NORD gratefully acknowledges Charles Williams, MD, Emeritus Professor, Division of Genetics and Metabolism, Department of Pediatrics, University of Florida College of Medicine; member of the Angelman Syndrome Foundation Scientific Advisory Committee, for assistance in the preparation of this report.
Angelman syndrome is a rare genetic and neurological disorder characterized by severe developmental delay and learning disabilities; absence or near absence of speech; inability to coordinate voluntary movements (ataxia); tremulousness with jerky movements of the arms and legs and a distinct behavioral pattern characterized by a happy disposition and unprovoked episodes of laughter and smiling. Although those with the syndrome may be unable to speak, many gradually learn to communicate through other means such as gesturing. In addition, children may have enough receptive language ability to understand simple forms of language communication. Additional symptoms may occur including seizures, sleep disorders and feeding difficulties. Some children with Angelman syndrome may have distinctive facial features but most facial features reflect the normal parental traits. Angelman syndrome is caused by deletion or abnormal expression of the UBE3A gene.Introduction
Angelman syndrome was first described in the medical literature in 1965 by Dr. Harry Angelman, an English physician. The characteristic findings of Angelman syndrome are not usually apparent at birth and diagnosis of the disorder is usually made between 1 and 4 years of age.
Angelman syndrome is associated with a broad spectrum of possible symptoms. The specific symptoms of Angelman syndrome vary from person to person. Individuals with Angelman syndrome will not have all of the symptoms discussed below. For example, some individuals with Angelman syndrome may have seizures, others may not. Most may be unable to speak while in a few there is some limited speech.
Children with Angelman syndrome experience delays in reaching developmental milestones (developmental delays) and have severe learning disabilities. Children with Angelman syndrome also have significant communication difficulties. Most children do not develop the ability to speak more than a few words. Children usually can understand simple commands. Older children and adults may be able to communicate through gesturing and or using communication boards.
An early finding in most children with Angelman syndrome is a movement or balance abnormality that includes jerky movements due to an inability to coordinate voluntary movements (ataxia). Children with Angelman syndrome may hold their arms up with the wrists and elbows bent and may flap their hands repeatedly when walking or excited. Diminished muscle tone (hypotonia) of the trunk, increased muscle tone (hypertonia) of the arms and legs, and abnormally exaggerated or brisk reflex responses (hyperreflexia) may also occur. Some children with Angelman syndrome experience subtle tremors of the arms and legs. These movement disorders may be apparent early during infancy (approximately 6-12 months of age). Motor milestones (e.g., walking) are usually delayed. In mild cases, children may begin to walk at 2-3 years of age. In more severe cases, walking may be noticeably slow, stiff and jerky. Some children may not be able to walk until they are 5-10 years of age. In approximately 10 percent of cases, children with Angelman syndrome do not walk unaided.
Infants and children with Angelman syndrome have a distinct behavioral pattern marked by a happy demeanor with frequent and often inappropriate episodes of unprovoked, prolonged laughter and smiling. Children with Angelman syndrome may be easily excited, hypermotoric and hyperactive. They are active explorers and often may appear to be constantly in motion.
Individuals with Angelman syndrome may have microcephaly in which the circumference of the head is smaller than would normally be expected for a child’s age and weight. In many cases, epileptic seizures may also occur. Seizures usually begin between one and five years of age and often improve by adolescence.
Some findings associated with Angelman syndrome occur less often than the above-mentioned symptoms. In some cases, individuals with Angelman syndrome may have distinctive facial features including a prominent chin, deep-set eyes, an abnormally wide mouth (marcostomia) with a protruding tongue, widely-spaced teeth and an abnormally flat back of the head (brachycephaly).
Feeding problems may occur during infancy often as a result of poor sucking ability. Infants with Angelman syndrome may also have swallowing difficulties. Feeding problems associated with Angelman syndrome are usually not severe. Children or adults with Angelman syndrome may experience constipation or gastroesophageal reflux disorder (GERD), a condition characterized by backflow (reflux) of the contents of stomach or small intestines into the tube that connects the mouth to the stomach (esophagus).
