Angelman Syndrome Clinical Management Guidelines

Management of Angelman Syndrome Angelman SyndromeGuideline DevelopmentGroup A ClinicalGuideline

Contents

iinadHaig 0 eulhat n uet 16 13 …Sexual healthandPuberty 14 …General healthandAnaesthesia 12 …DentalandDrooling 10 … … VisionandHearing Behaviour …SpeechandCommunication 8 … 7 11 … … SeizuresandCNS Sleep 9 … 6 Alternative … Development Scoliosis … FeedingandDiet therapies 17 and Skeletal … GeneticInvestigation 15 … Diagnosis SyndromeClinic … totheAngelman of Clinical SyndromeGuid … totheAngelman Angelman …Syndrome Introduction to 4 Angelman Diagnosis Syndrome 4 3 Acknowledgements APPENDIX: GeneticMechanisms in Angelman Syndrome Bibliography Information for Parents fortheManageme Recommendations

elines Development project 3 al Management Guidelines 3 19 to nemnSnrm 6 nt of Angelman Syndrome 2

18 5 3 25 24

Angelman Syndrome Clinical Management Guidelines

Introduction... plays a greater role. The members of the guideline development group are listed on page 25. on page25. are listed group development of theguideline members The a greaterrole. plays conditio tosuitrare adapted been has method The (SIGN). Network ba methodology a robust using developed havebeen The guidelines … tothe Angelman Syndrome Gu list useful resources. chin, and deep set eyes. It is caused by a variety ofgeneti byavariety seteyes.Itiscaused deep chin, and water, an a loveof inappropriate laughter, genomic imprinting. These include maternal deletion,paternalun genomic imprinting.Theseinclude with ASha speech doesnotdevelop.Patients slowin and milestones developmental in withdelay children present EE a characteristic with disorder a seizure ataxia, difficulties, occurs neurodevelopmental disorderthat is a Angelman syndrome Though these guidelines have been prepared principally forprofe prepared havebeen Though theseguidelines audience aEuropean relevantto information used themain we have in withAS, toall is relevant oftheinformation much Though individ careofan inthe involved anybody to accessible iseasily formatthat inaclear theserequirements out lay guidelines an referrals assessments, tests, screening and diagnostic various the synd of priorexperience much have had will with thecondition the co-ordinating and managing for responsible usually professionals ofthehealthcare thatmany unlikely itis rare, As ASis Who aretheyaimed at? Angelman Syndrome. and wher The guidelinesaimtoprovideclear What aretheaimsofguidelines? … tothe Angelman Syndrome Clin … to Angelman Syndrome(AS) Key references are provided at the bottom of the page if more in pageif bottom ofthe atthe areprovided Key references systems. Withineachsyst on thedifferentbody depending of Angelman on thediagnosis information contain The firstpages How arethey organised? deletions within the UBE3A gene, which lies within this region (see Appendix: Genetic Mechanisms in AS, p. 24 for more informat more 24for p. inAS, Mechanisms Genetic Appendix: (see region this within lies which theUBE3Agene, within deletions which may concern you with your child’s doctor. doctor. with yourchild’s you concern which may is anindividual. every child as herein complications mentioned parent readingtheseguidelines asa If youare syndrome children.

ideline DevelopmentProject d sleep disorder. The facial features are subtle and include a wide, smiling mouth, include awide,smiling subtle and are disorder.Thefacialfeatures sleep d ical ManagementGuidelines ever possible, evidence-based recommendati ever possible, ve a characteristic behavioural phenotype with jerky movements, frequent andsometi frequent movements, jerky with phenotype behavioural acharacteristic ve c abnormalities involving the chromosome 15q11-13 region, which is region, the chromosome 15q11-13 abnormalities involving c em, different age groups are considered where relevant. relevant. are consideredwhere agegroups em, different G, subtle dysmorphic facial features, and a happy, sociable di sociable ahappy, and features, facial G, subtledysmorphic We would recommend that you discuss any terminology orinformat terminology any discuss thatyou recommend would We d multidisciplinary interventions at different stagesoftheir atdifferent interventions d multidisciplinary -depth information is needed. At theendofguideline docum needed. -depth information is ssionals, they will also be of interest to the parents of Angel totheparents of interest also be will they ssionals, 3 syndrome. Thereafter, the guidelines have been organised into havebeen organised the guidelines Thereafter, syndrome. iparental disomy, imprinting defe disomy,imprinting iparental we would emphasise that your child may not be affected byal beaffected not may child your that would emphasise we in 1 in 20-40,000 births. It is characterised by severe learnin bysevere is characterised It 20-40,000births. in in 1 rome. As AS is a multisystem disorder, people with AS may re AS may people with disorder, a multisystem is As AS rome. sed on the one utilised bytheScottishIntercollegiateGuideli on theone sed ns where the evidence baseis ns wherethe g of head growth during the first year of life. In the majori life.Inthe of thefirstyear during of headgrowth g ons for the management of patients with ons forthemanagementofpatientswith limited, and where expert consen where and limited, cts, and point mutations or sm cts, andpointmutations sposition. Most sposition. lives.These care of people care of ual withAS. ual man prominent ty of cases subject to g nes nes ion). l the quire sections . ent we all ion sus mes

Angelman Syndrome Clinical Management Guidelines

Clinical Diagnosis of Angelman Syndrome

ConstipationScoliosis Obesity orientation towards food) appetite/increased behavioural increased items/apparent non-food (eating behaviours food-related Abnormal Fascination Abnormal Increased position orvalgus pronated gait withfeet Wide-based sleep walking on ofarms position Up-lifted, flexed sensitivity Increased Hypopigmentation pattern Strabismusto deep Wide Drooling, heat Prominenttendon mouth, hypotonia infancy/truncal in Feeding difficulties excessive Poor reflexes Tongue wide-spaced Protrudingchewing, suck Flat teeth (20-80%) features Associated mouthing and occiput with seizures) associated EEG(not Characteristic Seizures circumference swallowing with head growthwithmicrocephaly/disproportionate head Impaired (onset in80%) (seen features Frequent disorder occipital words) or no (minimal Speech impairment usually hypermotoric) excitable, (frequent laughter, uniqueness Behavioural groove Movement Severe developmentaldelay <3 in 100%) (seen Consistent ClinicalFeatures Disorder years) (ataxia/tremor) withthrusting ` havebeen clinical criteria those ofotherdisorders.Consensus canbedifficu Syndrome ofAngelman diagnosis aclinical Making chin tonguewater been made it should be confirmed by genetic testing (see page 5). genetictesting(seepage confirmed by it shouldbe been made clinicaldiagnos oncea and of diagnosis proof is notabsolute AS for clinicalcriteria Fulfilling the fulfil these. not who do of these criteria. It is importantto notethatalthoughthedi It of thesecriteria. Consensus DiagnosticCriteriaForAngelman Syndrome

agnostic criteria can be used as a guide, there will beexceptio there usedasaguide, agnostic criteriacanbe (Williams et al2006) (Williams developed to help with making a clinical diagnosis. Belowisa clinical diagnosis. a with making tohelp developed lt because the signs and symptoms evolve with age and overlapwi with age evolve lt becausethesignsandsymptoms 4

ATRX Syndrome mid-childhood from Hyperventilation Agenesis corpuscallosum Coarse facial features, prominent lips Pitt HopkinsSyndrome Uplifted earlobes heart defect Congenital constipation or Hirschsprung’s callosum with agenesisofcorpus Associated Mowat-Wilson Syndrome Hyperventilation Hand-wringing movements History of regression girls. in Important differential Rett Syndrome Seizures before 6months, handstereotypies Seizures before seizure onset Rett phenotype Early CDKL5 mutation analysis microarray Cri-du-chat/microdeletions—consider Chromosome abnormalities movements stereotypic Slim build, homocysteine Raised urine MTHFR Deficiency rhythm Fast EEG Dystonia syndrome” Angelman “X-linked disorder X-linked associated SLC9A6 upperlip Anteverted nares,tented Genital abnormalities infancy Severe hypotoniain disorder X-linked inboys. Consider motn ifrnilDansso S Diagnoses ofAS Important Differential

