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Angelman Syndrome

, MD, , MS, CGC, and , MD.

Author Information
, MD
Division of Genetics and Metabolism
Department of Pediatrics
University of Florida College of Medicine
Gainesville, Florida
, MS, CGC
Division of Genetics and Metabolism
Department of Pediatrics
University of Florida College of Medicine
Gainesville, Florida
, MD
Division of Genetics and Metabolism
Department of Pediatrics
University of Florida College of Medicine
Gainesville, Florida

Initial Posting: ; Last Update: May 14, 2015.

Summary

Clinical characteristics.

Angelman syndrome (AS) is characterized by severe developmental delay or intellectual disability, severe speech impairment, gait ataxia and/or tremulousness of the limbs, and a unique behavior with an inappropriate happy demeanor that includes frequent laughing, smiling, and excitability. Microcephaly and seizures are also common. Developmental delays are first noted at around age six months; however, the unique clinical features of AS do not become manifest until after age one year, and it can take several years before the correct clinical diagnosis is obvious.

Diagnosis/testing.

The diagnosis of AS is established in a proband who meets the consensus clinical diagnostic criteria and/or who has findings on molecular genetic testing that suggest deficient expression or function of the maternally inherited UBE3A allele. Analysis of parent-specific DNA methylation imprints in the 15q11.2-q13 chromosome region detects approximately 80% of individuals with AS, including those with a deletion, uniparental disomy (UPD), or an imprinting defect (ID); fewer than 1% of individuals have a cytogenetically visible chromosome rearrangement (i.e., translocation or inversion). UBE3A sequence analysis detects pathogenic variants in an additional approximately 11% of individuals. Therefore, molecular genetic testing (methylation analysis and UBE3A sequence analysis) identifies alterations in approximately 90% of individuals. The remaining 10% of individuals with classic phenotypic features of AS have the disorder as a result of an as-yet unidentified genetic mechanism and thus are not amenable to diagnostic testing.

Management.

Treatment of manifestations: Routine management of feeding difficulties, constipation, gastroesophageal reflux, strabismus. Antiepileptic drugs for seizures. Physical therapy, occupational therapy, and speech therapy with an emphasis on nonverbal methods of communication, including augmentative communication aids (e.g., picture cards or communication boards) and signing. Individualization and flexibility in school settings. Sedatives for nighttime wakefulness. Thoraco-lumbar jackets and/or surgical intervention for scoliosis.

Prevention of secondary complications: Children with seizures are at risk for medication overtreatment because movement abnormalities can be mistaken for seizures and because EEG abnormalities can persist even when seizures are controlled. Sedating agents such as risperidone or other atypical antipsychotic drugs can cause negative side effects.

Surveillance: Annual clinical examination for scoliosis. Evaluation of older children for obesity associated with an excessive appetite.

Agents/circumstances to avoid: Carbamezapine, vigabatrin, and tigabine as they may exacerbate seizures.

Genetic counseling.

AS is caused by disruption of maternally imprinted UBE3A located within the 15q11.2-q13 Angelman syndrome/Prader-Willi syndrome (AS/PWS) region. The risk to sibs of a proband depends on the genetic mechanism leading to the loss of UBE3A function: typically less than 1% risk for probands with a deletion or UPD, and as high as 50% for probands with an ID or a pathogenic variant of UBE3A. Members of the mother's extended family are also at increased risk when an ID or a UBE3A pathogenic variant is present. Cytogenetically visible chromosome rearrangements may be inherited but are usually de novo. Prenatal testing for pregnancies at increased risk is possible when the underlying genetic mechanism is a deletion, UPD, an ID, a UBE3A pathogenic variant, or a chromosome rearrangement.

Diagnosis

Consensus criteria for the clinical diagnosis of Angelman syndrome (AS) have been developed in conjunction with the Scientific Advisory Committee of the US Angelman Syndrome Foundation [Williams et al 2006]. Several recent reviews are available [Dagli et al 2012, Thibert et al 2013, Bird 2014].

Suggestive Findings

The diagnosis of Angelman syndrome may be suggested by the following clinical and/or laboratory findings.

Clinical Findings

Newborns typically have a normal phenotype. Developmental delays are first noted at around age six months. However, the unique clinical features of AS do not become manifest until after age one year, and it can take several years before the correct clinical diagnosis is obvious.

Findings typically present in affected individuals

  • Normal prenatal and birth history, normal head circumference at birth, no major birth defects
  • Normal metabolic, hematologic, and chemical laboratory profiles
  • Structurally normal brain by MRI or CT, although mild cortical atrophy or dysmyelination may be observed
  • Delayed attainment of developmental milestones without loss of skills
  • Evidence of developmental delay by age six to 12 months, eventually classified as severe
  • Speech impairment, with minimal to no use of words; receptive language skills and nonverbal communication skills higher than expressive language skills
  • Movement or balance disorder, usually ataxia of gait and/or tremulous movement of the limbs
  • Behavioral uniqueness, including any combination of frequent laughter/smiling; apparent happy demeanor; excitability, often with hand-flapping movements and hypermotoric behavior

Findings in more than 80% of affected individuals

  • Delayed or disproportionately slow growth in head circumference, usually resulting in absolute or relative microcephaly by age two years
  • Seizures, usually starting before age three years
  • Abnormal EEG, with a characteristic pattern of large-amplitude slow-spike waves

Findings in fewer than 80% of affected individuals

  • Flat occiput
  • Occipital groove
  • Protruding tongue
  • Tongue thrusting; suck/swallowing disorders
  • Feeding problems and/or muscle hypotonia during infancy
  • Prognathia
  • Wide mouth, widely spaced teeth
  • Frequent drooling
  • Excessive chewing/mouthing behaviors
  • Strabismus
  • Hypopigmented skin, light hair and eye color (compared to family); seen only in those with a deletion
  • Hyperactive lower-extremity deep-tendon reflexes
  • Uplifted, flexed arm position especially during ambulation
  • Wide-based gait with out-going (i.e., 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 child; more common in those who do not have a deletion)
  • Scoliosis
  • Constipation

See Figure 1 for clinical photographs of facial findings.

Figure 1. . Individuals depicted have a genetically confirmed diagnosis of Angelman syndrome.

Figure 1.

Individuals depicted have a genetically confirmed diagnosis of Angelman syndrome. Happy expression and an unstable gait accompanied by uplifted arms are commonly observed. At times, the facial appearance can suggest the diagnosis, but usually facial features (more...)

Laboratory Findings

Abnormality of 15q11.2-q13 detected by chromosomal microarray (CMA) or karyotype performed for non-specific clinical findings.

