What is Angelman Syndrome?
Angelman syndrome is a genetic disorder that affects the nervous system and causes severe physical and intellectual disability.
It’s relatively rare, occurring in around 1 in 15,000-20,000 people.
Typical characteristics of Angelman syndrome include:
- delayed development (usually noticeable from 6-12 months of age)
- severe language impairment with little or no speech
- movement and balance problems (ataxia)
- frequent seizures (epilepsy) in around 85% of cases
- a small head size (microcephaly)
- sociable behaviour with frequent smiling
In most cases, Angelman syndrome isn’t inherited from your parents, and the genetic anomaly responsible for the syndrome occurs by chance around the time of conception. However, in some families, more than one child is affected (see below).
Characteristics of Angelman syndrome
The typical characteristics of Angelman syndrome aren’t usually apparent at birth.
A child with the syndrome will begin to show signs of delayed development around 6-12 months, such as being unable to sit unsupported or make babbling noises. Later, they may not speak at all or may only be able to say a few words.
Children with Angelman syndrome are very sociable and frequently smile
The movement of a child with Angelman syndrome will also be affected. They may have difficulty walking due to problems with balance and co-ordination (ataxia), their arms may tremble or move jerkily, and their legs may be stiffer than normal.
A number of distinctive behaviours are also associated with Angelman syndrome. These may include:
- frequent laughter and smiling, with little stimulus
- being easily excitable, often flapping the hands
- being restless (hyperactive)
- having a short attention span
- problems sleeping and needing less sleep than other children
- Seizure disorder
Other possible features of the syndrome include:
- sticking the tongue out
- crossed eyes (strabismus)
- pale skin, and light-coloured hair and eyes
- a wide mouth with widely spaced teeth
- a side-to-side curvature of the spine (scoliosis)
- walking with arms in the air
- a fascination with water
- Problems with depth perception
- Excessive salivation
Some young babies with Angelman syndrome may have problems feeding because they’re unable to co-ordinate sucking and swallowing. In such cases, a high-calorie formula may be recommended to help the baby gain weight, or they may need to be treated for reflux.
Angelman Syndrome can be misdiagnosed with cerebral palsy or Autism. There are other genetic conditions that share characteristics which mimic AS, follow this link for information these syndromes; http://www.cureangelman.org.au/content/3836
What causes Angelman syndrome?
The typical characteristics of Angelman syndrome are caused when a gene, known as UBE3A, is either absent or malfunctions. A gene is a single unit of DNA.
A child usually inherits one copy of the UBE3A gene from each parent. Both copies are switched on (active) in most of the body’s tissues. However, in certain areas of the brain, only the gene inherited from the mother is active.
- Deletion – Chromosome 15q11.2-q13 – In most cases of Angelman syndrome (about 70%) the child’s maternal copy of the UBE3A gene is missing, (or deleted) which means there is no active copy of the UBE3A gene in the child’s brain (known as deletion positive
- UBE3A Mutations – In around 11% of cases, the maternal copy of the UBE3A gene is altered so these individuals do not have the appropriate levels of functional UBE3A in the brain.(known as UBE3A mutation)
- UPD – In a small percentage of cases (7% ) Angelman Syndrome occurs when a child inherits two copies of chromosome 15 from the father , rather than one from each parent.(known as Uni Parental Disomy or UPD )
- ICD – Angelman Syndrome can also occur (in about 3% of cases) when the copy of the UBE3A gene that comes from the mother, behaves like it came from the father known as (Imprinting Centre Defect)
- Clinical/Other In about 10-15% of cases, the causes of Angelman Syndrome traits is unknown. In these individuals, all testing for Angelman Syndrome is negative but they still meet the diagnostic criteria for AS (known as Clinical). These individuals may have as yet unrecognised mutations, that affect UBE3A or genomic imprinting on Chromosome 15. There are also several other syndromes that present with traits like AS.
These links to videos which feature some children & adults with Angelman Syndrome in WA show the variabilities and similarities in individuals:
A story about Individuals with Angelman Syndrome; https://www.youtube.com/watch?v=zPjg8uGVGbg
What Does Angelman Syndrome look like; https://www.youtube.com/watch?v=U5J0kvFSTtA
Diagnosing Angelman syndrome
Angelman syndrome may be suspected if a child’s development is delayed and they have the syndrome’s distinctive characteristics (see above).
A blood sample can be taken to confirm the diagnosis. A number of genetic tests will be carried out on the sample. These may include:
- chromosome analysis – to see if any parts of the chromosomes are missing
- fluorescence in situ hybridisation (FISH) – used to check chromosome 15 deletions
- DNA methylation – shows whether the genetic material on both the mother’s and father’s chromosomes is active; it can detect deletions, uniparental disomy and imprinting defects
- UBE3A gene mutation analysis – if the results of DNA methylation are normal, UBE3A gene sequencing can be used to see whether the maternal copy of the gene is altered
For each child with Angelman syndrome, it’s important to know the genetic change that caused the condition to determine the risk of it occurring again in another child.
