FACTS ABOUT ANGELMAN SYNDROME 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, Carolinas Medical Center, Charlotte, N.C.
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 but the condition was considered to be extremely rare at that time, and many physicians doubted its existence. The first reports from North America appeared in the early 1980s. Dr. Angelman relates the following regarding his discovery of this syndrome. 2 "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 (e.g., circa 1964) 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 1 in 15,000 to 1 in 20,000 seems reasonable based a general assessment of the few surveys that have been conducted. 3-9
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 been published for the purpose of establishing clinical criteria for the diagnosis and these are listed below. 10 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 • • •
Normal prenatal and birth history with normal head circumference; absence of major birth defects Developmental delay evident by 6 - 12 months of age Delayed but forward progression of development (no loss of skills)
• •
Normal metabolic, hematologic and chemical laboratory profiles Structurally normal brain using MRI or CT (may have mild cortical atrophy or dysmyelination)
Clinical Features in Angelman Syndrome Consistent (100%)
• • • •
Developmental delay, functionally severe Speech impairment, none or minimal use of words; receptive and non-verbal communication skills higher than verbal ones Movement or balance disorder, usually ataxia of gait and/or tremulous movement of limbs Behavioral uniqueness: any combination of frequent laughter/smiling; apparent happy demeanor; easily excitable personality, often with hand flapping movements; hypermotoric behavior; short attention span
Frequent (more than 80%)
• • •
Delayed, disproportionate growth in head circumference, usually resulting in microcephaly (absolute or relative) by age 2 Seizures, onset usually < 3 years of age Abnormal EEG, characteristic pattern with large amplitude slow-spike waves
Associated (20 - 80%)
• • • • • • • • • • • • • •
Strabismus Hypopigmented skin and eyes Tongue thrusting; suck/swallowing disorders Hyperactive tendon reflexes Feeding problems during infancy Uplifted, flexed arms during walking Prominent mandible Increased sensitivity to heat Wide mouth, wide-spaced teeth Sleep disturbance Frequent drooling, protruding tongue Attraction to/fascination with water Excessive chewing/mouthing behaviors Flat back of head
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. Newer chromosome testing 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 chromosome deletion region, called UBE3A, was discovered. 11, 12 Abnormalities of only this gene now appear to be the fundamental cause of AS. All mechanisms known to cause AS either disrupt, inactivate or lead to absence of this gene. UBE3A encodes an enzymatic protein called a ubiquitin protein ligase and it is a component of a complex protein degradation system termed the ubiquitin-proteasome pathway. This pathway is located in the cytoplasm of all cells and it enables a small protein molecule, ubiquitin, to be attached to certain proteins, thereby causing them to be degraded. 13 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”. A small percentage of AS individuals with imprinting defects have very small DNA deletions in a region called the Imprinting Center (IC) 14-17 but all AS individuals with IC defects have abnormal DNA methylation changes in this region. The IC is located some distance from the UBE3A gene but it is still able to regulate UBE3A by a complex mechanism that is the subject of intense research. In some cases, AS caused by imprinting defects can recur in more than one member of a family. It has recently been discovered that assisted reproductive technologies (ART), such as in vitro fertilization (IVF) or intra-cytoplasmic sperm injection (ICSI), are associated with a few cases of AS due to the non-deletion type of IC defect. 18-20 These discoveries indicate that there are several genetic “classes” or mechanisms that can cause AS. 14, 21 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 (figure 1) and summarized in the table (table 1).
