Facts About Angelman Syndrome

http://www.angelman.org/
Home page for the U.S. Angelman Syndrome Foundation and for many links to other AS web sites.

http://www.asclepius.com/iaso/
Home page for the International AS Organization and for other links

http://www.geneclinics.org
Detailed information about medical and genetic aspects of AS. This site requires a simple log-in procedure but
all individuals can access this site without charge.

http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?105830
Contains detailed information and medical reference links about the genetic aspects of AS.

Introduction

In 1965, Dr. Harry Angelman, an English physician, first described three children with characteristics now known as the Angelman syndrome (AS) (1). He noted that all had a stiff, jerky gait, absent speech, excessive laughter and seizures. Other cases were eventually published (2-8) but the condition was considered to be extremely rare and many physicians doubted its existence. The first reports from North America appeared in the early 1980s (9, 10) and within the last ten years many new reports have appeared (11-18). Dr. Angelman relates the following regarding his discovery of this syndrome (19).

"The history of medicine is full of interesting stories about the discovery of illnesses. The saga of Angelman's syndrome is one such story. It was purely by chance that nearly thirty years ago three handicapped children were admitted at various times to my children's ward in England. They had a variety of disabilities and although, at first sight, they seemed to be suffering from different conditions, I felt that there was a common cause for their illness. The diagnosis was purely a clinical one because, in spite of technical investigations which today are more refined, I was unable to establish scientific proof that the three children all had the same handicap. In view of this I hesitated to write about them in the medical journals. However, when on holiday in Italy I happened to see an oil painting in the Castelvecchio museum in Verona 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. It was not a name that pleased all parents but it served as a means of combining the three little patients into a single group. Later the name was changed to Angelman syndrome. This article was published in 1965, and after some initial interest, lay almost forgotten until the early eighties."

AS has been reported throughout the world among divergent racial groups. In North America, the great majority of known cases seem to be of Caucasian origin. Although the exact incidence of AS is unknown, an estimate of between 1 in 15,000 to 1 in 30,000 seems reasonable (16, 20).

Developmental and physical features

Angelman syndrome is usually not recognized at birth or in infancy since the developmental problems are nonspecific during this time. Parents may first suspect the diagnosis after reading about AS or meeting a child with the condition. The most common age of diagnosis is between three and seven years when the characteristic behaviors and features become most evident. A summary of the developmental and physical findings has recently been published (21) for the purpose of establishing clinical criteria for the diagnosis and these are listed below. All of the features do not need to be present for the diagnosis to be made, and the diagnosis is often first suspected when the typical behaviors are recognized.

Developmental History and Laboratory Findings

Consensus Criteria for Clinical Features in Angelman Syndrome

Genetic basis of AS

For several decades the chromosome study of AS individuals revealed no abnormalities, but with the development of improved methods a very small deleted area was found in chromosome 15. Molecular methods such as FISH (fluorescence in situ hybridization) now demonstrate a deletion in about 70% of individuals with AS. The deleted area, although extremely small, is actually quite large when viewed at the molecular level. It is believed to be about 4 million base pairs in length, enough to contain many genes.

The deleted region on chromosome 15 is known to contain genes that are activated or inactivated depending upon the chromosome's parent of origin (i.e., a gene may be turned on on the chromosome 15 inherited from the mother but off on the chromosome 15 inherited from the father). This parent-specific gene activation is referred to as genetic imprinting. Because the deletions seen in AS only occur on the chromosome 15 inherited from the mother, the gene(s) responsible for AS were predicted to be active only on the maternal chromosome 15. Disruption of genes that are active on the paternally-derived chromosome 15 is now known to cause another developmental disorder termed the Prader-Willi syndrome (PWS). The PWS gene(s) are actually located close to the AS gene, but they are different.

