Angelman Syndrome

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 a pregnancy at increased risk is possible when the underlying genetic mechanism is a deletion, UPD, an ID, a UBE3A pathogenic variant, or a chromosome rearrangement.

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 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. 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...)

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 due to one of the following:
  • Deletion of the maternally inherited 15q11.2-q13 locus (which includes UBE3A)
  • Uniparental disomy of the paternal chromosome 15
  • An imprinting defect of the maternal chromosome 15q11.2-q13 locus
• 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:

• DNA methylation analysis is typically the first test ordered. 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.
  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).
• If DNA methylation analysis is normal:
  • Testing of UBE3A may be considered. Sequence analysis is performed first. If a pathogenic variant is not identified, gene-targeted deletion/duplication analysis can be considered.
  • Use of a multigene panel that includes UBE3A and other genes of interest (see Differential Diagnosis) may be considered in individuals who have features of AS and normal DNA methylation analysis. Note: The genes included and sensitivity of multigene panels vary by laboratory and over time.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• More comprehensive genomic testing (when available) including exome sequencing, genome sequencing, and mitochondrial sequencing may be considered if testing of UBE3A (and/or use of a multigene panel) fails to confirm a diagnosis in an individual with features of AS.
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found 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.

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 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. Nonconvulsive 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. 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 15q11.2-q13 indicating the breakpoint regions BP1-BP6. Low copy repeat elements (LCRs) 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. 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 mutated UBE3A has (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].

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
• Consultation with a clinical geneticist and/or genetic counselor

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