Publication date: 2011-06-28
Version: 4.2
Q93.5
Angelman syndrome is associated with cognitive disability, epilepsy and balance disorder in combination with specific behavioural and communication patterns and characteristic facial features.
The syndrome is named after British paediatrician Harry Angelman who, in 1965, described three children, all with cognitive disabilites and displaying similar patterns of movement and behaviour.
The number of people with Angelman syndrome is estimated at eight per 100, 000. In Sweden approximately eight children are born with the syndrome annually. To date, mostly children have received the diagnosis although people of all ages can have the syndrome. More than 200 people in Sweden have been diagnosed with Angelman syndrome.
The cause is a change in one area of genetic material on the long arm of chromosome 15.
Approximately 70 to 75 per cent of those with the syndrome lack a small piece of chromosome 15 (15q11.2-q13). This deletion is always found on chromosome 15, which is inherited from the mother. In most instances the deletion occurs for the first time in the affected child and the risk of parents having more children with the syndrome is less than one per cent. Normally certain genes in the specific area on the strand of chromosome 15 inherited from the mother are active (unmethylated), while they are inactive (methylated) on the strand of chromosome 15 inherited from the father. This is called genomic imprinting. In Angelman syndrome the active, unmethylated genes from the mother are absent. This is the reverse of Prader-Willis syndrome (see specific information material in the Swedish Board of Health and Welfare’s Rare Disease Database). In Prader-Willis syndrome, only genes normally active on the strand of chromosome 15 inherited from the father are absent. The extent of the deletion varies between individuals. In Angelman syndrome the deletion can sometimes include a gene that plays a role in pigmentation, which may be the reason that some children have fairer hair than other family members.
Another trigger of Angelman syndrome occurs during conception when the child receives a double set of chromosome 15 from the father and none from the mother. This is called UPD (uniparental disomy) and is more rare, affecting between three and seven per cent of people with the syndrome. As both strands of the gene inherited from the father are inactive the result of UPD is basically the same as in a deletion of the mother’s strand of chromosome 15 - an absence of normal genetic function.
Angelman syndrome can also be caused by imprinting defects (ID). In such instances, the risk of having more children with the syndrome is usually less than one per cent. An exception is the deletion of an imprinting centre in a specific area of chromosome 15, in which case the risk may rise to 50 per cent.
In slightly more than ten per cent of instances the syndrome is caused by a mutation in gene UBE3A. If the mother is the carrier of this mutation, the risk of her having further children with the syndrome is 50 per cent. A man with a mutation in gene UBE3A will not have children with Angelman syndrome, but his daughters will have a 50 per cent risk of inheriting the mutation and in their turn having a child with the syndrome.
In a few cases a child may have more extensive chromosomal changes, not limited exclusively to the area associated with Angelman syndrome.
In ten percent of who receive a diagnosis of Angelman syndrome based on clinical indications, it is not currently possible to identify genetic defects.
Usually the risk of parents of a child with Angelman syndrome having another child with the disorder is very small (less than one per cent). The size of the risk depends on what has caused the syndrome in that particular case. In a small number of instances, the risk can rise to 50 per cent. (See under heading “Cause.”) At the same time that the diagnosis is made the family should be offered genetic information and counselling by a clinical geneticist.
The most common symptoms are cognitive disabilty, delayed motor development with movement, balance and coordination problems (ataxia), hyperactivity, very limited language development and distinctive, happy and positive behaviour patterns. Epilepsy is common. The heads of children with the syndrome are often small. When the cause of the syndrome is a deletion, symptoms are often more severe than when caused by other genetic factors.
Weight, length and head circumference in children with Angelman syndrome are often normal at birth, but afterwards both weight and head circumference increase more slowly than average. From the first months of life, motor development is greatly delayed. Most children have severe sucking and feeding difficulties. As a rule, delayed development can be observed from before the child is six months old.
From around the age of one it is clear that the child has problems with balance. The development of gross motor skills varies greatly between children. On average, they learn to sit without support by the age of 13 months, to crawl or shuffle on their bottoms by the age of 22 months, and to walk between the ages of two and seven. A few children never learn to walk without support. Low muscle tone, balance problems and a jerky gait caused by lack of motor control are common in young children with the syndrome. The children have a broad-based gait and maintain their balance by holding their arms at shoulder height and leaning slightly forward. Some have hyperactive deep tendon reflexes. Gradually they gain leg stability, sometimes in combination with stiffness and spasticity. Over time, there is a risk of developing joint stiffness and contractures in the knees and feet. Some children develop curvature of the spine (scoliosis). Fine motor skills also develop very late.
