years of age. Seizure severity usually decreases with age, but the seizure disorder lasts throughout adulthood
	• Abnormal EEG with a characteristic pattern. The EEG abnormalities can occur in the first 2 years of life and can precede clinical features, and are often not correlated to clinical seizure events
Associated (20% to 80%):
	• Flat occiput
	• Occipital groove
	• Protruding tongue
	• Tongue thrusting; suck or swallowing disorders
	• Feeding problems or truncal hypotonia in infancy
	• Prognathia
	• Wide mouth, wide-spaced teeth
	• Frequent drooling
	• Excessive chewing or mouthing behaviors
	• Strabismus
	• Hypopigmented skin, light hair, and eye color (compared to family), seen only in deletion cases
	• Hyperactive lower limb deep tendon reflexes
	• Uplifted, flexed arm position, especially during ambulation
	• Wide-based gait with pronated or valgus-positioned ankles
	• Increased sensitivity to heat
	• Abnormal sleep-wake cycles and diminished need for sleep
	• Attraction to or fascination with water; fascination with crinkly items such as certain papers and plastics
	• Abnormal food-related behaviors
	• Obesity (in the older children)
	• Scoliosis
	• Constipation
(115)

Natural history. Although children later diagnosed with Angelman syndrome are typically recognized to have developmental delays between 6 and 12 months of age (114), the median of diagnosis is 1.8 years (112). The cardinal features of Angelman syndrome evolve over the patient’s lifespan, and those present in the first 2 years of life are often nonspecific; they typically include developmental delay, hyperactivity, happy disposition, ataxia, and hypotonia (106; 17). Feeding difficulties may also be prominent in infancy (115). In young children, seizures, hypopigmentation, tongue protrusion, and acquired microcephaly are somewhat more specific and may lead a clinician to consider Angelman syndrome (13), though there is a dearth of prospective data in the young child.

Childhood is characterized by the features listed in the diagnostic criteria. Puberty occurs at the typical time. Scoliosis may begin during the adolescent growth spurt and often progresses unless corrected. Over time, communication may improve to the point that basic needs may be expressed, though adults with Angelman syndrome rarely have more than a few words. Hyperactivity typically resolves in adulthood, but a progressively sedentary lifestyle often gives rise to weight gain and obesity. Gastroesophageal reflux may be severe (48; 88).

Neuroimaging may be normal or may show mild cerebral atrophy or abnormal myelination (37).

Physical features. The facial features seen with Angelman syndrome include prognathism and macrostomia. These features typically are not recognizable at birth and often become more prominent over the lifespan. Hypopigmentation (relative to siblings) may be present at birth, but it is often not to a degree that it is recognized as abnormal. A horizontal occipital groove was described in Angelman’s first three patients but has not been seen frequently in subsequent patients (17).

Cognitive and behavioral features. Children with Angelman syndrome nearly always function in the range of severe-to-profound intellectual disability (74), with a maximal developmental level of approximately 24 to 30 months (115).

Receptive language has consistently been found to be better than expressive language (43). Communication skills do improve in later childhood as attention improves. Although adults with Angelman syndrome cannot use more than a few words, many have functional use of nonverbal gestures; some can sign proficiently. Older individuals with Angelman syndrome can often understand simple commands sufficiently to navigate everyday situations. Not surprisingly, adolescents and adults with the best communication seem to be at the lowest risk for frustration and maladaptive behaviors. In terms of adaptive abilities, one third to one half of adults with Angelman syndrome can stay continent during the day and carry out simple daily tasks; none can live without around-the-clock supervision (48; 88; 17).

The diagnosis of autism in children with Angelman syndrome presents something of a controversy. Children with Angelman syndrome often do have symptoms of autism or even meet diagnostic criteria for autism (90; 73). Some researchers suggest, however, that the autistic phenotype is consistent with the degree of intellectual disability and does not support an additional diagnosis of autism (101). In fact, the children with Angelman syndrome who merit a diagnosis of autism are those with the lowest cognitive function (73), and studies of the behavioral phenotype of Angelman syndrome have reported socialization as a particular strength (74).

The happy demeanor and laughing fits Dr. Angelman first noted in 1965 are often considered the most useful clinical diagnostic markers in Angelman syndrome (17). The happy demeanor typically persists into adulthood, whereas the bursts of laughter, often not seen until 14 months, typically resolve in adulthood. Hyperactivity is almost always present, though it resolves (or at least improves) in adulthood (13; 88; 35). Children and adults with Angelman syndrome have also been noted to have a fascination with water.

Despite the stereotype of happy demeanor, individuals with Angelman syndrome often have challenging behavior, such as self-injury and aggression. There is a relationship to the root cause of these challenging behaviors and frequently seen comorbidities of the gastrointestinal tract, sleep problems, and internalizing symptoms (52).

Sleep. Sleep is disordered in patients with Angelman syndrome, and the typical manifestations include difficulty in initiating sleep and difficulty in maintaining sleep through the night. Abnormal endogenous melatonin secretion may affect altered sleep in patients with neurodevelopmental disorders, such as Angelman syndrome (120). In a study, about one third of patients with Angelman syndrome took longer than 30 minutes to fall asleep. Parasomnias, nocturnal movement disorders (eg, hypnic jerks), and disordered breathing have been noted as well (10). Children with Angelman syndrome often require only 5 to 6 hours of sleep per night (35); the short sleep duration of sleep does not seem to interfere with daytime alertness and function. A sleep polysomnography study found significantly less efficient sleep in children younger than 8 years of age (65). There appears to be a correlation between sleep abnormalities and epilepsy (18), though the complex nature of causality in this relationship is not fully understood. Evidence suggests the UBE3A gene may play a role in regulating sleep homeostasis (25).

Epilepsy and electrophysiology. Seizures are common in Angelman syndrome, and epilepsy occurs in the neighborhood of 80% of patients older than 2 years of age (13). Febrile seizures may be an initial presentation. Atypical absence, atonic, and generalized tonic-clonic seizures are the most common semiologies, followed by complex partial seizures (97). Myoclonic seizures have also been widely reported and are common in Angelman syndrome (76). Flexor spasms (in the syndrome of infantile spasms) and tonic seizures (as well as Lennox-Gastaut syndrome) have also been reported (67; 97). Status epilepticus is common in Angelman syndrome and may present as prolonged cognitive regression or myoclonus (105), though the differentiation between abnormal background activity and nonconvulsive status epilepticus can be difficult. Estimates of the prevalence of convulsive and nonconvulsive status epilepticus vary.

In almost all patients with Angelman syndrome, the EEG shows abnormalities by 4 to 9 months of age, well before many of the other specific features of Angelman syndrome are evident. These abnormalities may evolve and become less evident over time. The abnormalities are typically divided into three categories:

	(1) Runs of rhythmic, high-voltage (on the order of 300 microvolts) delta activity, generalized with a frontal predominance; epileptiform activity may be superimposed.
	(2) Persistent, generalized high-voltage (200 µV) theta activity (typically present at younger than 12 years of age).
	(3) Spike and sharp waves (200 µV), with posterior predominance, admixed with high-amplitude delta and potentiated by eye closure.

These patterns have been reviewed extensively by Valente and colleagues (102) and Laan and Vein (49). These patterns do not necessarily represent epilepsy; neither are they completely specific for Angelman syndrome.

Motor development and orthopedic issues. Tremor, ataxia, axial hypotonia, and lower-extremity spasticity are seen in Angelman syndrome. The patterns of movement are distinct from spastic diplegic cerebral palsy and seem to represent a developmentally immature pattern, including aspects of both spasticity and ataxia (06).

People with Angelman syndrome often develop scoliosis during the adolescent growth spurt; this may be severe enough to cause respiratory complications. If not corrected, the scoliosis is likely to progress. Adults with Angelman syndrome often walk with a crouched gait, and contractures may develop secondary to limb hypertonia and limited exercise (48; 88).