Table: Genetic Classes of Angelman Syndrome Large typical 15q11.2-13 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
Other chromosome
Unknown
3-5
Some have DNA deletion in IC, most do not
1
Unusual chromosome rearrangements leading to 15q11.2-13 deletion
15
All diagnostic tests negative (FISH, DNA methylation, UBE3A mutation analysis)
Genetic Mechanisms Leading to AS Figure 1: Genetic mechanisms leading to AS. Rectangles represent chromosome 15. Hatched chromosomes have paternal pattern of gene functioning and DNA methylation; open chromosomes have 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 (paternal UPD). 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 Seizures More than 90% of individuals with AS are reported to have seizures but this may be an overestimate 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. The seizures can be of any seizure type (i.e. major motor involving jerking of all extremities; absence type involving brief periods of lack of awareness), and may require multiple anticonvulsant medications. Seizures may be difficult to recognize or distinguish from the childâ&#x20AC;&#x2122;s usual tremulousness, hyperkinetic limb movements or attention deficits. The typical EEG is often more abnormal than expected from the clinical appearance, and it may suggest seizures when in fact there are none.9, 22, 23 There is no agreement as to the optimal seizure medication although valproic acid (Depakote), topiramate (Topamax), lamotrigine (Lamictal), levetiracetam (Keppra), and clonazepam (Klonopin)are more commonly used in the North Amereica. Carbamazepine (Tegretol), ethosuximide (Zarontin), phenytoin (Dilantin), phenobarbital, and ACTH are less commonly used. Vigabatrin Sabril, an inhibitor of GABA metabolism, should not be used. 24 Single medication use is preferred but seizure breakthrough is common. Some children with uncontrollable seizures have been placed on a ketogenic diet, and this may be helpful in some cases. 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.
Gait and Movement Disorders Hyperkinetic movements of the trunk and limbs have been noted in early infancy 25 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 to 5 years. 26, 27 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. 28 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 helpful in improving ambulation and sometimes bracing or surgical intervention may be needed to properly align the legs.
Hyperactivity Hyperactivity is a very common behavior in AS and it is best described as hypermotoric. Essentially all young AS children have some component of this increased motor activity 26 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 eliminates these unwanted behaviors.
In infants, the attention span can be short and social interaction is hindered because the AS child cannot seemingly attend to facial and other social cues. In childhood however attention abilities may increase, often associated with apparent curiosity as well. Attentiveness may then become sufficient enough to begin teaching sign-gesture language and other communication techniques. 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 such medications. Use of calming or sedating medications like Risperidone (Risperdal) is not generally advised but may be useful in rare cases.
Laughter and Happiness 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 â&#x20AC;&#x153;bursts of laughterâ&#x20AC;? occurred in 70% in one study. 26 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.
Speech and Language 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 29 reported that a few individuals spoke 1-3 words, and in a survey of 47 individuals, Buntinx et al.26 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 may have higher verbal and cognitive skills; at times use of 10-20 words may occur, although pronunciation may be awkward. 30 Finally, it is now clear that there are some AS individuals with a mosaic form of an imprinting center defect can have use of many words (up to 50 or 60) and a few of them can speak in simple sentences. 31 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.
Mental Retardation and Developmental Testing
Developmental testing is compromised in AS individuals due to attention deficits, hyperactivity and lack of speech and motor control. In such situations, test results are invariably in the severe range of functional impairment. It is possible however that the cognitive abilities in AS are higher than indicated from developmental testing. Nevertheless the developmental delay is still consistently in the functionally severe range and formal psychometric testing seem to indicate a ceiling for developmental achievement at around the 24-30 month range. 32-34 Angelman syndrome individuals have relative strengths in visual skills and social interactions that are based on non-verbal events. As we learn more about the different genetic classes of AS it appears that patients with the common chromosome deletion type of AS have relative more severe developmental impairment. 9, 35 Older individuals with AS have been evaluated in terms of their adaptive functioning and table 2, adapted from Summers and Pittman, lists some aspects of these studies. 36
Table 2: Studies of Adaptive Functioning in AS Study and Details
Findings
Smith et al., 1996 37 Ages 3-34 years, all had deletions
Teenager and adults were all dependent on assistance with feeding, toileting and dressing.
Moncla et al., 1999 38 Ages 15-36 years; compared deletion to non-deletion cases.
Vast majority with deletions were dependent on assistance for feeding, toileting and dressing; majority of non-deletion cases did not need assistance for dressing and feeding.
Clayton-Smith, 2001 39 Adults 20-53 years; not in institutions and 82% had deletions.
85% could perform simple task such as holding a utensil. 50% helped to undress themselves. 57% remained dry during the day (clock-trained) and 11% overnight.
Sandanam et al., 1997 40 Adult 24-36 years, all in institutions and all had deletions.
All were dependent for activities of daily living.
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.
