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(medicine) A genetic disorder that is caused by defects on the maternally derived chromosome 15, causing severe mental retardation, absence of speech, microcephaly, facial dysmorphism, seizures, neonatal hypotonia, ataxic movements, and inappropriate laughter.
Angelman syndrome
Definition
Angelman syndrome (AS) is a genetic condition that causes severe mental retardation, severe speech impairment, and a characteristic happy and excitable demeanor.
Description
Individuals with AS show evidence of delayed development by 6–12 months of age. Eventually, this delay is recognized as severe mental retardation. Unlike some genetic conditions causing severe mental retardation, AS is not associated with developmental regression (loss of previously attained developmental milestones).
Severe speech impairment is a striking feature of AS. Speech is almost always limited to a few words. However, receptive language skills (listening to and understanding the speech of others) and non-verbal communication are not as severely affected.
Individuals with AS have a balance disorder, causing unstable and jerky movements. This typically includes gait ataxia (a slow, unbalanced way of walking) and tremulous movements of the limbs.
AS is also associated with a unique "happy" behavior, which may be the best-known feature of the condition. This may include frequent laughter or smiling, often with no apparent stimulus. Children with AS often appear happy, excited, and active. They may also sometimes flap their hands repeatedly. Generally, they have a short attention span. These characteristic behaviors led to the original name of this condition, the "Happy Puppet" syndrome. However, this name is no longer used as it is considered insensitive to AS individuals and their families.
Demographics
AS has been reported in individuals of diverse ethnic backgrounds. The incidence of the condition is estimated at 1/10,000 to 1/30,000.
Causes and symptoms
Most cases of AS have been traced to specific genetic defects on chromosomes received from the mother. In about 8% of individuals with AS, no genetic cause can be identified. This may reflect misdiagnosis, or the presence of additional, unrecognized mechanisms leading to AS.
The first abnormalities noted in an infant with AS are often delays in motor milestones (those related to physical skills, such as sitting up or walking), muscular hypotonia (poor muscle tone), and speech impairment. Some infants seem unaccountably happy and may exhibit fits of laughter. By age 12 months, 50% of infants with AS have microcephaly (a small head size). Tremulous movements are often noted during the first year of life.
Seizures occur in 80% of children with AS, usually by three years of age. No major brain lesions are typically seen on cranial imaging studies.
The achievement of walking is delayed, usually occurring between two-and-a-half and six years of age. The child with AS typically exhibits a jerky, stiff gait, often with uplifted and bent arms. About 10% of individuals with AS do not walk. Additionally, children may have drooling, protrusion of the tongue, hyperactivity, and a short attention span.
Many children have a decreased need for sleep and abnormal sleep/wake cycles. This problem may emerge in infancy and persist throughout childhood. Upon awakening at night, children may become very active and destructive to bedroom surroundings.
The language impairment associated with AS is severe. Most children with AS fail to learn appropriate and consistent use of more than a few words. Receptive language skills are less severely affected. Older children and adults are able to communicate by using gestures or communication boards (special devices bearing visual symbols corresponding to commonly used expressions or words).
Some individuals with AS may have a lighter skin complexion than would be expected given their family background.
Diagnosis
The clinical diagnosis of AS is made on the basis of physical examination and medical and developmental history. Confirmation requires specialized laboratory testing.
There is no single laboratory test that can identify all cases of AS. Several different tests may be performed to look for the various genetic causes of AS. When positive, these tests are considered diagnostic for AS. These include DNA methylation studies, UBE3A mutation analysis, and fluorescent in situ hybridization (FISH).
Treatment team
Children with Angelman syndrome will need help from a variety of professionals, including a general pediatrician and pediatric neurologist. A child psychiatrist and/or psychologist may be helpful as well, particularly to help design and implement various behavioral plans. Physical, occupational, and speech and language therapists may help support specific deficits. A learning specialist may be consulted for help with an individualized educational plan.
Treatment
There is no specific treatment for AS. A variety of symptomatic management strategies may be offered for hyperactivity, seizures, mental retardation, speech impairment, and other medical problems.