Most children with Angelman syndrome are diagnosed between the ages of 18 months and 6 years, when the typical physical and behavioural symptoms become apparent.
If your child is diagnosed with Angelman syndrome, you should be given the opportunity to discuss the genetic diagnosis and implications with a genetic doctor.
Managing Angelman syndrome
Some of the symptoms of Angelman syndrome can be difficult to manage, and you’re likely to need help from a wide range of different healthcare professionals.
Your child may benefit from some of the following treatments and aids:
- anti-epileptic medicine to control the seizures (sodium valproate, clonazepam or ethosuximide may be prescribed)
- physiotherapy may help to improve posture, balance and walking ability; it’s also important to prevent permanent stiffening (contractures) of the joints as they get older
- a back brace or spinal surgery may be recommended to prevent the spine from becoming more curved (see treating scoliosis)
- an ankle or foot orthosis (lower leg brace) may be recommended to help them walk independently
- communication therapy may be needed to help them develop non-verbal language skills, such as sign language and using visual aids; using iPad applications and similar devices may also help
- behavioural therapy may be recommended to help overcome problem behaviours, hyperactivity and a short attention span
- activities such as swimming, horseriding and music therapy have also been reported as being beneficial
While there’s currently no cure for Angelman syndrome, the results of preliminary genetic research carried out in America have been promising.
Following these studies, scientists believe that it may be possible to restore UBE3A function in the brains of people with Angelman syndrome.
Read more about the search for a cure for Angelman syndrome (external link).
With age, people with Angelman syndrome become less hyperactive and the sleeping problems tend to improve. Most people with the syndrome will have intellectual disability and limited speech throughout their life.
In later childhood, the seizures usually improve, although they may return in adulthood. In adults, some mobility may be lost and joints may stiffen up.
A person with Angelman syndrome will have a near-normal life expectancy, but will need support for the rest of their life.
Where does the name for the syndrome come from?
In 1965, Dr. Harry Angelman, an English physician, first described three children with characteristics now known as the Angelman syndrome (AS). He noted that all had a stiff, jerky gait, absent speech, excessive laughter and seizures. Other cases were eventually published but the condition was considered to be extremely rare and many physicians doubted its existence. The first reports from North America appeared in the early 1980s and within the last ten years many new reports have appeared. Dr. Angelman relates the following regarding his discovery of this syndrome.
“The history of medicine is full of interesting stories about the discovery of illnesses. The saga of Angelman’s syndrome is one such story. It was purely by chance that nearly thirty years ago three handicapped children were admitted at various times to my children’s ward in England. They had a variety of disabilities and although, at first sight, they seemed to be suffering from different conditions, I felt that there was a common cause for their illness. The diagnosis was purely a clinical one because, in spite of technical investigations which today are more refined, I was unable to establish scientific proof that the three children all had the same handicap. In view of this I hesitated to write about them in the medical journals. However, when on holiday in Italy I happened to see an oil painting in the Castelvecchio museum in Verona called . . . a Boy with a Puppet. The boy’s laughing face and the fact that my patients exhibited jerky movements gave me the idea of writing an article about the three children with a title of Puppet Children. It was not a name that pleased all parents but it served as a means of combining the three little patients into a single group. Later the name was changed to Angelman syndrome. This article was published in 1965, and after some initial interest, lay almost forgotten until the early eighties.”
Angelman syndrome is usually not recognized at birth or in infancy since the developmental problems are nonspecific during this time. Parents may first suspect the diagnosis after reading about AS or meeting a child with the condition. The most common age of diagnosis is between three and seven years when the characteristic behaviors and features become most evident. A summary of the developmental and physical findings has recently been published for the purpose of establishing clinical criteria for the diagnosis and these are listed below. All of the features do not need to be present for the diagnosis to be made, and the diagnosis is often first suspected when the typical behaviors are recognized.
For several decades the chromosome study of AS individuals revealed no abnormalities, but with the development of improved methods a very small deleted area was found in chromosome 15. Molecular methods such as FISH (fluorescence in situ hybridization) now demonstrate a deletion in about 70% of individuals with AS. The deleted area, although extremely small, is actually quite large when viewed at the molecular level. It is believed to be about 4 million base pairs in length, enough to contain many genes.
The deleted region on chromosome 15 is known to contain genes that are activated or inactivated depending upon the chromosome’s parent of origin (i.e., a gene may be turned on on the chromosome 15 inherited from the mother but off on the chromosome 15 inherited from the father). This parent-specific gene activation is referred to as genetic imprinting. Because the deletions seen in AS only occur on the chromosome 15 inherited from the mother, the gene(s) responsible for AS were predicted to be active only on the maternal chromosome 15. Disruption of genes that are active on the paternally-derived chromosome 15 is now known to cause another developmental disorder termed the Prader-Willi syndrome (PWS). The PWS gene(s) are actually located close to the AS gene, but they are different.
AS has been reported throughout the world among divergent racial groups. In North America, the great majority of known cases seem to be of Caucasian origin. Although the exact incidence of AS is unknown, an estimate of between 1 in 15,000 to 1 in 30,000 seems reasonable.