;

is of AS has of AShas is nal patients summary summary th

Angelman Syndrome Clinical Management Guidelines

Paediatric/neurology review fromtime to who are mosaic for a 15q11-13 imprinting defect and these indivi imprinting defectandthese a 15q11-13 for are mosaic who them all of thegroups, overlap between there isagreatdealof ov most able, being theUPDgroup features and ofthecharacteristic more showing group with thedeletion between thesegroups, orsmall deletionofth apoint mutation have 5-10% and 15q11-13 ∗ interf which abnormalities ofgenetic toavariety due AS arises involved. geneticmechanism underlying uponthe dependent is risk ofrecurrence assessment accurate an as further children geneticinvest confirmed by be should ofAS A clinicaldiagnosis (75%) have a deletion of 15q11-13, 2-3% have uniparental disomy of disomy 2-3% haveuniparental of 15q11-13, a deletion (75%) have future pregnancies and other family members. other family and future pregnancies implic maybe asthere discussion, clinicforfurther genetic local totheir offered referral be should parents made, of ASis di a When pregnancies. in future risk recurrence haveahigh thiswould as mother, inthe 15 rearrangement exclude achromosome below. shown is genetictestinginAS strategyfor A suggested Genetic Investigationof Angelman Syndrome time as situation may change andnew See Appendix: Genetic Mechanisms in AS, p. 24 for more information. information. formore 24 p. inAS, GeneticMechanisms See Appendix: NEGATIVE: AS DIAGNOSIS NOT CONFIRMED NOT CONFIRMED NEGATIVE: ASDIAGNOSIS CONSIDER OTHER POSSIBILITIES tests may become available. If ASstillsuspected clinically, ALL TESTS NEGATIVE? ALL TESTSNEGATIVE? next stageis to screenUBE3A gene forpoint mutations or UBE3A MUTATION Test mother and her (SEE PAGE 4). family members if Mutation found. small deletions. necessary. SCREEN Stochastic imprinting defect (mosaic in some cases) Family studies useful test.Looksfortypical METHYLATION TEST AS characteristic patterns. Starting point andmost In those individuals where deletions are identified, itisalso identified, In thoseindividualswheredeletionsare translocation hasbeenexcludedin ere with the normal expression of the normal ere with igation. This is particularly important if parents areconside ifparents important isparticularly This igation. Check maternalbloodto exclude having typical clinical characte typicalclinical having duals may show milder features, and often have more speech. oftenhavemore features,and may showmilder duals e UBE3A gene. Though there are subtle clinical differences clinical differences aresubtle Though there e UBE3Agene. chromosome rearrangement. 5 Check thatRobertsonian chromosome 15, 3-5% have impaired imprinting of thematernal imprinting impaired have 3-5% chromosome15, child and mother. Deletion found. UPD found.

Imprinting centre No mutation mutation ristics. A group of patients e ofpatients group ristics. A the UBE3A gene at 15q11-13. T theUBE3Ageneat15q11-13. POSITIVE: AS DIAGNOSIS CONFIRMED CONFIRMED POSITIVE: ASDIAGNOSIS Looks for the precise mutation disomy (UPD)andASdueto an on chromosome 15 which gave Used todifferentiate between rise to theimprinting defect. Specialised teststo check for AS caused by uniparental MUTATION TEST TEST MUTATION imprinting defect. IMPRINTING RFLP TEST FISH/MLPA -ve deletions important to ations for for ations ring having xists, however, xists, however, he majority erall agnosis copy of copy Angelman Syndrome Clinical Management Guidelines

Diet Constipation reflux Gastro-oesophageal maybeproblematic. Suck ineffectiveandbreastfeeding Feeding difficulties: Infancy andChildhood Gastro-oesophageal reflux Gastro-oesophageal Obesity Adolescence and Adulthood : often caused by excessive appetite. appetite. byexcessive caused : often : often caused by inadequate fluid intake. intake. fluid byinadequate : oftencaused Recommendations forthemanagementof Angelman Syndrome: seen in the majority ofinfants. seen inthe ~ Feeding&Diet 6

fluid. of source alternativeandoftenmore acceptable Jelly isan intake. Encourage fluid needed. be may (fundoplication) surgery In severecases, Ranitidine, to patient an anti-refluxmedicatione.g.Gaviscon, Administer and trainonfeeding. Refer tospecialisedteamadvise weight gaincarefully. Monitor Treat withanti-reflux medication. deteriorates. appears miserable orbehaviour distressed, becomes inexplicably Suspect ifanASperson AS individuals. in older is problematic Often returnsand activities. appropriate age- a regularexercise programmewith Encourage ifoverweight. Involve dietician basis. andBMIonanannual weight Check items. dangerous other or toxic, corrosive chewing/swallowing Advise cautionthatchildrenaren’t and textures). variedtastes (including age healthy eatinghabitsfromanearly Encourage in uprightposition.

. Angelman Syndrome Clinical Management Guidelines

Adulthood Communication Education Fine motorskills Gross motorskills General developmentaldelay Childhood adult care Transition frompaediatric to Adolescence Self-help skills Behaviour Communication Gross motorskills Recommendations forthemanagementof Angelman Syndrome:

Occupational therapy (OT) assessment. assessment. (OT) therapy Occupational deformities. toxinorsurgery for muscle Consider botulinum support. feet,ankle forflat ifneeded Refer fororthotics contractures. to advise assessment Refer forphysiotherapy scales are best. development—Bayley assess Use appropriatescalesto coordinated. should be programme intervention andindividualised active An early, (p.20). andSkills DepartmentforEducation the by published Toolkit SEN 14). See Contact withmulti-disciplinary transitionte 20% atnight. be achieved continencecan Daytime disabilities. learning with inchildren to besuccessful beenfound regimes have training Standard toilet andla byspeech intervention Early of most including consideration identified, appropriate support and fully assessed needsare strengths and Ensure that accommodation when ready. alternative move to respite, home, from away with nights independence Encourage Refer for OTassessment. living. aid daily skillsto functional ondeveloping Concentrate further. skills develop language as conc therapy andlanguage Pursue speech programme. Regular exercise Regular physiotherapyassessment withattention ~ Development 7 appropriate schoolplacement. nguage therapist (see page 12.) page (see nguage therapist am (UK statutory requirement from Year 9—age fromYear requirement (UK statutory am entration improves with age with potential to withpotential age with improves entration on balance, posture and management of management balance,posture and on groupswithincreased tone/musculo-skeletal in over 50% of AS children, but in less than less butin ofAS children, in over50% to posture and prevention of contractures. ofcontractures. andprevention to posture Angelman Syndrome Clinical Management Guidelines

Seizures occur in around 90% of patients and onset is commonly in the second year of life. year in thesecond iscommonly onset and 90%ofpatients around occur in Seizures Seizure Types—the followingaretypicalof AS: Treatment * Myoclonic jerkscanbea manifestation of epilepsy,butcan al It maybedifficult todistinguish an atypical ab Eye blinkingorslight jerking movements ofthelips may occur. Atypical absence seizures are characterised as staring spells,du Atypical absences Discontinuing treatment Discontinuing treatment Othertreatments Refractory epilepsy NCSE Atypical absences Type-specific treatments: epilepsy. forgeneralised regimens Follow standardtreatment * may manifest astransient regression which, while revers Whereas convulsive status epilepticus refersto anextremely prol Non-convulsive statusepilepticus (NCSE) The twitches are caused by suddenmusclecontractions, Myocolnic seizures arebrief jerksof a muscle orgroup ofmuscles, e.g.faceor hands. Myoclonic jerks more subtle epileptic activity andanindividual mayappear not Diagnosis can be facilitated by short video-clips of episodes. ofepisodes. video-clips can be facilitatedbyshort Diagnosis Therapy must be balanced with quality of life and side effects. andsideeffects. of life quality with must bebalanced Therapy Recommendations forthemanagementof Angelman Syndrome sence seizure from an individual’s usual behaviour. Cortical myoclonus Cortical myoclonus ~ SeizuresandCNS ible, may interferewith learningandquality oflife. or more rarely bybrief la so be duetoother causesthat may notrequire treatment. ring whichthepatientisnot, to betheir‘usual selves’,with onged and obvious (usually tonic-clonic) seizureand is lifet