In 1997, a gene within the AS deletion region called UBE3A was found to be mutated in approximately 5% of AS individuals (22, 23). These mutations can be as small as 1 base pair. This gene encodes a protein called a ubiquitin protein ligase, and UBE3A is believed to be the causative gene in AS. All mechanisms known to cause AS appear to cause inactivation or absence of this gene. UBE3A is an enzymatic component of a complex protein degradation system termed the ubiquitin-proteasome pathway. This pathway is located in the cytoplasm of all cells. The pathway involves a small protein molecule, ubiquitin, that can be attached to proteins thereby causing them to be degraded (24). In the normal brain, the copy of UBE3A inherited from the father is almost completely inactive, so the maternal copy performs most of the UBE3A function in the brain. Inheritance of a UBE3A mutation from the mother causes AS; inheritance of a UBE3A mutation from the father has no detectable effect on the child. In some families, AS caused by a UBE3A mutation can recur in more than one family member.

Another cause of AS (2-3% of cases) is paternal uniparental disomy (UPD), where the child inherits both copies of chromosome 15 from the father, with no copy inherited from the mother. In this case, there is no deletion or mutation, but the child is still missing the active UBE3A gene because the paternal-derived chromosomes only have brain-inactivated UBE3A genes.

A fourth class of AS individuals (3-5% of cases) have inherited chromosome 15 copies from both mother and father, but the copy inherited from the mother functions in the same way that a paternal chromosome 15 should function. This is referred to as an "imprinting defect". Some AS individuals with imprinting defects have very small deletions of a region called the Imprinting Center (IC) (25, 26). The IC regulates the activity of UBE3A from a distant location, but how this regulation occurs is not known. In some cases, AS caused by imprinting defects can recur in more than one member of a family.

These discoveries have led to the realization that there are several genetic "classes" or mechanisms that can cause AS (25, 27). All of these mechanisms lead to the typical clinical features of AS, although minor differences may occur between and within groups. These mechanisms are depicted on the diagram and summarized in the table.

Table: Genetic Classes of Angelman Syndrome

Large typical deletion	70%	Hypopigmentation is common
UBE3A mutation	5-7%	Possibility of normal carrier mother
Paternal uniparental disomy	2-3%	Inheritance of both 15s from father
Imprinting defect	3-5%	Some have IC deletion, some do not
Other chromosome abnormalities	2%	Unusual chromosome rearrangements
Unknown	15%	All diagnostic tests negative (FISH, methylation, UBE3A mutation analysis)

Genetic mechanisms leading to AS. Rectangles represent chromosome 15. Hatched chromosome has paternal pattern of gene functioning and DNA methylation; open chromosome has maternal pattern. AS can be caused by a large deletion of the region of the maternal chromosome 15 that contains UBE3A, or by a DNA sequence change (mutation) in the UBE3A gene inherited from the mother. AS can also be caused by inheritance of 2 normal copies of UBE3A from the father with no copy inherited from the mother. Another cause of AS, referred to as imprinting defect, occurs when the chromosome 15 inherited from the mother has the paternal pattern of gene functioning and DNA methylation.

Medical and developmental problems

More than 90% are reported to have seizures but this may be an overestimation because medical reports tend to dwell on the more severe cases. Less than 25% develop seizures before 12 months of age. Most have onset before 3 years, but occurrence in older children or in teenagers is not exceptional (13). The seizures can be of any seizure type (i.e. major motor involving jerking of all extremities; absence type involving brief periods with lack of awareness), and may require multiple anticonvulsant medications. Seizures may be difficult to recognize or distinguish from the child's usual tremulousness, hyperkinetic limb movements or attention deficits. The typical EEG is often more abnormal than expected and it may suggest seizures when in fact there are none.

There is no agreement as to the optimal seizure medication although valproic acid (e.g.,Depakote), topiramate (Topamax), carbamazepine (Tegretol), clonazepam (Klonopin), and ethosuximide (Zarontin) are more commonly prescribed than phenytoin (Dilantin), phenobarbital, or ACTH. Single medication use is preferred but seizure breakthrough is common. Some children with uncontrollable seizures have been placed on a ketogenic diet, but it is uncertain if this is beneficial. Children with AS are at risk for medication over-treatment because their movement abnormalities or attention deficits can be mistaken for seizures and because EEG abnormalities can persist even when seizures are controlled.

