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Angelman syndrome

This is part of Rare diseases.

Diagnosis: Angelman syndrome

Synonyms: --

Innehåll


Date of publication: 2014-10-16
Version: 5.0

ICD-10

Q93.5

The disease

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 of whom had cognitive disabilities and displayed similar patterns of movement and behaviour.

Occurrence

The occurrence of Angelman syndrome is estimated at eight per 100,000, meaning that in Sweden approximately eight children are born with the syndrome annually. To date, it is mostly children who have received the diagnosis although people of all ages may have the syndrome. More than 200 people in Sweden have been diagnosed with Angelman syndrome.

Cause

Angelman syndrome is caused by a deficiency in gene UBE3A, located on the long arm of chromosome 15 (15q11.2-q13), an area where genetic function is controlled by genomic imprinting. Imprinting means that genes are expressed selectively, depending on which parent they are inherited from. The UBE3A gene is expressed only in the copy of the gene inherited from the mother, while the father’s copy is inactive (methylated). In Angelman syndrome the function of UBE3A is impaired in some way. There are several types of genetic abnormalities which can cause this.

Approximately 70 to 75 per cent of those with the syndrome have a deletion on chromosome 15 (15q11.2-q13). The extent of the deletion varies between individuals. In Angelman syndrome the deletion can sometimes include a gene which plays a role in pigmentation, which may be the reason that some children have fairer hair than other family members.

Another occurrence which triggers Angelman syndrome takes place 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 the child has 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, i.e. an absence of normal UBE3A function.

Angelman syndrome can also be caused by an imprinting defect (ID) when genomic imprinting of chromosome 15 from the mother is defective and the gene is not activated in the usual way.

In slightly more than ten per cent of people, the syndrome is caused by a mutation in the UBE3A gene.

In a few cases a child may have more extensive chromosomal changes, not limited exclusively to the area associated with Angelman syndrome. Currently, in ten percent of those who receive a diagnosis of Angelman syndrome based on clinical indications, it is not possible to identify genetic defects.

Another condition caused by genetic abnormalities in chromosome 15 is Prader-Willis syndrome, although in this case genetic malfunction is limited to the genes active in the copy of the chromosome inherited from the father. Information on Prader-Willis syndrome can be found in the Swedish National Board of Health and Welfare database of rare diseases.

Heredity

The risk of parents of a child with Angelman syndrome having another child with the disorder depends on the cause of the syndrome in the particular case, but is usually small.

In most instances the deletion has occurred in the affected child and the risk of parents having more children with the syndrome is less than one per cent. Even when the cause of the condition is an imprinting defect (ID), the risk of having more children with the syndrome is usually less than one per cent. An exception is when the syndrome is caused by the deletion of an imprinting centre in a specific area of chromosome 15, in which case the risk may rise to 50 per cent.

If the mother is the carrier of a UBE3A mutation, the risk of her having further children with the syndrome is 50 per cent. A man with a UBE3A mutation will not have children with Angelman syndrome, but his daughters will have a 50 per cent risk of inheriting the mutation and having a child with the syndrome.

Symptoms

The most common symptoms of Angelman syndrome are cognitive disabilty, delayed motor development with movement, balance and coordination problems (ataxia), hyperactivity, very limited language development and characteristic 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. Children with a deletion which includes the OCA2 gene are blond and blue-eyed as this gene plays a role in the pigmentation of the skin, eyes and hair.

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. Delayed development can usually be detected 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, common in young children with the syndrome, balance problems and a jerky gait are features of the same disturbance in motor control. The children have a wide and stiff-legged gait and maintain their balance by holding their arms at shoulder height and leaning slightly forward. As time goes on, stability in the legs increases, sometimes in combination with stiffness and spasticity, and there is the risk of stiff joints and acquired 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. Tooth grinding is common, even during the day.

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 18 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 mouth, a prominent lower jaw (an under bite), a thin upper lip, and widely-spaced teeth and a gap between the front teeth. Their head circumference is small and the back of the head is flat. Squinting may also occur. 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 alternative communication methods. Many have well-developed visual perception skills, which may facilitate communication training which uses simple images and everyday objects. People with the syndrome are also often quite good at recognising familiar places or travel routes.

Most children and adolescents with the syndrome are very excitable and may be subject to sudden, unpredictable attacks of laughter. Stereotypical behaviour such as hand flapping, and of biting the backs of the hands, is common. Most people with the syndrome enjoy spending time with others, but this should be on their own terms. A few people have such severe behavioural problems and difficulties in engaging in social situations, as well as problems with language and other forms of communication, that they fulfil the criteria for autism.

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. It is easy to stimulate the children and they laugh easily.

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.

Diagnosis

Angelman syndrome is primarily a clinical diagnosis, based on a combination of characteristic developmental 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.

The results of laboratory tests used for evaluating metabolic diseases are normal. Brain scans using magnetic resonance imaging (MR) or computer tomography (CT) will show no specific abnormalities. As the symptoms vary greatly between different individuals, a child with suspected Angelman syndrome should be examined at a hospital where there is 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.

At the time of diagnosis it is important that the family is offered genetic counselling. Carrier and prenatal diagnosis, as well as pre-implantation genetic diagnosis (PGD) in association with IVF (in vitro fertilization), are available to families where the mutation is known.

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. In the Swedish National Board of Health and Welfare’s database of rare diseases information can be found on Mowat-Wilsons syndrome and Rett syndrome.

Treatment/interventions

There is no cure for Angelman syndrome but a great deal can be done to support the affected individual and compensate as much as possible for disabilities.

Medication is used to treat epilepsy. Experience to date indicates that sodium valproate, ethosuximide and benzodiazepines give the best results. Certain other epilepsy medications may sometimes exacerbate the condition. 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.

A neuropsychiatric evaluation should be performed early, in order to assess the child’s functional abilities and limitations. The child and family receive support from a habilitation team. Help is available within the medical, educational, psychological, social and technical fields. Habilitation may include assessments, treatment, assistance with choice of aids and information about disabilities and counselling. Information is also available about support offered by public services as well as advice on adapting accommodation and other environments to the child’s needs. Parents and siblings can also receive support.

There should be close contact with the local authority, which can offer different kinds of help including personal assistance, a contact family or short-term accommodation, to make daily life easier.

As children with Angelman syndrome are often hyperactive, impressionable and have concentration difficulties, they need structured activities and settled routines. Distractions should be minimized as far as possible. Restlessness and stereotypical behaviour then tend to decrease. The inability to make themselves understood can be an additional source of frustration for people with the syndrome. It is important that language stimulation and augmentative and alternative communication (AAC) are initiated at an early stage. A speech therapist makes an evaluation of the individual’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 as far as possible.

Oral motor training may improve eating skills and reduce drooling in both children and adults. Scopolamine plasters or atropine drops under the tongue can also be used to reduce saliva production and 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. When necessary, tooth-grinding should be followed up and a dental bite guard provided.

People with Angelman syndrome should be regularly monitored for scoliosis and contractures by an orthopaedic surgeon and a physiotherapist. An exercise programme in combination with individually designed orthoses (braces) can be used to prevent the development of joint deformities. A surgical corset can be used to treat the early stages of scoliosis, but surgery may also be required.

Adults with Angelman syndrome need continued, individually-tailored habilitation and support in their daily lives. This may take the form of support and care in accommodation offering special service and daily activities.

Practical advice

The disturbed sleeping patterns associated with Angelman syndrome often create a heavy burden for the family. It is a good idea to accustom the child at a very early age to sleeping in a dark, quiet 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 monitor tendencies to develop stereotypical behaviour patterns and habits. Children with the syndrome are easily overstimulated, and in stimuli-rich environments and in large groups they often become hyperactive. Establishing regular routines and habits is helpful.

National and regional resources in Sweden

Clinical diagnoses of Angelman syndrome are usually carried out at Swedish paediatric clinics. Genetic tests are performed by departments for 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. Senior Physician Mårten Kyllerman is responsible for Angelman syndrome.

Expertise in orofacial problems can be found at Mun-H-Center, Institute of Odontology, Medicinaregatan 12A, SE-413 90 Gothenburg, Sweden. Tel: +46 31 750 92 00, email: mun-h-center@vgregion.se, www.mun-h-center.se.