Establishing the Diagnosis

The diagnosis of AS is established in a proband who meets the consensus clinical diagnostic criteria and/or who has findings on molecular genetic testing that suggest deficient expression or function of the maternally inherited UBE3A allele (see Table 1) through one of the following mechanisms:

  • Abnormal methylation at 15q11.2-q13
  • A pathogenic variant in the maternally derived UBE3A

Molecular genetic testing approaches to establish the diagnosis can be based on either the clinical findings or the laboratory findings that suggested the diagnosis of AS.

Based on clinical findings in a symptomatic individual who has not had any prior molecular genetic testing:

1.

DNA methylation analysis. Individuals with AS caused by a 5- to 7-Mb deletion of 15q11.2-q13, uniparental disomy (UPD), or an imprinting defect (ID) have only an unmethylated (i.e., "paternal") contribution (i.e., an abnormal parent-specific DNA methylation imprint). DNA methylation analysis identifies approximately 80% of individuals with AS and is typically the first test ordered.

Note: Most commercially available DNA methylation analysis tests cannot distinguish between AS resulting from a deletion, UPD, or an ID. Further testing is required to identify the underlying molecular mechanism (see Genetic Counseling).

2.

If DNA methylation analysis is normal, either testing of UBE3A or use of a multi-gene panel.

3.

If single gene testing (and/or use of a multi-gene panel) has not confirmed a diagnosis in an individual with features of AS, genomic testing may be considered. Such testing may include whole exome sequencing (WES), whole genome sequencing (WGS), and whole mitochondrial sequencing (WMitoSeq). For issues to consider in interpretation of genomic test results, click here.

Based on laboratory findings in an individual who has been found to have a deletion of 15q11.2-q13 through chromosomal microarray (CMA), fluorescent in situ hybridization (FISH), or karyotype*, perform DNA methylation analysis to determine if the deletion is on the maternally derived chromosome 15.

*Fewer than 1% of individuals with AS have a cytogenetically visible chromosome rearrangement (i.e., translocation or inversion) of one number 15 chromosome involving 15q11.2-q13.

Table 1.

Summary of Testing Used in Angelman Syndrome (AS)

Test MethodGenetic Mechanism Detected 1Total Proportion of AS Detected by Test Method 2
15q11.2-q13delUPDIDUBE3A seqUBE3A del/dup
DNA methylation analysis 3, 4XX5~80%
MS-MLPA 6XXX~80%
FISH 7X~68%
CMA 8X9~68%
UPD study 10X~7%
AS IC deletion analysis 11, 12X~3%
UBE3A sequence analysis13~11% 14
UBE3A gene-targeted deletion/duplication analysis 11, 15XRare

UPD = uniparental disomy

ID = imprinting defect

IC = imprinting center

1.

See Molecular Genetics for more details.

2.

11% of individuals with the presumptive clinical diagnosis of AS have normal results for all testing methods described in this table.

3.

Individuals with AS caused by a 5- to 7-Mb deletion of 15q11.2-q13, uniparental disomy (UPD), or an imprinting defect (ID) have only an unmethylated (i.e., "paternal") contribution (i.e., an abnormal parent-specific DNA methylation imprint).

4.

Will not distinguish genetic mechanism

5.

80%-90% of IDs are thought to be epigenetic pathogenic variants occurring during maternal oogenesis or in early embryogenesis [Buiting 2010].Characterization of the ID as either an IC deletion or epigenetic defect is available primarily through research laboratories.

6.

Methylation-specific multiplex ligation-dependent probe amplification (MLPA) can test for deletion along with the methylation assay amplification [Nygren et al 2005, Procter et al 2006, Ramsden et al 2010].

7.

FISH analysis with the D15S10 and/or the SNRPN probe can identify the common 15q11.2-q13 deletion, but typically this deletion is not detected by routine cytogenetic analysis.

8.

Chromosomal microarray (CMA) has a slightly higher detection frequency than FISH and will provide detailed information regarding size of the deletion. Also, it gives information regarding deletions and duplication in the remainder of the genome.

9.

SNP-based chromosomal microarray may diagnose whole-chromosome and segmental uniparental isodisomies but cannot detect all instances of uniparental disomy.

10.

UPD is detected using polymorphic DNA markers, which requires a DNA sample from the affected individual and both parents.

11.

Gene-targeted deletion/duplication analysis detects deletions or duplications in intragenic or other targeted regions. Methods that may be used can include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single exon deletions or duplications.

12.

Deletion analysis of the AS imprinting center (IC) detects small deletions (6- 200-kb reported), which account for 8%-15% of all imprinting defects (IDs) [Buiting 2010]

13.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

14.

Malzac et al [1998], Fang et al [1999], Lossie et al [2001]

15.

Although CMA usually detects large 15q11.2-q13 deletions, in rare instances CMA has detected UBE3A multiexon or whole-gene deletions [Lawson-Yuen et al 2006, Sato et al 2007].

Possible explanations for the failure to detect AS-causing genetic abnormalities in the 11% or more of individuals with clinically diagnosed AS:

  • Incorrect clinical diagnosis
  • Undetected pathogenic variants in the regulatory region(s) of UBE3A
  • Other unidentified mechanisms or gene(s) involved in UBE3A function

Clinical Characteristics

Clinical Description

Prenatal history, birth weight, and head circumference at birth are usually normal. Young infants with Angelman syndrome (AS) may have difficulties with breast feeding or bottle feeding (as a result of sucking difficulties) and muscular hypotonia. Gastroesophageal reflux may occur.

Some infants have an apparent happy affect with excessive chortling or paroxysms of laughter. 50% of children develop microcephaly by age 12 months. Strabismus may also occur. Tremulous movements may be noted prior to age 12 months, associated with increased deep-tendon reflexes.

AS may first be suspected in a toddler because of delayed gross motor milestones, muscular hypotonia, and/or speech delay [Williams et al 2006].

Seizures typically occur between ages one and three years and can be associated with generalized, somewhat specific EEG changes: runs of high-amplitude delta activity with intermittent spike and slow-wave discharges (at times observed as a notched delta pattern); runs of rhythmic theta activity over a wide area; and runs of rhythmic sharp theta activity of 5-6/s over the posterior third of the head, forming complexes with small spikes. These are usually facilitated by or seen only with eye closure [Boyd et al 1997, Rubin et al 1997, Korff et al 2005].

Seizure types can be quite varied and include both major motor and minor motor types (e.g., petit mal, atonic) [Galván-Manso et al 2005, Pelc et al 2008a, Thibert et al 2009, Fiumara et al 2010]. Infantile spasms are rare. Non-convulsive status epilepticus may occur [Pelc et al 2008a]. Brain MRI may show mild atrophy and mild dysmyelination, but no structural lesions [Harting et al 2009, Castro-Gago et al 2010].

The average child with AS walks between ages 2.5 and six years [Lossie et al 2001] and at that time may have a jerky, robot-like, stiff gait, with uplifted, flexed, and pronated forearms, hypermotoric activity, excessive laughter, protruding tongue, drooling, absent speech, and social-seeking behavior. 10% of children are nonambulatory.

