Angelman syndrome – symptoms, diagnosis, treatment, prognosis

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They concern the loss of a small fragment of chromosome 15. If the chromosome with the defect is passed on by the father, the child has Prader-Willi syndrome, if the mother – Angelman. The former occurs in 1 in 10-000 live births, the latter is slightly more common.

Angelman Syndrome and Prader-Willi Syndrome

Symptoms of Prader-Willi are visible after birth, although their different picture than in older age makes it difficult to make a correct diagnosis. Initially, these are: reduction in muscle tension and feeding difficulties due to a lack of suckling reflex. Psychomotor development is delayed from the beginning. In 2-3 r. excessive appetite appears, leading to obesity in a relatively short time. The hands and feet are small. Other features include short stature, a small dimension between the temples (narrow face), almond-shaped eyelid fissures, corners of the mouth pointing downwards, and hair usually very light-colored. Behavioral disturbances and tantrums appear with age.

Angelman’s syndrome was called the happy puppet syndrome because patients have a characteristic smile and make weird movements (they walk like puppets), which is why they were formerly called “puppet children”. The disease is estimated to occur in 1 in 15 births. The name itself comes from the name of the pediatrician who first described this syndrome – Henry Angelman.

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Angelman syndrome – history

The disease was first described in 1965 by Henry Angelman, an American pediatrician, who described cases of people with very specific symptoms, namely: facial dysmorphia, neurological disorders, a very strange way of moving, mental retardation and sudden and uncontrolled bursts of laughter. These bouts of laughter and the characteristic gait made the researcher, inspired by the painting by the Italian painter Giovanni Francesca Caroto entitled “Puppet Boy,” described his patients as “puppet children.”

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Angelman syndrome – symptoms

The first symptoms of abnormal development usually appear around 6-9 months of age. The disease picture is dominated by significant mental retardation, balance disorders and epilepsy. Children with Angelaman Syndrome begin crawling around 22 months of age, and do not start sitting up until between the ages of 1 and 3. The ability to walk, in turn, develops very late, around the age of 5, but it should be noted that some children cannot walk at all. The aforementioned imbalance and movement disorders are manifested by a very characteristic unsteady gait on widely spaced legs (gait ataxia). A child is said to move a bit like a puppet.

The distinctive features of the appearance include, among others prominent mandible, protruding tongue, flat occiput, widely spaced teeth. Most children with Angelman syndrome have significant speech impairment. About 30% of children do not speak and the rest use only single words. For this reason, children should be allowed to use special aids as early as possible to develop other means of communication. Patients have bouts of laughter inadequate to the situation.

However, these are not the only problems of children with Angelman syndrome as they also suffer from behavioral disorders. Sudden and uncontrolled bouts of laughter and peculiar gaiety are the second characteristic elements of the disease, right after walking. Children are very often extremely mobile and hyperactive, which in turn manifests itself by flapping their hands. This feature also somehow brings to mind the name of the disease, children with Angelman syndrome look a bit like little angelsthat flap their wings as they try to take to the air. This is the reason why children suffering from this condition are also called “angels”.

It should be added that most sick children also have problems with microcephaly and convulsions, which usually occur up to the age of 3. In addition, there are difficulties with swallowing, constipation, trouble sleeping, scoliosis, and obesity.

A characteristic symptom in most ill children is also hypopigmentation of the skin, hair and eyes (this applies to children with a deletion of the 15q11-q13 region). The hair is light and the skin is also sensitive to sunlight. Interestingly, more than 40 percent of all patients suffer from vision problems (strabismus and myopia).

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Angelman syndrome in newborns

In the case of Angelman syndrome in newborns and younger infants, the disease is difficult to diagnose. This is due to the fact that most such children are born from pregnancy and childbirth in an uncomplicated course, having normal body length and weight (although sometimes lower than the birth weight of healthy children), have a head and chest circumference within the normal range.

Most often, shortly after birth, eating disorders in the form of difficulties in sucking can be observed in childrenvomiting after meals (gastroesophageal reflux disease) and slight weight gain. Breathing problems develop due to choking, which in turn can lead to hospitalization.

However, it should be noted that the most characteristic symptom of Angelman’s disease in newborns is their unnatural calmness (compared to healthy newborns). Sick children are quite flaccid, and when you hold them in your hands, you can feel their body trembling. Additionally, nystagmus may be noticed in some of them.

Angelman syndrome – causes

In the case of Angelman syndrome, there can be many causes, although it must be admitted that they are all related to the UBE3A gene, which is located on chromosome 15 and is responsible for the proper functioning of the nervous system. This gene is inherited from both parents, but, interestingly, it is the copy from the child’s mother’s side that usually dominates (when the father’s genetic material is the cause of the disorder, it means that we are dealing with Prader-Willi syndrome).

Sometimes this copy is missing for some reason or it becomes damaged, and then the child develops Angelman syndrome.

There are currently four such reasons.