Hyperkinetic movements of the trunk and limbs have been noted in early infancy (15) and jitteriness or tremulousness may be present in the first 6 months of life. Voluntary movements are often irregular, varying from slight jerkiness to uncoordinated coarse movements that prevent walking, feeding, and reaching for objects. Gross motor milestones are delayed; sitting usually occurring after age 12 months and walking often delayed until age 3 or 4 years (11, 17).

In early childhood, the mildly impaired child can have almost normal walking. There may be only mild toe-walking or an apparent prancing gait. This may be accompanied by a tendency to lean or lurch forward. The tendency to lean forward is accentuated during running and, in addition, the arms are held uplifted. For these children, balance and coordination does not appear to be a major problem. More severely affected children can be very stiff and robot-like or extremely shaky and jerky when walking. Although they can crawl fairly effectively, they may "freeze up" or appear to become anxious when placed in the standing position. The legs are kept wide-based and the feet are flat and turned outward. This, accompanied by uplifted arms, flexed elbows and downward turned hands, produces the characteristic gait of AS. Some children are so ataxic and jerky that walking is not possible until they are older and better able to compensate motorically for the jerkiness; about 10% may fail to achieve walking (16). In situations where AS has not been diagnosed, the nonspecific diagnosis of cerebral palsy is often given to account for the abnormal walking. Physical therapy is usually helpful in improving ambulation and sometimes bracing or surgical intervention may be needed to properly align the legs.

Hyperactivity is probably the most typical behavior in AS. It is best described as hypermotoric with a short attention span. Essentially all young AS children have some component of hyperactivity (17) and males and females appear equally affected. Infants and toddlers may have seemingly ceaseless activity, constantly keeping their hands or toys in their mouth, moving from object to object. In extreme cases, the constant movement can cause accidental bruises and abrasions. Grabbing, pinching and biting in older children have also been noted and may be heightened by the hypermotoric activity. Persistent and consistent behavior modification helps decrease or eliminate these unwanted behaviors.

Attention span can be so short that social interaction is prevented because the AS child cannot attend to facial and other social cues. In milder cases, attention may be sufficient enough to learn sign language and other communication techniques. For these children, educational and developmental training programs are much easier to structure and are generally more effective. Observations in young adults suggest that the hypermotoric state decreases with age. Most AS children do not receive drug therapy for hyperactivity although some may benefit from use of medications such as methylphenidate (Ritalin). Use of sedating agents such as phenothiazines is not recommended due to their potency and side effects.

It is not known why laughter is so frequent in AS. Even laughter in normal individuals is not well understood. Studies of the brain in AS, using MRI or CT scans, have not shown any defect suggesting a site for a laughter-inducing abnormality. Although there is a type of seizure associated with laughter, termed gelastic epilepsy, this is not what occurs in AS. The laughter in AS seems mostly to be an expressive motor event; most reactions to stimuli, physical or mental, are accompanied by laughter or laughter-like facial grimacing. Although AS children experience a variety of emotions, apparent happiness predominates.

The first evidence of this distinctive behavior may be the onset of early or persistent social smiling at the age of 1-3 months. Giggling, chortling and constant smiling soon develop and appear to represent normal reflexive laughter but cooing and babbling are delayed or reduced. Later, several types of facial or behavioral expressions characterize the infant's personality. A few have pronounced laughing that is truly paroxysmal or contagious and "bursts of laughter" occurred in 70% in one study (17). More often, happy grimacing and a happy disposition are the predominant behaviors. In rare cases, the apparent happy disposition is fleeting as irritability and hyperactivity are the prevailing personality traits; crying, shrieking, screaming or short guttural sounds may then be the predominant behaviors.

Some AS children seem to have enough comprehension to be able to speak, but in even the highest functioning, conversational speech does not develop. Clayton-Smith (28) reported that a few individuals spoke 1-3 words, and in a survey of 47 individuals, Buntinx et al.(17) reported that 39% spoke up to 4 words, but it was not noted if these words were used meaningfully. Children with AS caused by uniparental disomy or extremely small deletions may have higher verbal and cognitive skills; at times use of 10-20 words may occur, although pronunciation may be awkward (29).