Resource personnel

Senior Physician 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.

Courses, exchanges of experience, recreation

Ågrenska is a national competence centre for rare diseases and its families’ programme arranges stays for children and young people with disabilities 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. In addition, a number of programmes every year is provided for adults with rare diseases. Information is available from Ågrenska, Box 2058, SE-436 02 Hovås, Sweden. Tel: +46 31 750 91 00, fax: +46 31 91 19 79, email: agrenska@agrenska.se, www.agrenska.se.

Organizations for the disabled/patient associations etc.

Angelman Syndrome Parents’ Association (ASF). Contact 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.

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.

Courses, exchanges of experience for personnel

During the weeks of the Ågrenska Family Program, 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 31 750 91 00, fax: +46 31 91 19 79, email: agrenska@agrenska.se, www.agrenska.se.

The Autism and Asperger Association organizes courses for personnel working with children at early stages of development. For further information, see the association’s course descriptions: www.autism.se.

Research and development

Research, primarily within the area of molecular genetics, is on-going in various international centres.

Information material

Short summaries of all the database texts are available as leaflets, in Swedish only. These leaflets may be ordered or printed out. (See under “Mer hos oss” in the right hand column.)

Annorlunda Barn. (In Swedish only.) Angelman syndrome. Published by the Angelman Syndrome Parent Association. May be ordered from the association.(See address under heading, “Organizations for the disabled/patient associations etc.”)

Ågrenska has published information on Angelman syndrome, nr 403 (2012). (In Swedish only.) These newsletters are edited summaries of lectures delivered at family and adult stays at Ågrenska. They may be ordered from Ågrenska, Box 2058, SE-436 02 Hovås, Sweden. Tel: +46 31 750 91 00, fax: +46 31 91 19 79, email: agrenska@agrenska.se. They are 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 telephone,+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 see: www.csh.dk.

The International Angelman Syndrome Organisation (IASO) has a lot of information on its website and many useful links: www.international.angelmansyndrome.org.

Films

Ett gott liv för Niklas (in Swedish only). May be ordered from FUB (find 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

Extensive information on autism, in languages including English, is available on Autism Forum: www.autismforum.se. Autism Forum is part of the Stockholm County Council habilitation services.

Literature

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. Angelman syndrome. Handb Clin Neurol 2013; 111: 287-90.

Kyllerman M. On the prevalence of Angelman syndrome. Am J Med Genet 1995; 59: 405.

Leyser M, Penna PS, de Almeida AC, Vasconcelos MM, Nascimento OJ. Revisiting epilepsy and the electroencephalogram patterns in Angelman syndrome. Neurol Sci 2014 Jan 7. [Epub ahead of print].

Mertz LG, Christensen R, Vogel I, Hertz JM, Nielsen KB, Grønskov K et al. Angelman syndrome in Denmark. Birth incidence, genetic findings, and age at diagnosis. Am J Med Genet A 2013; 16: 2197-203.

Mertz LG, Thaulov P, Trillingsgaard A, Christensen R, Vogel I, Hertz JM et al. Neurodevelopmental outcome in Angelman syndrome: Genotype-phenotype correlations. Res Dev Disabil 2014 Mar 18 [Epub ahead of print].

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.

Database references

OMIM (Online Mendelian Inheritance in Man)
www.ncbi.nlm.nih.gov/omim 
Search: angelman syndrome

GeneReviews (University of Washington)
www.genetests.org (klicka på GeneReviews, sedan Titles)
Search: angelman syndrome

Orphanet (European database)
www.orpha.net 
Search: angelman syndrome

Document information

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.

Date of publication: 2014-10-16
Version: 5.0
Publication date of the Swedish version: 2014-06-23

For enquiries contact The Swedish Information Centre for Rare Diseases, The Sahlgrenska Academy at the University of Gothenburg, Box 422, SE-405 30 Gothenburg, Sweden. Tel: +46 31 786 55 90, email: ovanligadiagnoser@gu.se.

 

About the database

This knowledge database provides information on rare diseases and conditions. The information is not intended to be a substitute for professional medical care, nor is it intended to be used as a basis for diagnosis or treatment.