Angelman syndrome (AS) is a rare genetic disorder that affects approximately 1 in 15,000 individuals. AS impairs the function of the nervous system, producing symptoms such as severe intellectual disability, developmental disability, limited to no functional speech, balance and movement problems, seizures, hyperactivity, and sleep problems. Physical symptoms include a small head and a specific facial appearance. Additionally, those affected often have a happy personality.
Epidemiology Although the prevalence of Angelman syndrome is not known, some estimates are available. The best data available are from studies of school-age children (ages 6–13 years) in Sweden and Denmark, in which the diagnosis frequencies of AS among children attending medical clinics were compared with those over an 8-year period with 45,000 births. The Swedish study showed an AS prevalence of about 1 per 20,000, and the Danish study showed a minimum AS prevalence of about 1 per 10,000. AS rates are similar between males and females.
History Harry Angelman, a pediatrician working in Warrington, England, first reported three children with this condition in 1965. Angelman later described his choice of the title "Puppet Children" to describe these cases as being related to an oil painting he had seen while vacationing in Italy:
Case reports from the United States first began appearing in the medical literature in the early 1980s. Specifically, in 1982, Dr. Charles Williams and Dr. Jaime Frias saw their first patients they believed had "happy puppet syndrome". In 1987, Ellen Magenis, a physician, discovered a genetic marker of AS. Specifically, it was noted that around half of the children with AS have a small piece of chromosome 15 missing. In 1992, the AS foundation was created to further research for treatments and a cure for Angelman syndrome. In 1997, Dr. Arthur Beaudet discovered the cause of AS was the mutation of the UBE3A gene.
Signs and symptoms Consistent 100% of AS diagnoses have the following symptoms:
developmental delay: considered to be functionally severe; includes the inability for infants to support their heads and pull themselves up to stand, and feeding issues due to problems with sucking and/or swallowing; speech impairment: no or minimal use of words, and use of receptive and non-verbal communication, such as cooing or babbling; movement or balance disorder: movement dysfunction can range on a spectrum of mild to more severe movement disorders, such as ataxia; typically, AS cases present ataxia or gait and/or tremulous movement of limbs; behavioral characteristics: broader category including any combination of atypical frequent laughter/smiling; atypically happy demeanor; easily excitable personality, often with hand flapping movements; hypermotoric behavior; short attention span.
Frequent Roughly 80% of AS diagnoses have the following symptoms:
microcephaly: delayed, disproportionate growth in head circumference, with (absolute or relative) microcephaly by age 2; seizures: onset usually occurs under age 3; abnormal EEG: characteristic pattern with large amplitude slow-spike waves
Associated Roughly 20–80% of AS diagnoses are made in the setting of the following symptoms:
strabismus; hypopigmentation of skin and eyes; tongue thrusting; suck and/or swallowing disorders; hyperactive tendon reflexes; feeding problems during infancy; uplifted, flexed arms while walking; prominent mandible; increased sensitivity to heat; wide mouth, wide-spaced teeth; sleep disturbance, total sleep time is decreased due to nighttime waking; frequent drooling, protruding tongue; attraction to/fascination with water; excessive chewing/mouthing behaviors; flat back of the head; smooth palms; gastroesophageal reflux disease (GERD); constipation
Diagnostic criteria for the disorder were initially established in 1995 in collaboration with the Angelman Syndrome Foundation, based in the US; those criteria underwent revision in 2005.
Cause
Angelman syndrome is caused by mutations in the UBE3A gene. This gene is located within a region of chromosome 15 known as 15q11-q13. UBE3A is implicated in the ubiquitin pathway, which tags proteins to be degraded by a proteasome. Specifically, UBE3A codes for a very selective E6-AP ubiquitin ligase which targets MAPK1, PRMT5, CDK1, CDK4, β-catenin, and UBXD8 for ubiquitination. Alternative splicing of UBE3A results in three isoforms or variants of UBE3A with varying N-terminus.
Typically, a fetus inherits a maternal copy of UBE3A and a paternal copy of UBE3A. In certain areas of the developing brain, the paternal copy of UBE3A is inactivated through a process known as imprinting, and the fetus relies solely on the functioning maternal copy of UBE3A in order to develop normally. In an individual with AS, the maternal UBE3A copy is absent or not functioning normally, which negatively impacts fetal brain development. There are four main maternal UBE3A geneotypes which make up a majority of the AS cases, which are listed below.
Deletion Positive (70% of AS cases): The most common genetic defect leading to Angelman syndrome is a 5- to 7-Mb (megabase) maternal deletion in chromosomal region 15q11.2-q13. Essentially, the maternal copy of the UBE3A allele is completely deleted, and only the paternal copy of the UBE3A gene is present.
Mutation (11% of AS cases): This genotype of AS entails a mutation of the maternal UBE3A which prevents the expression of maternal UBE3A or alters its function.
Imprinting Center Defect (6% of AS cases): Individuals with an imprinting center defect have an abnormality in the imprinting center of the maternal copy of the UBE3A gene. The imprinting center is an area on the chromosome that regulates whether genes are turned on or turned off. Therefore, the maternal copy of the UBE3A gene may be present in an individual with AS; however, if the AS patient has an imprinting center defect the maternal UBE3A gene is unavailable in the brain.
Paternal Uniparental Disomy (UPD) (3% of AS cases): This genotype occurs when there are two paternal copies of UBE3A and no maternal copy. Since the paternal copy of UBE3A is silent in the brain and the maternal copy is still absent, this genotype is still problematic for CNS development.
Importantly, the genotypes are predictive of the severity of symptoms. For example, the most common genotype of AS, deletion positive, is associated with more severe symptoms such as microcephaly, seizures, hypopigmentation, less weight gain, while the more rare genetic causes of AS, paternal uniparental disomy is associated with less severe symptoms.
Diagnosis The presence of the consistent features of AS is required for the diagnosis of AS. However, additional genetic testing can be performed to confirm a proper diagnosis of AS.
Methylation studies: In 80% of AS patients, the maternal copy of UBE3A is methylated. Therefore, methylation studies can be done to confirm AS in patients.
Fluorescence in situ hybridization (FISH): is conducted following methylation studies to detect if there is a maternal deletion of UBE3A on chromosome 15
DNA marker analysis: Imprinting defects or paternal disomy must also be considered using other molecular tests or DNA marker analysis, respectively. Myethylation studies can miss a mutation of UBE3A. Therefore, DNA sequencing can be done.
Electroencephalograms: Lastly, electroencephalograms can indicate characteristic patterns of AS brain activity and also reveal epileptic activity, a common symptom in AS.
Differential diagnosis Other conditions that can appear similar include:
Autism spectrum; Angelman syndrome involves genes that have also been linked to 1–2% of autism spectrum disorder cases. Cerebral palsy; Rett syndrome; Mowat–Wilson syndrome; Adenylosuccinate lyase deficiency; Pitt–Hopkins syndrome; Phelan–McDermid syndrome; Skraban–Deardorff syndrome; Prader–Willi syndrome (PWS): Region 15q11-13 is implicated in both Angelman syndrome and PWS. While AS results from mutation, loss or abnormal imprinting involving the UBE3A gene within this region on the maternal chromosome, loss of a different cluster of genes within the same region on the paternal chromosome causes PWS.
Treatment
There is currently no approved cure available. The epilepsy can be controlled by the use of one or more types of anticonvulsant medications. However, there are difficulties in ascertaining the levels and types of anticonvulsant medications needed to establish control, because people with AS often have multiple types of seizures. Many families use melatonin to promote sleep in a condition which often affects sleep patterns. Mild laxatives are also used frequently to encourage regular bowel movements. Additionally, among a cohort of 163 individuals with AS, ranitidine was shown to be the most frequently prescribed medication for treating gastroesophageal reflux disease (GERD). Early intervention with physiotherapy is sometimes used to encourage joint mobility and prevent stiffening of the joints.
Occupational therapists can contribute to the development and enhancement of non-verbal communication skills by addressing foundational skills such as finger isolation, motor planning, hand-eye coordination, spatial awareness, and gesture refinement. This is important because individuals with Angelman syndrome who already possess some form of non-verbal communication have a much harder time adapting to changes in a new or existing AAC device because they can communicate their needs much faster nonverbally.
Occupational therapists can assist individuals with Angelman syndrome with many other skills as well. Many individuals with Angelman syndrome also have difficulty processing sensory information and responding appropriately to sensory stimuli. Occupational therapists can work together with these individuals to improve their visual perceptual skills and increase their sensory awareness.
AS limits expressive verbal communication, but many people with the disorder can learn nonverbal communication skills to express their needs. Deictic gesturing (i.e., pointing to an object) is the most commonly used form of non-symbolic communication in AS, followed by physically manipulating others (such as moving a caregiver's hand to a specific object or guiding a person to a new location) and non-speech vocalizations. Some are able to use symbolic communication such as signing, though the prevalence of this ability is related to both genetic etiology and epilepsy status, with non-deletion etiologies without epilepsy showing the highest prevalence of symbolic communication skills. People with AS tend to have much higher receptive language abilities than expressive; recent studies have shown that patients with AS have typical auditory brain region responses to speech but atypical memory responses, suggesting that word meaning recall is delayed or processed differently in AS. This may be caused by the altered cortical morphology seen in AS in the precuneus, a region of the brain involved in self-reflection and memory. Similarly, both adults and children with AS show a delay in processing speed in speech processing, and this should be accounted for during communication.
An experimental treatment, currently in clinical development by Roche, targets the GABAA α5 receptor. Alogabat is a small molecule that acts as a positive allosteric modulator (PAMs) of the receptor. It does not involve replacing or activating the UBE3A gene; instead, it is a mechanism aimed at improving various symptoms of AS, such as learning, sleep, and seizure control.
Novel therapeutic approaches
Rodent models