Children often have poor oral motor control so the mouth is often open and the tongue frequently protruding. Drooling is common. In some individuals, abnormalities in oral motor development cause problems when eating and drinking.
Children with Angelman syndrome have irregular sleeping patterns and need little sleep. They find it difficult to fall asleep and wake easily during the night, which can put a severe strain on the whole family. Sleeping patterns usually improve as the child gets older.
Epilepsy is very common. An EEG examination often reveals a characteristic pattern (slow spike-waves with very high amplitude activity). Seizures usually begin during the first eighteen months of life, either in the form of a rapid and sudden increase in muscle tension (tonic spasms), absence seizures, or brief, minor muscle contractions (myoclonus). As a rule, the number of seizures decreases as the child becomes older.
Individuals with the syndrome usually have a characteristic appearance, with a wide and often cheerfully smiling open mouth, a prominent lower jaw (an underbite), a thin upper lip and widely spaced teeth. Their head circumference is small and the back of the head is flat. Many children are fair-haired and blue-eyed. They may also squint.
Some people with the condition have an increased sensitivity to heat.
The majority have severe cognitive impairments. Generally, people with Angelman syndrome learn to speak only a few words. The ability to understand others’ speech is better developed, but is still very limited. Communication is usually aided by gestures, and some individuals learn a simple signing system. Many have well-developed visual perception skills, which may facilitate communication training using simple images and everyday objects. Children with the syndrome are also often quite good at recognising familiar places or travel routes.
Most children and adolescents with the syndrome are easily excitable and may be subject to sudden, unpredictable attacks of laughter. Stereotypic behaviour such as hand flapping is common. Sometimes self-harming behaviour may occur, such as repeated biting of the back of the hand. Most people with the syndrome enjoy spending time with others, but this should be on their own terms. A few individuals fulfil the behaviour criteria for autism. These criteria include severe difficulties in engaging in social situations, problems with language and other forms of communication and other characteristic behaviours.
Hyperactivity and concentration problems are common, especially in environments or situations giving rise to many impressions. These children are in constant motion and may initiate various activities which they then do not complete. They often enjoy simple activities such as leafing through magazines or looking at pictures. They are often fascinated by water and enjoy water games.
Adults
Hyperactivity, sleep disorders and epilepsy often improve with age. Adults with the syndrome are usually thin and of normal stature. They tend to have a forward-leaning posture, and the physical features associated with the syndrome become more pronounced over the years. Scoliosis, and knee and foot deformities may also develop.
Angelman syndrome is primarily a clinical diagnosis, based on a combination of characteristic development and behavioural patterns. The diagnosis is supported by internationally-agreed diagnostic criteria. The condition is not associated with congenital malformations, and weight and head circumference are usually normal in newborns with the syndrome. However, the result of an EEG brain scan is usually decisive, revealing characteristic patterns associated with the syndrome.
The results of laboratory tests used for evaluating metabolic diseases will be normal. Brain scans using magnetic resonance imaging (MR) or computer tomography (CT) will show no abnormalities. As the symptoms vary between different individuals, a child with suspected Angelman syndrome should be examined at a hospital with experience of the syndrome.
DNA-based diagnostics can confirm the diagnosis in up to 90 per cent of cases. If the diagnosis is clinically proven and a methylation test shows no abnormalities, a mutation analysis may be carried out to establish whether there is a mutation in gene UBE3A.
Pre-natal testing is possible if the genetic abnormality in the family has already been identified. As Angelman syndrome is caused by a number of genetic defects and the pattern of inheritance is complex, the parents of children with the syndrome should be offered information and counselling by a specialist in clinical genetics.
Several similar syndromes have been identified in recent years and may need to be considered. Examples include CDKL5 mutation, Mowat-Wilson syndrome, Pitt-Hopkins syndrome, X-linked Angelman (Angelman-like) syndrome with SLC9A6 mutation, 2q23.1 microdeletion syndrome, MTHFR deficiency, adenyl succinate deficiency and Rett syndrome. (Special information material on Rett syndrome is available in the Swedish Board of Health and Welfare’s Database of Rare Diseases.)
There is no cure for Angelman syndrome, but symptoms may be treated in various ways. Much can be done to support the individual and compensate as much as possible for functional limitations.