Phenotype-genotype correlations. There is a trend in the literature toward separating children with Angelman syndrome by the underlying genetics, though nondeletional subjects are relatively rare. Patients with deletion of 15q11.2-13 are typically the most severely affected, particularly with regard to the severity of epilepsy, impairment of cognitive and linguistic development, microcephaly, and degree of hypopigmentation. Children with uniparental disomy have been noted to have language skills well above what is typical for Angelman syndrome, a lower rate of epilepsy (104), and better motoric ability (88; 108). Patients with an imprinting defect also have a relatively mild phenotype compared to those with a deletion (56).

Furthermore, there is increasing recognition of the overlap in the clinical spectra of Angelman syndrome, Rett syndrome, and Prader-Willi syndrome.

Prognosis and complications

Even though developmental delay is often recognized between 6 and 12 months of age, the median age of diagnosis of Angelman syndrome is 6 years. The cardinal features of Angelman syndrome evolve over the patient’s lifespan, and those present in the first 2 years of life are often nonspecific (developmental delay, hyperactivity, happy disposition, ataxia, hypotonia) (106; 17). Seizures, hypopigmentation, tongue protrusion, and acquired microcephaly may lead to further consideration of Angelman syndrome (13), though there is a dearth of prospective data in the young child.

Childhood is characterized by the features noted in the diagnostic criteria. Puberty occurs at the typical time. Scoliosis may occur with the adolescent growth spurt and often progresses unless corrected. Epilepsy often improves around puberty (105). Communication may improve to the point that basic needs may be expressed, though adults with Angelman syndrome rarely have more than a few words. Hyperactivity typically resolves as well, but a progressively sedentary lifestyle often gives rise to weight gain and obesity. Gastroesophageal reflux in adulthood may be severe (48; 88). The lack of standardized treatment protocols or approved therapies, combined with the severity of the condition, results in high unmet clinical needs in the areas of motor functioning, communication, behavior, and sleep for individuals with Angelman syndrome and their families (113).

Clinical vignette

An 8-month-old girl was referred by her primary care doctor to a pediatric neurologist to evaluate developmental delay. Following a benign pregnancy, she was born by caesarian section secondary to breech presentation and abnormal stress test. The girl’s mother first had concerns at 3 months of age when the patient was less attentive and less interactive than other children her age. The girl was floppy and demonstrated tongue thrusting. By 8 months, she was just starting to roll over. The remainder of her past medical history and family history were unremarkable. Head circumference was at the second percentile. No dysmorphic facial features were noted, and neurologic examination was significant only for mild hyperreflexia. Testing showed cognitive skills were at the 3- to 4-month level.

By 18 months, the child had developed seizures: most were atonic, but she also had staring spells and an occasional generalized tonic-clonic seizure. A CT of the brain was normal.

A karyotype was pursued, which showed 15q11.2-13 deletion. The girl was lost to follow-up but returned at 4 years of age.

By that time, it was evident that her coloration was lighter than her family’s. She had an ataxic gait and had been prescribed ankle-foot orthoses. She had not developed any verbal expressive language. She had developed a significantly reduced need for sleep, and she was referred to behavioral psychologists for management. Seizures were well controlled with a combination of valproic acid and phenytoin.

By early adolescence, the girl had developed a strong appetite as well as pica, and behavioral psychologists were once again consulted for management. At this point, however, the girl had developed aggressive behaviors and responded poorly to attempts to control her intake. As adolescence progressed, scoliosis developed, and surgery was performed.

Biological basis

Etiology and pathogenesis

Angelman syndrome has generally been felt to result from an impaired expression of the maternal allele for the UBE3A gene, which encodes ubiquitin-protein ligase E3A (75).

UBE3A resides in chromosome 15q11.2-q13, a region, which is differentially imprinted, based on the parent from whom the chromosome originated. Imprinting of 15q11.2-q13 is controlled by an imprinting center on chromosome 15.

There are four known genetic mechanisms that impair the expression of maternal UBE3A and result in Angelman syndrome:

(1) A deletion of the maternally derived 15q11.2-q13
(2) Uniparental disomy (ie, both copies of the region are derived from the father)
(3) A mutation of the imprinting center
(4) A mutation of the UBE3A gene itself

Deletion of maternal 15q11.2-13 is responsible for 70% of Angelman syndrome cases. Children with deletion of this region are generally the most severely affected in terms of cognition, motor skills, epilepsy, microcephaly, and hypopigmentation (115). Deletions can be detected by methylation studies, fluorescent in situ hybridization for 15q11.2-q13 (though this cannot differentiate between Angelman syndrome and Prader-Willi syndrome), comparative genomic hybridization, and, rarely, karyotype.

Uniparental disomy is found in 1% to 3% of cases and results in a phenotype with less cognitive and motoric impairment and more mild epilepsy (104). Uniparental disomy can be detected by methylation studies and DNA polymorphism analysis (115). Angelman syndrome resulting from paternal uniparental disomy caused by de novo balanced translocation t(15q; 15q) of a single paternal chromosome has been reported by several groups (41).

Children with imprinting defects constitute approximately 5% of cases and have a phenotype similar to children with uniparental disomy. Imprinting defects can be discovered by methylation studies, real-time PCR, and single-copy fluorescent in situ hybridization (115).

Mutations of UBE3A account for about 8% of cases. These are detected by sequencing. Epigenetics plays a role in UBE3A regulation in Angelman syndrome and other neurodevelopmental disorders (51).

The remaining 10% to 15% of individuals who fit the clinical profile of Angelman syndrome do not have any abnormalities on genetic testing. It is possible that the promoter for UBE3A is affected in some of these cases (17; 35). There have been several reported cases of individuals with an Angelman phenotype who have mutations of MeCP2. MeCP2 mutations may result in abnormal expression of UBE3A (60).

Emerging evidence suggests that assisted reproductive technologies (in vitro fertilization, intracytoplasmic sperm injection) may be associated with an increased risk for imprinting disorders, including Angelman syndrome (70).

The ubiquitin-protein ligase encoded by UBE3A marks proteins in the brain for degradation. It is also involved in regulating GABAergic synapse strength, and work has demonstrated its relationship to the neocortical glutamatergic system (32). Although both alleles are active in most of the body, the maternally imprinted UBE3A allele is the exclusive source in the brain. Mice with UBE3A mutations have many aspects of the Angelman neurologic phenotype, including learning impairments, motor deficits, and seizures. Maternal UBE3A knock-out mice show impaired experience-dependent neocortical plasticity (84). Hippocampal NMDA-dependent long-term potentiation is also affected in UBE3A knock-out mice (111), which is associated with increased inhibitory phosphorylation of alpha-calcium/calmodulin-dependent kinase type 2 (αCaMKII). The introduction of genetic mutations of αCaMKII that decreased inhibitory phosphorylation of αCaMKII resulted in partial or complete rescue of the neurologic deficits in mice with UBE3A mutations (107). Sun and colleagues demonstrated that UBE3A suppresses neuronal hyperexcitability via ubiquitin-mediated degradation of calcium- and voltage-dependent big potassium channels (92). Augmented big potassium channel activity manifests as increased intrinsic excitability in individual neurons and subsequent network synchronization. Big potassium antagonists normalized neuronal excitability in both human and mouse neurons and ameliorated seizure susceptibility in an Angelman syndrome mouse model. Their findings suggest that big potassium channelopathy underlies epilepsy in Angelman syndrome and supports using human cells to model human developmental diseases (92).