The speech disorder in AS has a somewhat typical evolution. Babies and young infants cry less often and have decreased cooing and babbling. A single apparent word, such as "mama," may develop around 10-18 months but it is used infrequently and indiscriminately without symbolic meaning. By 2-3 years of age, it is clear that speech is delayed but it may not be evident how little the AS child is verbally communicating; crying and other vocal outbursts may also be reduced. By 3 years of age, higher functioning AS children are initiating some type of non-verbal language. Some point to body parts and indicate some of their needs by use of simple gestures, but they are much better at following and understanding commands. Others, especially those with severe seizures or extreme hyperactivity cannot be attentive enough to achieve the first stages of communication, such as establishing sustained eye contact. The nonverbal language skills of AS children vary greatly; with the most advanced ones able to learn some sign language and to use such aids as picture-based communication boards.

Developmental testing is compromised by the attention deficit, hyperactivity and lack of speech and motor control. In such situations, test results are invariably in the severe range of functional impairment. More attentive children can perform in the moderate range and a minority can perform in some categories, like receptive social skills, in the mildly impaired range. As we learn more about the different genetic classes of AS it appears that patients with uniparental disomy have less severe clinical manifestations than those with large deletions (29).

It is known that the cognitive abilities in AS are higher than indicated from developmental testing. The most striking area where this is evident is in the disparity between understanding language and speaking language. Because of their ability to understand language, AS children soon distinguish themselves from other severe mental retardation conditions. Young adults with AS are usually socially adept and respond to most personal cues and interactions. Because of their interest in people they establish rewarding friendships and communicate a broad repertoire of feelings and sentiments, enriching their relationship to families and friends. They participate in group activities, household chores and in the activities and responsibilities of daily living. Like others, they enjoy most recreational activities such as TV, sports, going to the beach, etc.

There is a wide range however in the developmental outcome so that not all individuals with AS attain the above noted skills. A few will be more impaired in terms of their mental retardation and lack of attention, and this seems especially the case in those with difficult to control seizures or those with extremely pronounced ataxia and movement problems. Fortunately, most children with AS do not have these severe problems, but even for the less impaired child, inattentiveness and hyperactivity during early childhood often give the impression that profound functional impairment is the only outcome possible. However, with a secure home and consistent behavioral intervention and stimulation, the AS child begins to overcome these problems and developmental progress occurs.

When AS is caused by the large deletion, skin and eye hypopigmentation usually result. This occurs because there is a pigment gene (the P gene), located close to the AS gene, that is also missing (30). This pigment gene produces a protein (called the P protein ) that is believed to be crucial in melanin synthesis. Melanin is the main pigment molecule in our skin. In some children with AS, this hypopigmentation can be so severe that a form of albinism is suspected (31). In those with uniparental disomy or very small deletions, this gene is not missing and normal skin and eye pigmentation are seen. AS children with hypopigmentation are sun sensitive, so use of a protective sun screen is important. Not all AS children with deletions of the P gene are obviously hypopigmented, but may only have relatively lighter skin color than either parent.

Surveys of AS patients demonstrate 30-60% incidence of strabismus. This problem appears to be more common in children with eye hypopigmentation, since pigment in the retina is crucial to normal development of the optic nerve pathways. Management of strabismus in AS is similar to that in other children: evaluation by an ophthalmologist, correction of any visual deficit, and where appropriate, patching and surgical adjustment of the extraocular muscles. The hypermotoric activities of some AS children will make wearing of patches or glasses difficult.

The brain in AS is structurally normal although occasional abnormalities have been reported. The most common MRI or CT change, when any is detected, is mild cortical atrophy (i.e. a small decrease in the thickness of the cortex of the cerebrum) and/or mildly decreased myelination (i.e. the more central parts of the brain appear to have a slight degree of diminished white matter) (11, 12). Several detailed microscopic and chemical studies of the brain in AS have been reported but the findings generally have been nonspecific or the number of cases has been too few to make meaningful conclusions.