Additional findings include excessive drooling, crossed eyes (strabismus), lack of normal color of the (hypopigmentation) of the skin, eyes and hair due to lack of certain melanin pigments. This lack of pigment in the eye may cause sensitivity to light (photophobia), rapid, involuntary eye movements (nystagmus) and decreased clarity of vision (visual acuity). Sleep disturbances such as a decreased need for sleep and disrupted or abnormal sleep/wake cycles (e.g., awaking at night or rising earlier than normal) are frequent findings in children with Angelman syndrome. Children with Angelman syndrome may also have a fascination with water, love music, and be attracted to shiny objects. Some children may have an increased sensitivity to heat. As children with Angelman syndrome age, progressive side-to-side curvature of the spine (scoliosis) may become apparent. Puberty is usually unaffected in children with Angelman syndrome and fertility is possible.
Adults with Angelman syndrome may have more pronounced facial features such as a more prominent lower jaw (mandibular prognathism). Some individuals may develop abnormal protrusion of the cornea (keratoconus). Mobility may decrease as some individuals grow older and stiffening of the joints (contractures) may also develop. Some older children and adults may be prone to obesity.
Deficiency of the E3 ubiquitin protein ligase (UBE3A) gene expression causes Angelman syndrome. The gene is located in chromosome region 15 (15q11-q13).
Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 15q11-q13” refers to bands 11-13 on the long arm of chromosome 15. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
The abnormalities of UBE3A that can cause Angelman syndrome involve absence of the gene, changes in the structure of the gene, or changes in the function or expression of the gene. Genetic mechanisms that can disrupt UBE3A include chromosome deletion, imprinting error, paternal uniparental disomy and UBE3A mutation (see below). In approximately 10 percent of cases, no cause can be identified. In most cases of Angelman syndrome, these genetic changes appear to occur randomly (sporadically) but in about 3-5% they can be inherited.
In approximately 70-75 percent of cases there is a microdeletion of region 15q11-13 of the maternally-derived chromosome 15 that includes deletion of the UBE3A gene. This deletion usually occurs sporadically (de novo) and is not inherited. The risk of recurrence for the deletion in a family is estimated to be 1-2 percent or less.
In about 1 percent of cases, a deletion of this chromosomal region may occur due to a complex chromosomal rearrangement, in which a segment of chromosome 15 breaks off and moves to another chromosomal location. Those with this type of mechanism for the deletion are at a greater risk for recurrence.
A unique genetic phenomenon associated with Angelman syndrome is “imprinting.” Everyone has two copies of every gene (except for genes on the Y chromosome): one received from the father and the other from the mother. In most cases both genes are turned on and are thus active. However, in some cases, one gene is preferentially silenced or turned off depending upon which parent that gene came from. This process of “parent-of-origin” inactivation is an example of “genomic imprinting”. Genomic imprinting is controlled by molecular switches, and some of these switches act through a process called DNA methylation. Proper genetic imprinting is necessary for normal development. Imprinted genes tend to be found clustered or grouped together. Several imprinted genes are found in region 15q11-13 of chromosome 15. This region also contains an area known as the Imprinting Center, and this area regulates the imprinted genes in this region.
Some individuals with Angelman syndrome (approximately 3-5 percent) have a defect in genetic imprinting caused by errors in DNA methylation (see above for imprinting definition). In approximately 20 percent of cases (of the 3-5%) this is caused by a deletion of DNA within the Imprinting Center; the remaining 80 percent of cases are caused by as yet unknown or unidentified defects in genetic imprinting. There may be as high as a 50 percent risk of recurrence of Angelman syndrome due to imprinting defects that have DNA deletions.
Approximately 2-5 percent of Angelman syndrome cases are caused by uniparental disomy, an abnormality in which a person receives both copies of a chromosome from one parent instead of receiving one from each parent. In Angelman syndrome, both copies of chromosome 15 can be received from the father (paternal uniparental disomy). As a result, there are only paternally-expressed genes in this region and UBE3A is thus not expressed at all in the brain since it is normally only expressed on the maternal-derived chromosome. The risk of recurrence of uniparental disomy is less than 1 percent.