The typical hyperactivity in AS may not respond to traditional behavior modification strategies. Children with AS may have a decreased need for sleep and a tendency to awaken during the night. Drug therapy may be prescribed to counteract hyperactivity or aid sleep. Most families make special accommodations for their child by providing a safe yet confining environment.
Seizures in AS are usually controllable with one or more anti-seizure medications. In some individuals with severe seizures, dietary manipulations may be tried in combination with medication.
Individuals with AS may be more likely to develop particular medical problems which are treated accordingly. Newborn babies may have difficulty feeding and special bottle nipples or other interventions may be necessary. Gastroesophageal reflux (heartburn) may lead to vomiting or poor weight gain and may be treated with drugs or surgery. Constipation is a frequent problem and is treated with laxative medications. Many individuals with AS have strabismus (crossed eyes), which may require surgical correction. Orthopedic problems, such as tightening of tendons or scoliosis, are common. These problems may be treated with physical therapy, bracing, or surgery.
Prognosis
Individuals with AS have significant mental retardation and speech impairment that are considered to occur in all cases. However, they do have capacity to learn and should receive appropriate educational training.
Young people with AS typically have good physical health aside from seizures. Although life span data are not available, the life span of people with AS is expected to be normal.
Special concerns
Educational concerns
Children with AS appear to benefit from targeted educational training. Physical and occupational therapy may improve the disordered, unbalanced movements typical of AS. Children with a severe balance disorder may require special supportive chairs. Speech therapy is often directed towards the development of nonverbal communication strategies, such as picture cards, communication boards, or basic signing gestures.
Legal issues
The most pressing long-term concern for patients with AS is working out a life plan for ongoing care, since many are likely to outlive their parents. The parents of a child diagnosed with AS should consult an estate planner, an attorney, and a certified public accountant (CPA) in order to draft a life plan and letter of intent. A letter of intent is not a legally binding document, but it gives the patient's siblings and other relatives or caregivers necessary information on providing for her in the future. The attorney can help the parents decide about such matters as guardianship as well as guide them through the legal process of appointing a guardian, which varies from state to state.
Resources
PERIODICALS
"Angelman syndrome." The Exceptional Parent 30, no. 3 (March 2000): S2.
Lombroso, Paul J. "Genetics of Childhood Disorders: XVI. Angelman Syndrome: A Failure to Process." Journal of the American Academy of Child and Adolescent Psychiatry 39, no. 7 (July 2000): 931.
ORGANIZATION
Angelman Syndrome Foundation, Inc. 414 Plaza Drive, Suite 209, Westmont, IL 60559. (800) IF-ANGEL or (630) 734-9267. Fax: (630) 655-0391. Info@angelman.org. http://www.angelman.org.
WEBSITES
Williams, Charles A., M.D., Amy C. Lossie, Ph.D., and Daniel J. Driscoll, Ph.D. "Angelman Syndrome." (November 21, 2000). GeneClinics. University of Washington, Seattle. http://www.geneclinics.org/profiles/angelman/details.
Jennifer Ann Roggenbuck, MS, CGC
Rosalyn Carson-Dewitt, MD
Definition
Angelman's syndrome is a relatively rare genetic disorder that causes a variety of neurological problems, including developmental delay, seizures, speech impairment, and problems with movement and balance.
Description
Angelman's syndrome was first described in 1965 by Harold Angelman, who noted that a group of children in his medical practice had flat heads, made jerky movements, held their tongues in a protruding way, and had curious bouts of laughter.
Demographics
Angelman's syndrome is relatively rare. As of the early 2000s there were only about 1,000 to 5,000 known cases of the syndrome in the United States. There is no predilection for either sex or for any particular ethnicity.
Causes and Symptoms
Most cases of Angelman's syndrome can be traced to a genetic abnormality inherited from a maternal chromosome (15). A particular area of genes that should control the production and function of a protein called ubiquitin is either absent or ineffective. A minority of cases of Angelman's syndrome are due to new mutations in this same area of genes.