Chromosome 15q11.2-q13 also encodes several subunits of the GABA-A receptor. Mice deficient for the beta 3 subunit have excessively synchronized thalamocortical oscillations, a pathophysiology similar to absence epilepsy. Their EEGs had excessive slow-wave and spiking activity (36). Abnormal function of the GABAergic system may affect not only epilepsy and EEG findings but sleep and motor performance as well (10; 65). A Drosophila model of Angelman syndrome has demonstrated the role of UBE3A in regulating dendritic morphogenesis (57). Furthermore, neuron-subtype-specific synaptic deficits in UBE3a (m-/p+) mice reflect excitatory-inhibitory imbalance at the cellular and circuit levels (110). Proteomic studies show a higher level of complexity than previously appreciated in UBE3A/E6AP protein function, and E6AP regulation may depend on a number of cellular proteins (62). Phenotypic, genetic, and biochemical studies suggest similarities between Angelman syndrome and Rett syndrome. E6AP acts as an essential cofactor for a subset of MeCP2 functions, suggesting a shared molecular mechanism (47). These findings support a mechanistic model of impaired plasticity and multiple levels.

The presence or absence of expression of other genes in the 15q11.2-q13 region may modulate the language delay and autism components of an individual’s phenotype (83). Yi and colleagues identified protein kinase A as an upstream regulator of UBE3A activity and showed that an autism-linked mutation disrupts this phosphorylation control (122). These findings implicate excessive UBE3A activity and the resulting synaptic dysfunction to autism pathogenesis.

Several lines of research have begun to tentatively connect the molecular level with the behavioral level of pathophysiology in Angelman syndrome. One line of investigation has examined the role of altered receptor distribution on the electrophysiological functioning of brain networks, and cerebellar networks in particular (19). Another study found abnormalities in arcuate fasciculus development and suggested that altered ubiquitination leads to abnormal development of white matter tracts, resuting in cognitive deficits, such as language impairment (118). A study tested the hypothesis that α1-NaKA overexpression drives axon initial segment protein abnormalities and that by reducing its expression, these and other phenotypes could be corrected in model mice (44). They found genetic normalization of α1-NaKA levels in Angelman model mice corrects multiple hippocampal phenotypes, including alterations in the axon initial segment, aberrant intrinsic membrane properties, impaired synaptic plasticity, and memory deficits. Synaptic SK2 levels are regulated by the E3 ubiquitin ligase UBE3A, whose deficiency results in Angelman syndrome and overexpression in increased risk of autistic spectrum disorder (54; 93). Sun and colleagues showed that impairments in both synaptic plasticity and fear conditioning memory in UBE3A-deficient mice are significantly ameliorated by blocking SK2 (93).

Abnormal monoamine levels, including serotonin, dopamine, and norepinephrine, were found in mouse models of Angelman syndrome (27).

Diagnostic workup

Given the broad number of genetic abnormalities associated with Angelman syndrome, several genetic tests may be necessary for diagnosis. As methods develop in this area, the suggested testing regimen changes rapidly.

A typical workup for Angelman syndrome begins with a methylation study. There are several types of methylation studies, including those specific to the SNRPN locus and methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) methods. A set of practice guidelines is perhaps the most authoritative source (78). However, 10% of clinically diagnosed Angelman syndrome patients test negative for the syndrome. With the advancement of genomic technology like array comparative genomic hybridization and next-generation sequencing methods, some of these negative-test patients actually have alternative diagnoses (58).

Fluorescent in situ hybridization (targeted to 15q11.2-13) has been the traditional method for assessing for deletions, but comparative genomic hybridization microarrays are now being used (09). Standard karyotypes still have a role in finding cases that result from a balanced chromosomal translocation in the mother. Uniparental disomy studies are typically used after a deletion is excluded, and assessment for microdeletions of the imprinting center is warranted if uniparental disomy studies are normal.

In a patient for whom there is strong clinical suspicion but a normal karyotype and a normal methylation study, a strong clinical suspicion would warrant sequencing of the UBE3A gene (17; 35). One group has suggested including copy number analysis (07). If sequencing is normal (as it is in approximately 15% of patients with strong clinical suspicion of Angelman syndrome), testing for MeCP2 mutations is warranted. A mutation update for UBE3A variants has been published and their clinical interpretations have been submitted to NCBI ClinVar, a freely accessible human variation and phenotype database (82). About 10% of individuals with a clinical diagnosis of Angelman syndrome have no identifiable molecular defect (96). Most of those individuals likely have an Angelman-like syndrome that is clinically and molecularly distinct from Angelman syndrome. These Angelman-like syndromes can be broadly classified into chromosomal microdeletion and microduplication syndromes and single-gene disorders. The microdeletion/microduplication syndromes are now easily identified by chromosomal microarray analysis and include Phelan-McDermid syndrome (chromosome 22q13.3 deletion), MBD5 haploinsufficiency syndrome (chromosome 2q23.1 deletion), and KANSL1 haploinsufficiency syndrome (chromosome 17q21.31 deletion). The single-gene disorders include Pitt-Hopkins syndrome (TCF4), Christianson syndrome (SLC9A6), Mowat-Wilson syndrome (ZEB2), Kleefstra syndrome (EHMT1), and Rett syndrome (MECP2). They also include disorders due to mutations in HERC2, adenylosuccinase lyase (ADSL), CDKL5, FOXG1, MECP2 (duplications), MEF2C, and ATRX. Tan and colleagues provide an overview of the clinical features of these syndromes (96).

A large study of 115 patients with Angelman syndrome allowed the prediction of deletions class-1 (5.9 Mb) in patients with intermittent theta waves in less than 50% of EEG and interictal epileptiform abnormalities; uniparental disomy, UBE3A mutation, or imprinting defects in patients with intermittent theta waves in less than 50% of EEG without interictal epileptiform abnormalities; deletions class-2 (5.0 Mb) in patients with more than 50% theta and normal posterior rhythm; and atypical deletions in patients with more than 50% theta but abnormal posterior rhythm (109). These findings suggest EEG patterns are important biomarkers and may suggest the underlying genetic etiology.

Advanced neuroimaging findings reveal bilateral gray matter volume loss in Angelman syndrome compared to control children in the striatum, limbic structures, and insular and orbitofrontal cortices (02). Voxel-wise correlation analysis with the principal components of the PCA output revealed a strong relationship with gray matter volume in the superior parietal lobule and precuneus on the left hemisphere. The anatomical distribution of cortical and subcortical gray matter changes plausibly related to several clinical features of the disease and may provide an important morphological underpinning for clinical and neurobehavioral symptoms.

Management

There has been publication of a multidisciplinary approach and a consensus statement with comprehensive literature review to develop standard-of-care practices for managing Angelman syndrome at a critical time when therapeutics to alter the natural history of the disease are on the horizon (23). Parent perceptions, beliefs, and fears around genetic treatments and cures for children with Angelman syndrome result in the need for true family and patient engagement in all stages of the research design and treatment evaluation (01). Complex management may be optimized when a multidisciplinary team approach is used (98). Centers for the specialized care of individuals with Angelman syndrome have been established. Primary areas of clinical management identified include the following: seizures, sleep, aspiration risk, GERD, constipation, dental care, vision, obesity, scoliosis, bone density, mobility, communication, behavior, and anxiety (50). A study from Spain identified the most frequent causes of hospitalization were the following: oral-dental care (28.9%), seizures (19.6%), orthopedic problems (14.4%), and acute respiratory disorders (12.4%) (22). Inability to walk, falls or drops, sleep problems, and seizures significantly affect quality of life (121).