Hypopigmentation 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. 41 This pigment gene produces a 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.42 When AS is caused by the other genetic mechanisms, this gene is not missing and thus normal skin and eye pigmentation is 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.
Strabismus and Ocular Albinism Surveys of AS patients demonstrate an increased incidence of strabismus. This problem appears to be more common in children with hypopigmentation (as above), 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.
CNS Structure The brain in AS is structurally normal although occasional abnormalities have been reported that probably are coincidental findings. 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). 27, 43 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 to few to make meaningful conclusions.
Sleep Disorders Parent reports and recent studies indicate that decreased need for sleep and abnormal sleep/wake cycles are common in AS. 44-46 An AS child, with abnormal sleep/wake cycles, has been reported to benefit from a behavioral treatment program. 47 Administration of melatonin one hour before has also 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. 48 Use of sedatives such a chloral hydrate or diphenylhydramine (Benadryl) may be helpful if wakefulness excessively disrupts home life. Some families construct safe but confining bedrooms to accommodate disruptive nighttime wakefulness. There are also many AS infants and children who apparently sleep fairly well and do not receive any sleep-related medications.
Feeding Problems and Oral-Motor Behaviors Feeding problems are frequent but not generally severe and usually manifest early as difficulty in sucking or swallowing. 25, 27, 43 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 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 3050%, 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. Surgical procedures to ameliorate drooling are possible 49 but apparently rarely used in AS.
Physical Growth 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% 27 to 34% 50 and may be as low as 25% when non-deletion cases are also included. 28 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. In later childhood obesity can occur. 29 Foodrelated behaviors (e.g., eating non-food items, apparent increased appetite, increased behavioral orientation to food) are common in AS 51 and may contribute to obesity onset.
Education 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 oralmotor 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.
Young Adulthood 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. Although the severity of seizures, or the frequency of seizures, may improve with age there is likely to still be the need for some type of anticonvulsant medication. Mobility issues become a more predominant concern as the AS child ages, often associated with concerns about obesity. 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 who are non-ambulatory. 9, 29 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 in AS but may be decreased by 10-15 years.
Laboratory Testing for AS Laboratory evaluation of an individual in whom the diagnosis of AS is suspected should start with chromosome analysis and DNA methylation analysis of the AS/PWS imprinting center region. The purpose of standard chromosome analysis is not to look for chromosome 15q11.213 deletions (which are reliably diagnosed only by fluorescence in situ hybridization (FISH)) but to look for other visible chromosome rearrangements that may give an AS-like phenotype. The DNA methylation test is positive in AS when one of three mechanisms is present: the large common deletion, uniparental disomy, and defects in the imprinting center (IC). So if the methylation test is positive more study is needed. In such situations, the next step typically is to perform a FISH (fluorescent in situ hybridization) chromosome test in order to verify that the common 15q11.2-13 deletion is causing the methylation abnormality. At this point, a general chromosome study is also advised (if it has not been performed already). If the FISH test is normal, the next step is to rule out paternal uniparental disomy by additional molecular testing (may require study of parental bloods). Individuals with a positive AS DNA methylation study, who have normal FISH and normal uniparental disomy studies, are then presumed to have an IC defect. Further confirmation of an IC defect requires additional study, often including DNA deletion analysis of the IC area. About 80-85% of individuals with AS will be diagnosed by a combination of these tests, but there still remains a group in which additional genetic testing of the UBE3A gene may detect an abnormality. Molecular analysis for UBE3A is available for clinical use in a few referral laboratories but the testing is expensive. Molecular testing for IC region deletions is available clinically from a small number of laboratories.
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 much less than 1%. For deletion AS cases, this less than 1% figure applies only if the mother (and the AS childâ&#x20AC;&#x2122;s) number 15 chromosomes do not have any type of complex rearrangement in addition to the deletion. Prenatal diagnosis is available by use of cytogenetic or molecular testing. Individuals with AS due to IC defect 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 defects, can have either received the mutation from a normal mother or acquired it by spontaneous mutation. Recurrence risk is felt to be 50% in inherited cases and less than 1% in apparent spontaneous mutation cases. 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). Until more is known about this group, caution is warranted during genetic counseling. 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. 52, 53
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