Sleep problems are well known in individuals with AS; frequent awakening at night is common [Bruni et al 2004, Didden et al 2004]. Dyssomnias (difficulties in initiating or maintaining sleep), irregular sleep-wake cycles, disruptive night behaviors such as periods of laughter, and sleep-related seizures have been reported [Pelc et al 2008b].

Essentially all young children with AS have some component of hyperactivity; males and females appear equally affected. Infants and toddlers may have seemingly ceaseless activity, constantly keeping their hands or toys in their mouth, and/or moving from object to object. Some behaviors may suggest an autism spectrum problem but social engagement is typically good and stereotypic behaviors such as lining up of toys or fascination with spinning objects or flashing lights rarely occur [Walz 2007].

Language impairment is severe. Appropriate use of even one or two words in a consistent manner is rare. Receptive language skills are always more advanced than expressive language skills [Gentile et al 2010]. Most older children and adults with AS are able to communicate by pointing and using gestures and by using communication boards. Effective fluent use of sign language does not occur [Clayton-Smith 1993]. Relatively higher language skills can be seen in those with mosaic imprinting defects.

Pubertal onset and development are generally normal in AS. Fertility appears to be normal; procreation appears possible for both males and females. Lossie & Driscoll [1999] reported transmission of an AS deletion to a fetus by the affected mother.

Young adults appear to have generally good physical health, although seizures continue to be present throughout adulthood. Constipation is common. Many are treated for gastroesophageal reflux symptoms. Scoliosis becomes more common with advancing age [Giroud et al 2015, Larson et al 2015].

Independent living is not possible for adults with AS; many live at home or in home-like placements.

Life span data are not available, but life span appears to be nearly normal.

Genotype-Phenotype Correlations

All genetic mechanisms that give rise to AS lead to a somewhat uniform clinical picture of severe-to-profound intellectual disability, movement disorder, characteristic behaviors, and severe limitations in speech and language. However, some clinical differences correlate with genotype [Fridman et al 2000, Lossie et al 2001, Varela et al 2004, Tan et al 2011, Valente et al 2013]. These correlations are broadly summarized below:

  • The 5- to 7-Mb deletion class results in the most severe phenotype with microcephaly, seizures, motor difficulties (e.g., ataxia, muscular hypotonia, feeding difficulties), and language impairment. They also have lower body mass index compared to individuals with UPD or imprinting defects [Tan et al 2011]. There is some suggestion that individuals with larger deletions (e.g., BP1-BP3 [class I; ISCA-37404] break points) may have more language impairment or autistic traits than those with BP2-BP3 (class II; ISCA-37478) break points [Sahoo et al 2006] (see Figure 2).
  • Individuals with UPD have better physical growth (e.g., less likelihood of microcephaly), fewer movement abnormalities, less ataxia, and a lower prevalence (but not absence) of seizures than do those with other underlying molecular mechanisms [Lossie et al 2001, Saitoh et al 2005, Valente et al 2013].
  • Individuals with IDs or UPD have higher developmental and language ability than those with other underlying molecular mechanisms. Individuals who are mosaic for the nondeletion ID (approximately 20% of the ID group) have the most advanced speech abilities [Nazlican et al 2004]; they may speak up to 50-60 words and use simple sentences.
  • Individuals with chromosome deletions encompassing OCA2 frequently have hypopigmented irides, skin, and hair. OCA2 encodes a protein important in tyrosine metabolism that is associated with the development of pigment in the skin, hair, and irides (see Oculocutaneous Albinism Type 2). However, other factors in addition to haploinsufficiency of OCA2 appear to account for the relative hypopigmentation in individuals with AS, as UBE3A has now been shown to modulate melanocortin 1 receptor (MC1R) activity in somatic tissues [Low & Chen 2011].
Figure 2. . Schematic drawing of chromosome region 15q11.

Figure 2.

Schematic drawing of chromosome region 15q11.2-q13 indicating the breakpoint regions BP1-BP6. Low copy repeat elements (LCR's) are located within these breakpoint regions (see text for details). Approximately 90% of chromosome deletions resulting in Angelman (more...)

Penetrance

Inherited UBE3A pathogenic variants, IC deletions, very small 15q11.2-q13 deletions that include UBE3A [Kuroda et al 2014] and certain chromosome translocations follow an imprinting (or inheritance) pattern in which an individual who inherits a paternally transmitted pathogenic variant is asymptomatic (see Figure 3).

Figure 3. . The pedigree illustrates imprinting inheritance in AS.

Figure 3.

The pedigree illustrates imprinting inheritance in AS. Inheritance of a deleterious UBE3A pathogenic variant from the male (top left, I-1) has no effect on the two children (II-2, II-4) who inherit his pathogenic variant because the mutant UBE3A has already (more...)

Prevalence

The prevalence of AS is one in 12,000-24,000 population [Clayton-Smith & Pembrey 1992, Steffenburg et al 1996, Mertz et al 2013].

Differential Diagnosis

Infants with AS commonly present with nonspecific psychomotor delay and/or seizures; therefore, the differential diagnosis is often broad and nonspecific, encompassing such entities as cerebral palsy, static encephalopathy, or mitochondrial encephalomyopathy. The tremulousness and jerky limb movements seen in most infants with AS may help distinguish AS from these conditions.

The following disorders that mimic AS need to be considered in the differential diagnosis [Tan et al 2014]:

  • Mowat-Wilson syndrome can present with happy affect, seizures, prominent mandible, upturned prominent ear lobes, diminished speech, microcephaly, constipation, and, on occasion Hirschsprung disease [Zweier et al 2005]. Congenital heart defects or agenesis of the corpus callosum can also occur. Mowat-Wilson syndrome is typically the result of a dominant de novo pathogenic variant in, or deletion of, ZEB2.
  • The characteristic features of the Pitt-Hopkins syndrome (PTHS) are intellectual disability, wide mouth and distinctive facial features, and intermittent hyperventilation followed by apnea [Zweier et al 2007]. Features that may overlap with AS include microcephaly, seizures, ataxic gait, and happy personality [Takano et al 2010]. Diurnal hyperventilation, a salient feature in some, occurs after age three years [Peippo et al 2006]. PTHS is caused by haploinsufficiency of TCF4 resulting from either a pathogenic variant in TCF4 or a deletion of the chromosomal region in which TCF4 is located (18q21.2). Most affected individuals reported to date represent simplex cases (i.e., a single occurrence in a family) resulting from a de novo pathogenic variant or deletion.
  • Christianson syndrome (OMIM 300243) can mimic AS. The clinical features include apparently happy disposition, severe cognitive delays, ataxia, microcephaly, and a seizure disorder [Christianson et al 1999, Gilfillan et al 2008, Schroer et al 2010]. Affected individuals may have a thin body appearance and may lose ambulation after age ten years. Some may have cerebellar and brain stem atrophy [Gilfillan et al 2008]. Although seizures are present in both conditions, the EEG pattern appears to differ: AS typically shows a generalized high amplitude, slow spike/wave (1.5-3 Hz) pattern while those with an SLC9A6 pathogenic variant lack the AS EEG pattern and have a more rapid (10-14 Hz) background frequency [Gilfillan et al 2008]. Christianson syndrome is an X-linked disorder caused by mutation of SLC9A6.
  • Female infants with seizures, acquired microcephaly, and severe speech impairment can resemble girls with Rett syndrome. Girls with Rett syndrome usually do not have a distinctive happy demeanor and girls with AS do not have a neuroregressive course or lack purposeful use of their hands. Older girls with undiagnosed Rett syndrome may have features that resemble AS [Watson et al 2001]. Rett syndrome is an X-linked disorder caused by mutation of MECP2.
  • Sometimes infants with AS who present with feeding difficulties and muscle hypotonia are misdiagnosed as having Prader-Willi syndrome because the 15q11.2-q13 deletion, detected by chromosomal microarray or FISH, was not proven by DNA methylation analysis to be of maternal origin.
  • Microdeletions of 2q23.1 involving MBD5 may result in severe speech delay, seizures, behavioral disorders, and microcephaly (OMIM 156200). Some individuals present with an AS-like phenotype [van Bon et al 2010, Williams et al 2010b].
  • Other chromosome disorders can mimic some of the features of AS, especially 22q13.3 deletion syndrome (Phelan-McDermid syndrome) [Precht et al 1998], characterized by nondysmorphic facial features, absent or minimal speech, and moderate to severe developmental delay, sometimes with behavioral features in the autism disorders spectrum. Additional microdeletion disorders, especially newer ones detected by chromosomal microarray, may be associated with some features of AS [Brunetti-Pierri et al 2008, Sharkey et al 2009].
  • MECP2 duplication (typically encompassing an approximately 500-kb region at Xq28) in males is characterized by severe developmental impairment, absent speech, seizures, and ataxic gait with spastic paraparesis. Although adult males are typically nonambulatory and are prone to infectious illnesses, children may have relatively nonspecific findings that include features of intellectual disability with autism, absent speech, and unstable gait [Van Esch et al 2005, Friez et al 2006, Lugtenberg et al 2009]. MECP2 duplication syndrome is inherited in an X-linked manner.
  • Adenylosuccinate lyase deficiency (OMIM 103050) results in accumulation of succinylpurines leading to psychomotor retardation, autistic features, hypotonia, and seizures [Spiegel et al 2006]. Motor apraxia, severe speech deficits, excessive laughter, a very happy disposition, hyperactivity, a short attention span, mouthing of objects, tantrums, and stereotyped movements have been reported in female sibs [Gitiaux et al 2009]. Diagnostic testing involves detection of succinylaminoimidazole carboxamide riboside (SAICA riboside) and succinyladenosine (S-Ado) in cerebrospinal fluid, urine, and (to a lesser extent) in plasma. Adenylosuccinate lyase deficiency is inherited in an autosomal recessive manner and is caused by pathogenic variants in ADSL.
  • The rare metabolic disorder of severe methylene-tetrahydrofolate-reductase (MTHFR) deficiency (OMIM 236250) associated with low methionine and elevated homocysteine blood levels was reported in a boy with happy demeanor, ataxic gait, absent speech, and flattened occiput [Arn et al 1998]. MTHFR deficiency is inherited in an autosomal recessive manner and is caused by pathogenic variants in MTHFR.
  • On rare occasions, congenital disorders of glycosylation (CDG) can mimic the features of AS especially if the affected child has unstable gait, speech impairment, and seizures.
  • Kleefstra syndrome is caused by haploinsufficiency of EHMT1 on chromosome 9q34.3 [Willemsen et al 2012]. The clinical features that have been reported in both AS and Kleefstra syndrome include: moderate-to-severe intellectual disability with minimal speech; better receptive language as compared to expressive language skills; hypotonia in childhood; sleep disturbances with multiple awakenings; and midface retrusion with prognathism. Facial features that differentiate Kleefstra syndrome from AS include synophrys and everted vermilion of the lower lip. Some mildly affected individuals with Kleefstra syndrome have a greater than 100-word vocabulary and speak in sentences, which would be very unusual in an individual with AS.
  • HERC2-related cognitive impairment (OMIM 615516). HERC2 is located on chromosome 15q13.1 and encodes a protein that binds to and affects the ubiquitin ligase activity of E6AP. A homozygous c.1781C>T (p.Pro594Leu) pathogenic variant in HERC2 has been identified in 22 members of four Amish families and one mixed Amish-Mennonite family who presented with global developmental delay and intellectual disability, hypotonia, delayed independent ambulation at between age 2.5 and 5 years, and a broad-based gait with arms upheld and flexed at the elbow when running [Harlalka et al 2013]. Many of these findings are reminiscent of those observed in mildly affected individuals with AS, but the lack of easily provoked laughter and the relatively mild intellectual disability in at least some of these individuals distinguish it from AS

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Angelman syndrome (AS), the following evaluations focused on neurologic assessment and good preventive practice are recommended:

  • Baseline brain MRI and EEG
    Note: Typically, management of seizures (or assessment of risk for seizures) is not significantly helped by repetitive EEG or MRI testing.
  • Musculoskeletal examination for scoliosis and gait impairment (e.g., extent of foot pronation or ankle subluxation; tight Achilles tendons) and the extent of muscular hypotonia; orthopedic referral as needed
  • Ophthalmology examination for strabismus, evidence of ocular albinism (in deletion-positive AS), and visual acuity
  • Developmental evaluation focused on: (1) nonverbal language ability and related educational and teaching strategies; and (2) physical therapy to enable optimal ambulation
  • Evaluation for gastroesophageal reflux in infants and young children; dietary evaluation to assure optimal nutritional status
  • Medical genetics consultation

Treatment of Manifestations

Feeding problems in newborns may require special nipples and other strategies to manage weak or uncoordinated sucking.

Gastroesophageal reflux can be associated with poor weight gain and emesis; the customary medical treatment (i.e., upright positioning, motility drugs) is usually effective; sometimes fundoplication as required.

Many antiepileptic drugs (AEDs) have been used to treat seizures in individuals with AS; no one drug has proven superior. Medications used for minor motor seizures (e.g., valproic acid, clonazepam, topiramate, lamotrigine, ethosuximide) are more commonly prescribed than medications for major motor seizures (e.g., diphenylhydantoin, phenobarbital) [Thibert et al 2009]. Carbamezapine, although not contraindicated, is less frequently used than other common anticonvulsants. Single medication use is preferred, but seizure breakthrough is common. A few individuals with AS have infrequent seizures and are not on AEDs. Some with uncontrollable seizures have benefited from a ketogenic or low glycemic diet [Thibert et al 2012].