Parents report that decreased need for sleep and abnormal sleep/wake cycles are characteristic of AS. Sleep disturbances have been reported in AS infants and abnormal sleep/wake cycles have been studied in one AS child who benefited from a behavioral treatment program. Many families construct safe but confining bedrooms to accommodate disruptive nighttime wakefulness. Use of sedatives such a chloral hydrate or diphenylhydramine (Benadryl) may be helpful if wakefulness excessively disrupts home life. Recently, administration of 0.3 mg melatonin one hour before has been shown to be of help in some children but this should not be given in the middle of the night if the child awakens (32). Nevertheless, most AS infants and children do not receive sleep medications and those who do usually do not require long term use.

Feeding problems are frequent but not generally severe and usually manifest early as difficulty in sucking or swallowing (11, 12, 15). Tongue movements may be uncoordinated with thrusting and generalized oral-motor incoordination. There may be trouble initiating sucking and sustaining breast feeding, and bottle feeding may prove easier. Frequent spitting up may be interpreted as formula intolerance or gastroesophageal reflux. The feeding difficulties are often first present to the physician as a problem of poor weight gain or as a "failure to thrive" concern. Infrequently, severe gastroesophageal reflux may require surgery.

AS children are notorious for putting everything in their mouths. In early infancy, hand sucking (and sometimes foot sucking) is frequent. Later, most exploratory play is by oral manipulation and chewing. The tongue appears to be of normal shape and size, but in 30-50%, persistent tongue protrusion is a distinctive feature. Some have constant protrusion and drooling while others have protrusion that is noticeable only during laughter. Some infants with protrusion eventually have no noticeable problem during later childhood (some seem to improve after oral-motor therapy). For the usual AS child with protruding tongue behavior, the problem remains throughout childhood and can persist into adulthood. Drooling is frequently a persistent problem, often requiring bibs. Use of medications, such as scopolamine to dry secretions usually does not provide an adequate long term effect.

Newborns appear to be physically well formed, but by 12 months of age some show a deceleration of cranial growth which may represent relative or absolute microcephaly (absolute microcephaly means having a head circumference in the lower 2.5 percentile). The prevalence of absolute microcephaly varies from 88% (11) to 34% (13) and may be as low as 25% when non-deletion cases are also included (16). Most AS individuals however have head circumferences less than the 25th percentile by age 3 years, often accompanied by a flattened back of the head. Average height is lower than the mean for normal children but most AS children will plot within the normal range. Final adult height has ranged from 4 foot 9 inches to 5 foot 10 inches in a series of 8 adults with AS. Familial factors will influence growth so that taller parents have AS children that tend to be taller than the average AS child. During infancy, weight gain may be slow due to feeding problems but by early childhood, most AS children appear to have near normal subcutaneous fat. Obesity is rare but by late childhood some increased weight gain can occur. (23)

The severe developmental delay in AS mandates that a full range of early training and enrichment programs be made available. Unstable or nonambulatory children may also benefit from physical therapy. Occupational therapy may help improve fine motor and oral-motor control. Special adaptive chairs or positioners may be required at various times, especially for hypotonic or extremely ataxic children. Speech and communication 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.

Extremely active and hypermotoric AS children will require special provisions in the classroom and teacher aides or assistants may be needed to integrate the child into the classroom. AS children with attention deficits and hyperactivity need room to express themselves and to "grapple" with their hypermotoric activities. The classroom setting should be structured, in its physical design and its curricular program, so that the active AS child can fit in or adjust to the school environment. Individualization and flexibility are important factors. Consistent behavior modification in the school and at home can enable the AS child to be toilet trained (schedule-trained), and to perform most self help skills related to eating, dressing and performing general activities in the home.

During adolescence, puberty may be delayed by 1-3 years but sexual maturation occurs with development of normal secondary sexual characteristics. Some weight gain can be evident in this period but frank obesity is rare. Young AS adults continue to learn and are not known to have significant deterioration in their mental abilities. Physical health in AS appears to be remarkably good. For some, seizure medications can be discontinued in the early adolescent or adult years. AS individuals with severe ataxia may lose their ability to walk if ambulation is not encouraged. Scoliosis can develop in adolescence and is especially a problem in those that are nonambulatory. Scoliosis is treated with early bracing to prevent progression, and surgical correction or stabilization may be necessary for severe cases. Life span does not appear to be dramatically shortened and we are aware of a 58-year-old woman with AS and know of many in their third or fourth decades of life.

