Angelman Syndrome: Signs, Therapy

Brief overview

  • What is Angelman syndrome? Rare genetic disorder characterized by mental and physical impairments in child development.
  • Symptoms: doll-like facial features, developmental disorder, impaired coordination, little or no language development, decreased intelligence, seizures, laughing for no reason, fits of laughter, excessive drooling, waving arms joyfully
  • Causes: Genetic defect on chromosome 15.
  • Diagnosis: including interview, physical examination, genetic testing
  • Therapy: No causal therapy available; supportive e.g. physiotherapy, speech therapy, occupational therapy; possibly medication to alleviate symptoms (e.g. seizures)
  • Prognosis: Normal life expectancy; no independent life possible

Angelman syndrome: Definition

The name “Angelman syndrome” comes from the discoverer of the disease, the English pediatrician Harry Angelman. In 1965, he compared the clinical pictures of three children who had doll-like facial features. The children laughed a lot and made jerky movements – like puppets. This led to the English name “happy puppet syndrome”.

Angelman syndrome occurs in both sexes. The risk of the disease is about 1:20,000, which makes the syndrome one of the rare diseases.

Angelman syndrome: symptoms

At birth, children with Angelman syndrome are still inconspicuous. Only in infancy and toddlerhood do the motor and cognitive developmental disorders become increasingly noticeable. Features of the genetic disorder are:

  • delayed motor development
  • impaired coordination
  • often no or hardly any language development
  • reduced intelligence
  • hyperactive, hyperactive behavior
  • laughter without reason
  • laughing fits
  • joyful gestures (e.g. waving arms)
  • frequent sticking out of the tongue

In some children with Angelman syndrome, one additionally observes:

  • microcephaly (abnormally small head) – not at birth, but in the course of further development
  • Seizures @
  • changes in the electrical activity of the brain
  • very light skin and eyes due to reduced pigmentation (hypopigmentation)
  • squint (strabismus)

Angelman syndrome: Causes

The cause of Angelman syndrome is a genetic defect on chromosome 15: in affected individuals, the function of the gene UBE3A is impaired. This gene normally produces an enzyme that is involved in the breakdown of damaged or excess proteins in cells. It thus helps the cell to function normally.

In many body cells, the gene is active on both chromosomes, but not in the nerve cells of the brain: there, in many people, the UBE3A gene on the paternal chromosome 15 is switched off by imprinting. Consequently, UBE3A is active in the brain only on the maternal chromosome 15. This also means that if the maternal gene copy has an error, this cannot be compensated for by the silenced paternal gene copy. And exactly this combination is present in Angelman syndrome: The paternal gene copy is switched off, the maternal one is defective.

The underlying genetic defect can be of different types:

  • Mutation in the UBE3A gene: Due to a spontaneously occurring change in the gene, the information it contains is lost. This applies to five to ten percent of people with Angelman syndrome. In about one in five cases, there is a familial mutation: In this case, the mother already carries the gene alteration on her paternal chromosome.
  • Two paternal chromosomes 15: The affected person has inherited both chromosomes 15 from his father, none from his mother (medically called “paternal uniparental disomy 15”). Thus, there is no active gene UBE3A. This is true for about one to two percent of all Angelman syndrome patients.
  • Imprinting error: The UBE3A gene on the maternal chromosome 15 – as well as that on the paternal chromosome 15 – is switched off by imprinting. In addition, a certain part of the chromosome may be missing (deletion). An imprinting defect is found in one to four percent of cases of Angelman syndrome.

Is Angelman syndrome hereditary?

In principle, the risk of recurrence is low in Angelman syndrome. This refers to the risk that parents of an affected child will have other children who also have the syndrome. In individual cases, however, this risk depends largely on the genetic defect on which the Angelman syndrome is based.

For example, in the case of Angelman syndrome resulting from two paternal chromosomes 15 (paternal uniparental disomy 15), the risk is less than one percent. In contrast, an Angelman syndrome due to an imprinting defect with loss of a certain gene segment (IC deletion) can occur in half of all cases in a sibling.

Patients with Angelman syndrome can theoretically reproduce. Depending on when the causative chromosomal changes occurred (e.g. already during germ cell development or immediately after fertilization), the risk that affected individuals will pass on the disease is sometimes very high (up to 100 percent). However, there are no reliable data on this. There was an isolated case in September 1999, for example, when a mother suffering from Angelman syndrome passed on the disease.

Angelman syndrome: Diagnosis

If you notice the symptoms described above in your child, the pediatrician is the first person to contact. He or she can narrow down the possible causes more precisely and refer you and your child to a specialist if necessary.

Medical history

The first step in diagnosis is a thorough medical history. During this process, the doctor will ask you several questions about your child such as:

  • What changes have you noticed in your child?
  • Does your child have any physical complaints?
  • Does your child reach for objects?
  • Does your child talk?
  • Is your child often noticeably cheerful or hyper?
  • Does your child laugh in inappropriate situations, such as when in pain?

Physical examination

This is followed by a physical examination. The pediatrician tests the child’s regular motor and mental development. Simple exercises are used for this purpose: For example, the child is asked to concentrate on toys or to reach specifically for a building block. The doctor also pays attention to the child’s facial expressions. Frequent laughter, doll-like facial features and drooling are signs of Angelman syndrome.

If the doctor suspects the rare disorder after the physical examination, he or she will refer you to a neurologist and a human geneticist.

Genetic testing

In a first step, the physicians pay attention to the methylation pattern of the chromosome segment (methylation analysis/test). Further tests on the same samples (deletion analysis, mutation analysis) help to determine the cause of Angelman syndrome in more detail. For this purpose, it may also be necessary to examine the genetic material of the parents. In this way, doctors determine whether a genetic defect is already present there.

Further examinations

Further examinations are often useful. For example, EEG can be used to detect changes in electrical brain activity, as often occurs in Angelman syndrome. Ophthalmological examinations may also be indicated.

Angelman syndrome: Therapy

Some symptoms and complaints associated with Angelman syndrome may also require specific treatment. For example, anticonvulsant medications (antiepileptics) help against seizures, and tranquilizers (sedatives) help with severe sleep disorders.

On the website of the Angelman e.V. association you will find a lot of information about Angelman syndrome, experience reports and events for affected persons as well as contact persons for affected persons in all regions of Germany.

Angelman syndrome: course of the disease and prognosis

First year of life

Babies with Angelman syndrome have more frequent problems with breastfeeding, sucking and swallowing. They often stick out their tongues or drool a lot. In addition, children with Angelman syndrome often spit up (when this happens, food intolerance or reflux disease is often mistakenly suspected). The frequent vomiting can lead to dangerous weight loss.

Delayed motor development is usually noticed between the 6th and 12th month of life: Children do not crawl or sit. The movements of the upper body are often shaky. This in turn makes sitting difficult.

A fraction of those affected experience seizures as early as 12 months of age.

One to three years

Within the first three years of life, the developmental disorder in Angelman syndrome becomes very apparent. The children suffer more from mild seizures. They are sometimes hyperactive, overstimulated and always on the move. Many tend to constantly put their hands or toys in their mouths or stick out their tongues frequently and drool. If the children are particularly excited, they often laugh excessively and wave their arms outstretched.

Puberty and adulthood

Puberty often occurs three to five years late in children with Angelman syndrome. However, sexual maturity then develops normally. Speech development continues to be absent, although speech comprehension is often present. The seizures are usually well controlled with medication in adulthood.

People with Angelman syndrome have a normal life expectancy. However, an independent life is not possible due to the mental limitations.