Abnormal changes (mutations) within UBE3A have been detected in 10-20 percent of individuals with Angelman syndrome. Loss of function of this gene causes all the cardinal clinical features of Angelman syndrome. UBE3A contains instructions for creating (encoding) the ubiquitin ligase protein. This protein marks other proteins so that the body is able to degrade targeted proteins, a process known as ubiquitination. There may be as high as a 50 percent risk of recurrence of Angelman syndrome due to a mutation of the UBE3A gene.
Some individuals with the symptoms of Angelman syndrome have no identifiable abnormality of chromosome 15. Some individuals in this group may have a disorder different from Angelman syndrome, but others may have an undetected mutation of the UBE3A gene or a mutation in another, yet-to-be-identified gene that can also cause or mimic Angelman syndrome.
Angelman syndrome affects males and females in equal numbers. The prevalence of Angelman syndrome is estimated to be approximately 1 in 12,000-20,000 people in the general population. However, many cases may go undiagnosed making it difficult to determine the disorder’s prevalence in the general population.
A diagnosis of Angelman syndrome may be made based upon a detailed patient history, a thorough clinical evaluation and identification of characteristic findings. About 80% of cases can be confirmed through a variety of specialized blood tests such as DNA methylation (detects, but does not discriminate between chromosome deletion, imprinting center defect and paternal uniparental disomy). Fluorescent in situ hybridization (FISH) or, most commonly, microarray chromosome analysis can detect the characteristic deletion (seen in 70% of cases) of chromosome 15q11-q13 in cells of the body. Mutation analysis of the Angelman gene, UBE3A, can detect about 10% of individuals with Angelman syndrome who have negative DNA methylation studies. Mutation analysis of UBE3A can be either ordered specifically as a single test but, more often now, UBE3A mutations are identified by use of a whole exome sequencing panel that includes a group of many genes known to cause intellectual deficiency or when one performs a complete whole exome sequencing test (e.g., a screening test on approximately 20,000 genes).
At this time, therapies for Angelman syndrome are symptomatic and supportive. Several clinical trials on Angelman syndrome are ongoing (see below) but there is no genetic therapy or curative medication available. Advances in neuroscience and in gene therapy techniques however hold great potential for providing meaningful treatment and/or cure of the syndrome.
The general physical health of those with Angelman syndrome is good and usual pediatric care, including customary childhood immunizations, can be provided.
Anti-seizure medications (anticonvulsants) are helpful to those experiencing seizures. Usually seizures can be adequately controlled with a single medication but in some cases seizure control may be difficult and multiple medications are needed. No one anticonvulsant drug has been proven to be most effective in all cases. Sleep disorders are common and may require behavioral therapy and adherence to strict bedtime routines. At time, sedating medications can be helpful.
Feeding difficulties may be treated by modified breast feeding methods and by means such as special nipples to assist infants with a poor ability to suck. Gastroesophageal reflux may be treated by upright positioning and drugs that aid the movement of food through the digestive system (motility drugs). Surgical tightening of the valve that connects the esophagus to the stomach (esophageal sphincter) may be required in some cases. Laxatives may be used to treat constipation.
Ankle braces/supports and physical therapy can help in achievement of walking. Scoliosis can develop in about 10% and may require braces or surgical correction. In some cases, strabismus may require surgical correction.
Early intervention is important to ensure that children with Angelman syndrome reach their potential. Special services that may be beneficial to children with Angelman syndrome may include special social support and other medical, social, and/or vocational services. Most children with Angelman syndrome benefit from physical, speech and occupational therapy. Behavioral modification therapy may be used to discourage unwanted behaviors. Use of special communication devices such as computer picture-based systems, voice emitting devices and other modern uses of technology all help Angelman syndrome individuals provide for improved learning and social communication.
Genetic counseling is recommended for the families of those with Angelman syndrome.
Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/ All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
Contact for additional information about Angelman syndrome:
Charles Williams, MD, Emeritus Professor
Division of Genetics and Metabolism
Department of Pediatrics, Univ. of Florida
Member of the ASF Scientific Advisory Committee
Office: (352) 294-5050
Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder.
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Dagli AI, Mueller J, Williams CA. Angelman Syndrome. 1998 Sep 15 [Updated 2017 Dec 21]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1144/ Accessed January 25, 2018.
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