Angelman syndrome: what is diagnosis and treatment

It is the joyful and smiling aspect that characterizes children with Angelman syndrome, a rare genetic disease that – behind an apparent happiness – hides severe motor and cognitive disabilities. To inspire the name with which she was often identified in the past, that is perennial smile syndromewas the painting “Child with drawing” by Giovanni Francesco Caroto, which convinced the English pediatrician Harry Angelman to describe this genetic syndrome for the first time: the doctor, in fact, recognized precisely in the features of Caroto’s boy the characteristics of some of his young patients, who had unmotivated bursts of laughter and jerking limbs and trunk. “The smile is a distinctive trait of children with Angelman syndrome, who appear cheerful, laugh often, love physical contact and wave their arms pretending to fly”, says the doctor Silvia Russoresearcher in the field of Rare Diseases at the Laboratory of Cytogenetics and Molecular Genetics of the Irccs Istituto Auxologico Italiano (Milan).

What is perennial smile syndrome and the symptoms

The estimate on the frequency of Angelman syndrome in the general population is not accurate: it is thought to affect about 1 birth in 12,000-24,000 and does not affect life expectancy, which remains completely normal. To characterize the children who suffer from it are the intellectual disability (medium to severe), the almost always complete absence of the ability to speak and the presence of epilepsy which is associated with an electroencephalographic trace well recognizable for experienced epilepticologists, which suggests the suspicion of the disease. “Epileptic seizures are often controllable with drugs, but not all antiepileptics are adequate and that is why it is always necessary contact doctors who have specific knowledge of the diseaseDr. Russo is keen to specify.

“Another very frequent symptom isalteration of the sleep-wake cycle; in fact, these children sleep little and badly. Distinctive of the syndrome is also a typical behavior, characterized by bursts of laughter sometimes triggered by non-specific situations or which occurs in inappropriate circumstances, such as a blood sample. And then there are one poor attention span, a motor hyperactivity and a pro-social attitude, that is the ease of establishing eye contact and curiosity towards other people “. In addition, depending on the genetic defect, other characteristic features of the patients may take over, such as microcephaly (reduced head circumference), seizures or hypopigmentation of the skin and eyes.

What are the causes and how much does genetics weigh

At the basis of Angelman syndrome there is a genetic defect, that is, an “error” present in the DNA. “If we imagine our genes as so many instruction manuals that teach cells how to make a certain protein, in Angelman syndrome the error lies in the stretch of DNA found on chromosome 15the one that normally produces the UBE3A protein, ”explains the expert.

“The peculiarity of this disease lies in a mechanism called genetic imprinting. Basically, each of us inherits one chromosome 15 from mom and another chromosome 15 from dad. Generally both work in the same way, but in neurons the gene that is inherited from the father remains “dormant”, so it does not work, so the only one to produce UBE3A is the maternal one. Hence the fact that if the latter is defective, the child develops the disease ».

Why is the UBE3A protein? «Its deficiency alters the communication between the two“ buttons ”, called synapses, which unite neurons, which at that point function badly and cause important deficits in learning and memory. UBE3A performs many functions in the nervous system: it is important for regulating neuronal plasticity, it is involved in the disposal of proteins that must be degraded and interacts with specific proteins in neurons, those of sleep, and this explains why patients with Angelman syndrome have difficulty. to sleep”.

How is the diagnosis made

At the time of birth, babies with Angelman syndrome look absolutely healthy, but from 5-6 months they begin to show small signs of something wrong, such as unspecific feeding difficulties (for example, sucking or swallowing), sleep disturbances, or easy excitability. But the actual diagnosis arrives around 12 months thanks to a neuropsychiatric evaluation, after having found that the normal stages of growth are not respected: children start walking late (between 2 and 4 years) and, when they do, they adopt a particular ataxic gait (with spread legs, as if they were marching in the middle of tall grass); there are more or less important cognitive delays; even severe seizures can occur.

«To put pen to paper that it is Angelman syndrome is a genetic test, called MS-MLPA, which goes to study that region of the DNA to understand if there is a defect. From there we start to understand exactly what defect it is, because the evolution of the disease, the therapeutic perspectives, but also the need or not to study family members to understand the reproductive risk in the case of subsequent pregnancies depend on that.

Sometimes, however, the MLPA is not enough and it is necessary to continue the study by sequencing the DNA: «I defects that determine the absence or malfunction of UBE3A are different, mainly four. The most frequent, which characterizes 60-70% of cases, is called deletion and consists precisely in the lack on chromosome 15 transmitted by the mother of the piece of DNA that contains UBE3A. In this case, the parents are healthy and their risk of having a second child with this disease is very low. In less than 10% of diagnoses, however, the parents are healthy carriers and therefore have a higher reproductive risk. It is important to know what genetic defect the child with Angelman’s syndrome has, both to know the type of clinical picture, more or less severe, he will develop, and to establish the reproductive risk of the parents and their close relatives “.

What are the complications

«In general, children with Angelman syndrome do not speak, but alternative augmentative communication can be used with them, a particular technique that is used in many congenital or acquired pathologies where more or less severe language deficits are present. In practice, children are taught to associate words, objects or feelings with a drawn symbol, starting from the simplest concepts such as “mom”, “dad”, “bed” or “baby food”, so that they can indicate them when necessary ” . In fact, these children are often mistakenly associated with subjects with autism spectrum due to the fact that they struggle to develop verbal language for communication purposes, but in Angelman’s syndrome there is a form of interaction with the outside world, which can be strengthened. .

How it comes

As with all rare diseases, it is essential to contact a specialized center with a proven track record. To better navigate the national territory, you can consult the website of the OR.SA association, born from the meeting of some families with children suffering from Angelman syndrome who have generated a series of experiences and an ever deeper knowledge of the disease.

On the site you can find a special section dedicated to Italian reference centers, where children are taken care of by a multidisciplinary team to manage – pharmacologically or through specific habilitation-rehabilitation interventions – the Cepileptic laughter, movement and behavioral disorders, incorrect posture, disturbed sleep, lack of language, the cognitive and relational dimension, in order to favor the development of skills and autonomy. “In the meantime, they are underway several searches to find a cure, which at the moment is not there. There are promising clinical trials that are aiming to make the paternal gene work to “compensate” for the defect in the gene inherited from the mother: the experiments on mice are encouraging, but now it is a question of transferring them to humans. We are only at the beginning, the path is still long, but research has made great strides. It is necessary to continue working on this front in order to obtain the desired results ”, concludes Dr. Russo.