Children with Angelman's syndrome have an abnormally small, flat appearance to their skull. By one to two months of age, infants with the syndrome develop feeding difficulties. By six to 12 months, developmental delay is usually noted. Most children develop seizures by three years of age. Other characteristics of the syndrome include abnormally decreased muscle tone, fair skin and hair, protruding jaw, hyperactivity, episodes of uncontrollable laughter, difficulty sleeping, and severe problems with movement and balance. The disorder is sometimes called "happy puppet syndrome," because many children with the disorder have jerky, flapping movements of the arms; a stiff, jerky style of walking (gait); a happy, excited demeanor; and regular episodes of uncontrollable laughter.
Diagnosis
Diagnosis is made by noting the characteristic cluster of symptoms. Careful chromosomal study can reveal abnormalities on chromosome 15 that are consistent with those identified in Angelman's syndrome.
Treatment
As of 2004 there is no cure for Angelman's syndrome. Treatments attempt to ameliorate the symptoms in order to improve the quality of life. Treatments may include anti-seizure medications, physical and occupational therapy, and speech and language therapy.
Prognosis
Most children with Angelman syndrome are severely developmentally delayed. They never acquire normal speech, and they require care and supervision throughout their lives.
Prevention
There are no methods to prevent Angelman syndrome. However, if the disorder is known to run in a family, genetic counseling may help parents evaluate their level of risk for having a child with this disorder. Specialized testing of chromosome 15 will be required; the usual tests done during amniocentesis or chorionic villi sampling will not reveal the specific, small genetic flaw that causes Angelman syndrome.
Parental Concerns
Caring for a child with Angelman syndrome constitutes a complex challenge. Parents should be encouraged to seek out parental and sibling support groups and respite care in order to help them face these challenges.
Resources
Books
Hall, Judith G. "Chromosomal Clinical Abnormalities." In Nelson Textbook of Pediatrics. Edited by Richard E. Behrman, et al. Philadelphia: Saunders, 2004.
Jankovic, Joseph. "Movement Disorders." In Textbook of Clinical Neurology. Edited by Christopher G. Goetz. Philadelphia: Saunders, 2003.
Periodicals
Didden, R. "Sleep problems in individuals with Angelman syndrome." In American Journal of Mental Retardation 109 (July 2004): 275–84.
Oliver, C. "Effects of environmental events on smiling and laughing behavior in Angelman syndrome." In American Journal of Mental Retardation 107 (May 2002): 194–200.
Peters, S. U. "Cognitive and adaptive behavior profiles of children with Angelman syndrome." In American Journal of Medical Genetics 128A (July 2004): 110–3.
Organizations
American Academy of Pediatrics. 141 Northwest Point Blvd., Elk Grove Village, IL 60007-1098. Web site: www.aap.org.
Web Sites
"Angelman Syndrome: Just because I can't talk doesn't mean I don't have anything to say." Available online at www.armyofangels.org/ (accessed December 19, 2004).
"Facts about Angelman Syndrome: Information for Families [Internet links]." Available online at www.asclepius.com/angel/asinfo.html (accessed December 19, 2004).
[Article by: Rosalyn Carson-DeWitt, MD]
| ICD-10 | Q93.5 |
|---|---|
| ICD-9 | 759.89 |
| OMIM | 105830 |
| DiseasesDB | 712 |
| MeSH | D017204 |
Angelman Syndrome (AS) is a rare neuro-genetic disorder named after a British pediatrician, Dr. Harry Angelman, who first described the syndrome in 1965.[1] AS is characterised by intellectual and developmental delay, speech impediment, sleep disturbance, unstable jerky gait, seizures, hand flapping movements, frequent laughter/smiling and usually a happy demeanour. AS is a classic example of genetic imprinting caused by deletion or inactivation of critical genes on the maternally inherited chromosome 15. The sister syndrome is called Prader-Willi syndrome, and is caused by loss of paternal genes.
An older, alternative term for AS, happy puppet syndrome, is generally considered pejorative and stigmatizing so it is no longer used, though it remains useful as a diagnostic heuristic.