Seizures. Seizures in Angelman syndrome patients are often difficult to control, particularly in childhood. Only about 15% respond to the first medication (97). Medications reported to be most effective include valproic acid, phenobarbital, clonazepam, ethosuximide, topiramate, lamotrigine, and levetiracetam (71; 17; 35; 69; 105; 21; 97; 87). The ketogenic diet and vagus nerve stimulator have also been reported to be helpful (105; 97; 100). One group has reported a reduction in clinical seizures with corticosteroid therapy (29). Carbamazepine, oxcarbazepine, and vigabatrin have been associated with worsening of epilepsy. The low glycemic index treatment is a high fat, limited carbohydrate diet that has been shown in a small prospective study to have a higher degree of efficacy for the treatment of seizures in Angelman syndrome than in the general epilepsy population (99; 87). Epilepsy severity may assume a bimodal age distribution: seizures are typically most severe in early childhood but may recur in adulthood (50). Low-frequency "delta" EEG rhythms are increased in individuals with Angelman syndrome during all stages of overnight sleep and can be used as a tool to measure improvement in future clinical trials (53).

Development. Appropriate developmental care is little different in Angelman syndrome than in other developmental disabilities. The diagnosis of Angelman syndrome may alert the clinician that receptive language and nonverbal communication may be more advanced than expressive language would predict. Knowing that a child has Angelman syndrome does assist with prognosis, which allows the family to have appropriate expectations of the child and plan appropriately for the child’s future. It also helps educators and therapists determine appropriate goals for school and therapy. A study by Sadhwani and colleagues described the development of 236 children with Angelman syndrome using the Bayley Scales of Infant and Toddler Development, third edition (81). The findings suggest that individuals with Angelman syndrome continue to make slow gains in development through at least 12 years of age at about 1 to 2 months per year based on age equivalent score and 1 to 16 growth score points per year, depending on molecular subtype and domain. Children with a deletion have lower scores at baseline and a slower rate of gaining skills, whereas children with the UBE3A variant subtype demonstrated higher scores as well as greater rates of skill attainment in all domains. The developmental profiles of uniparental disomy and imprinting defects were similar.

Behavioral problems (including sleep disorders) can be addressed with behavioral therapy and psychotropic medication therapy (72); melatonin may be helpful for sleep issues. Although late-adolescent and adult sleep patterns were improved when compared to the degree of sleep dysfunction present during infancy and childhood, the prevalence of poor sleep in adults remained quite high (50). One review found provisional but weak evidence for the effectiveness of behavioral interventions, and it also found mixed outcomes for the effectiveness of melatonin for the treatment of sleep problems in Angelman syndrome (24). Sleep difficulties in Angelman syndrome, though multifactorial, may be in part related to iron deficiency. Treatment with iron improved sleep to a modest degree in this population (80). Further high-quality research is needed to evaluate interventions for treating sleep problems in this population. Stimulant medications for hyperactivity and inattentiveness may be ineffective and poorly tolerated in children with Angelman syndrome (45).

One should suspect that behavioral problems may be due to frustration from poor expressive language skills, and alternative strategies (such as signing and assistive technology) should be tried. Some studies exploring the benefit of applied behavior analysis have yielded results that show a trend toward improved cognitive, adaptive, and language functioning, but further studies are required to determine benefit (91). Physical therapy may help prevent scoliosis, and occupational therapy may be useful in feeding as well as fine motor training. Diagnosis also permits appropriate surveillance for associated medical problems, such as scoliosis and gastroesophageal reflux. Caregivers and healthcare providers should be aware of the high prevalence of these issues as proper treatment may improve gastrointestinal dysfunction and sleep and behavioral issues (31). A study of assistive communication device use in Angelman syndrome revealed strong evidence for the capability of successful use and overall acceptance (14; 15).

Genetic counseling is essential to provide parents with information about recurrence risk. Spontaneous deletions and uniparental disomy have less than 1% recurrence risk. Mutations to the imprinting center or to UBE3A have a recurrence risk of up to 50%. Complex chromosomal rearrangements carry different recurrence risks (89).

Psychological distress may be even greater in parents of children with Angelman syndrome than in parents of children with other developmental disabilities (34). Referring parents to a support group, such as the Angelman Syndrome Foundation, puts them in touch with an essential source of support and practical advice.

Treatments on the horizon. Although medication trials in humans are few, animal studies show promise for therapy in Angelman syndrome. Ampakines have been shown to promote spine actin polymerization, long-term potentiation, and learning in a mouse model of Angelman syndrome (05). Studies showing that topoisomerase inhibitors unsilence the dormant allele of UBE3A in neurons show promise for therapy in Angelman syndrome (42; 66). According to a review on Angelman syndrome, all clinical trials to date have been unsuccessful in improving neurodevelopment in Angelman syndrome (94). Attempts at hypermethylating the maternal locus through dietary compounds were ineffective. The results of an 8-week open-label trial using minocycline as a matrix metalloproteinase-9 inhibitor were inconclusive, whereas a subsequent randomized placebo-controlled trial suggested that treatment with minocycline for 8 weeks did not result in any neurodevelopmental gains. A 1-year randomized placebo-controlled trial using levodopa to alter the phosphorylation of calcium/calmodulin-dependent kinase II did not lead to any improvement in neurodevelopment. Topoisomerase inhibitors and antisense oligonucleotides are being developed to directly inhibit UBE3A-AS. Artificial transcription factors are being developed to "super-activate" UBE3A or inhibit UBE3A-AS.

A pilot study of minocycline was performed on 25 children with Angelman syndrome. The clinical and neuropsychological measures suggest minocycline was well-tolerated and causes improvements in the adaptive behaviors of this sample of children with Angelman syndrome. Although the optimal dosage and the effects of long-term use still need to be determined, these findings suggest that further investigation into the effect minocycline has on patients with Angelman syndrome is warranted (33). The A-MANECE study is a clinical trial studying minocycline in treating developmental delays in Angelman syndrome (79). As therapeutics transition from preclinical to clinical studies, it is vital to establish outcome measures that can quantitatively evaluate putative treatments for Angelman syndrome and neurologic disorders with distinctive EEG patterns. Quantitative EEG (qEEG) analysis may be useful in evaluating therapeutic efficacy in Angelman syndrome (61).

A potential therapeutic intervention for Angelman syndrome was developed by reducing UBE3A antisense transcript with antisense oligonucleotides (ASOs) (63). ASO treatment achieved a specific reduction of UBE3A antisense transcript and sustained unsilencing of paternal UBE3A in neurons in vitro and in vivo. Partial restoration of UBE3A protein in an Angelman syndrome mouse model ameliorated some cognitive deficits associated with the disease. This study developed a sequence-specific and clinically feasible method to activate expression of the paternal UBE3A allele (63). From the perspective of the UBE3A substrate, some believe there may be a common pathway for treatment that can impact Angelman syndrome and a number of disorders with overlapping phenotypes (86). Reelin supplementation recovered synaptic plasticity and cognitive deficits in a mouse model for Angelman syndrome (39). Administration of a CoQ10 analogue ameliorated dysfunction of the mitochondrial respiratory chain in a mouse model of Angelman syndrome (55). The underlying pathophysiology of Angelman syndrome was explored using induced pluripotent stem cell-derived neurons from patients with Angelman syndrome and unaffected controls. Patient-specific differences were mimicked by knocking out UBE3A using CRISPR/Cas9 or by knocking down UBE3A using antisense oligonucleotides. Importantly, these phenotypes could be rescued by pharmacologically unsilencing paternal UBE3A expression. Moreover, selective effects of UBE3A disruption at late stages of in vitro development suggest that changes in action potential firing and synaptic activity may be secondary to altered resting membrane potential (28). CRISPR/Cas9 directed to the Ube3a antisense transcript improves the Angelman syndrome phenotype in mice (85).