pses of concentration. concentration. of pses years—joint decision between parents & neurologist. Consider discontinuation oftreatment after2seizure free Re-evaluate medication at eachvisit. Ketogenic diet &vagalnerv Steroids used withsuccess insmall study. Leviteracetam &benzodiazepines both used. Ethosuximide hasproveneffe Piracetam isarecommended treatment. not absolutely contra-indicated ifotherdrugsareineffective. been associatedwithworsening of Some drugs (carbamazepine, oxcarbazepine, vigabatrin) have effective. Lamotrigine, levetiracetam and topiramate may also be often effective. Valproate and benzodiazepinesar

or onlyminimally, responsive. furtherimpairment of cognitio

e stimulation both used. used. both e stimulation ctive in asmallstudy. e mostcommonly used andare seizures insome cases but are

hreatening, NCSEcauses n or behaviour.This Angelman Syndrome Clinical Management Guidelines

Improving sleep is also of significant bene significant of isalso sleep Improving behaviour, onactivitylevelsand positive impact a sleep had the improving sleep, ofdaily amount short a very AS with with a child of study one In behaviour. morechallenging demonstrate However many children do not show the usual signs of sleep depriv signs of sleep do notshowtheusual However manychildren Several studies Syndrome. Angelman in iscommon Sleep disturbance benefits many (but not all) patients. not all) patients. (but benefits many Other hypnotics en improves but treatment Melatonin Sleep routine Restless Sleep Improve SleepHygiene All Ages : baseline levels inASare usually normal : baselinelevels Recommendations forthemanagementof Angelman Syndrome : underpins sleep management. sleepmanagement. : underpins

dogenous secretion and dogenous secretion fit to parents and other family members. otherfamily parents and fit to

~ Sleep and a maintenance of more expected total sleep amounts. amounts. totalsleep moreexpected a maintenanceof and ation that are seen in adults but may instead become more acti more become instead but may inadults thatareseen ation 9 Use blackout curtains. Use blackout prolonged. not betoo which should routine Follow thesamebedtime time andgettingupeachday. Maintain thesamebed bedroom. TVin bed—no activities before Avoid stimulatory Avoid caffeine. of bedding. amount and roomtemperature Ensure correct side effects. about tocommunicate AS individuals of andinability of dependence the risk becauseof basis a short-term on use benzodiazepines Only seizure improveon melatonin). frequency (may e.g.for monitor foranychanges but minimal Side effects areusually to theirbodyweight. comparison dosesin needhigher been suggestedthatsmaller children has ifneeded—it up to10mg increase dose 0.5-2mg, Start onlow adoctor. monitoredby properly ensure and food prep. nothealth medication, Use aprescription-only useful. canbe home circumstances toassessindividual A homevisit programme. behavioural an individualised Design asleepdiary. keep parents to Encourage AS. in common –more sleep apnoea Obstructive Gastro-oesophageal constipation. or teeth,ears from Pain e.g. causes: Check formedical evaluated. reflux. tobe remains medication though behavioural ismainly Management It ismultifactorial. withAS. inchildren iscommon Restless sleep

have mentioned that AS children have a decreased need for sle adecreased needfor children have have mentionedthatAS length of ve and ep. Angelman Syndrome Clinical Management Guidelines

be kept under regular review. The problems below can be can problems below regularreview. The be keptunder an vision normal have will Syndrome withAngelman Most children on other allele. on other ofType onecopy of deletion due to albinism have signsofTypeIIoculucutaneous with mainly inindividuals Retinal hypopigmentation/O Strabismus General screening Vision Hearing Keratoconus: Otitis media Recommendations forthemanagementof Angelman Syndrome increased curvature ofthecornea. increased

15q11-13deletionswhomay II OCA gene plus mutation IIOCAgeneplusmutation culo-cutaneaous albinism: ~ Vision &Hearing~

seen at a higher frequency in Angelman Syndrome. Syndrome. inAngelman frequency atahigher seen

10 d hearing, but like any other child with learning disability the child withlearning other likeany d hearing,but require surgical correction. require surgical service—may If suspectedrefertoorthopic/ophthalmology hypopigmented. especiallyif younger children, in Common concerns. checks ifany foradditional alowthreshold with protocol local as per ups schoolmedicalcheck At pre-schooland transplant. corneal require may Severe keratoconus discouraged. be whichshould eye-rubbing frequent result from Can patients. older some in Has beenreported visual impairment. associated with May be acuity. visual and vision affects binocular which optic chiasm of of decussation fibres at signs aberrant electrodiagnostic for issuspectedVEPs arehelpful—look If OCA (particularly macula). fundus—assesshypopigmentation toexamine Dilate pupils dilation). before pupil lamp, (at slit transillumination iris Look for treat appropriately. fever and or unexplained distress if thereis Examine ears tube. angle ofEustachian because of drainage due toalteredmiddleear likely tobe most children, young frequency in increased Occurs atan y should Angelman Syndrome Clinical Management Guidelines

One of the main diagnostic features of Angelman Syndrome isa Syndrome featuresofAngelman main diagnostic One ofthe activities. is management keytobehaviour The encountered. however be sti wide-based, and with ataxia, disorder movement “exuberance”, addressed. AS individuals for hair-pulling. Thiscanbestressful characteristic ofthesyndrome Hyperactivity/impulsive behaviour: Mouthing andchewing All Ages Autistic behaviour Self injury Fascination withwater behaviour Aggressive and Recommendations forthemanagementof Angelman Syndrome parents/carerssoshouldbe : e.g. pulling, grabbing, grabbing, : e.g.pulling,

~ Behaviour CONSISTENCY CONSISTENCY characteristic pattern of behaviour with easily provoked laughter provoked with easily patternofbehaviour characteristic Splints are usually not helpful long term. longterm. not helpful Splints areusually distraction. approach using a behavioural Try 11 autism. educational and Refer forassessment of pain. a source are hitting If hittingthemselves checkifthey look particul occurs If head-banging of educationalprogrammes. and aspart behaviour forgood asre-inforcers activities water-based Useful touse occurred. has drowning accidental water as near Advise supervision in”. “giving or by contact)from others, eye attention (especially by orrewarded reinforced be not should behaviour Challenging occurs. problem behaviour why Explain toparents modification. behaviour Refer forexperthelpwith as communicationsuggest intr an behaviour leadstothe what Analyse constipation. Check first want todosometh doesn’t when achild occur may may help.It providing entertainment/activities and orboredom byupset becaused behaviour may challenging Difficult or patient.) reported AS effectofextremelethargyina causedside have known to they are used because not usually are as methylphenidate such (Psychostimulants *NB amitryptiline. with or Risperidone dose withlow betreated If severe,can ff-legged gait with arms upheld. The problem behaviours below m below problem behaviours The with armsupheld. gait ff-legged —Risperidone can cause weight gain or sedation. gain orsedation. —Risperidone cancauseweight

for pain or discomfort e.g. toothache, earache, reflux, earache, e.g. toothache, discomfort or for pain and involving everyone at home, school, respite and leisure leisure and respite school, at home, involving everyone and ing e.g. sit in car seat. sit incarseat. ing e.g. oducing communication aid. communicationaid. oducing arly for signs of otitis media. ofotitis signs arly for approaches/intervention used in used approaches/intervention d try to address cause e.g. if used used d trytoaddresscausee.g. if

, ay, Angelman Syndrome Clinical Management Guidelines

One of the key characteristics of Angelman Syndrome is a lack of alack is Syndrome ofAngelman key characteristics One ofthe Recommended interventions are listed below. Individuals without are listedbelow.Individuals Recommended interventions theirmanagement. partof an important is therapy andlanguage speech and way insome communicate AScannot children with make to ability limited expressive speech.Thereisa better than Impact on behaviour Speech andlanguage assessment Adolescence and Adulthood Interventions Speech andlanguageassessment Childhood Recommendations forthemanagementof Angelman Syndrome