Prescription drugs to control epilepsy usually work relatively well. Experience to date indicates that sodium valproate, ethosuximide and benzodiazepines give the best results. Certain other epilepsy medications may sometimes exacerbate the condition. Seizures may affect the child’s perceptions and can be very upsetting for the family. However, experience indicates that not even repeated seizures result in permanent brain damage or dysfunction. In some cases, central stimulant treatment for hyperactivity and attention deficit disorders has proved highly beneficial. Sleep medications can bring about a change in sleep routines and melatonin can sometimes be used to normalise sleeping patterns. Children should have their own bedrooms, which can be made dark and quiet to aid sleep.
A neuropsychiatric evaluation should be performed early, in order to assess the child’s functional abilities and limitations. After this examination has been carried out, the child and family should be offered support from a habilitation team. A habilitation team includes professionals with special expertise in how disability affects everyday life, health and development. Help is available within the medical, educational, psychological, social and technical fields. Habilitation may include assessments, treatment, assistance with choice of aids, information about disabilities and counselling. It also includes information about support offered by the local authority as well as advice on the way accommodation and other environments can be adapted to the child’s needs. Parents and siblings may also receive support.
Treatment and support are planned according to individual needs and may change over time. They always take place in collaboration with those close to the child. The family may also require assistance in coordinating the various interventions.
The local authority can offer different forms of support to facilitate everyday life. Support may include a contact family offering respite care.
As children with Angelman syndrome are usually hyperactive and have concentration difficulties, they need structured activities and settled routines. Restlessness and stereotypic behaviour then tend to decrease. The inability to make themselves understood can be an additional source of anxiety for people with the syndrome. It is therefore important that language is stimulated, and alternative and augmentative communication (AAC) offered to the child at an early stage. A speech therapist makes an evaluation of the child’s abilities, providing the basis for the choice of communication methods. (AAC methods include the use of simple objects, pictograms and signs.) The child also needs practice in managing everyday activities and routines.
Oral motor training may improve eating skills and reduce drooling in both children and adults. Scopolamine plasters can also be used to prevent drooling. Frequent dental appointments may be necessary for prophylactic dental care. Paediatric dental specialists should be consulted and bite abnormalities should be treated by an orthodontist.
People with Angelman syndrome should be regularly monitored for scoliosis and contractures by an orthopaedic surgeon and a physiotherapist. Stretching exercises in combination with individually fitted braces can be used to prevent the development of joint deformities. Tendon surgery may help in restoring joint flexibility after contractures. A surgical corset can be used to treat the early stages of scoliosis, but surgery may also be required.
Adults with Angelman syndrome require continued support from habilitation services, or their equivalent, in their daily lives. This may take the form of support and care in accommodation offering specialist services and daily activities.
Sleep disturbances associated with Angelman syndrome can be a major problem for the family. It is a good idea to accustom the child to sleeping in a room alone at night, so that he or she may wake up, play for a while, and then go back to sleep without disturbing the rest of the family.
Children with Angelman syndrome often greatly enjoy looking at pictures and films, and listening to music. They are usually fascinated by water and love to play with it. If possible, the bathroom in the child’s home should be spacious and have a bathtub.
It is important to be attentive to the tendencies of these children to develop stereotypic behaviour patterns and habits. Children with the syndrome are easily over stimulated, and in stimuli-rich environments and in large groups they often become hyperactive. Establishing regular routines and habits is helpful.
Clinical diagnoses of Angelman syndrome are usually made at Swedish paediatric clinics. Genetic diagnoses and family evaluations are carried out at departments of clinical genetics at Swedish university hospitals. Genetic counselling is also provided.
A multi-disciplinary team is located at The Children’s Centre for Rare Diseases at The Queen Silvia Children’s Hospital, Gothenburg, Sweden. Associate Professor Mårten Kyllerman is responsible for Angelman syndrome.
Expertise in orofacial problems can be found at Mun-H-Center, Institute of Odontology, Gothenburg, Medicinaregatan 12A, SE-413 90 Gothenburg, Sweden. Tel: +46 31 750 92 00, fax: +46 31 750 92 01, email: mun-h-center@vgregion.se, www.mun-h-center.se.