![Dr. Angelman stated this painting led him to write his seminal paper in 1965 - "I happened to see an oil painting...called... "a Boy with a Puppet". The boy's laughing face and the fact that my patients exhibited jerky movements gave me the idea of writing an article about the three children with a title of Puppet Children."[1]](http://content.answers.com/main/content/wp/en/thumb/e/e4/150px-Ritratto_di_fanciullo_con_disegno_Giovanni_Francesco_Caroto.jpg)
Dr. Harry Angelman, a pediatrician working in Warrington (then in Lancashire) first reported three children with this condition in 1965.[1] It was initially incorrectly presumed to be rare.
In 1987, it was first noted that around half of the children with Angelman syndrome have a small piece of chromosome 15 missing (chromosome 15q partial deletion).
Though the prevalance of Angelman syndrome is not precisely known, there are some estimates. The best data available is from studies of school age children, ages 6-13 years, living in Sweden and from Denmark where the diagnosis of AS children in medical clinics was compared to an 8 year period of about 45,000 births. The Swedish study showed an AS prevalence of about 1/12,000[2] and the Danish study showed a minimum AS prevalence of about 1/10,000.[3] Note that it is desirable to use the term prevalence, since estimates of AS diagnosis have been made in relatively small cohorts of children over various periods of time.
There appear to be no reported prevalence studies that have screened newborns to detect rates of AS. Population wide prevalence figures would need to take into consideration that longevity in AS is probably reduced (severe mental delay and seizure presence would be risk factors) but no actuarial or other data are available on life span shortening. Likewise, it is not known what percent of individuals with AS are undiagnosed, although this is expected to be significant. Accordingly, to estimate the number of people with AS living in the society, it would be inaccurate to divide any estimated AS prevalence figure into a total population number.
Given this information, it appears that the prevalence of AS among children and young adults is between 1/10,000 and 1/20,000. It is suggested to use a 1/15,000 figure if a single figure is needed. For population projections, estimates using birth rates can be used. For example, if an area has a birth rate of about 200,000/year it would be estimated that about 13 babies would be born each year with AS.
Angelman syndrome is caused by the loss of the normal maternal contribution to a region of chromosome 15, most commonly by deletion of a segment of that chromosome. Other causes include uniparental disomy, translocation, or single gene mutation in that region. A healthy person receives two copies of chromosome 15, one from mother, the other from father. However, in the region of the chromosome that is critical for Angelman syndrome, the maternal and paternal contribution express certain genes very differently. This is due to sex-related epigenetic imprinting; the biochemical mechanism is DNA methylation. If the maternal contribution is lost or mutated, the result is Angelman syndrome. (When the paternal contribution is lost, by similar mechanisms, the result is Prader-Willi syndrome.)
Angelman syndrome can also be the result of mutation of a single gene. This gene (Ube3a,[4] part of the ubiquitin pathway) is present on both the maternal and paternal chromosomes, but differs in the pattern of methylation (Imprinting). The paternal silencing of the Ube3a gene occurs in a brain region-specific manner; the maternal allele is active almost exclusively in the hippocampus and cerebellum. The most common genetic defect leading to Angelman syndrome is an ~4Mb (mega base) maternal deletion in chromosomal region 15q11-13 causing an absence of Ube3a expression in the maternally imprinted brain regions. Ube3a codes for an E6-AP ubiquitin ligase, which chooses its substrates very selectively and the four identified E6-AP substrates have shed little light on the possible molecular mechanisms underlying the human Angelman syndrome mental retardation state.
Initial studies of mice that do not express maternal Ube3a show severe impairments in hippocampal memory formation. Most notably, there is a deficit in a learning paradigm that involves hippocampus-dependent contextual fear conditioning. In addition, maintenance of long-term synaptic plasticity in hippocampal area CA1 in vitro is disrupted in Ube3a-/- mice. These results provide links amongst hippocampal synaptic plasticity in vitro, formation of hippocampus-dependent memory in vitro, and the molecular pathology of Angelman syndrome.