A study by Wolter and colleagues examined whether targeted genomic integration of a gene therapy vector can restore the function of paternally inherited UBE3A throughout life, providing a path toward a disease-modifying treatment for a syndromic neurodevelopmental disorder (119). The study demonstrated that Cas9 can be used to activate (“unsilence”) paternal Ube3a in cultured mouse and human neurons when targeted to Snord115 genes, which are small nucleolar ribonucleic acids that are clustered in the 3' region of Ube3a-ATS. This early treatment unsilenced paternal Ube3a throughout the brain for at least 17 months and rescued anatomical and behavioral phenotypes in mice with Angelman syndrome. Genomic integration of the adeno-associated virus vector into Cas9 target sites caused premature termination of Ube3a-ATS at the vector-derived polyA cassette, or when integrated in the reverse orientation, by transcriptional collision with the vector-derived Cas9 transcript.

Although the ketogenic diet has successfully treated refractory epilepsy in Angelman syndrome case studies, issues arise due to its strict adherence requirements in addition to selective eating habits and weight issues reported in patients. Investigators are studying ketone ester administration in Angelman syndrome mice, with results showing improved motor coordination, learning and memory, and synaptic plasticity (16).

A multicenter, double-blind, randomized, placebo-controlled 1-year trial of levodopa/carbidopa with either 10 or 15 mg/kg/day of levodopa in children with Angelman syndrome was well tolerated but failed to improve neurodevelopment or behavioral outcome (95).

Auditory event-related potentials have been shown to be tolerable in Angelman syndrome patients and may represent a modality that can be used to evaluate learning and memory (46).

Ketogenic and low-glycemic-index diets are being investigated in randomized controlled crossover studies to provide data on nutritional approaches for patients with Angelman syndrome (38).

