Clinical manifestations

Presentation and course

Children with Angelman syndrome share many physical, cognitive, behavioral, and motoric characteristics; the vast majority have epilepsy as well. Criteria for the clinical diagnosis of Angelman syndrome were put forth in 1995 and were updated a decade later in light of subsequent research (113; 114). 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. 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 when compared to 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 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/swallowing disorders
	• Feeding problems and/or truncal hypotonia in infancy
	• Prognathia
	• Wide mouth, wide-spaced teeth
	• Frequent drooling
	• Excessive chewing/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/fascination with water; fascination with crinkly items such as certain papers and plastics
	• Abnormal food-related behaviors
	• Obesity (in the older children)
	• Scoliosis
	• Constipation
(114)

Natural history. Although children later diagnosed with Angelman syndrome are typically recognized to have developmental delays between 6 and 12 months of age (113), the median age for a specific 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; they typically include developmental delay, hyperactivity, happy disposition, ataxia, and hypotonia (106; 17). Feeding difficulties may also be prominent in infancy (114). 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 they often become more prominent over the lifespan. Hypopigmentation (relative to siblings) may be present at birth, but it is often not of 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 (114).

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 are not able to use more than a few words, many have functional use of nonverbal gestures; some are able to sign proficiently. Older individuals with Angelman syndrome are often able to understand simple commands sufficiently to navigate everyday situations. Not surprisingly, the 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 are able to stay continent during the day and can carry out simple daily tasks; none is able to 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 felt to be 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 play a role in altered sleep in patients with neurodevelopmental disorders, such as Angelman syndrome (119). 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 required only 5 to 6 hours of sleep per night (35); the short 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 is suggesting 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 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; 110). Patients with an imprinting defect also have a relatively mild phenotype compared with those who have 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

Despite the fact that 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 (112).

Clinical vignette

An 8-month-old girl was referred by her primary care doctor to a pediatric neurologist for evaluation of 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 past medical history and family history were unremarkable. Head circumference was at the second percentile. No dysmorphic facial features were noted, and neurologic exam 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 at this point and 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. A significantly reduced need for sleep had developed in the meanwhile, and she was referred to behavioral psychologists for management. Seizures were well controlled on 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 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 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 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 (114). 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 (114). 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 (114).

Mutations of UBE3A account for about 8% of cases. These are detected by sequencing. Epigenetics play 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 that is encoded by UBE3A marks proteins in the brain for degradation. It is also involved in the regulation of 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). 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 the use of 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 (109). Proteomic studies show that there is a higher level of complexity than previously appreciated in UBE3A/E6AP protein function, and E6AP regulation may be dependent on a number of newly discovered cellular proteins (62). There are phenotypic, genetic, and biochemical studies that 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.

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 (120). 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 has found abnormalities of development of the arcuate fasciculus and has suggested that altered ubiquitination leads to abnormal development of white matter tracts, which subsequently results in cognitive deficits, such as language impairment (117). A study tested the hypothesis that α1-NaKA overexpression drives axon initial segment (AIS) 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 AIS, 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).

Epidemiology

Various studies put the prevalence of Angelman syndrome in the range of 1:24,000 to 1:12,000 (90; 11; 64). Estimates of the prevalence of Angelman syndrome in undifferentiated populations of individuals with developmental delay and seizures (without more specific findings of Angelman) range from 1.5% to 6% (20; 58). Within the past decade there has been evidence of increased incidence of imprinting disorders including Angelman syndrome in children conceived by assistive reproductive technology (26). There are efforts to establish a global web-based, patient-driven registry for Angelman syndrome (68).

Differential diagnosis

Confusing conditions

The differential diagnosis of Angelman syndrome depends on the features being considered.

Table 2. Differential Diagnosis of Angelman Syndrome

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 (116) • 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

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 a number of types of methylation studies, including those that are specific to the SNRPN locus and methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) methods. Currently, 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). In about 10% of individuals with a clinical diagnosis of Angelman syndrome, there is no identifiable molecular defect (96). It is likely that most of those individuals 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 (108). 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, and limbic structures as well as 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 the management of 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).

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 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 the treatment of 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 be helpful in preventing 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 not only gastrointestinal dysfunction but also sleep and behavioral issues (31). A study of assistive communication device use in Angelman syndrome revealed strong evidence for 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 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 are showing 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 an update review on Angelman Syndrome, all clinical trials to date that strove to improve neurodevelopment in Angelman syndrome have been unsuccessful (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 treatment of 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 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 that 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 (118). 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 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).

Special considerations

Anesthesia

There are at least three significant issues in anesthetic and perioperative care of individuals with Angelman syndrome. The first is airway management challenges associated with macroglossia and muscular hypotonia. The second is decreased or inconsistent response to GABAergic medications and inhaled general anesthetics (77). The third is increased vagal tone, resulting in bradycardia and/or asystole, with decreased responsiveness to atropine (12; 30).