The diagnosis of Angelman syndrome is based on:
The Angelman Syndrome Foundation defined criteria for diagnosis in 1995,[5], and updated these criteria in 2005.[6]
Because Angelman Syndrome is not an illness, but a genetic condition, there is no currently available cure for AS. 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 AS is usually associated with having multiple varieties of seizures, rather than just the one as is normal cases of epilepsy. Many families use melatonin to promote sleep in a condition which often affects sleep patterns. Many individuals with Angelman Syndrome sleep for a maximum of 5 hours at any one time. Mild laxatives are also used frequently to encourage regular bowel movements and early intervention with physiotherapy is important to encourage joint mobility and prevent stiffening of the joints. Occupational therapy, speech therapy, hydrotherapy and music therapy are also used in the management of this condition.
Although a diagnosis of AS is life changing, it needn't be life destroying. Individuals with Angelman Syndrome are generally happy and contented individuals, who like human contact and play. AS individuals exhibit a profound desire for personal interaction with others. Communication can be difficult at first, but as an AS child develops, there is a definite character and ability to make themselves understood. It is widely accepted that their understanding of communication directed to them is much larger than their ability to return conversation. Most afflicted individuals will not develop more than 5-10 words, if at all.[7] The infectious laughter, coupled with the desire for play can and does lead to a fantastic parental relationship.
Note that the severity of the symptoms associated with AS varies significantly across the population of affected persons. Some speech and a greater degree of self-care are possible among the least profoundly affected. Unfortunately, walking and the use of simple sign language may be beyond the reach of the more profoundly affected. Early and continued participation in physical, occupational (related to the development of fine-motor control skills), and communication (speech) therapies are believed to improve significantly the prognosis (in the areas of cognition and communication) of individuals affected by AS. Further, the specific genetic mechanism underlying the condition is thought to correlate to the general prognosis of the affected person. On one end of the spectrum, a mutation to the UBE3A gene is thought to correlate to the least affected, whereas larger deletions on chromosome 15 are thought to correspond to the most affected.
The clinical features of Angelman syndrome alter with age. As adulthood approaches, hyperactivity and poor sleep patterns improve. The seizures decrease in frequency and often cease altogether and the EEG abnormalities are less obvious. Medication is typically advisable to those with seizure disorders. Often overlooked is the contribution of the poor sleep patterns to the frequency and/or severity of the seizures. Medication may be worthwhile in order to help deal with this issue and improve the prognosis with respect to seizures and sleep. Also noteworthy are the reports that the frequency and severity of seizures temporarily escalate in pubescent AS girls but do not seem to affect long-term health.
The facial features remain recognizable but many adults with AS look remarkably youthful for their age.
Puberty and menstruation begin at around the normal time. Sexual development is thought to be normal, as evidenced by a single reported case of a woman with Angelman syndrome conceiving a female child who also had Angelman syndrome. [8]
The majority of those with AS achieve continence by day and some by night.
Dressing skills are variable and usually limited to items of clothing without buttons or zippers. Most adults are able to eat with a knife or spoon and fork and can learn to perform simple household tasks. General health is fairly good and life-span near normal. Particular problems which have arisen in adults are a tendency to obesity (more in females), and worsening of scoliosis[9] if it is present. The affectionate nature which is also a positive aspect in the younger children may also persist into adult life where it can pose a problem socially, but this problem is not insurmountable.
| Pathology: chromosome abnormalities (Q90-Q99, 758) | |
|---|---|
| Autosomal trisomies | Down syndrome (21), Edwards syndrome (18), Patau syndrome (13), Trisomy 9, Warkany syndrome 2 (8), Cat eye syndrome (22) |
| Autosomal monosomies/deletions | Wolf-Hirschhorn syndrome (4), Cri du chat (5), Angelman syndrome/Prader-Willi syndrome (15), Miller-Dieker syndrome/Smith-Magenis syndrome (17), 22q11.2 deletion syndrome (22) |
| X/Y linked | Turner syndrome (XO), Triple X syndrome (XXX), Klinefelter's syndrome (XXY), XYY |
| Translocations | Philadelphia chromosome, Burkitt's lymphoma |
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| Neurological Disorder. Gale Encyclopedia of Neurological Disorders. Copyright © 2005 by The Gale Group, Inc. All rights reserved. Read more |
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