~ SpeechandCommunication

intervention. plan effective stageto atanearly expert byan out be carried should This behaviours. can curbproblem meansof communication Having aneffective interactions. social terminate and maintain initiate, that theycan so communication isessential of non-verbal havesome means adults Ensuring life-long learning. AS person’s an partof and be into adulthood be continued should therapy and language sospeech age with Receptive languageimproves Introduce augmentative communicati information. ofsharing asmethod useful also are diaries Video communication. photoframecanaid digital onto a andtaking andmeanings gestures used of photos with dictionary” “gesture a making aid communication: Utilise ITto naming. choices ratherthanjust and express is which oncommunication Concentrate othernetworks. all in and home, school systemat Use thesame of communication. work betterwithdifferent modes will different children child. Trydiffe individual Tailor tothe speech sounds and to vary voice tone and quality. Despite thi quality.Despite tovaryvoicetoneand and speechsounds speech development. Verbal comprehension is also impaired, but comprehension isalsoimpaired, Verbal development. speech deletions appear to have slightly better communication skills. communication better to haveslightly deletions appear 12

on aids e.g. Dynavox early. Dynavox e.g. on aids rent approaches e.g. signing/PECS, as signing/PECS, e.g. rent approaches photos of daily activities downloaded dailyactivitiesdownloaded photos of functional functional i.e. to communicate needs i.e. tocommunicate s, very few s, very is Angelman Syndrome Clinical Management Guidelines

Dental Care Mouthing/Chewing age butpersistentinsome. Maydecreasewith Common inyoungchildren. mouth. of open Drooling All Ages : caused by pooling of saliva atfront bypoolingofsaliva : caused Recommendations forthemanagementof Angelman Syndrome Treatment ~ Dental&Drooling

them. The latter leaves more residual saliva and is preferable. ispreferable. and saliva residual more leaves them. Thelatter liga used areto The twoapproaches not successful. Surgery: months. tofour up flowfor reduce saliva Botulinum toxin: needed. patch andtitrateupas With scopolaminepatchesstartwith Watch forsideeffectse.g.consti glycopyrrolate. Anticholinergics: Be consistent. gently closingthemouth. of encourageclosure Parents should TREATMENT WHICH DECREASES TREATMENT * METICULOUS DENTAL HYGIENE ISIMPERATIVE WHEN ANY dentist. paediatric 14). Referto Invasive dental treatmentusuallyre care. for preventative dentist to local Regular visits may be effective. toothbrush Curve) A curved(Collis anytooth assistwith and supervise and hygiene dental ofgood emphasise importance Parents should objectsnearmouth. allowsharportoxic Do not boredom. ar if mouthing/chewing Look tosee page 11). (see thansplints rather withdistraction approach Use abehavioural 13 Refer for surgery if behavioural and medical treatments are are medical treatments and ifbehavioural forsurgery Refer Injecting botulinumtoxinintosalivaryglandscan Use anticholinergics e.g. scopolamine patches, patches, scopolamine e.g. Use anticholinergics ain hc ugscein. secretions. pation, thicklung e being caused by stress, or by stress, e beingcaused brushing carried out by patient. patient. outby carried brushing quires general anaesthetic(seepage te salivary ducts or to re-direct ducts orto te salivary the moutheitherverballyorby low dose e.g. quarter or half a e.g. quarterorhalf dose low SALIVA PRODUCTION ISUSED. Angelman Syndrome Clinical Management Guidelines

is unexplained distress, reluctance to eat, misery. reluctance toeat,misery. distress, is unexplained ifthere adults suspect in infants.In ages butespecially in NS. childhood immunisations. childhood Anaesthesia: Anaesthesia Hypopigmentation Temperature Control: Immunisation: reflux: Gastro-oesophageal Cardiorespiratory Growth General health to overheat. Recommendations forthemanagementof Angelman Syndrome Few reports of problems with anaesthesia anaesthesia with ofproblems Few reports no contra-indication to normal tonormal no contra-indication

may be poor with atendency may bepoor be aware of GORat all aware be ~ Generalhealth& Anaesthesia ~

14 Treat withanti-refluxmedication. vagaltone. increase which Avoid medications monitoring. hour ECG refer for24 Ifthishappens, syncope. provoke may oflaughter outbursts Rarely, severescoliosis. develop who in individuals beconsidered should occur and may compromise Cardiorespiratory and checkBMI. annually andweight height Monitor Anecdotal reports of high pain threshold in AS patients. inAS threshold pain Anecdotal reports ofhigh occur. may butseizures toanaesthesia acontra-indication not Epilepsy is muscle wasting. Increased vigilance post-op—riskof as normal. to betaken medication All regular appropriately. and treats risk of reflux aware anaesthetist Ensure tone). highvagal to (due for bradycardias perioperatively Monitor agents. choice ofanaesthetic ensurecareful and assessment pre-operative Refer forrigorous withsunexposure. sunscreen Use highfactor response. immune impair asitmay recommended with immunisations isnot paracetamol prophylactically thatgiving with paracetamolbutnote promptly Treat fever increase fluidsinhotclimates. and Avoid overdressing immunisation. offeredseasonalflu be AS individualsshould delayed recovery if there is recovery ifthere delayed Angelman Syndrome Clinical Management Guidelines

and over 50% adultswithAS. and over50% Scoliosis: Skeletal All Ages treatment. drug (AED) anti-epileptic bility andprolonged Bone density: occurs in 20% children occurs in20% Recommendations forthemanagementof Angelman Syndrome reduced with immo- reduced Surveillance Treatment Radiology

~ Scoliosis&Skeletal two years. measured every theirbone density have 16) should Depo-Provera (seepage on Women scoliosis. disabi with can bedifficult inindividuals surgeon. with discussed tobe ofsurgery Optimal timing likely toneedsurgicaltreatment. are >45 degrees degreesofscoliosis—curves for significant may beneeded Surgery immediately. it fitchange whichdoesn’t brace witha Ifissued mild curvature. Bracing for physiotherapist. by treatment for initial refer scoliosis, For mild visit. clinic outatspinal tobecarried forX-ray appropriate more It maybe spine. of visualisation accurate allow to correctposition in with child betaken X-rays should radiologically. measured beconfirmedand Scoliosis should 14). scoliosis(seepage develop severe who in individuals beconsidered should occur and may compromise Cardiorespiratory quickly. may progress scoliosis spurtwhen growth adolescent during carefully more Monitor surgeon. refer tospinal issuspected If scoliosis examine spine. child outto take wheelchair, If ina visit. each scoliosis Monitor for adulthood. throughout including time, from timeto andseating onposture foradvice therapist and occupational Refer tophysiotherapist scoliosis. can preventoralleviate age early an from ofposture Good management required. be difficultasgeneralanaestheticmay for spec considered maybe Botulinum toxin treatment. surgical require Severe contracturesmay contractures. prevent developmentof mobility to Encourage for appropriate investigation. Measurement of Measurement investigation. for appropriate disorders metabolic bone interest in an with specialist toa occursrefer If afracture if necessary). or supplements in diet daily (400 IU/10micrograms vitaminDintake adequate Ensure Encourage mobility. 15

lity and especially those with treated lity andespecially thosewith ific tight musclesbutadministrationmay ific bone density using standard techniques standard bone density using Angelman Syndrome Clinical Management Guidelines

arrangements whichshouldbeofferedtoall arrangements considered. emotional developmentneedtobe in thannormal slightlylater maybe thatpuberty reports suggest Som characteristics. sexual secondary normal anddevelop puberty normal through a go Syndrome Angelman with girls and Both boys Management ofmenstruation All Ages Fertility: Sexual health/activity Depo-Provera injection Combined OralContraceptive parent has a deletion or UBE3A mutation. UBE3A mutation. or deletion a parent has a if offspring to risk a significant is fertile. There Both males and females with AS are Recommendations forthemanagementof Angelman Syndrome