Associate Professor Mårten Kyllerman and Dr Gill Nilsson, Unit for Neurology, Neuropsychiatry, Paediatric Psychiatry and Habilitation, The Queen Silvia Children’s Hospital, SE-416 85 Gothenburg, Sweden. Tel: +46 31 343 40 00.
Ågrenska is a national competence centre for rare diseases and its families’ programme arranges stays for children and young people with rare diseases and their families. Ågrenska is open to families from the whole of Sweden and focuses particularly on the needs of children and young people with rare diseases. Every year a number of adults with rare diseases also visits Ågrenska. Information is available from Ågrenska, Box 2058, SE-436 02 Hovås. Tel: +46 31750 91 00, fax: +46 31 91 19 79, email: agrenska@agrenska.se, www.agrenska.se.
Angelman Syndrome Parents' Association (ASF). Contact person is Ottilia Barnard, tel: +46 70 203 19 02, email: angelmansverige@yahoo.se.
ASF is a network within FUB, The Swedish National Association for Children, Young People and Adults with Intellectual Disabilities. Gävlegatan 18 C, Box 6436, SE-113 82 Stockholm, Sweden. Tel: +46 8 508 866 00, fax: +46 8 508 866 66, email: fub@fub.se, www.fub.se.
ASF is part of a network within the International Angelman Syndrome Organisation (IASO), www.international.angelmansyndrome.org.
The Autism and Asperger Association, Bellmansgatan 30, SE-118 47 Stockholm, Sweden. Tel: +46 8 702 05 80, fax: +46 8 644 02 88, email: info@autism.se, www.autism.se.
SEF, The Swedish Epilepsy Association, Sturegatan 4A, Box 1386, SE-172 27 Sundbyberg, Sweden. Tel: +46 8 669 41 06, fax: +46 8 669 15 88, email: info@epilepsi.se, www.epilepsi.se.
During the Ågrenska Family Program weeks, training days are organized for personnel working with the children who are participating. Information is available from Ågrenska, Box 2058, SE-436 02 Hovås, Sweden. Tel: +46 31750 91 00, fax: +46 31 91 19 79, email: agrenska@agrenska.se, www.agrenska.se.
The Autism and Asperger Association organises courses for personnel working with children with developmental problems. For further information see the Association’s catalogue of courses, www.autism.se.
Research, primarily within the area of molecular genetics, is on-going at various international centres.
An information leaflet on Angelman syndrome summarising the information in this database text is available free of charge from the customer service department of the Swedish National Board of Health and Welfare (in Swedish only, article number 2010-10-24). Address: SE-120 88 Stockholm, fax: +46 8 779 96 67, email: socialstyrelsen.se@strd.se or tel: +46 8 779 96 66. Postage will be charged for bulk orders.
Brochure, Annorlunda Barn. (In Swedish only.) Angelman syndrom.
Brochure from the Angelman Syndrome Parent Association. May be ordered from the network.(See address under heading, “Organizations for the disabled/patient associations etc.”)
Newsletter from Ågrenska, nr 318 (2008). Can be ordered from Ågrenska, Box 2058, 436 02 Hovås, Sweden. Tel: +46 31 750 91 00, fax: +46 3191 19 79, email: agrenska@agrenska.se. Newsletter also available at www.agrenska.se.
Kamp och glädje. (In Swedish only.) Book by Inga-Lill Morell, mother of two boys with Angelman syndrome. Gothia förlag, 2004. Can be ordered by telephoning +46 8 462 26 70 or email: info.gothia@verbum.se.
Pojkarna: en berättelse om två utvecklingsstörda bröder (in Swedish only). A book by Anders Hansson, father of two boys with Angelman syndrome. Instant Book, 2010, IBSN 9789185671854.
A brochure on Angelman syndrome (in Norwegian only, 2007) can be ordered from; Frambu, Senter for sjeldne funksjonshemninger, Sandbakkveien 18, NO-1404 Siggerud, Norway.Tel: +47 64 85 60 00, fax: +47 64 85 60 99. email: info@frambu.no, www.frambu.no.
Att leva med Angelmans syndrom (in Danish only, 2006). The Danish Centre for Rare Diseases and Disabilities, Copenhagen, Denmark. Can be ordered by telephoning +45 339 140 20, or www.csh.dk.
On the website of the Angelman Syndrome Associaton there is extensive information in English as well as many informative links. www.international.angelmansyndrome.org.
Video films
Angelmans syndrom, Angelman x 3. (In Swedish only.) May be ordered from the Queen Silvia Children’s Hospital, SE-416 85 Gothenburg, Sweden.