References

01: Adams D, Roche L, Heussler H. Parent perceptions, beliefs, and fears around genetic treatments and cures for children with Angelman syndrome. Am J Med Genet A 2020;182(7):1716-24. PMID 32449301
02: Aghakhanyan G, Bonanni P, Randazzo G, et al. From cortical and subcortical grey matter abnormalities to neurobehavioral phenotype of Angelman syndrome: a voxel-based morphometry study. PLoS One 2016;11(9):e0162817. PMID 27626634
03: Angelman H. “Puppet” children: a report on three cases. Dev Med Child Neurol 1965;7:681-8.
04: Bai JL, Qu YJ, Jin YW, et al. Molecular and clinical characterization of Angelman syndrome in Chinese patients. Clin Genet 2014;85(3):273-7. PMID 23551092
05: Baudry M, Kramar E, Xu X, et al. Ampakines promote spine actin polymerization, long-term potentiation, and learning in a mouse model of Angelman syndrome. Neurobiol Dis 2012;47(2):210-5. PMID 22525571
06: Beckung E, Steffenburg S, Kyllerman M. Motor impairments, neurological signs and developmental level in individuals with Angelman syndrome. Dev Med Child Neurol 2004;46:239-43. PMID 15077701
07: Beleza-Meireles A, Cerqueira R, Sousa SB, Palmeiro A, Ramos L. Novel deletion encompassing exons 5-12 of the UBE3A gene in a girl with Angelman syndrome. Eur J Med Genet 2011;54(3):348-50. PMID 21397058
08: Bissell S, Oliver C, Moss J, et al. The behavioural phenotype of SATB2-associated syndrome: a within-group and cross-syndrome analysis. J Neurodev Disord 2022;14(1):25. PMID 35350986
09: Brunetti-Pierri N, Sahoo T, Frioux S, et al. 15q13q14 deletions: phenotypic characterization and molecular delineation by comparative genomic hybridization. Am J Med Genet A 2008;146A(15):1933-41. PMID 18561338
10: Bruni O, Ferri R, D’Agostino G, Miano S, Roccella M, Elia M. Sleep disturbances in Angelman syndrome. Brain Dev 2004;26:233-40. PMID 15130689
11: Buckley RH, Dinno N, Weber P. Angelman syndrome: are the estimates too low. Am J Med Genet 1998;80:385-90. PMID 9856568
12: Bujok G, Knapik P. Angelman syndrome as a rare anaesthetic problem. Paediatr Anaesth 2004;14:281-3. PMID 14996273
13: Buntinx IM, Hennekam RC, Brouwer OF, et al. Clinical profile of Angelman syndrome at different ages. Am J Med Genet 1995;56(2):176-83. PMID 7625442
14: Calculator SN. Parents' reports of patterns of use and exposure to practices associated with AAC acceptance by individuals with Angelman syndrome. Augment Altern Commun 2013a;29(2):146-58. PMID 23621361
15: Calculator SN. Use and acceptance of AAC systems by children with Angelman syndrome. J Appl Res Intellect Disabil 2013b;26(6):557-67. PMID 23606637
16: Ciarlone SL, Grieco JC, D'Agostino DP, Weeber EJ. Ketone ester supplementation attenuates seizure activity, and improves behavior and hippocampal synaptic plasticity in an Angelman syndrome mouse model. Neurobiol Dis 2016;96:38-46. PMID 27546058
17: Clayton-Smith J, Laan L. Angelman syndrome: a review of the clinical and genetic aspects. J Med Genet 2003;40:87-95. PMID 12566516
18: Conant KD, Thibert RL, Thiele EA. Epilepsy and the sleep-wake patterns found in Angelman syndrome. Epilepsia 2009;50(11):2497-500. PMID 19453716
19: Dan B. Angelman syndrome: current understanding and research prospects. Epilepsia 2009;50(11):2331-9. PMID 19874386
20: Davies AF, Ogilvie CM. Prevalence of Angelman syndrome amongst referrals with epilepsy and developmental delay. Am J Med Genet A 2007;143A(18):2189-91. PMID 17676602
21: Dion MH, Novotny EJ, Carmant L, Cossette P, Nguyen DK. Lamotrigine therapy of epilepsy with Angelman’s syndrome. Epilepsia 2007;48(3):593-6. PMID 17326790
22: Dominguez-Berjon MF, Zoni AC, Esteban-Vasallo MD, Sendra-Gutiérrez JM, Astray-Mochales J. Main causes of hospitalization in people with Angelman syndrome. J Appl Res Intellect Disabil 2018;31(3):466-9. PMID 28869323
23: Duis J, Nespeca M, Summers J, et al. A multidisciplinary approach and consensus statement to establish standards of care for Angelman syndrome. Mol Genet Genomic Med 2022;10(3):e1843. PMID 35150089
24: Egan M, Farrell K, Hoey E, McGuire BE, Lydon HK. Interventions to improve sleep for individuals with Angelman syndrome: a systematic review. Res Dev Disabil 2020;97:103554. PMID 31869773
25: Ehlen JC, Jones KA, Pinckney L, et al. Maternal Ube3a loss disrupts sleep homeostasis but leaves circadian rhythmicity largely intact. J Neurosci 2015;35(40):13587-98. PMID 26446213
26: Eroglu A, Layman LC. Role of ART in imprinting disorders. Semin Reprod Med 2012;30(2):92-104. PMID 22549709
27: Farook MF, Decuypere M, Hyland K, Takumi T, Ledoux MS, Reiter LT. Altered serotonin, dopamine and norepinepherine levels in 15q duplication and angelman syndrome mouse models. PLoS One 2012;7(8):e43030. PMID 22916201
28: Fink JJ, Robinson TM, Germain ND, et al. Disrupted neuronal maturation in Angelman syndrome-derived induced pluripotent stem cells. Nat Commun 2017;8:15038. PMID 28436452
29: Forrest KM, Young H, Dale RC, Gill DS. Benefit of corticosteroid therapy in Angelman syndrome. J Child Neurol 2009;24(8):952-8. PMID 19666884
30: Gardner JC, Turner CS, Ririe DG. Vagal hypertonia and anesthesia in Angelman syndrome. Paediatr Anaesth 2008;18(4):348-9. PMID 18315655
31: Glassman LW, Grocott OR, Kunz PA, et al. Prevalence of gastrointestinal symptoms in Angelman syndrome. Am J Med Genet A 2017;173(10):2703-9. PMID 28816003
32: Greer PL, Hanayama R, Bloodgood BL, et al. The Angelman Syndrome protein Ube3A regulates synapse development by ubiquitinating arc. Cell 2010;140(5):704-16. PMID 20211139
33: Grieco JC, Ciarlone SL, Gieron-Korthals M, et al. An open-label pilot trial of minocycline in children as a treatment for Angelman syndrome. BMC Neurol 2014;14(1):232. PMID 25491305
34: Griffith GM, Hastings RP, Oliver C, et al. Psychological well-being in parents of children with Angelman, Cornelia de Lange and Cri du Chat syndromes. J Intellect Disabil Res 2011;55(4):397-410. PMID 21323782
35: Guerrini R, Carrozzo R, Rinaldi R, Bonanni P. Angelman syndrome: etiology, clinical features, diagnosis, and management of symptoms. Paediatr Drugs 2003;5(10):647-61. PMID 14510623
36: Handforth A, DeLorey TM, Homanics GE, Olsen RW. Pharmacologic evidence for abnormal thalamocortical functioning in GABAA receptor beta3 subunit-deficient mice, a model of Angelman syndrome. Epilepsia 2005;46:1860-70. PMID 16393151
37: Harting I, Seitz A, Rating D, et al. Abnormal myelination in Angelman syndrome. Eur J Paediatr Neurol 2009;13(3):271-6. PMID 18573670
38: Herber DL, Weeber EJ, D'Agostino DP, Duis J. Evaluation of the safety and tolerability of a nutritional Formulation in patients with ANgelman Syndrome (FANS): study protocol for a randomized controlled trial. Trials 2020;21(1):60. PMID 31918761
39: Hethorn WR, Ciarlone SL, Filonova I, et al. Reelin supplementation recovers synaptic plasticity and cognitive deficits in a mouse model for Angelman syndrome. Eur J Neurosci 2015;41(10):1372-80. PMID 25864922
40: Hong SY, Chou IC, Lin WD, Tsai FJ. A case of Pitt-Hopkins syndrome presented with Angelman-like syndromic phenotypes. Biomedicine (Taipei) 2016;6(4):25. PMID 27864810
41: Horvath E, Horváth Z, Isaszegi D, et al. Early detection of Angelman syndrome resulting from de novo paternal isodisomic 15q UPD and review of comparable cases. Mol Cytogenet. 2013;6(1):35. PMID 24011290
42: Huang HS, Allen JA, Mabb AM, et al. Topoisomerase inhibitors unsilence the dormant allele of Ube3a in neurons. Nature 2011;481(7380):185-9. PMID 22190039
43: Jolleff N, Ryan MM. Communication development in Angelman’s syndrome. Arch Dis Child 1993;69:148-50. PMID 8024300
44: Kaphzan H, Buffington SA, Ramaraj AB, et al. Genetic reduction of the α1 subunit of Na/K-ATPase corrects multiple hippocampal phenotypes in Angelman syndrome. Cell Rep 2013;4(3):405-12. PMID 23911285
45: Keary CJ, Thom RP, McDougle CJ. Stimulant intolerance in children with Angelman syndrome with hyperactivity: a case series. Psychiatr Genet 2022;32(2):80-6. PMID 35348128
46: Key AP, Jones D, Peters S, Dold C. Feasibility of using auditory event-related potentials to investigate learning and memory in nonverbal individuals with Angelman syndrome. Brain Cogn 2018;128:73-9. PMID 30471990
47: Kim S, Chahrour M, Ben-Shachar S, Lim J. Ube3a/E6AP is involved in a subset of MeCP2 functions. Biochem Biophys Res Commun 2013;437(1):67-73. PMID 23791832
48: Laan LA, den Boer AT, Hannekam RC, Renier WO, Brouwer OF. Angelman syndrome in adulthood. Am J Med Genet 1996;66:356-60. PMID 9072912
49: Laan LA, Vein AA. Angelman syndrome: is there a characteristic EEG. Brain Dev 2005;27(2):80-7. PMID 15668045
50: Larson AM, Shinnick JE, Shaaya EA, Thiele EA, Thibert RL. Angelman syndrome in adulthood. Am J Med Genet A 2015;167(2):331-44. PMID 25428759
51: LaSalle JM, Reiter LT, Chamberlain SJ. Epigenetic regulation of UBE3A and roles in human neurodevelopmental disorders. Epigenomics 2015; 7(7):1213-28. PMID 26585570
52: Leader G, Gilligan R, Whelan S, et al. Relationships between challenging behavior and gastrointestinal symptoms, sleep problems, and internalizing and externalizing symptoms in children and adolescents with Angelman syndrome. Res Dev Disabil 2022;128:104293. PMID 35797778
53: Levin Y, Hosamane NS, McNair TE, et al. Evaluation of electroencephalography biomarkers for Angelman syndrome during overnight sleep. Autism Res 2022;15(6):1031-42. PMID 35304979
54: Lizarraga SB, Morrow EM. Uncovering a role for SK2 in Angelman syndrome. Cell Rep 2015;12(3):359-60. PMID 26200312
55: Llewellyn KJ, Nalbandian A, Gomez A, Wei D, Walker N, Kimonis VE. Administration of CoQ10 analogue ameliorates dysfunction of the mitochondrial respiratory chain in a mouse model of Angelman syndrome. Neurobiol Dis 2015;76:77-86. PMID 25684537
56: Lossie AC, Whitney MM, Amidon D, et al. Distinct phenotypes distinguish the molecular classes of Angelman syndrome. J Med Genet 2001;38(12):834-45. PMID 11748306
57: Lu Y, Wang F, Li Y, Ferris J, Lee JA, Gao FB. The Drosophila homologue of the Angelman syndrome ubiquitin ligase regulates the formation of terminal dendritic branches. Hum Mol Genet 2009;18(3):454-62. PMID 18996915
58: Luk HM. Angelman-like syndrome: a genetic approach to diagnosis with illustrative cases. Case Rep Genet 2016;2016:9790169. PMID 26942024
59: Luk HM, Lo IF. Angelman syndrome in Hong Kong Chinese: a 20 years' experience. Eur J Med Genet 2016;59(6-7):315-9. PMID 27174604
60: Makedonski K, Abuhatzira L, Kaufman Y, Razin A, Shemer R. MeCP2 deficiency in Rett syndrome causes epigenetic aberrations at the PWS/AS imprinting center that affects UBE3A expression. Hum Mol Genet 2005;14:1049-58. PMID 15757975
61: Martinez LA, Born HA, Harris S, et al. Quantitative EEG analysis in Angelman syndrome: candidate method for assessing therapeutics. Clin EEG Neurosci 2020. PMID 33203220
62: Martinez-Noel G, Galligan JT, Sowa ME, et al. Identification and proteomic analysis of distinct UBE3A/E6AP protein complexes. Mol Cell Biol 2012;32(15):3095-106. PMID 22645313
63: Meng L, Ward AJ, Chun S, Bennett CF, Beaudet AL, Rigo F. Towards a therapy for Angelman syndrome by targeting a long non-coding RNA. Nature 2015;518(7539):409-12. PMID 25470045
64: Mertz LG, Christensen R, Vogel I, et al. Angelman syndrome in Denmark. birth incidence, genetic findings, and age at diagnosis. Am J Med Genet A 2013;161(9):2197-203. PMID 23913711
65: Miano S, Bruni O, Leuzzi V, Elia M, Verrillo E, Ferri R. Sleep polygraphy in Angelman syndrome. Clin Neurophysiol 2004;115:938-45. PMID 15003776
66: Miller G. Neurodevelopmental disorders. New hope for a devastating neurological disorder. Science 2011;334(6063):1615. PMID 22194537
67: Minassian BA, DeLorey TM, Olsen RW, et al. Angelman syndrome: correlation between epilepsy phenotypes and genotypes. Ann Neurol 1998;43(4):485-93. PMID 9546330
68: Napier KR, Tones M, Simons C, et al. A web-based, patient driven registry for Angelman syndrome: the global Angelman syndrome registry. Orphanet J Rare Dis 2017;12(1):134. PMID 28764722
69: Nolt DH, Mott JM, Lopez WL. Assessment of anticonvulsant effectiveness and safety in patients with Angelman’s syndrome using an Internet questionnaire. Am J Health Syst Pharm 2003;60:2583-7. PMID 14735775
70: Odom LN, Segars J. Imprinting disorders and assisted reproductive technology. Curr Opin Endocrinol Diabetes Obes 2010;17(6):517-22. PMID 20962636
71: Ostergaard JR, Balslev T. Efficacy of different antiepileptic drugs in children with Angelman syndrome associated with 15q11-13 deletion. Dev Med Child Neurol 2001;43:718-9. PMID 11665831
72: Pelc K, Cheron G, Dan B. Behavior and neuropsychiatric manifestations in Angelman syndrome. Neuropsychiatr Dis Treat 2008;4(3):577-84. PMID 18830393
73: Peters SU, Beaudet AL, Madduri N, Bacino CA. Autism in Angelman syndrome: implications for autism research. Clin Genet 2004a;66(6):530-6. PMID 15521981
74: Peters SU, Goddard-Finegold J, Beaudet AL, Madduri N, Turcich M, Bacino CA. Cognitive and adaptive behavior profiles of children with Angelman syndrome. Am J Med Genet 2004b;128(2):110-3. PMID 15213998
75: Philpot BD, Thompson CE, Franco L, Williams CA. Angelman syndrome: advancing the research frontier of neurodevelopmental disorders. J Neurodev Disord 2011;3(1):50-6. PMID 21484597
76: Pollack SF, Grocott OR, Parkin KA, Larson AM, Thibert RL. Myoclonus in Angelman syndrome. Epilepsy Behav 2018;82:170-4. PMID 29555100
77: Ramanathan KR, Muthuswamy D, Jenkins BJ. Anaesthesia for Angelman syndrome. Anaesthesia 2008;63(6):659-61. PMID 18477280
78: Ramsden SC, Clayton-Smith J, Birch R, Buiting K. Practice guidelines for the molecular analysis of Prader-Willi and Angelman syndromes. BMC Med Genet 2010;11:70. PMID 20459762
79: Ruiz-Antoran B, Sancho-López A, Cazorla-Calleja R, et al. A randomized placebo controlled clinical trial to evaluate the efficacy and safety of minocycline in patients with Angelman syndrome (A-MANECE study). Orphanet J Rare Dis 2018;13(1):144. PMID 30126448
80: Ryan CS, Edlund W, Mandrekar J, Wong-Kisiel LC, Gavrilova RH, Kotagal S. Iron deficiency and its role in sleep disruption in patients with Angelman syndrome. J Child Neurol 2020;35(14):963-9. PMID 32713229
81: Sadhwani A, Wheeler A, Gwaltney A, et al. Developmental skills of individuals with Angelman syndrome assessed using the Bayley-III. J Autism Dev Disord 2021. [Epub ahead of print] PMID 33517526
82: Sadikovic B, Fernandes P, Zhang VW, et al. Mutation update for UBE3A variants in Angelman syndrome. Hum Mutat 2014;35(12):1407-17. PMID 25212744
83: Sahoo T, Peters SU, Madduri NS, et al. Microarray based comparative genomic hybridization testing in deletion bearing patients with Angelman syndrome: genotype-phenotype correlations. J Med Genet 2006;43:512-6. PMID 16183798
84: Sato M, Stryker MP. Genomic imprinting of experience-dependent cortical plasticity by the ubiquitin ligase gene Ube3a. Proc Natl Acad Sci U S A 2010;107(12):5611-6. PMID 20212164
85: Schmid RS, Deng X, Panikker P, Msackyi M, Breton C, Wilson JM. CRISPR/Cas9 directed to the Ube3a antisense transcript improves Angelman syndrome phenotype in mice. J Clin Invest 2021;131(5). PMID 33411694
86: Sell GL, Margolis SS. From UBE3A to Angelman syndrome: a substrate perspective. Front Neurosci 2015;9:322. PMID 26441497
87: Shaaya EA, Grocott OR, Laing O, Thibert RL. Seizure treatment in Angelman syndrome: a case series from the Angelman syndrome clinic at Massachusetts General Hospital. Epilepsy Behav 2016;60:138-41. PMID 27206232
88: Smith JC. Angelman syndrome: evolution of the phenotype in adolescents and adults. Dev Med Child Neurol 2001;43:476-80. PMID 11463179
89: Stalker HJ, Williams CA. Genetic counseling in Angelman syndrome: the challenges of multiple causes. Am J Med Genet 1998;77:54-9. PMID 9557895
90: Steffenburg S, Gillberg CL, Steffenburg U, Kyllerman M. Autism in Angelman syndrome: a population-based study. Pediatr Neurol 1996;14:131-6. PMID 8703225
91: Summers J. Neurodevelopmental outcomes in children with Angelman syndrome after 1 year of behavioural intervention. Dev Neurorehabil 2012;15(4):239-52. PMID 22646082
92: Sun AX, Yuan Q, Fukuda M, et al. Potassium channel dysfunction in human neuronal models of Angelman syndrome. Science 2019;366(6472):1486-92. PMID 31857479
93: Sun J, Zhu G, Liu Y, et al. UBE3A regulates synaptic plasticity and learning and memory by controlling SK2 channel endocytosis. Cell Rep 2015;12(3):449-61. PMID 26166566
94: Tan WH, Bird LM. Angelman syndrome: current and emerging therapies in 2016. Am J Med Genet C Semin Med Genet 2016;172(4):384-401. PMID 27860204
95: Tan WH, Bird LM, Sadhwani A, et al. A randomized controlled trial of levodopa in patients with Angelman syndrome. Am J Med Genet A 2018;176(5):1099-107. PMID 28944563
96: Tan WH, Bird LM, Thibert RL, Williams CA. If not Angelman, what is it? A review of Angelman-like syndromes. Am J Med Genet A 2014;164A(4):975-92. PMID 24779060
97: Thibert RL, Conant KD, Braun EK, et al. Epilepsy in Angelman syndrome: A questionnaire-based assessment of the natural history and current treatment options. Epilepsia 2009;50(11):2369-76. PMID 19453717
98: Thibert RL, Larson AM, Hsieh DT, Raby AR, Thiele EA. Neurologic manifestations of angelman syndrome. Pediatr Neurol. 2013;48(4):271-9. PMID 23498559
99: Thibert RL, Pfeifer HH, Larson AM, et al. Low glycemic index treatment for seizures in Angelman syndrome. Epilepsia 2012;53(9):1498-502. PMID 22779920
100: Tomei KL, Mau CY, Ghali M, Pak J, Goldstein IM. Vagal nerve stimulation for medically refractory epilepsy in Angelman syndrome: a series of three cases. Childs Nerv Syst 2018;34(3):395-400. PMID 29350262
101: Trillingsgaard A, Ostergaard J. Autism in Angelman syndrome. Autism 2004;8:163-74. PMID 15165432
102: Valente KD. Another Rett patient with a typical Angelman EEG. Epilepsia 2003;44:873-4. PMID 12790908
103: Valente KD, Andrade JQ, Grossmann RM, et al. Angelman syndrome: difficulties in EEG pattern recognition and possible misinterpretations. Epilepsia 2003;44:1051-63. PMID 12887436
104: Valente KD, Fridman C, Varela MC, et al. Angelman syndrome: uniparental paternal disomy 15 determines mild epilepsy, but has no influence on EEG patterns. Epilepsy Res 2005;67:163-8. PMID 16226874
105: Valente KD, Koiffmann CP, Fridman C, et al. Epilepsy in patients with Angelman syndrome caused by deletion of the chromosome 15q11-q13. Arch Neurol 2006;63:122-8. PMID 16401744
106: Van Lierde A, Atza MG, Giardino F. Angelman’s Syndrome in the first year of life. Dev Med Child Neurol 1990;23:1005-21. PMID 2269397
107: van Woerden GM, Harris KD, Hojjati MR, et al. Rescue of neurological deficits in a mouse model for Angelman syndrome by reduction of αCaMKII inhibitory phosphorylation. Nat Neurosci 2007;10:280-2. PMID 17259980
108: Varela MC, Kok F, Otto PA, Koiffmann CP. Phenotypic variability in Angelman syndrome: comparison among different deletion classes and between deletion and UPD subjects. Eur J Hum Genet 2004;12(12):987-92. PMID 15470370
109: Vendrame M, Loddenkemper T, Zarowski M, et al. Analysis of EEG patterns and genotypes in patients with Angelman syndrome. Epilepsy Behav 2012;23(3):261-5. PMID 22341959
110: Wallace ML, Burette AC, Weinberg RJ, Philpot BD. Maternal loss of Ube3a produces an excitatory/inhibitory imbalance through neuron type-specific synaptic defects. Neuron 2012;74(5):793-800. PMID 22681684
111: Weeber EJ, Jiang YH, Elgersma Y, et al. Derangements of hippocampal calcium/calmodulin-dependent protein kinase II in a mouse model for Angelman mental retardation syndrome. J Neurosci 2003;23(7):2634-44. PMID 12684449
112: Wheeler AC, Gantz MG, Cope H, et al. Age of diagnosis for children with chromosome 15q syndromes. J Neurodev Disord 2023;15(1):37. PMID 37936142
113: Wheeler AC, Sacco P, Cabo R. Unmet clinical needs and burden in Angelman syndrome: a review of the literature. Orphanet J Rare Dis 2017;12(1):164. PMID 29037196
114: Williams CA, Angelman H, Clayton-Smith J, et al. Angelman syndrome: consensus for diagnostic criteria. Am J Med Genet 1995;56:237-8. PMID 7625452
115: Williams CA, Beaudet AL, Clayton-Smith J, et al. Angelman syndrome 2005: updated consensus for diagnostic criteria. Am J Med Genet 2006;140A:413-8. PMID 16470747
116: Williams CA, Frias JL. The Angelman (“happy puppet”) syndrome. Am J Med Genet 1982;11:453-60. PMID 7091188
117: Williams CA, Lossie A, Driscoll D. Angelman syndrome: mimicking conditions and phenotypes. Am J Med Genet 2001;101:59-64. PMID 11343340
118: Wilson BJ, Sundaram SK, Huq AH, et al. Abnormal language pathway in children with Angelman syndrome. Pediatr Neurol 2011;44(5):350-6. PMID 21481743
119: Wolter JM, Mao H, Fragola G, et al. Cas9 gene therapy for Angelman syndrome traps Ube3a-ATS long non-coding RNA. Nature 2020;587(7833):281-4. PMID 33087932
120: Woodford EC, McLay L, France KG, et al. Endogenous melatonin and sleep in individuals with Rare Genetic Neurodevelopmental Disorders (RGND): a systematic review. Sleep Med Rev 2021;57:101433. PMID 33561678
121: Xia NY, Grant ML, Benjamin NL, Valencia I. Quality of life in Angelman syndrome: a caregivers' survey. Pediatr Neurol 2023;149:19-25. PMID 37757661
122: Yi JJ, Berrios J, Newbern JM, et al. An autism-linked mutation disables phosphorylation control of UBE3A. Cell 2015;162(4):795-807. PMID 26255772