~ Puberty&SexualHealth

from age of 14 (DfES (2001) SEN Toolkit). (DfES (2001)SENToolkit). from ageof14 The management issues below should be addressed as part of the transitional care care of thetransitional aspart beaddressed below should issues The management

some individuals. All aspects of a teenager’s sexual health a sexual of ateenager’s All aspects individuals. some considered vulnerable. are ifwomen and arises ifsituation considered be should Contraception suggested. been has libido andlow these areusually platonic formedrelationship have AS adults room. their own privately in ma only to them encourage adults and approachescan Behavioural be us prevented. recommended. normally is hysterectomy or ablation asendometrial such Surgical management in somecases. may influencethedecisiontotreat which effectivecontraception, provides also thesemethods of Using one often. most used COCis InUK periods. suppress/lighten to Depo-Provera (COC)or contraceptive oral ofcombined use Consider treatment. pubertybeforeconsidering through normally progress to Allow girls be discussed fully. be discussed should children pregnant/fathering ofbecoming issues and ethical Social Masturbation isanormal activity duringtreatment. years two density before useandevery Check bone especially considered, May alsobe me with annualreview and Follow up weeks for10 continuously Often used very immobile. Do apply. Normal contraindications 16 not

use if there is a history ofthromb thereisa if use in both sexes and should not be not both sexesandshould in ed toguideASadolescents and if contraindications to COC. to if contraindications s with those of theoppositesexbut s withthose dical checks e.g.bloodpressure. dical checks with a break for the eleventh week. with abreakforthe sturbate in appropriate placese.g. in appropriate sturbate oembolism or in patients who are are who patients in or oembolism nd e not

Angelman Syndrome Clinical Management Guidelines

It must be noted that there is no strong scientific there isno noted that It mustbe to bebeneficial. have found parents therapiesthat afewofthe just The vignettesbelowintroduce and forchildren therapies alternative reportthat Many families

M t o u c A s o t d h i m h c t i s e s e ou f M t k m f t u c l t u i p h r d h c u e e l u g e l n u c ie h p s p C m ni r iq l i h a t e a o s r t c n r e c s i op p r u a e Recommendations forthemanagementof Angelman Syndrome w a e t i a t q e n a y e h m t s h ni n l d u i e ic i e h e n a d ex e a n a t h n l w w w g r h i f s a n ip o p a f i e i n a p h r b s u t t p t r e d A u ic t h es h o l e it S la e l y e i v h w ot i . n s l m e t o e n r e t p a g t p e S h a t d h y s h u d o at e r r h e . . e s o m a n u e r i e v N b h s i c n r e n d e e b o o y

i d g s s e n n p n s e s a c e s a le h r i f e y e o e p n it n specific partsofthefeetthat are other parts ofthebody)hasbeen f people withlearning difficulties. invasive approach to therapy for p e t t

described as a beneficial, non- beneficial, described as a o . r s if t f h believed to correspond with a h ic c t e application of pressure to to pressure of application a h Reflexology (massage or t iv v is e i t y ~ Alternative therapies~ Reflexology evidence to support the use of these therapies in AS. AS. of thesetherapiesin evidencetosupporttheuse evidence that itbenefits children with Therapy aided byahorse, utilising the hippotherapy inASbutsome scientific can beimproved byhippotherapy. No balance, sensory/motordevelopment as well speech and language skills posture, muscle tone, coordination, horse’s movements. Reports that formal studies oftheefficacy of A maintained exerciseroutine can behugely beneficial, and Cycling—Static and trikes carer-controlled bikestobe in particular, manyAS families have found adults with Angelman syndrome have a positive effect haveapositive on well-b syndrome with Angelman adults Hippotherapy cerebral palsy. 17 invaluable.

Water-based therapies havebeen mon love of waterinindividuals aspects of AS, duetothe com- used successfullyinmanaging

Hydrotherapy with AS.

e o

n p

i a

t an

o i

y x

n h

p p

a r

e o

d i

c e

f i

o e

l e

s B

f w

m t e

o a

e o

i xe l

t n r a n e m i

y h

. n

s t

a i

o l A b

a n d e

, a

S r

t r c

u c

s e

d e

m e e h g g

eing.

d a

y i j

n e

r y

f g

d r

g—a

p t

t u

v s

s r

e t

e o c

v u h e

n t

l l

i h

N i

n e

. S S

n i

r —

h r

s t

Angelman Syndrome Clinical Management Guidelines

Information forParents their carers. and supporting children educatinganddirectly holdlo telephonesupportline, Theyrunafree,24 hour professionals. facedbypeople of problems wide range support ona adviceand • • • • ha who by volunteers , run group support UK-based ASSERT is a • Support Sources ofInformationand projects,clinicaltrials andpatientregistries loss of expression of this genetic region at the molecular level. atthe geneticregion of this loss ofexpression negligible risk of recurrence to a possible 50% risk. risk. 50% toapossible recurrence of negligible risk Genetic counselling to assess risks to siblings and other family otherfamily and to siblings risks assess Genetic counselling to Genetic Counselling budgets and direct payments to allow individuals more individuals directpayments toallow budgets and This website contains information on how the delivery of social care is being ‘personalised’. This new approach uses individual uses approach new This being‘personalised’. is care of social delivery the on how information contains website This Department ofHealth—Personalisation

5,000 conditions, including Angelman Syndrome, and lists specialise andlists Syndrome, Angelman including 5,000 conditions, serv and related diseases rare of database an online is Orphanet Orphanet (www.orpha.net) 1,000 on over theyhaveinformation theirchild, of condition themedical parents whatever adviceto and support providing charity only UK is the Family ContactA their needs. more about o tofind are interested thenor with work who and whose child disabled havea who families isfor website The ContactaFamily (www.cafamily.org.uk) aFamily Contact resear through conditions brainrelated andacquired traumatic both with livesofchildren improve the uptohelp set A charity (www.cerebra.org.uk) People Young and Children Injured Brain For Cerebra— ASSERT—Angelman SyndromeSupportEducatio

(www.dh.gov.uk/en/SocialC relating specifically to Angelman Syndrome. Syndrome. toAngelman specifically relating n & Research Trust (www.angelmanuk.org choice and control over the support they receive. theyreceive. support overthe andcontrol choice cal and regional meetings and fund research into AS. AS. into fundresearch meetings and regional cal and members is based upon knowing the mechanism involved in causin the mechanisminvolved knowing is based upon members Recurrence risks to parents and extended family members vary vary family members extended and riskstoparents Recurrence rare syndromes and can often put families in touch with each othe touch with familiesin oftenput and can syndromes rare ve direct contact with people with AS. The organisation can off with AS.Theorganisation people contactwith ve direct 18 ices provided throughout Europe. It contains information on ove on information Itcontains Europe. throughout ices provided with/affected by AS. It can also provide information to carers tocarers information provide byAS.Itcanalso with/affected d clinics, diagnostic tests, patient organisations, research patient organisations, tests, diagnostic d clinics, are/Socialcarereform/Pers ) onalisation/index.htm)

from a er

ch, g the g the and and r. r. r ut Angelman Syndrome Clinical Management Guidelines