1. Most often (70 percent of cases) the fragment of chromosome 15 on which the UBE3A gene is located is lost (the so-called deletion).
2. Probably the rarest case (2 to 3 percent) when it comes to the so-called paternal disomy, i.e. a situation where a child inherits both (inactive) copies of the UBE3A gene from the father, and the mother’s (active) copy is absent. 
3. An equally rare situation (3 percent of cases) when, due to some abnormalities (imprinting defect), the mother’s copy of the gene is inactive.
4. The last case (5 to 11 percent) where the UBE3A gene undergoes a mutation that contributes to the onset of the disease.

It should be added that, according to a study conducted in 2017, in healthy children around 5 weeks of age, there is a rapid increase in the activity of brain cells, but in children with Angelman syndrome, such a jump does not occur. Researchers believe that this may be the direct cause of developmental disorders.

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Angelman syndrome – risk factors

Angelman syndrome has many causes, but some can be mentioned factors that increase the risk of developing this condition:

Age of parents (cases caused by uniparental disomy, i.e. caused by chromosomal nondisjunctions occurring during the process of chromosome propagation to the emerging gametes) – the frequency of abnormalities increases over the years (systems controlling cell physiology are impaired). Due to the small number of reported cases, no specific data are available.

The presence of microaberration (microdeletion) of the critical methylation region 15q11-q13 on one of the chromosomes 15 of the mother’s pair – Microdeletion changes are hereditary (a woman always inherits her from her father – she does not suffer from disease because the paternal region of the 15th chromosome of the pair is always inactive). Finding the presence of such a change on the chromosome 15 of the mother’s pair increases the chance of having Angelman syndrome to 50 percent.

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Angelman syndrome – diagnosis

Diagnostics in the case of Angelman syndrome consists in recognizing the aforementioned symptoms and examining the chromosomes of the 15th pair in the child and his parents. (full diagnostics of the child’s mother is required to exclude hereditary forms of the syndrome). Peripheral blood (maximum 10 ml) is drawn from a vein for testing. First, cytogenetic examination of the karyotype is performed, but of the HRT type (high-resolution stripe examination enabling the detection of structural changes in chromosomes).

Molecular tests are also performed, in which the methylation pattern of the chromosomes of the 15th pair is analyzed in the child, as well as in the parents. Thanks to this, it will be possible to exclude or confirm a uniparental disomy, and at the same time it can provide grounds for inferring about genetic changes within the stigmatization center.

Prenatal tests are also carried out, although it must be added that in the case of Angelman syndrome, the detection of the disease is quite difficult. During the ultrasound examination (USG), the image of the fetus does not differ from the norm. On the other hand, the results of biochemical tests, e.g. the triple test, also do not indicate any abnormalities. If there are suspicions of a family and hereditary form of the disease, such as Angelman’s syndrome, the aforementioned tests should be performed on cells collected directly from the fetus. In such cases, doctors have to carry out invasive tests, such as amniocentesis or chorionic villus sampling, which are the only ones to obtain fetal cells.

In the case of chorionic villus sampling, it is performed transabdominally or transcervically under ultrasound guidance. On the other hand, amniocentesis involves the percutaneous extraction of amniotic fluid with a thin needle under ultrasound guidance. It should be added that amniocentesis is offered only to women at high risk of developing the disease. This is because in about 0,5-1% of cases there is a risk of complications related to damage to the fetus, possible bleeding, or the risk of immunization when the mother is Rh-deficient.

In the diagnosis of Angelman syndrome, it is also important to exclude other neurological diseases, such as autism or cerebral palsy. It happens that the Angelman team is confused with them.

Keep in mind that although the genetic changes that result in Angelman syndrome are spontaneous in most cases, there is a chance that the next child born will also have the condition.

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Angelman syndrome – treatment

Treatment for Angelman syndrome is mainly rehabilitation. Water exercises, which sick children are extremely interested in, play a particularly important role here. Water is important because it increases the child’s balance and coordination. Exercising in the water is also great at preventing the development of scoliosis (early orthopedic treatment is required) and cramps. In the case of Angelman syndrome, epileptic seizures often occur (even at a young age), therefore constant care of a neurologist is needed, as well as administration of antiepileptic drugs. Pharmacological treatment also uses drugs that prolong sleep (melatonin). It is worth adding that sleep problems may improve with age.

In addition, children with Angelman syndrome are taught gestures, symbols, graphic symbols and images, thanks to which they have the opportunity to convey information. Thanks to these methods, children have the conditions to express their needs, make choices, ask questions, negate or have a conversation.

It should also be added that as a result of health problems, there is also a need for gastrological, ophthalmological, psychological and other consultations.

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Angelman syndrome – prognosis

As for the prognosis in the case of Angelman syndrome, it should be said that they are relatively good. General health problems are similar to those found in society. At this point, of course, we omit the symptoms characteristic of this disease. It is assumed that some patients live for quite a long time, reaching the age of over 70 years. People with Angelman Syndrome can master many simple activities, but they must receive the support of the people who care for them throughout their lives.

Angelman syndrome – prevention

Prophylaxis and prevention in the case of Angelman syndrome, as in the case of other genetic diseases, is extremely difficult, and sometimes even impossible. There is a possibility of genetic counseling along with attempts to calculate the probability of an event in the case of a planned pregnancy, but we are only talking about cases of couples at an increased risk of Angelman syndrome (confirmed family carrier of 15q11-q13 microdeletions).

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