Hypermotoric behaviors are typically resistant to behavioral therapies; accommodation by the family and provision of a safe environment are important.

Most children with AS do not receive drug therapy for hyperactivity, although some may benefit from the use of stimulant medications such as methylphenidate (Ritalin®).

Behavioral modification is effective in treating undesirable behaviors that are socially disruptive or self-injurious.

A full range of educational training and enrichment programs should be available.

Unstable or nonambulatory children may benefit from physical therapy. Occupational therapy may help improve fine motor and oral-motor control. Special adaptive chairs or positioners may be required, especially for extremely ataxic children.

Speech therapy is essential and should focus on nonverbal methods of communication. Augmentative communication aids such as picture cards or communication boards should be used at the earliest appropriate time. Attempts to teach signing should begin as soon as the child is sufficiently attentive.

Individualization and flexibility in the school are important educational strategies.

Special physical provisions in the classroom, along with teacher aides or assistants, may be needed for effective class integration. Children with AS with excessive hypermotoric behaviors need an accommodating classroom space.

Many families construct safe but confining bedrooms to accommodate disruptive nighttime wakefulness. Administration of 0.3 mg melatonin one hour before sleep may be helpful in some, but should not be given in the middle of the night if the child awakens.

Strabismus may require surgical correction.

Constipation often requires regular use of laxatives such as high fiber or lubricating agents.

Orthopedic problems, particularly subluxed or pronated ankles or tight Achilles tendons, can be corrected by orthotic bracing or surgery.

Thoraco-lumbar jackets may be needed for scoliosis, and individuals with severe curvature may benefit from surgical rod stabilization.

Prevention of Secondary Complications

Children with AS are at risk for medication overtreatment because their movement abnormalities can be mistaken for seizures and because EEG abnormalities can persist even when seizures are controlled.

The behavioral phenotype of Angelman syndrome includes hyperexcitability, hypermotoric behaviors, and deficits in social communication. These limitations place them at risk for social disruptions. On occasion, the use of risperidone (Risperdal®) or other atypical antipsychotic drugs provides some but often limited benefit. When such drugs are needed, care must be taken to avoid over-sedation and other side effects.

Older adults tend to become less mobile and less active; attention to activity schedules may be helpful in reducing the extent of scoliosis and obesity.

Surveillance

The following are appropriate:

  • Annual clinical examination for scoliosis
  • For older children, evaluation for the development of obesity associated with excessive appetite and decreased physical activity

Agents/Circumstances to Avoid

Carbamezapine, although not contraindicated, is less frequently used than other common anticonvulsants.

Vigabatrin and tigabine (anticonvulsants that increase brain GABA levels) are contraindicated in individuals with Angelman syndrome. For unknown reasons, carbamazapine, vigabatrine, and tigabine can cause development of other seizure types or non-convulsive status epilepticus. This paradoxic seizure development is not limited to individuals with Angelman syndrome [Pelc et al 2008a]

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Clinical trials involving oral administration of folate, vitamin B12, creatine, and betaine have been undertaken in an attempt to augment DNA methylation pathways and possibly increase expression of the paternal UBE3A allele in the central nervous system; however, the initial trial did not demonstrate significant clinical benefit [Peters et al 2010]. See full text for more information. More recent therapeutic efforts have focused on activating the otherwise silenced paternal UBE3A allele by use of telomerase inhibitors [Huang et al 2012] and antisense oligonucleotides [Meng et al 2015].

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

Excessive tongue protrusion causes drooling; available surgical or medication treatments (e.g., surgical reimplantation of the salivary ducts or use of local scopolamine patches) are generally not effective.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Angelman syndrome (AS) is caused by one of the following:

  • Deletion of the AS/PWS region on the maternally inherited chromosome 15
  • UPD of the paternal chromosome 15
  • An imprinting defect (ID)
  • A pathogenic variant in UBE3A
  • Unidentified mechanism(s)

Risk to Family Members

Parents of a proband

  • The parents of a proband are unaffected.
  • Recommendations for genetic testing of the parents depend on the cause of AS in the proband.

Sibs of a proband. The risk to the sibs of an individual with AS depends on the genetic mechanism of AS in the proband (summarized in Table 2).

For recurrence risk assessment. If the DNA methylation pattern is characteristic for absence of the maternal contribution, the underlying genetic mechanism (deletion, UPD, or ID) should be determined for genetic counseling purposes.

  • Deletion analysis should be performed first.
  • If no deletion is found, analysis of DNA polymorphisms on chromosome 15 can be used to detect UPD.
  • If UPD is not detected, the presumption is that an ID is present; additional studies can then determine if there is a deletion in the IC.

Table 2.

Risks to Sibs of a Proband with AS by Genetic Mechanism

Molecular Class 1FamiliesGenetic MechanismRisk to Sibs
Ia65%-75%5- to 7-Mb deletion<1%
Ib<1%Unbalanced chromosome translocation or inherited small interstitial deletionPossibly as high as 50%
IIa3%-7%Paternal UPD<1%
IIb<1%Paternal UPD with predisposing parental translocationApproaching 100% if father has a 15;15 Robertsonian translocation
IIIa0.5%ID with deletion in the ICAs high as 50% if mother also has IC deletion
IIIb2.5%ID without deletion in the IC<1%
IV11%UBE3A pathogenic variantAs high as 50% if mother also has a pathogenic variant
V10%-15%"Other" - no identifiable molecular abnormalityUndetermined risk

UPD= uniparental disomy

ID=imprinting defect

IC=imprinting center

1.

Based on terminology by Jiang et al [1999]

Ia. Mothers of individuals with deletions should have chromosomal and FISH analyses to determine if they have a chromosomal rearrangement. For probands with a de novo large deletion, the risk to sibs is less than 1%. Germline mosaicism for these large deletions has been reported [Kokkonen & Leisti 2000, Sánchez et al 2014].

Ib. If a chromosome rearrangement or small gene region deletion has been identified in a proband, the risks to sibs and other family members depends on whether the rearrangement is inherited or de novo [Horsthemke et al 1996, Stalker & Williams 1998, Gimelli et al 2003, Collinson et al 2004, Kuroda et al 2014].

IIa. In families in which AS is the result of paternal UPD and in which no Robertsonian chromosomal translocation is identified in the proband, the risk to sibs of having AS is less than 1%. This risk figure is based on the lack of recurrence among all known cases of UPD in AS with normal chromosomes, the experience with UPD in other disorders, and theoretic consideration regarding the mechanism of UPD. Recurrent meiotic nondisjunction of maternal chromosome 15 has been observed and therefore the recurrence risk is not zero [Harpey et al 1998].

If an individual has AS resulting from paternal UPD and has a normal karyotype, chromosomal analysis should be offered to the mother in order to exclude the rare possibility that a Robertsonian translocation or marker chromosome was a predisposing factor (e.g., via generation of maternal gamete that was nullisomic for chromosome 15, with subsequent postzygotic “correction” to paternal disomy).

IIb. Individuals with UPD should have chromosomal analysis to ensure that they do not have a paternally inherited Robertsonian translocation that would increase the family's recurrence risk.

IIIa. Individuals with an imprinting center (IC) deletion can have a phenotypically normal mother who also has an IC deletion. In these situations, the mother has either acquired her IC deletion by a de novo pathogenic variant on her paternally derived chromosome 15 or inherited the IC deletion from her father, consistent with the imprinting mechanisms governing the 15q11.2-q13 region [Buiting et al 2001, Horsthemke & Buiting 2008]. Additionally, some of these mothers may have germline mosaicism for the IC deletion. This complicates genetic counseling when the mother of a proband with an IC deletion has normal peripheral blood IC genetic studies. If a proband's mother has a known IC deletion, the risk to the sibs is 50%.

IIIb. To date, recurrence of AS in families of probands who have IDs without deletion in the IC has not been reported. Thus, the proband’s ID probably represents a de novo defect in the imprinting process in 15q11.2-q13 during the mother's oogenesis [Buiting et al 1998]. The risk to the sibs of a proband in such families is less than 1%. There is a single report of a pair of siblings with AS who had a 1-1.5 Mb inversion separating the two IC elements, but no actual IC deletion [Buiting et al 2001].

IV. UBE3A pathogenic variants can be inherited or de novo [Kishino et al 1997, Matsuura et al 1997, Lossie et al 2001, Bürger et al 2002]. Approximately 30% of pathogenic variants are inherited. Familial studies should be offered to establish maternal inheritance or lack of paternal inheritance [Sadikovic et al 2014]. In addition, several cases of somatic and germline mosaicism for a UBE3A pathogenic variant have been noted [Malzac et al 1998, Hosoki et al 2005]. If a proband's mother has a UBE3A pathogenic variant, the risk to the sibs is 50%.

V. In this molecular class, clinical features of AS are present but an AS-causing genetic mechanism has not yet been identified.

Offspring of a proband. To date, only one individual with AS has been reported to have reproduced [Lossie & Driscoll 1999]. The risk to offspring should be determined in the context of formal genetic counseling.

Other family members of a proband. If a UBE3A pathogenic variant, IC deletion, or structural chromosomal rearrangement has been identified in the mother (or father in the case of UPD and Robertsonian translocations) of a proband, the sibs of the carrier parent should be offered genetic counseling and the option of genetic testing:

  • IC deletions or UBE3A pathogenic variants. If a proband's mother carries a known IC deletion or UBE3A pathogenic variant, the mother's siblings are also at risk of carrying the IC deletion or the pathogenic variant. Each child of the unaffected carrier sister is at a 50% risk of having AS. Unaffected maternal uncles of the proband who are carriers are not at risk of having affected children, but are at risk of having affected grandchildren through their unaffected daughters who inherited the IC deletion or UBE3A pathogenic variant from them.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having children with AS.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for high risk pregnancies require prior identification of the disease-causing mechanism in the family.

High risk. Prenatal detection of all the known molecular genetic alterations (i.e., molecular classes Ia, Ib, IIa, IIb, IIIa, IIIb, IV; see Table 2) in the 15q11.2-q13 region that give rise to AS is possible through DNA and/or chromosomal/FISH analysis of fetal cells obtained by chorionic villus sampling (usually performed at ~10-12 weeks' gestation) or amniocentesis (usually performed at ~15-18 weeks' gestation) [Kubota et al 1996, Glenn et al 2000, Chang et al 2014].

DNA methylation analysis (for 5- to 7-Mb deletions, UPD, and IC defects) on cells obtained by CVS is theoretically possible [Kubota et al 1996, Glenn et al 2000]. However, the few clinical laboratories doing prenatal testing using DNA methylation analysis prefer using amniocytes because of the relative hypomethylation of cells derived from the placenta. FISH analysis, IC deletion analysis, and sequence analysis of UBE3A should be technically possible for CVS.

Prenatal testing should be undertaken only after the genetic mechanism in the index case has been established and the couple has been counseled regarding the risk to their unborn child, as the risks and the type of molecular genetic testing used vary according to the type of molecular defect in the proband (see Establishing the Diagnosis).

  • Parents with normal chromosomes who have had one child with AS caused by either deletion or UPD, have a low recurrence risk but may be offered prenatal testing for reassurance.
  • Parents who have had one child with AS caused by a UBE3A pathogenic variant should be offered prenatal testing even if the mother does not have a UBE3A pathogenic variant because of the possibility of germline mosaicism.
  • Prenatal testing for an inherited translocation involving chromosome 15 is relevant because of the increased recurrence risk. FISH analysis and parent-of-origin (DNA methylation and/or polymorphism) studies should be considered if an inherited translocation involving chromosome 15 is present.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Low risk. For low-risk pregnancies with no family history of AS, AS needs to be considered in the following instances:

  • If a 15q11.2-q13 deletion is suspected on cytogenetic studies from CVS or amniocentesis, FISH analysis or chromosomal microarray analysis (CMA) is indicated to confirm the deletion. If the deletion is confirmed, parent-of-origin studies [Kubota et al 1996, Glenn et al 2000] can be performed to determine if the deletion is maternally derived (fetus has AS) or paternally derived (fetus has PWS).
  • If trisomy 15 or mosaic trisomy 15 is detected on CVS, and if subsequent amniocentesis reveals 46 chromosomes, the possibility of trisomy rescue leading to AS (paternal UPD) or PWS (maternal UPD) through the loss of a parental chromosome 15 must be considered. In this instance, parent-of-origin (DNA) studies on amniocytes can be performed.
  • If a de novo translocation involving chromosome 15 or a supernumerary chromosome 15 marker is detected, FISH analysis or CMA and parent-of-origin studies should be considered to evaluate for a possible deletion (of variable size) or UPD.

Preimplantation genetic diagnosis (PGD) may be an option for families in which the underlying mechanism has been identified in the proband to be UBE3A pathogenic variants or IC deletions. (The relative hypomethylation of the early embryo makes PGD problematic for DNA methylation testing.)

Other

Assisted reproductive technology (ART). In vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) have been demonstrated to increase the chance of certain imprinting disorders, like Beckwith-Wiedemann syndrome, in offspring. However, recent studies demonstrate that there is no significant association between AS and IVF or ICSI [Vermeiden & Bernardus 2013].

Fertility. Research from the Netherlands and Germany demonstrate an association between fertility issues and incidence of AS. The percent of couples who experienced fertility issues before having a child with AS ranged from 19% to 25%. There was no positive association with fertility issues and AS in families queried in the United Kingdom [Ludwig et al 2005, Doornbos et al 2007, Vermeiden & Bernardus 2013].