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Ryan W Y Lee MD

Dr. Lee of the John A Burns School of Medicine at the University of Hawaii has no relevant financial relationships to disclose.
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Ann Tilton MD

Dr. Tilton has received honorariums from Allergan and Ipsen as an educator, advisor, and consultant.
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Joshua Ewen MD
Michael V Johnston MD†

Patient Profile

Age range of presentation: 0 month to 65+ years
Sex preponderance: male=female
Heredity: heredity may be a factor
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

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Angelman syndrome

Associated Disorders

Autism
Gastroesophageal reflux
Scoliosis

Differential Diagnosis

idiopathic intellectual disability
idiopathic autism
Landau-Kleffner syndrome
Prader-Willi syndrome
Rett syndrome
- Pitt-Hopkins syndrome
- 22q13.3 (22qter) deletion syndrome
- other chromosomal abnormalities
- methylene tetrahydrofolate reductase deficiency
- alpha-thalassemia/X-linked mental retardation syndrome
- Gurrieri syndrome
- Mowat-Wilson syndrome
- spastic diplegic cerebral palsy
- ataxic cerebral palsy
- Nonconvulsive status epilepticus (of various causes)
- West syndrome
- Lennox-Gastaut syndrome
- Doose syndrome
- occipital epilepsy

Also Relevant

Autism spectrum disorder
Disorders of articulation
Epilepsy
Intellectual disability
Microcephaly
- Pathologic laughter: neurologic aspects
- Prader-Willi syndrome
- Scoliosis and kyphoscoliosis
- Sleep and intellectual disability
- Split cord malformation

Cognitive or communication delay
	• Idiopathic intellectual disability • Idiopathic autism • Landau-Kleffner syndrome • Prader-Willi syndrome • Rett syndrome • Pitt-Hopkins syndrome (40) • 22q13.3 (22qter) deletion syndrome • Other chromosomal abnormalities (117) • Methylene tetrahydrofolate reductase deficiency • Alpha-thalassemia/X-linked mental retardation syndrome • Gurrieri syndrome • Mowat-Wilson syndrome • SATB2-associated syndrome (SAS) (08)
Motoric abnormalities (06)
	• Spastic diplegic cerebral palsy • Ataxic cerebral palsy
Epilepsy and EEG findings (67; 102)
	• Nonconvulsive status epilepticus (of various causes) • Landau-Kleffner syndrome • West syndrome • Lennox-Gastaut syndrome • Doose syndrome • Occipital epilepsy • Rett syndrome (102) • Pitt-Hopkins syndrome (40) • Methylene tetrahydrofolate reductase deficiency • Alpha-thalassemia/X-linked mental retardation syndrome • Gurrieri syndrome • Mowat-Wilson syndrome

Angelman syndrome …

Angelman syndrome

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Table 1. Clinical Features of Angelman Syndrome

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Differential diagnosis

Confusing conditions

Table 2. Differential Diagnosis of Angelman Syndrome

Diagnostic workup

Management

Special considerations

Anesthesia

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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Also in This Category

Acute cerebellar ataxia in children

Wilson disease

Zika virus: neurologic complications

Anti-LGI1 encephalitis

Cerebral edema in childhood

Fatal familial insomnia

CNS germinoma

Vein of Galen malformations

Angelman syndrome

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Table 1. Clinical Features of Angelman Syndrome

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Differential diagnosis

Confusing conditions

Table 2. Differential Diagnosis of Angelman Syndrome

Diagnostic workup

Management

Special considerations

Anesthesia

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Acute cerebellar ataxia in children

Wilson disease

Zika virus: neurologic complications

Anti-LGI1 encephalitis

Cerebral edema in childhood

Fatal familial insomnia

CNS germinoma

Vein of Galen malformations

This is an article preview.
Start a Free Account
to access the full version.