Ett gott liv för Niklas. (In Swedish only.) May be ordered from FUB (see under “Organizations for the disabled/patient associations etc.”) or email: ingalill.morell@glocalnet.net.
Angelman Syndrome: Making the Diagnosis (DVD from The Angelman Project 2004, www.geneticalens.com).
Autism
Beckman V, Kärnevik Måbrink M, Schaumann H. Gång på gång - pedagogik vid autism och autismliknande tillstånd. (In Swedish only.) Natur och kultur 1998.
Extensive information on autism, in languages including English, is available on Autismforum: www.autismforum.se. Autismforum is part of the habilitation services within Stockholm County Council.
Angelman H. “Puppet children”: a report of three cases. Dev Med Child Neurol 1965; 7: 681-688.
Bruni O, Ferri B, D’Agostino G, Miano S, Roccella M, Elia M. Sleep disturbances in Angelman syndrome: a questionnaire study. Brain Dev 2004; 26: 233-240.
Clayton-Smith J. Clinical research on Angelman syndrome in the United Kingdom: Observations on 82 affected individuals. Am J Med Genet 1993; 46: 12-15.
Clayton-Smith J. Angelman syndrome: evolution of the phenotype in adolescents and adults. Dev Med & Child Neur 2001; 43: 476-480.
Clayton-Smith J. On the prevalence of Angelman syndrome. Am J Med Genet 1995; 59: 403-404.
Galván-Manso M, Campistol J, Conill J, Sanmarti FX. Analysis of the characteristics of epilepsy in 37 patients with the molecular diagnosis of Angelman syndrome. Epileptic Disord 2005; 7: 19-25.
Gentile JK, Tan WH, Horowitz LT, Bacino CA, Skinner SA, Barbieri-Welge R et al. A neurodevelopmental survey of Angelman syndrome with genotype-phenotype correlations. J Dev Behav Pediatr 2010; 31: 592-601.
Kyllerman M. On the prevalence of Angelman syndrome. Am J Med Genet 1995; 59: 405.
Miano S, Bruni O, Leuzzi V, Elia M, Verrillo E, Ferri R. Sleep polygraphy in Angelman syndrome. Clin Neurophysiol 2004; 115: 938-945.
Påhlsson-Stråe U, Wadelius C, Eeg-Olofsson O. Angelmans syndrom: utvecklingsstörning som fått stor betydelse för förståelsen av genetisk prägling. Läkartidningen 1996; 93: 921-924.
Ramsden SC, Clayton-Smith J, Birch R, Buiting K. Practice guidelines for the molecular analysis of Prader-Willi and Angelman syndromes. BMC Med Genet 2010; 11:70.
Trillingsgaard A, Ostergaard JR. Autism in Angelman syndrome: an exploration of comorbidity. Autism 2004; 8: 168-1174.
Williams CA, Beaudet AL, Clayton-Smith J, Knoll JH, Kyllerman M, Laan LA et al. Angelman syndrome 2005: updated consensus for diagnostic criteria. Am J Med Genet 2006; 140A: 413-418.
Wulffaert J, Scholte EM, van Berckelaer-Onnes IA. Maternal parenting stress in families with a child with Angelman syndrome or Prader-Willi syndrome. J Intellect Dev Disabil 2010; 35: 165-174.
OMIM (Online Mendelian Inheritance in Man)
www.ncbi.nlm.nih.gov/omim
Search: Angelman Syndrome
GeneReviews (University of Washington)
www.genetests.org (find GeneReviews, then Titles)
Search: Angelman Syndrome
The Swedish Information Centre for Rare Diseases produced and edited this information material.
The medical expert who wrote the draft of this information material is Associate Professor Mårten Kyllerman, The Queen Silvia Children’s Hospital, Gothenburg, Sweden.
The relevant organisations for the disabled/patient associations have been given the opportunity to comment on the content of the text.
An expert group on rare diseases, affiliated with the University of Gothenburg, approved the material prior to publication.
Publication date: 2011-06-28
Version: 4.2
Publication date of the Swedish version: 2011-03-17
For enquiries contact The Swedish Information Centre for Rare Diseases, The Sahlgrenska Academy at the University of Gothenburg, Box 400, SE-405 30 Gothenburg, Sweden. Tel: + 46 31 786 55 90, email: ovanligadiagnoser@gu.se.