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Angelman Syndrome Foundation, Inc. (ASF)
    4255 Westbrook Drive
    Suite 219
    Aurora IL 60504
    Phone: 800-432-6435 (toll-free); 630-978-4245
    Fax: 630-978-7408
    Email: info@angelman.org
  • Foundation for Angelman Syndrome Therapeutics (FAST)
    PO Box 608
    Downers Grove IL 60515
    Phone: 866-783-0078; 630-852-3278
    Fax: 630-852-3270
  • National Library of Medicine Genetics Home Reference
  • NCBI Genes and Disease
  • American Epilepsy Society (AES)
  • Epilepsy Foundation
    8301 Professional Place East
    Suite 200
    Landover MD 20785-7223
    Phone: 800-332-1000 (toll-free)
    Email: ContactUs@efa.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Angelman Syndrome: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
UBE3A15q11​.2Ubiquitin-protein ligase E3AUBE3A at NGRL, Manchester LOVDUBE3A

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B.

OMIM Entries for Angelman Syndrome (View All in OMIM)

105830ANGELMAN SYNDROME; AS
601623UBIQUITIN-PROTEIN LIGASE E3A; UBE3A

Molecular Genetic Pathogenesis

Genomic imprinting is a phenomenon in mammals in which particular genes, depending on the sex of the parent of origin, are not equally expressed. The cardinal features of AS result from deficient expression or function of the maternally inherited UBE3A allele [Jiang et al 1999, Lossie et al 2001, Nicholls & Knepper 2001]. Ubiquitin-protein ligase E3A is involved in the ubiquitination pathway, which targets selected proteins for degradation.

UBE3A displays predominant maternal expression in human fetal brain and adult frontal cortex [Rougeulle et al 1997, Vu & Hoffman 1997, Herzing et al 2001]. In mouse, maternal allele-specific expression is detected in specific brain subregions including hippocampus, Purkinje cells of the cerebellum, mitral cells of the olfactory bulb, and visual cortex [Albrecht et al 1997, Jiang et al 1998, Yashiro et al 2009]. It is possible that there is widespread, if not global, UBE3A allele-specific expression in mouse and in human brain neurons. Primary cell cultures from fetal mouse brain have demonstrated that UBE3A imprinting is limited to neurons, but glial cells show biallelic expression [Yamasaki et al 2003]. Studies with RNA-FISH suggest that preferential maternal expression of UBE3A occurs in lymphoblasts and fibroblasts, but the differential expression between the parental alleles is not as striking as it is in brain [Herzing et al 2002].

UBE3A has a large 5' CpG island, but in contrast to genes in the "PWS critical region," DNA methylation does not differ between the maternal and paternal alleles [Lossie et al 2001].

Because no differentially methylated region is present in UBE3A, it has been proposed that the imprinted expression of UBE3A may be regulated indirectly through a paternally expressed antisense transcript [Rougeulle et al 1998]. Runte et al [2001] have shown that a long SNURF-SNRPN sense/UBE3A antisense RNA transcript exists in the AS/PWS region, starting from the SNURF-SNRPN IC and extending more than 460 kb to at least the 5' end of UBE3A. It has been proposed that this UBE3A antisense transcript blocks paternal UBE3A expression.

Gene structure. UBE3A spans approximately 120 kb of genomic DNA and contains 16 exons. The 5' untranslated region (UTR) extends several kilobases upstream from the initiation site and spans an additional six to nine exons [Kishino et al 1997, Vu & Hoffman 1997, Yamamoto et al 1997, Kishino & Wagstaff 1998], whereas the 3' UTR extends an additional 2.0 kb [Kishino & Wagstaff 1998]. To date, alternative splicing of the 5' UTR accounts for the production of nine adult and two fetal transcripts [Kishino et al 1997, Vu & Hoffman 1997, Yamamoto et al 1997, Kishino & Wagstaff 1998], which are translated into three different protein isoforms. The functions of the different protein isoforms are unknown.

For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants

  • Deletions of 15q11.2-q13 (65%-75%). Three chromosomal break points (proximal BP1, BP2, and a distal BP3) are involved in most AS-causing deletion events involving 15q11.1-q13. These deletions span approximately 5-7 Mb [Knoll et al 1990, Amos-Landgraf et al 1999, Christian et al 1999] (see Figure 2). Fewer than 10% of individuals with AS may have deletions extending from the BP1/BP2 region to regions more distal, at BP4 or BP5 locations (see Figure 2) [Sahoo et al 2007].

    The BP1, BP2, and BP3 regions are characterized by low-copy repeat regions (LCRs) that contain repeats mainly derived from the ancestral HECT domain and RCC1 domain protein 2 (HERC2) genes [Pujana et al 2002]. The BP sites distal to BP3 contain other LCRs (e.g., without HERC2 duplications) that share chromosome 15-derived repeated DNA elements.

    Note: Microdeletions that flank the typical deletion region and include areas between BP1 and BP2 [Doornbos et al 2009], BP3 and BP4 [Rosenfeld et al 2011], and the more distal microdeletion syndrome involving region 15q13.3 [Masurel-Paulet et al 2010] have been described. However, these deletions should not be considered to be pathogenic alleles for AS as individuals with these deletions do not exhibit features of AS.
  • Genomic abnormalities of 15q11.1-q13. It is possible that in otherwise normal individuals preexisting genomic abnormalities may predispose to deletion of 15q11.1-q13 in the germline resulting in offspring with AS.
    • A proportion of mothers who have a child with an AS deletion have been found to have inversions in the 15q11.2-q13 region (the region deleted in the offspring with AS) [Gimelli et al 2003].
    • A kindred in which two individuals had deletions (one deletion causing PWS and the other causing AS) has been previously reported to be associated with an inherited inverted intrachromosomal insertion of 15q11.2-q13 [Collinson et al 2004].
  • Paternal uniparental disomy of chromosome 15 (3%-7%). In contrast to PWS, the paternal UPD observed in AS is most likely to be postzygotic in origin [Robinson et al 2000]. Paternal UPD of meiotic origin does occur but this mechanism is less common than the maternal UPD associated with PWS.
  • Imprinting defects (3%). This subset of individuals with AS have a defect in the IC that disrupts the resetting of the normal imprint during gametogenesis. Even though these individuals have biparental inheritance of chromosome 15, the maternal 15q11.2-q13 region has a paternal epigenotype and is, therefore, transcriptionally incompetent for the maternal-only expressed gene(s) in this region [Glenn et al 1993, Buiting et al 2001, Buiting et al 2003].

    Mapping of these deletions (as well as mapping of the IC deletions that are associated with PWS) has delineated two small regions of deletion overlap (SRO) that define two critical elements in the IC region, the AS-SRO and the PWS-SRO [Buiting et al 1995] (see Figure 2). The PWS-SRO is 4.3 kb in size and overlaps with the SNURF-SNRPN exon1/promoter region [Ohta et al 1999]. IC deletions found in individuals with AS affect the more centromeric SNURF-SNRPN promoter/exon 1 region. The smallest region of overlap in patients with AS and an IC deletion (AS-SRO) is 880 bp in size and maps 35 kb proximal to SNURF-SNRPN exon 1 [Buiting et al 1999, Horsthemke & Buiting 2008]. Most individuals with AS caused by IC defects do not have a deletion of the AS IC region, but rather have epigenetic defects that disrupt IC function.
  • UBE3A (5%-11%). More than 150 pathogenic variants have been reported and 60%-70% of these involve small deletions and duplications leading to frameshifts [Camprubí et al 2009, Stenson et al 2009, Abaied et al 2010, Sadikovic et al 2014]. Another approximately 25% involve missense and nonsense pathogenic variants with the remainder representing splicing defects, gross deletions, and complex rearrangements [Stenson et al 2009, Sadikovic et al 2014].

    Most pathogenic variants noted thus far are predicted to disrupt the HECT ligase domain. Exons 9 and 16, which code for part of the HECT domain, account for a high percentage of all pathogenic variants but these coding regions are disproportionately large so the high percentage probably does not represent true hot spots for mutation. It is possible that individuals with milder-effect pathogenic variants (e.g., certain missense and in-frame deletions or duplications) may show some, but not all, of the clinical features associated with AS. A few individuals with AS have been found to have complete or partial deletions of UBE3A or to have intragenic deletions. Some types of deletion testing methods may be able to detect some of these deletions (see Table 1) [Lawson-Yuen et al 2006, Sato et al 2007].

For more information, see Table A.

Normal gene product. UBE3A produces an 865-amino acid E6-associated protein (E6AP). E6AP was first recognized as a protein that binds to p53 and mediates its association with human papilloma virus E6 protein. This binding leads to degradation of the p53 tumor suppressor via the ubiquitin proteasome pathway and thus promotes development of cervical carcinoma [Huibregtse et al 1991, Huang et al 1999]. E6AP facilitates the transfer and covalent linkage of activated ubiquitin (a 76-amino acid protein) to the target protein. The polyubiquitylated substrates are then identified and degraded by the 26S proteasome pathway. E6AP belongs to the HECT (homologous to E6AP COOH-terminus) class of E3 enzymes that share a 40-kd conserved COOH-terminal catalytic domain. The HECT domain of E6AP is a bi-lobed structure with a broad catalytic cleft at the junction of the two lobes. The domain is encoded by exons 9 through 16. The E6-binding site is encoded by exon 9 and the active site cysteine residue that accepts ubiquitin from the E2 ubiquitin-conjugating enzyme is encoded within exon 16 [Yamamoto et al 1997, Kishino & Wagstaff 1998]. Pathogenic variants within the cleft interfere with ubiquitin-thioester bond formation. Indeed, most AS pathogenic variants occur in the HECT domain region or are predicted to ablate HECT domain function [Huang et al 1999].

A steroid receptor coactivation domain is located upstream of the HECT region but its role in neuronal development is uncertain. E6AP appears to have at least two independent functions since the ligase region and the HECT domain are not required for function of the coactivation domain [El Hokayem & Nawaz 2014].

Abnormal gene product. Disruption of UBE3A could affect crucial neuronal processes of protein degradation and replacement that would otherwise be balanced or maintained by a functional ubiquitin-proteasome system. The ubiquitin-proteasome pathway is essential for cellular functioning including signal transduction, cell cycle progression, DNA repair, and transcriptional regulation [Ciechanover 1998, Hershko & Ciechanover 1998].

Several E6AP protein targets have been discovered [Kühne & Banks 1998, Kumar et al 1999, Oda et al 1999, Khan et al 2006, Li et al 2006, Reiter et al 2006, Louria-Hayon et al 2009, Shimoji et al 2009, Margolis et al 2010, Scheiffele & Beg 2010, Gossan et al 2014].

The guanine exchange protein, ephexin-5, is known to regulate activity of EphB receptor signaling that is a crucial component of dendritic growth [Margolis et al 2010]. Eph receptors are known to be enriched at synapses and are important in regulating dendritic spine density. The EphB receptors interact with ephrin ligands and regulate dendritic development through small GTPases of the Rho family (Rho, Rac, and Cdc42) by activation of guanine nucleotide exchange factors (GEFs) [Murai & Pasquale 2003]. It is unknown how abnormalities in E6AP-target protein interactions lead to AS but the recently identified targets strongly indicate that the E6AP protein is crucial to development of normal synapses and neural plasticity.

References

Published Guidelines/Consensus Statements

  1. American Society of Human Genetics/American College of Medical Genetics Test and Technology Transfer Committee. Diagnostic testing for Prader-Willi and Angelman syndromes: Report of the ASHG/ACMG Test and Technology Transfer Committee (pdf). 1996. Available online. Accessed 5-8-15.
  2. Shaffer LG, Agan N, Goldberg JD, Ledbetter DH, Longshore JW, Cassidy SB. American College of Medical Genetics statement on diagnostic testing for uniparental disomy (pdf). 2001. Available online. Accessed 5-8-15.
  3. Williams CA, Beaudet AL, Clayton-Smith J, Knoll JH, Kyllerman M, Laan LA, Magenis RE, Moncla A, Schinzel AA, Summers JA, Wagstaff J. Angelman syndrome 2005: updated consensus for diagnostic criteria. 2006. Available online. Accessed 5-8-15. [PubMed: 16470747]

Literature Cited

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Chapter Notes

Author History

Adati I Dagli, MD (2008-present)
Hui-Ja Dong; University of Florida College of Medicine (2003-2005)
Daniel J Driscoll, PhD, MD; University of Florida College of Medicine (1998-2011)
Amy C Lossie, PhD; University of Florida College of Medicine (1998-2003)
Jennifer Mueller, GC, (2015-present)
Charles A Williams, MD (1998-present)

Revision History

  • 14 May 2015 (me) Comprehensive update posted live
  • 16 June 2011 (me) Comprehensive update posted live
  • 5 September 2008 (me) Comprehensive update posted live
  • 30 July 2007 (cd) Revision: targeted mutation analysis no longer available clinically
  • 21 February 2007 (cd) Revision: clarification of Genetic Counseling section
  • 8 November 2005 (me) Comprehensive update posted to live Web site
  • 3 September 2004 (cw) Author revisions
  • 29 July 2003 (me) Comprehensive update posted to live Web site
  • 2 April 2002 (cw) Author revision
  • 21 November 2000 (me) Comprehensive update posted to live Web site
  • 15 September 1998 (pb) Review posted to live Web site
  • April 1998 (cw) Original submission
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