Bibliography • Behaviour • • • • • • General papers &Guidelines • • Alternative therapies • • • • • • • • • • • • • • • • Anaesthesia • • Barry, R.J.,P.Leitner, etal.(200 disability." JournalofIntellect Didden, R.,H.Korzilius, etal.(2008)."Preference forwater-re 61. Steffenburg, S., C.L.Gillberg, etal.(1996). "Autismin Ramanathan, K. R., D. Muthuswamy, et Ramanathan, Muthuswamy, K.R.,D. Genet Res Didden, R.etal(2006)."Preferences in individuals withAngelm Williams, C. A. etal.(2006). Buntinx, I.M.etal.(1995)."Cli Patil, J.and S.Sindhakar(2008)."Angelma Laan, L. A.,A.T.den Boer, etal.(1996)."A Maguire, M.(2009)."Anaesthesia for an ad Gardner, J. C.etal(2008)."Vagalhype Clayton-Smith, J.and L.Laan(2003). Errando, C.L.(2008)."Comments ona case report Smith, J.C.(2001)."Angelman syndrome: evolution of th Van Buggenhout, G. and J. P. Fryns (2009). "Angelman syndrome (AS, MIM 105830)." Eur J Hum Genet Hum EurJ MIM105830)." (AS, syndrome "Angelman (2009). G.andJ.P.Fryns Van Buggenhout, Hersh, J.H.et al.(1981). "B Guerrini, R.etal.(2003)."Angelman syndro Dan, B.“Angelman Syndrome”,Clinics inDevelopmentalMe Oliver, C.,J. Moss,etal.(2009)."Underst Clayton-Smith, J.(1993)."Clini Ishmael, H.A., M.L.Begleiter,etal.(2002). "Drowningas Horsler, K.and C.Oliver(2006)."Thebe Leitner, R.P.andA.Smith (1996)."A Bujok, G.and P.Knapik(2004)."Angelman syndrome Pelc K, C.G.,DanB. (2008). Neurodevelopmental Disorders atthe Univ Gale, E.(2002).“Advocating theuseofrefl Medicine & Child Neurology 49(1):68-73. Sterba, J.A. (2007). "Does horseb guide for health professionals”, Churchill Livingstone, ElsevierScience.

(Pt 1): 54-60. 46 (1): 12-5. ehavioral correlates inthe happypuppetsyndrome: "Behavior and neuropsychiatric manifestations in manifestations and neuropsychiatric "Behavior "Angelman syndrome2005:updatedconsensus fo ual andDevelopmental Disability cal research on Angelman syndrome intheUnited nical profile of Angelman syndrome atdifferent ages."AmJ Med Genet ack riding therapy or therapist-directed hippothe n Angelman syndrome clinic: reporton 24 patients."J Paediatr Child Health 5). "Behavioral aspects of Angelman syndrome "Angelman syndrome: areview oftheclinical and genetic aspects." JMed Genet rtonia andanesthesia in Angelman syndro al. (2008)."Anaesthesia for Angelman havioural phenotype of Angelman syndrome." anding and Changing Challenging Behaviour in ersity ofBirmingham: www.cndd.bham.ac.uk. ult withAngelman sy exology forpeoplewith alearning disabi me: etiology, clinical features, diagnosis, and management of symptoms." Paediatr D ngelman syndromeinadulthood." Am J Med Genet n syndrome and anesthesia."n syndromePaediatr and Anaesth of Angelman syndrome anaesthesia." Anaesthesia asarare anaesthetic problem." Paediatr Anaesth Angelman syndrome: a population Angelman syndrome: e phenotype inadolescents and adults." DevMed ChildNeurol a cause of deathin Angelman syndrome." Am J Ment Retard dicine, MacKeithPress,Wile ndrome." Anaesthesia lated itemsinAngelman syndrome, Downsyndrome and non-specif

an syndrome assessed bya modified Choice Assessment Scale."J 33 (1): 59-64. 19 r diagnostic criteria." Am J Med GenetA syndrome." Anaesthesia 63(6):659-661. Angelman syndrome." Neuropsychiatr Dis Treat. Kingdom: observations82 affected on individual a characteristic profile?" DevMed ChildNeuro me." Pediatric Anesthesia 18(4): 348-349. rapy rehabilitate children withcerebral pal : a case control study." AmJMed Genet A lity” in Mackereth, P.,TiranD.(eds.)“C

64 Journal ofIntellectual Disability Research Angelman Syndrome."Available fromThe (11): 1250-3. y-Blackwell, London (2008). -based study." Pediatr Neurol -based study."

(12): 1219-20. 1219-20. (12): 66 (3): 356-60.

14 56 (10): 1145-6. (11): 1367-73. 1367-73. (11): (3): 281-3. (2): 176-83.

32 (2): 94-8.

140

107 43 14 (2): 87-95. (7): 476-80. (2): 131-6. (5): 413-8. (1): 69-70. linical reflexology: a a reflexology: linical

132A sy?" Developmental l 4

23 50(1): 33-53. (3): 577-84. Intellect Disabil rugs s." AmJ Med Centre for for Centre ic intellectual (6): 792-800. (1): 8-12.

5 (10): 647- Angelman Syndrome Clinical Management Guidelines

Bibliography continued... • • • Feeding and Diet • • Diagnosis

• • • • • • Behaviour continued… • Dental andDrooling • • • • • Development • • tralia: 1953—2003." Disability &Rehabilitation Thomson, A.K.,E.J.Glasson,etal.(2 port." SpecCareDentist. 28(1): 8-11. Peters, S.U.,J.Goddard-Finegold,etal. ( Boyce, H.W.and M.R.Bakheet(2005). "S Moncla, A.,P.Malzac,etal. ( tions and genetic counselling." JMedGenet to speak inpatientswith Angelman syndrome ca Gillessen-Kaesbach, G., S. Demuth, etal.( Gillessen-Kaesbach, G.,S. A Clin Gastroenterol Vanagt, W.Y.etal.(2005). "Asystole during outbursts ofla ties." Journal of IntellectualDisa Toolan, P.G.,Coleman,S.Y.(1994)."Music Smith, A.,C.Wiles,etal. (1996). "Clini Summers, J. A., D.B. Allison, etal. of common syndromes associated with person Summers, J. A,. Pittman., D.(2004)."Angelman Syndrome." pp.161- tal Disabilities 4(24): 216-226. Summers, J. A. andS.P(2009)."Using Discre Murakami C,NahásPiresCorr N. P.C.M., information of parents of children with Prader-Willi syndrome van denBorne vanGestel HW, v.H.R., M, RienmeijerP,Fryns Steffenburg, S., C.L.Gillberg,etal.(1996)."Autism in 12. Pelc K,C.G.,DanB.(2008). Department forEducation and Skills(2001) Beckung, E.,S.Steffenburg,etal.(2004)."Motorimpairments, ne drome." DevMedChildNeurol Zori, R.T.,J. Hendrickson, etal.(1992)."Ang Trillingsgaard, A.andO.S. JR(20

128A (2): 110-3.

39 (2): 89-97. "Behavior and neuropsychiatric manifestations in manifestations andneuropsychiatric "Behavior 1999). "Angelman syndrome resulting from UBE3A mu

46 bility Research 38(4): 433-444. (4): 239-43. 04). "Autism inAngelman syndrome: anexploration of comorbidity." Autism (1995). "Behaviour problemsinAngelm 006). "Along-term population-based clinical and morbidity profile ofAngelman syndrome cal features in 27patients with Angelman êa F,NahásPiresCorrêaJP. ialorrhea: areview ofavexing, oftenunrec 2004). "Cognitive and adaptive behavior profiles of childrenwith Angelman syndrome SENToolkit. Available fr 1999). "Apreviouslyunrecogn

therapy, adescription ofprocess: engagement andavoidance infivepeople withle 36 te Trial Instruction to teachChildren Angelman Syndrome." Focus on Autism andOth s with intellectual disabilities, National

elman syndrome: clinical profile." JChild Neurol 28 (7): 554-60. used byanimprinting defect." EurJHumGenet (5): 299-305. Angelman syndrome: a population Angelman syndrome: ughing inachildwith Angelman syndrome." Pediatr Cardiol and Angelman syndrome." PatientEducCouns. 38(3): 205-16.

JP, Curfs LM. (1999). "Psychosocia urological signs,anddevelopmental levelinindividualswith 20 om teachernet ‘OnlinePublications’: www.teachernet.gov.uk 188 in Griffiths, D.M andKing,R.K(Eds.) Clinical andeduca (2008). "Dentaltreatmentof ch ised phenotype characterisedbyobesity,muscular hypot an syndrome." J Intellect DisabilRes Angelman syndrome." Neuropsychiatr DisTreat. syndrome resulting from DNAdeletion."JMe tations in 14patients Association ForThe Dually Diagnosed. ognized sign of oropharyngeal andesophage -based study." Pediatr Neurol -based study."