Laboratory testing for AS

In the child in whom the diagnosis is suspected, a high resolution chromosome analysis is often first performed to insure that no other chromosome disorder is present, since features such as mental delay, microcephaly, or seizures can be seen in other chromosome abnormalities. Concurrent with the chromosome test, a fluorescent in situ hybridization (FISH) analysis is usually ordered. This test uses molecular tags to detect the deletion on chromosome 15. The tags are directly applied to the chromosome and it is examined under a microscope after special stains are applied. The FISH test is far superior to the usual chromosome test. The child with AS should have their chromosomes 15 fully studied to insure that they are structurally normal; a maternal chromosome study as well provides additional confirmation that the maternal chromosome 15 is structurally normal. In the diagnostic testing for AS, a "DNA methylation" test may be ordered first or ordered in conjunction with chromosome and FISH testing. The methylation test can detect the large common deletion type of AS, as well as those with uniparental disomy or defects in the imprinting center (IC). Confirmation of uniparental disomy needs to be made by additional molecular testing (usually, study of parental blood is required) and confirmation of IC mutations requires specific molecular deletion analysis in the IC area. About 80-85% of individuals with AS will be diagnosed by a combination of these tests, but there still remain a small group in whom additional genetic testing of the UBE3A gene may then detect an abnormality. At this time, molecular analysis for UBE3A is available for clinical use in a few referral laboratories but the testing is expensive. Molecular testing of the IC region is not commercially available for clinical use but is being performed in some research labs.

Genetic counseling

About 70-75% of cases of AS are caused by spontaneously occurring large common deletions or by paternal uniparental disomy. Recurrence in this group is extremely rare, and the recurrence risk is estimated to be less than 1%. Prenatal diagnosis is available by use of cytogenetic or molecular testing.

Individuals with AS due to IC mutations can have either inherited this mutation from a normal mother or have received the mutation spontaneously ( i.e., not inherited). In the former case, the theoretical recurrence risk is 50% and in the latter (i.e., spontaneous mutation) the risk is believed to be less than 1%.

Those with AS due to UBE3A mutations, as is the case with IC mutations, can have either received the mutation from a normal mother or acquired it by spontaneous mutation. Recurrence risk is felt to be 50% in the former and less than 1% in the latter. When IC or UBE3A mutations have been molecularly characterized, prenatal diagnosis is available via molecular testing.

Cases of AS that are associated with a structurally abnormal chromosome 15 (i.e., a chromosome translocation) may have an increased risk for recurrence. In these instances, the recurrence risk must be based upon the specific chromosome abnormality and what is known about its risk of recurrence. Prenatal diagnosis by cytogenetic and/or molecular techniques is generally available in these instances.

Estimating recurrence risk is very difficult for individuals with AS who have normal genetic studies (i.e., have none of the above etiologies). Familial occurrence in this group does occur, so it is apparent that the recurrence risk is higher than it is for those with, for example, a typical large common deletion. Until more is known about this group, caution is warranted during genetic counseling since the theoretical recurrence risk can be as high as 50% (if one assumes that an undetected AS-causing mutation has been inherited from the mother).

It should be noted that the customary chromosome study, performed during routine prenatal diagnosis is often interpreted as normal in AS fetuses with deletions, since the small abnormalities on chromosome 15 would not be detected by this type of study. Specialized chromosome 15/FISH studies are needed for prenatal diagnosis in cases where the testing seeks to establish normal chromosome 15 structure. Also, fetal ultrasound offers no help in detecting physical abnormalities related to AS since the affected fetus is expected to be well formed. Amniotic fluid volume and alpha-feto-protein levels also appear normal.

Because of the complexities of evaluating recurrence risk, genetic counseling from an expert familiar with AS is advised (33).

Acknowledgements:

This document was developed by the Angelman Syndrome Foundation with assistance from Charles Williams, M.D., Raymond C. Philips Unit, Division of Genetics, Department of Pediatrics, University of Florida, Gainesville; and Joseph Wagstaff, M.D., Ph.D., Department of Pediatrics and Department of Biochemical and Molecular Genetics, University of Virginia School of Medicine, Charlottesville.

Internet Resources: