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Angelman Syndrome

Summary

Disease characteristics. Angelman syndrome (AS) is characterized by severe developmental delay or mental retardation, severe speech impairment, gait ataxia and/or tremulousness of the limbs, and a unique behavior with an inappropriate happy demeanor that includes frequent laughing, smiling, and excitability. In addition, microcephaly and seizures are common. Developmental delays are first noted at around six months of age; however, the unique clinical features of AS do not become manifest until after one year of age, and it can take several years before the correct clinical diagnosis is obvious.

Diagnosis/testing. The diagnosis of Angelman syndrome rests upon a combination of clinical features and molecular genetic testing and/or cytogenetic analysis. Consensus clinical diagnostic criteria for AS have been developed. Analysis of parent-specific DNA methylation imprints in the 15q11.2-q13 chromosome region detects approximately 78% of individuals with AS, including those with a deletion, uniparental disomy, or an imprinting defect; fewer than 1% of individuals have a cytogenetically visible chromosome rearrangement (i.e., translocation or inversion). UBE3A sequence analysis detects mutations in an additional ~11% of individuals. Accordingly, molecular genetic testing (methylation analysis and UBE3A sequence analysis) identifies alterations in about 90% of individuals. The remaining 10% of individuals with classic phenotypic features of AS have a presently unidentified genetic mechanism and thus are not amenable to diagnostic testing.

Management. Feeding difficulties in newborns with AS may require special nipples; gastroesophageal reflux associated with poor weight gain and emesis is treated with upright positioning and motility drugs; fundoplication is sometimes required. Anticonvulsant medications such as valproic acid, clonazepam, topiramate, lamotrigine, and ethosuximid, are used to treat seizures; vigabatrin and tigabine should be avoided. Unstable or non-ambulatory children may benefit from physical therapy. Occupational therapy may help improve fine motor and oral-motor control. Adaptive chairs or positioners may be required for extremely ataxic children. Speech therapy should focus on nonverbal methods of communication; augmentative communication aids such as picture cards or communication boards are used at the earliest appropriate time and signing should be taught as soon as the child is sufficiently attentive. Children with AS with excessive hypermotoric behaviors need an accommodating classroom space; some children may benefit from the use of stimulant medications such as methylphenidate. Individualization and flexibility in the school are important educational strategies. Sedatives such as chloral hydrate or diphenylhydramines may accommodate nighttime wakefulness. Strabismus may require surgical correction. Laxatives such as high fiber or lubricating agents are used to treat constipation. Orthopedic problems can be corrected by orthotic bracing or surgery. Thoraco-lumbar jackets may be needed for scoliosis; individuals with severe spinal curvature may benefit from surgical rod stabilization.

Genetic counseling.  AS is caused by the loss of the maternally imprinted contribution in the 15q11.2-q13 (AS/PWS) region that can occur by one of at least five different known genetic mechanisms. The risk to sibs of an affected child of having AS depends upon the genetic mechanism of the loss of the maternally contributed AS/PWS region. The risk to sibs of an affected child who has a deletion or uniparental disomy is typically less than 1%. The risk is as high as 50% to the sibs of a child with an imprinting defect or a mutation of the UBE3A gene. Members of the mother's extended family are also at increased risk when an imprinting defect or a UBE3A mutation is present. Cytogenetically visible chromosome rearrangements may be inherited or de novo. Prenatal testing is possible when the underlying genetic mechanism is a deletion, uniparental disomy, an imprinting defect, a UBE3A mutation, or a chromosome rearrangement.

Diagnosis

Clinical Diagnosis

Consensus criteria for the clinical diagnosis of Angelman syndrome (AS) have been developed in conjunction with the Scientific Advisory Committee of the US Angelman Syndrome Foundation [Williams, Angelman et al 1995]. Newborns typically have a normal phenotype. Developmental delays are first noted at around six months of age. However, the unique clinical features of AS do not become manifest until after one year of age, and it can take several years before the correct clinical diagnosis is obvious.

All affected individuals typically have:

• Normal prenatal and birth history, normal head circumference at birth, no major birth defects
• Normal metabolic, hematologic, and chemical laboratory profiles
• Structurally normal brain by MRI or CT, although mild cortical atrophy or dysmyelination may be observed
• Delayed attainment of developmental milestones without loss of skills
• Evidence of developmental delay by six to 12 months of age, eventually classified as severe
• Speech impairment, with minimal to no use of words; receptive language skills and nonverbal communication skills are higher than expressive language skills
• Movement or balance disorder, usually ataxia of gait and/or tremulous movement of the limbs
• Behavioral uniqueness, including any combination of frequent laughter/smiling; apparent happy demeanor; excitability, often with hand-flapping movements; hypermotoric behavior; short attention span

More than 80% of affected individuals have:

• Delayed or disproportionately slow growth in head circumference, usually resulting in absolute or relative microcephaly by age two years
• Seizures, usually starting before three years of age
• Abnormal EEG, with a characteristic pattern of large amplitude slow-spike waves

Fewer than 80% of affected individuals have:

• Flat back of the head (brachycephaly)
• Strabismus
• Hypopigmentation of the skin and eyes
• Tongue thrusting, sucking and swallowing disorders, frequent drooling, excessive chewing and mouthing behaviors
• Feeding problems during infancy
• Wide mouth, wide-spaced teeth, prominent mandible
• Hyperactive tendon reflexes
• Uplifted, flexed arms during walking
• Increased sensitivity to heat
• Sleep disturbance
• Attraction to/fascination with water

Testing

Fluorescent in situ hybridization (FISH).  Approximately 70% of individuals with AS have a 4- to 6-Mb deletion of 15q11.2-q13.

Note: Fluorescent in situ hybridization (FISH) analysis with the D15S10 and/or the SNRPN probe is the preferred method of identifying the deletion since it is typically not detected by routine chromosome study. Alternatively, comparative genomic hybridization (CGH) can be used to detect the deletion. See for laboratories offering CGH.

Cytogenetic analysis.  Fewer than 1% of individuals with AS have a cytogenetically visible chromosome rearrangement (i.e., translocation or inversion) of one number 15 chromosome involving 15q11.2-q13 that can usually be detected using chromosome and FISH studies.

Molecular Genetic Testing

GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information. —ED.

Gene.  The cardinal features of AS are caused by deficient expression or function of the maternally inherited UBE3A allele in certain brain regions [Jiang et al 1999 , Lossie et al 2001 , Nicholls & Knepper 2001 , Clayton-Smith & Laan 2003].

Clinical uses

• Diagnostic testing
• Prenatal diagnosis

Clinical testing

• DNA methylation analysis

  • Unaffected individuals have a methylated and an unmethylated SNRPN allele in both the Southern blot analysis [Glenn et al 1996] and methylation-specific PCR (MSP) assay [Kubota et al 1997 , Zeschnighk et al 1997].
  • Individuals with AS caused by a 4- to 6-Mb deletion of 15q11.2-q13, uniparental disomy (UPD), or an imprinting defect (ID) have only an unmethylated (i.e., "paternal") contribution (i.e., an abnormal parent-specific DNA methylation imprint).
    
    
  Note: Because an abnormal parent-specific DNA methylation imprint cannot distinguish between AS resulting from a deletion, from UPD, or from ID, further testing of individuals with an abnormal parent-specific DNA methylation imprint using the following methods is required to identify the underlying molecular mechanism:

  • Fluorescent in situ hybridization (FISH).  In 68% of individuals, 4- to 6-Mb deletions are detected by cytogenetic analysis using FISH.

  • Uniparental disomy (UPD) study.  In approximately 7% of individuals, uniparental disomy (UPD) is detected using DNA polymorphism testing.

• Sequence analysis.   UBE3A sequence analysis is available for individuals with a normal parent-specific DNA methylation imprint who are suspected of having AS. It is estimated that approximately 11% of probands with AS have identifiable UBE3A mutations [Malzac et al 1998 , Fang et al 1999 , Lossie et al 2001].

Research testing

• Targeted mutation analysis.  Individuals with an imprinting defect (ID) account for about 3% of affected individuals. They have abnormal (paternal-only pattern) DNA methylation imprint, but inheritance of 15q11.2-q13 DNA polymorphisms from both parents. Data suggest that about 10%-20% of the imprinting defects are microdeletions (6-200 kb) that include the AS imprinting center (IC). The nature of the other 80%-90% is thought to be an epigenetic mutation occurring during maternal oogenesis or in early embryogenesis [Buiting et al 2001 , Buiting et al 2003]. Characterization of the imprinting defect as either an imprinting center deletion or epigenetic defect is available in only a few research laboratories.

Table 1 summarizes molecular genetic testing for this disorder.

Table 1. Molecular Genetic Testing Used in AS Parent-Specific DNA Methylation Imprint Test Method Abnormality Detected Prevalence of Abnormality  1 Test Availability Abnormal FISH 4- to 6-Mb deletion 15q11.2-q13 ~68% Clinical Uniparental disomy (UPD) study UPD ~7% Targeted mutation analysis  2 Imprinting defect (ID) ~3% Research only Normal Sequence analysis UBE3A sequence variant ~11% Clinical

1. In 11% of individuals with Angelman syndrome, all testing for Angelman syndrome described in this table is normal. 2. Targeted mutation analysis detects small deletions, which account for 10%-20% of imprinting defects.

Interpretation of test results.  For issues to consider in interpretation of sequence analysis results, click here.

Possible explanations for the failure to detect mutations in the 11% or more of individuals with clinically diagnosed AS who do not have laboratory proof of AS include: (1) incorrect clinical diagnosis, (2) undetected mutations in the regulatory region(s) of UBE3A, and (3) other unidentified mechanisms or gene(s) involved in UBE3A function that can result in AS when a mutation occurs.

Testing Strategy

For diagnosis

• DNA methylation analysis identifies approximately 80% of individuals with AS and thus is the single most sensitive diagnostic test for AS.
• If DNA methylation analysis is normal, UBE3A sequence analysis is the next appropriate diagnostic test.
• Note: For an older child (>5 years old) with classic AS features and hypopigmentation (see Genotype-Phenotype Correlations) some clinicians may opt to start with FISH analysis rather than DNA methylation.

For genetic counseling

• If the DNA methylation analysis is positive, the next step is FISH analysis.
• If the FISH analysis is normal, studies using DNA polymorphism analysis can be used to distinguish between UPD and ID.
• If an ID is present, further DNA studies can determine if an ID deletion is present.
• For all affected individuals, it is appropriate to have standard or high-resolution chromosome analysis in addition to the specific diagnostic test because it is possible (though rare; see Table 1) to have a chromosomal rearrangement that alters the recurrence risks. Note: DNA analyses (methylation and uniparental disomy studies) do not detect chromosomal rearrangements.

Genetically Related (Allelic) Disorders

Prader-Willi syndrome (PWS) is caused by loss of the paternally contributed 15q11.2-q13 region. While PWS and Angelman syndrome are clinically distinct in older children, some clinical overlap exists (e.g., feeding difficulties, hypotonia, developmental delay) [Cassidy et al 2000] in children younger than age two years.

Maternally inherited interstitial duplications of 15q11.2-q13 can cause a disorder clinically distinct from either AS or PWS. Individuals with dup15q11.2-1q13 do not have facial dysmorphism but have mild to moderately severe learning deficits and may have behaviors in the autism spectrum [Boyar et al 2001].

Clinical Description

Natural History

Prenatal history, fetal development, birth weight, and head circumference at birth are usually normal. Young infants with AS may have breast or bottle feeding difficulties (as a result of sucking difficulties) and muscular hypotonia. Angelman syndrome may be first suspected in the toddlers because of delayed gross motor milestones, muscular hypotonia, and speech delay [Williams, Angelman et al 1995 ; Williams, Zori et al 1995]. Some infants have a happy affect with excessive chortling or paroxysms of laughter. Fifty percent of children develop microcephaly by 12 months of age. Strabismus may also occur. Tremulous movements may be noted prior to 12 months of age, often with increased deep tendon reflexes.

Seizures typically occur between one and three years of age and can be associated with generalized, somewhat specific EEG changes: runs of high-amplitude delta activity with intermittent spike and slow wave discharges; runs of rhythmic theta activity over a wide area; and runs of rhythmic sharp theta activity of 5-6/s over the posterior third of the head, forming complexes with small spikes. These are usually facilitated by or seen only with eye closure [Boyd et al 1997 , Rubin et al 1997]. Seizure types can be quite varied and include both major motor (e.g., grand mal) and minor motor types (e.g., petit mal, atonic) [Galvan-Manso et al 2005]. Infantile spasms are rare. Brain MRI may show mild atrophy and mild dysmyelination, but no structural lesions.

The average child with AS walks between two and one-half and six years of age [Lossie et al 2001] and at that time may have a jerky, robot-like, stiff gait, with uplifted, flexed, and pronated forearms, hypermotoric activity, excessive laughter, protruding tongue, drooling, absent speech, and social-seeking behavior [Zori et al 1992]. Ten percent of children are non-ambulatory. Sleep disorders are common, especially frequent night waking and early awakening [Didden et al 2004 , Bruni et al 2004]. Essentially all young children with AS have some component of hyperactivity; 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. Parents report that decreased need for sleep and abnormal sleep/wake cycles are characteristic of AS. Sleep disturbances have been reported in infants with AS and abnormal sleep/wake cycles have been studied in one affected child who benefited from a behavioral treatment program [Summers et al 1992].

Short attention span is present in most. Language impairment is severe. Appropriate use of even one or two words in a consistent manner is rare. Receptive language skills are always more advanced than expressive language skills. Most older children and adults with AS are able to communicate by pointing and using gestures and by using communication boards. Effective fluent use of sign language does not occur [Clayton-Smith 1993].

Puberty is generally normal in adolescents with AS and procreation appears possible for both males and females [Williams, Zori et al 1995]. Until recently no cases of reproduction in either a male or female with AS had been documented. Lossie and Driscoll (1999) reported transmission of AS by an affected mother who has a 15q11.2-q13 deletion. Therefore, the absence of reproduction previously seen in individuals with AS was most likely social or cognitive rather than physiologic in origin.

Young adults appear to have good physical health with the exception of possible seizures. Constipation is common. Scoliosis becomes more common with advancing age. Independent living is not possible for adults with AS, but most can live at home or in home-like placements. Life span data are not available, but life span appears to be nearly normal.

Genotype-Phenotype Correlations

In general, all of the AS genetic mechanisms lead to a somewhat uniform clinical picture of severe-to-profound mental retardation, movement disorder, characteristic behaviors, and severe limitations in speech and language. Despite great variability within each group, some clinical differences correlate with genotype [Bottani et al 1994 , Fridman et al 2000 , Lossie et al 2001 , Smith et al 1997 , Varela et al 2004]. These correlations are broadly summarized below:

• The 4- to 6-Mb deletion class results in the most severe phenotype with microcephaly, seizures, motor difficulties (e.g., ataxia, muscular hypotonia, feeding difficulties) and language impairment. There is some suggestion that individuals with larger deletions (e.g., BP1-BP3 breakpoints compared to those with BP2-BP3 deletions) may have more impaired ability to speak single words.
• Individuals with UPD have better physical growth (e.g., less likelihood of microcephaly), fewer movement abnormalities, less ataxia, and a lower prevalence (but not absence) of seizures [Lossie et al 2001].
• Individuals with ID and UPD have relatively higher developmental and language ability. Individuals who are mosaic for the non-deletion imprinting defect (about 20% of the ID group) have the most advanced speech abilities [Nazlican et al 2004]; they may speak up to 50-60 words and use simple sentences.
• Individuals with chromosome deletions encompassing the P gene frequently have hypopigmented irides, skin, and hair. The P gene encodes a protein important in tyrosine metabolism that is associated with the development of pigment in the skin, hair, and irides.

Penetrance

Inherited UBE3A and ID deletions follow an imprinting (or inheritance) pattern in which the paternally transmitted mutation is asymptomatic.

Nomenclature

Prior to the 1980s, AS was called the "happy puppet syndrome," based in large part on the original paper published by Dr. Harry Angelman who made note of a puppet-like gait and laughter present in his three patients.

Prevalence

The prevalence of Angelman syndrome is one in 12,000-20,000 population [Clayton-Smith & Pembrey 1992 , Steffenburg et al 1996].

Differential Diagnosis

For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.

The disorders most commonly considered in the differential diagnosis of Angelman syndrome are cerebral palsy of undetermined etiology, Rett syndrome (in infant girls) and idiopathic static encephalopathy [Williams et al 2001].

• Hypotonia and seizures in the child with AS may raise the possibility of an inborn error of metabolism or a defect in oxidative phosphorylation, such as a mitochondrial encephalomyopathy (see Mitochondrial Disorders Overview).
• Sometimes infants with AS with feeding difficulties, hypotonia, and developmental delay have been misdiagnosed as having Prader-Willi syndrome (PWS) because of the presence of a 15q11.2-q13 deletion detected by FISH analysis. FISH analysis typically does not determine the origin of the deletion (i.e., maternal in AS and paternal in PWS); however, parent-specific DNA methylation analysis can distinguish between AS and PWS.
• Infants with AS commonly present with either nonspecific psychomotor delay and/or seizures; thus, the differential diagnosis is often broad and nonspecific, encompassing such entities as cerebral palsy, static encephalopathy, and idiopathic epilepsy.
• Other rare chromosome anomalies can also mimic some of the features of AS, especially the 22q13.3 deletion syndrome [Precht et al 1998]. This condition may present with nondysmorphic facial features, absent or minimal speech, and moderate to severe developmental delay, sometimes with behavioral features in the autism spectrum.
• Hypotonia and diminished muscle mass may raise the possibility of a myopathic disorder, but muscle biopsy and EMG are normal in individuals with AS. The tremulousness, jerkiness, and ballistic-like limb movements seen in individuals with AS distinguish AS from cerebral palsy with ataxia and abnormal speech.
• Infant girls with AS having seizures and severe speech impairment can resemble girls with Rett syndrome , but children with AS do not have a neuro-regressive course nor do they lose purposeful use of their hands, as do individuals with Rett syndrome. Furthermore, individuals with Rett syndrome do not have the distinctive happy affect characteristic of AS. However, Rett sydrome in older girls can escape earlier diagnosis and may resemble features of the AS, and occasionally a girl with Rett syndrome is mislabeled as having AS [Watson et al 2001]. Testing for mutations of the MCP2 gene, which causes Rett syndrome, is available.
• Some individuals with Mowat syndrome can present with features suggestive of AS [Zweier et al 2005]. These include happy affect, diminished speech, microcephaly, and history of constipation.

Management

Evaluations Following Initial Diagnosis

Evaluations at the time of diagnosis are focused on neurologic assessment and good preventive practice.

• Baseline brain MRI and EEG are advised. Typically, management of seizures (or assessment of risk for seizures) is not significantly helped by repetitive EEG or MRI testing.
• Musculoskeletal examination should assess the possibility of scoliosis and gait impairment (e.g., extent of foot pronation or ankle subluxation; tight Achilles tendons) and the extent of muscular hypotonia. Orthopedic referral should be made if needed.
• Ophthalmology examination should evaluate for strabismus, determine the extent of ocular albinism (in deletion-positive AS), and assess visual acuity.
• Developmental evaluation should focus on: (1) nonverbal language ability and related educational and teaching strategies and (2) physical therapy needs to enable optimal ambulation.
• Infants and young children should be assessed for gastroesophageal reflux; diet should be evaluated to assure optimal nutritional status.

Treatment of Manifestations

• Feeding problems in newborns may require special nipples and other strategies to deal with weak or uncoordinated sucking.
• Gastroesophageal reflux can be associated with poor weight gain and emesis; the customary medical treatment (i.e., upright positioning, motility drugs) is usually effective; sometimes surgical tightening of the esophageal sphincter is required.
• Many anticonvulsant medications have been used to treat seizures in individuals with AS; no one drug has proven superior. Medications used for minor motor seizures (e.g., valproic acid, clonazepam, topiramate, lamotrigine, ethosuximide) are more commonly prescribed than are ones for major motor seizures (e.g., diphenylhydantion, phenobarbital) [Nolt et al 2003]. Single medication use is preferred, but seizure breakthrough is common. A few individuals with AS have infrequent seizures and are not on anticonvulsant drugs. Some with uncontrollable seizures have benefited from a ketogenic diet. Children with AS are at risk for medication over-treatment because their movement abnormalities can be mistaken for seizures and because EEG abnormalities can persist even when seizures are controlled.
• Hypermotoric behaviors are typically resistant to behavioral therapies; accommodation by the family and provision of a safe environment are important.
• Most children with AS do not receive drug therapy for hyperactivity, although some may benefit from the use of stimulant medications such as methylphenidate (Ritalin). Use of sedating agents such as phenothiazines is not advised because they cause negative side effects.
• Behavioral modification is effective in treating undesirable behaviors that are socially disruptive or self-injurious.
• A full range of educational training and enrichment programs should be available. Unstable or non-ambulatory children may benefit from physical therapy. Occupational therapy may help improve fine motor and oral-motor control. Special adaptive chairs or positioners may be required, especially for extremely ataxic children. Speech 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. Attempts to teach signing should begin as soon as the child is sufficiently attentive. Special physical provisions in the classroom, along with teacher aides or assistants, may be needed for effective class integration. Children with AS with excessive hypermotoric behaviors need an accommodating classroom space. Individualization and flexibility in the school are important educational strategies.
• Many families construct safe but confining bedrooms to accommodate disruptive nighttime wakefulness. Use of sedatives such as chloral hydrate or diphenylhydramines (Benadryl) may be helpful. Administration of 0.3 mg melatonin one hour before sleep may be helpful in some, but should not be given in the middle of the night if the child awakens.
• Strabismus may require surgical correction.
• Constipation often requires regular use of laxatives such as high fiber or lubricating agents.
• Orthopedic problems, particularly subluxed or pronated ankles or tight Achilles tendons, can be corrected by orthotic bracing or surgery.
• Thoraco-lumbar jackets may be needed for scoliosis, and individuals with severe curvature may benefit from surgical rod stabilization.
• Most individuals with AS significantly benefit from speech, physical and occupational therapy, in combination with educational and behavioral interventions.

Prevention of Secondary Complications

Older adults tend to become less mobile and less active; attention to activity schedules may be helpful and may help reduce extent of scoliosis and obesity.

Surveillance

• Vigilant observation for the onset of scoliosis is advised.
• Older children should be evaluated for the development of obesity associated with an excessive appetite.

Agents/Circumstances to Avoid

Vigabatrin and tigabine (anticonvulsants that increase brain GABA levels) should not be used to treat seizures.

Therapies Under Investigation

Clinical trials involving the use of high-dose, orally administered folate and betaine are ongoing. The therapeutic rationale is to augment DNA methylation pathways and possibly increase UBE3A expression of the paternal allele in the CNS. No published results are available yet. Click here for more information.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

Excessive tongue protrusion causes drooling; available surgical or medication treatments (e.g., surgical reimplants of the salivary ducts or use of local scopolamine patches) are generally not effective.

Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory. —ED.

Mode of Inheritance

AS can be caused by: (1) deletion of the AS/PWS region on the copy of chromosome 15 inherited from the mother; (2) paternal uniparental disomy (UPD) in which the father contributes two copies of chromosome 15; (3) an imprinting defect (ID); (4) a mutation in the UBE3A gene; or (5) unidentified mechanism(s).

Risk to Family Members

Parents of a proband

• The parents of a proband are unaffected.
• Recommendations for genetic testing of the parents depends upon the cause of AS in the proband.

Sibs of a proband.   The risk to the sibs of an individual with AS depends on the genetic mechanism of AS in the proband and is summarized in Table 2 .

Ia.   Mothers of individuals with deletions should have chromosomal and FISH analyses to determine if the mother has a balanced subtle chromosomal rearrangement [Burke et al 1996]. In addition, in spite of the reduced fertility in the Prader-Willi syndrome, a woman with PWS (caused by a paternally derived 15q11.2-q13 deletion) gave birth to an infant with classic AS. This occurrence illustrates the imprinted aspect of the chromosome 15q11.2-q13 region [Schulze et al 2001].

• For probands with a de novo large deletion, the risk to sibs is less than 1% [Connerton-Moyer et al 1997]. Germline mosaicism for these large deletions has been reported on one occasion [Kokkonen & Leisti 2000].

Ib.   If a chromosome rearrangement has been identified in a proband, the risks to sibs and other family members depends on whether the rearrangement is inherited or de novo [Horsthemke et al 1996 , Stalker & Williams 1998]. Smaller interstitial deletions that cause AS when inherited maternally and result in a normal phenotype when inherited paternally are rare, but significantly change the recurrence risk for sibs [Saitoh et al 1992].

IIa.   In families in which AS is the result of paternal UPD and in which no Robertsonian chromosomal translocation is identified in the proband, the risk to sibs of having AS is less than 1%. This risk figure is based upon the lack of recurrence among all known cases of UPD in AS with normal chromosomes, the experience with UPD in other disorders, and theoretical consideration regarding the mechanism of UPD. The recurrence risk is not zero, however, as recurrent meiotic nondisjunction of maternal chromosome 15 has been observed [Harpey et al 1998]. In addition, if an individual has AS as a result of paternal UPD and has a normal karyotype, a chromosomal analysis of the mother should be offered in order to exclude the rare possibility that a Robertsonian translocation or marker chromosome was a predisposing factor (e.g., via generation of maternal gamete that was nullisomic for chromosome 15, with subsequent post-zygotic "correction" to paternal disomy).

IIb.   Individuals with UPD should have chromosomal analysis to ensure that they do not have a paternally inherited Robertsonian translocation that would increase the family's recurrence risk.

IIIa.   Individuals with an IC deletion can have a phenotypically normal mother who also has an IC deletion. In these situations, the mother has either acquired her defect by a spontaneous mutation on her paternally derived chromosome 15 or inherited the IC deletion from her father, consistent with the imprinting mechanisms governing the 15q11.2-q13 region [Buiting et al 2001]. Additionally, some of these mothers may have germline mosaicism for the IC deletion [Saitoh et al 1996]; this complicates genetic counseling when the mother of a proband with an IC deletion has normal peripheral blood IC genetic studies. If a proband's mother has a known IC deletion, the risk to the sibs is 50%.

IIIb.   All imprinting defects without an IC deletion have been in individuals with no known family history of AS and thus probably represent a de novo defect in the imprinting process in 15q11.2-q13 during the mother's oogenesis [Buiting et al 1998]. Therefore, the risk to the sibs of a proband in such families is less than 1%.

IV.   UBE3A mutations can be inherited or de novo [Kishino et al 1997 , Matsuura et al 1997 , Lossie et al 2001 , Burger et al 2002]. In addition, several cases of mosaicism for a UBE3A mutation have been noted [Malzac et al 1998]. If a proband's mother has a UBE3A mutation, the risk to the sibs is 50%.

V.   The majority of cases in this molecular class have not been familial, but some families with more than one affected sibling have been reported.

Offspring of a proband.   To date, only one individual with AS has been reported to have reproduced [Lossie & Driscoll 1999]. The risk to offspring should be determined in the context of formal genetic counseling.

Other family members.   If a UBE3A mutation, IC deletion, or structural chromosomal rearrangement has been identified in the mother (or father in the case of UPD and Robertsonian translocations) of a proband, the sibs of the carrier parent should be offered genetic counseling and the option of genetic testing.

• IC deletions or UBE3 mutations.   If a proband's mother carries a known IC deletion or UBE3A mutation, the mother's sisters are also at risk of carrying the IC deletion or the mutation. Each child of the unaffected sisters who are carriers is at a 50% risk of having AS. Unaffected maternal uncles of the proband who are carriers are not at risk of having affected children, but are at risk of having affected grandchildren through their unaffected daughters who have inherited the IC deletion or UBE3A mutation from them.

Related Genetic Counseling Issues

Family planning.  The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.

DNA banking.   DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA particularly for probands in whom the underlying mechanism is unidentified. See DNA Banking for a list of laboratories offering this service.