(3): 270-80. 7 l problems,coping strategies, (6): 638-44. ildren withAngelmansyndr from eight families: cli

8 (2): 163-74.

39 (Pt 2)

26 14 : 97-106. (6): 866-8. (2): 131-6. Angelmansyn- d Genet 4 and theneedfor nical manifesta- ." Am J MedGenet in Western Aus- (3): 577-84. arning disabili- tional implications ome: a case re- case a ome: onia, andability er Developmen- er al disease." J J al disease."

33 (2): 107- Angelman Syndrome Clinical Management Guidelines

Bibliography continued... • • • • General health • • • • • • andSkeletal Scoliosis • • • • • • • • • • • • • Seizures andCNS • 43 Kuenzle, C., M. Steinlin,etal.(1998)."Adverseeffe Kuenzle, C., Guerrini, R.,T.M.DeLorey,etal. (1996)."Cortical Pelc, K., S. G. Boyd,etal.(2008)."EpilepsyinAngelmanPelc, K.,S.G. syndrome."Seizure Dev rosurg 39 Galvan-Manso, M., J.Campistol, etal.(20 syndrome." Epileptic Disord Buckley, R.H.,N.Dinno,etal.(1998)."Angelman 16 Franz, D.N.,T.A.Glauser, etal.(2000). "Topiramate therapy Laan, L. A.,W.O.Renier, etal.(1997)."Evolutionofep Ruggieri, M.andA.McShane (1998). "Par Nolt, D. H., J. M. Mott, et al. (2003)."A Nolt, D.H.,J.M.Mott,et net questionnaire." Am J Health SystPharm Coppola, G.,A.Verrotti,etal. Gardner, etal.(2008)."Vagal hypertonia J. C.,S.T.Charles, Sinclair, D.B., M.Berg,etal.(2004)."V Egawa, K.,N.Asahina, et al. (2008)."Abe Dulac, O.,P.Plouin,etal.(1998)."Myoclonus and epilepsy Scully, S. P. and R.Ferguson (1993)."Associa Scully, S.P. Ohtsuka, Y.,K.Kobayashi, etal.(2005). Stecker, M. M. and S. M. Myers (2003)."Reser Stecker, M. andS.M. Smith, J.C.(2001). "Angelman syndrome:evolution of thephen 502. Pelc, K.,G.Cheron,etal. (2008)."Aretheredistinct Forrest, K. M., H. Young, et al.(2009) Forrest, K.M.,H.Young, Matsumoto, A., T. Kumagai, etal.(1992). "Epilepsy inAngelman flow." Acta PaediatrScand Bjerre, I.,B.Fagher,etal.(1984)."TheAngelman or"happy drome." DevMedChildNeurol46(4):239-43. Beckung, E.,S.Steffenburg,etal.(2004)."Motorimpairments, ne Schlanger, S.,M.Shinitzky, etal.(2002)."Dietenrichedwithome 79(5): 423-426. (1): 103-4. (2): 593-9. (11): 1270-3.

105 (2): 95-100. (3): 183-7. (Growth, Cardiorespiratory problems, Gastro-oesophageal refl

7 (1): 19-25. (3): 398-402. (2007). "Bone mineral densityinangelman syndrome." Pediatr Neurol . "Benefit of corticosteroid therapy ssessment of anticonvulsant effectiveness and safety inpatients with Angelman's synd alproic acid-induced pancreatitis inchildh "Relationship betweenseverity ofepilepsy anddevelopmental outcomeinAngelman synd rrant somatosensory-evoked responses imply 05). "Analysis of thecharacteristics of epilepsy in 37 patients with themolecular d

ental viewofepilepsy inAngelmansyndro 60 tion ofmetatarsus adductovarus (skewfo pine responsive myoclonus andhyperpyrexia (24): 2583-7. syndrome: arethe estimates toolow?"Am J Med Genet cts of vigabatrin inAngelman syndrome." Epilepsia myoclonus in Angelman syndrome." Ann Neurol 40(1): 39-48. ive sleepproblemsin Angelman syndrome?"SleepMed ilepsy and EEG findings inAngelman syndrome." Epilepsia in childhood: 1996 Royaumont meeting." Epilepsy Res30(2): 91-106. puppet" syndrome. Clinical andelectroencephalographic features a and anesthesia in Angelman synd of epilepsy associated withAngelman's syndrome." Neurology otype inadolescents and adults." DevMed ChildNeurol 43(7):476 syndrome associated withchromosome 15q deletion." Epilepsia ga-3 fattyacidsalleviates conv urological signs,anddevelopmental levelinindividualswith 21 in Angelman syndrome." JChild Neurol ux, Immunisations, Temperature

17 (3): 211-7. ood epilepsy: case series and review." J me: aquestionnaire study." Archives of Dis ot) withAngelman's(HappyPuppet)syndro GABAergic dysfunction in Angelman syndrome in a patientwith Angelmansyndrome." C rome." Pediatricrome." Anesthesia18(4 ulsion symptoms in epilepsy

39 (6): 411-6.

(11): 1213-5. 80

9 (4): 434-41. (4): 385-90. control, Hypopigmentation)

38 (8): 952-8. (2): 195-9. Child Neurol

iagnosis of Angelman Angelman of iagnosis 54 patients." Epilepsia patients." rome using an Inter- Angelmansyn- ): 348-349. (5): 1185-8.

nd cerebralblood ease inChildhood 33 me." Orthopedics -80. -80. rome." Brain lin NeurolNeu- (6): 1083-90. ." Neuroimage

19 (7): 498-

Angelman Syndrome Clinical Management Guidelines

Bibliography continued... • • • Seizures andCNScontinued... • • • Sexual health andPuberty • • • • Speech and Communication • • • • • • • • • • Sleep • • • drome." JDevBehav Pediatr Summers, J. A., P.S.Lynch,etal.(1992). Neurophysiol Med ChildNeurol rology Intellect DisabilRes Genet crinol Metab Zhdanova, I. V., R. J. Wurtman, etal.(19 Zhdanova, I.V.,R.J.Wurtman, Sugiura, C., K. Ogura,et al. (2001)."Hig Pelc, K.,G.Cheron,etal. (2008)."Aretheredistinct Miano, S.,O.Bruni,etal.(2005)."Sleep Albanese, A. and N.W.Hopper(2007)."Suppression of menstruation Weber, P.(2009)."Levetiracetam in Noncon Bruni, O., R.Ferri,et al. (2004)."S Clayton-Smith, J.andL.Laan(2003). Logoped Phoniatr Vocol Rasmussen,etal. Andersen, W.H.,R.K. Forrest, K. M., H. Young, et al.(2009) Forrest, K.M.,H.Young, Braam, W.,R.Didden,etal.(2008)."Melat Miano, S.,O.Bruni,etal. (2004). "Sleeppolygr Coppola, G.,G.Iervolino, etal.(2004). or withoutepilepsy:adouble-blind, cross- Calculator, S.N. and T.Black (2009). "Validation of an inventor Clayton-Smith, J.(1992)."Angelman's Sy Clayton-Smith, J.(1993)."Clini Viani, F., A.Romeo,et al.(199 treatment options."Epilepsia 50(11):2369-2376. Thibert, R.L., etal.(2009). "EpilepsyinAngelm D.C.Kerry, Bazil, C.W.(2003)."Effectsofan Didden, R.,H.Korzilius, etal.(2004)."Sleepproblems Braam, W.,M.G.Smits,et al.(2009)."E 649-654. 23(6): rol services tostudents withsevere Didden, R.,H.Korzilius, etal.(2006). "Preferences in indivi

46 57 (1): 12-5. (8): 1518-9.

12 116 (1): 57-67.

(11): 2685-92. 51

(5): 340-9. 50 (Pt 1): 54-60.(Pt 1):

26 (1): 2-9.

cal research on Angelman syndrome intheUnited 5). "Seizure andEEGpatterns in Angelman's syndrome." JChildNeurol (4): 284-7. disabilities in general education tiepileptic drugs onsleepstructure :arealldrugsequal?" CNSDrugs leep disturbancesinAngelman syndro . "Benefit of corticosteroid therapy "Angelman syndrome: areview oftheclinical and genetic aspects." JMed Genet h-dose ethosuximide for epilepsy in Angelman syndrome: implication of GABA(A) recepto "Melatonin in wake-sleep disorders in chil ndrome." Arch DisChild. 67(7): 889-90. xogenous melatonin for sleep problemsin breathing and periodic legmovementpattern (2001). "Levelsof cognitive andlinguistic 99). "Effects ofalow dose of melatonin onsleep in childrenwith Angelman syndrome. over, placebo-controlledtrial."Brain Dev "A combined behavioral/pharmacological treatment ofsleep-wake schedule disorder in onin for Chronic Insomnia inAngelman Sy vulsive StatusEpilepticus inaChild With aphy inAngelmansyndrome." Clin Neurophysiol ive sleepproblemsin Angelman syndrome?"SleepMed in individualswithAngelman syndrome." AmJMent Retard duals withAngelman syndrome assessed byamodified Choice Asses an syndrome: Aquestionnaire-base y ofbest practicesintheprovision ofaugmentative and alter classrooms." Am JSpeech Lang Pathol 22 inadolescents withsevere le me: a questionnaire study." Brain Dev in Angelman syndrome." JChild Neurol Kingdom: observations82 affected on individual dren, adolescents and young adults with men adults with adolescents andyoung dren, development in Angelman syndrome: a study study a syndrome: Angelman in development

26 ndrome: ARandomizedPlacebo-ControlledTria dividuals withintellectualdisability: am Angelman Syndrome." JChildNeurol [EPuba inAngelman Syndrome: apolysomnographic (6): 373-6.

115 d assessment of arning disabilities." ArchDis (4): 938-45.

10 17

18 (6): 467-71. (10): 719-28. 719-28. (10): (4): 329-42.

9 (4): 434-41.

26 the naturalhis

24 (4): 233-40.

109 (8): 952-8.

(4): 275-84. 40 (2): 87-95. native communication eta-analysis." Dev Child tory andcurrent tal retardation with sment Scale." J " J PediatrEndo- of 20 children."of 20 r subunit."Neu- s." AmJMed head ofprint.] Angelman syn- study." Clin study."

l." JChild Neu- 92 (7): 629-32. Angelman Syndrome Clinical Management Guidelines

Bibliography continued... • • • • • • • Speech and Communication continued... Speech and Communication • • • • • Vision and Hearing • • with noocular featuresof Thompson, D.A.,A.Kriss, etal.(1999). Penner, K.A.,J.Johnston, etal.(1993). "Communication, cognitio Jolleff N,Ryan, M. (1993)."Communication development in Rufa, A.,M.T.Dotti,etal.(2003)."Retin Schraermeyer, U. and K. Heimann Schraermeyer, U.andK. Res mental disorder."JIntellectDisabilRes 26 Saadeh, R.,E.C.Lisi,etal.(2007)."Alb Didden, R.,H.Korzilius, etal.(2004)."C Dickinson, A. J.,A.R.Fielder, etal.( King, R.A.,G.L.Wiesner, et al.(1993). "Hypop Smith, J.C.(2001)."Angelman syndrome: evolution of th 34-9. Jolleff, N.,F. Emmerson,McConaM. Ryan,H. dromes and with human OCA2." PigmentCellRes al.(1994)."ThemouseBrilliant, M.H.,R.King,et pink-eyed Duker, P. C., S. vanDriel,etal.(2002).Duker, P.C., Mah, M. L., D. K.Wallace,etal.(2000).Mah, M.L.,D. "Ophthal International Journal ofSpeech-La (21-22): 1263-7.

12 (4): 219-36.

albinism." DevMedChildNeurol (1999). "Current understanding ontherole of nguage Pathology 8(1): 28-33. 1990). "Ocularfindings in Angelman's (happy

46 inism and developmental delay:theneedto

"Communication profiles of individuals with "Visual evoked potential evidence of albino-like chiasmal misrouting in a patient wit ommunicative functioning inindividuals withAngelman syndrome: acomparative study. ochoroidal atrophyintwo adultpatients withAngelman syndrome." Am JMed GenetA (Pt 1):35-40. chie (2006)."CommunicationskillsinAnge igmentation in Angelman syndrome." Am JMed Genet

mic manifestations of Angelman syndrome." JAAPOS 7 (6): 398-402. e phenotype inadolescents and adults." DevMed ChildNeurol

41 Angelman's syndrome." Arch Dis Child.69(1): 148-50. dilution gene:associationwith hy (9): 633-8. n, andsocial interaction in theAngelman syndrome." AmJMe 23 retinal pigmentepitheliumandits pigmentation." puppet)syndrome."OphthalmicPaediatrGe Down's syndrome, Angelmanp Down's syndrome, syndromeand test for15q11-q13 deletion." Pediatr Neu lman Syndrome:Matchingphenotype to geno popigmentationPrader-Willi in

46 4 (4): 248-9. (1): 40-4.

43 (7): 476-80. h Angelmansyndrome and Angelmansyn- rol net

" DisabilRehabil 122A

ervasive develop- d Genet 37 Pigment Cell Pigment

11 (4): 299-302. type." (1): 1-6. (2): 155-8.

46 (1):

Angelman Syndrome Clinical Management Guidelines

GENETIC MECHANISM: pat mat pat mat pat pat mat APPENDIX: GeneticMechanismsin Angelman Syndrome = 5-10% UBE3A mutationon maternal15 mat 15behaves asapat15 = 5% Imprinting defect = 2-3% Paternal uniparentaldisomy = 75% Deletion ofmaternallyinherited 15 24 - FISH,MLPA, microarray - Maybemosaic (milder) - Pursuefurther studiesof - Methylationtest - Confirm byUBE3A sequencing - Methylation test - Methylationtest - Confirmedbycheckingparental - Methylationtest DETECTED BY: origin of15s imprinting centre but noUPD/deletion abnormal normal abnormal abnormal

Angelman Syndrome Clinical Management Guidelines

Acknowledgements andRosemary Teggin, Parent. • • • • • The GuidelineDevelopment Angelman Syndrome Team The GuidelineDevelopmentGroup Angelman Syndrome ASSERT—The Angelman Syndrome SupportEducat DYSCERNE: A NetworkofCentres ofExpert Kate Strong, University ofManchester Caroline Harrison,Univ Pam Griffiths, University of Manchester Nowgen—A CentreforGeneticsinHealthcare (www.nowgen.org.uk) a oeto Idpnet PatientRepresentative Dental Vision Communication & Speech Behaviour BlenheimHouseChildDevelopmen StMary’sHospit Independent Manchester Royal EyeHospital RoyalManchester UniversityofManchester Megan Thomas Independent/ASSERT UniversityofBrussels Pam Robertson University of Manchester & University of Birmingham Zulf Mughal Ralph MacKinnon Chris Lloyd Instytut Pomnick- Malgorzata Krajewska-Walasek Kay Hood Finn Emerson Un Bernard Dan Dawn Adams Jill Clayton-Smith (Lead) Expert These guidelines were produced thanks tofunding fromDYSCERNE: ANetwork ofCentre ofExpertise forDysmorphology (funded byt

ersity ofManchester European Commission PublicHealthExecut Institution iversity ofManchester

l acetr Bonedensity al, Manchester etu doi zek,Wra Development Centrum Zdrowia Dziecka, Warsaw hlrnsHsia Anaesthesia Children’s Hospital UB Neurological, Seizures, Ataxia (ULB) ise inDysmorphology(www.dyscerne.org) n aiySpotCnr,Bakol Sleep t and FamilySupportCentre, Blackpool 25 ion andResearch Trust (www.angelman.org)

DYSCERNE— Angelman Syndrome GuidelineDevelopment Group 1 24/01/2010 00/00/0000 24/01/2011 :[email protected] Management of AngelmanSyndrome:A Clinical Guideline

Review Area Skin, Diagnosis Feeding, Bowel,Orthopaedics, Puberty,