Angelman syndrome is a genetic disease characterized by the presence of neurological symptoms, mental retardation. It is manifested by intellectual lag, poor formation of speech, sitting and walking skills, chaotic movements, hyperactivity, symptomatic epilepsy, causeless fun and laughter, scoliosis, peculiar gait. Patients have a special appearance: the mouth is large, the teeth are rarely located, the chin protrudes forward. The diagnosis is established on the basis of clinical data, the results of genetic analysis. There is no specific treatment, symptomatic therapy is carried out, psychological and pedagogical assistance is provided.
ICD 10
Q93.5 Other chromosome part deletions
General information
The syndrome is named after the British pediatrician G. Angelman. In 1965, he was the first to describe the symptoms of the disease and called it “happy puppet syndrome”, because patients reminded him of the hero of the painting “The Puppet Boy”. In those years, the methods of genetic research were not yet developed, it was impossible to determine the cause of the pathology. In 1987, researchers determined the etiology of the disease and renamed it Angelman syndrome. Now this term is official, but you can find synonymous names – “puppet syndrome”, “Parsley syndrome”, “happy doll syndrome”. The prevalence is 1 case per 10-20 thousand newborns. The disease is detected after the first year of life (sometimes by 3-7 years), boys are more often ill.
Causes
Factors of development of Angelman syndrome continue to be investigated. The genetic defect was found in chromosome 15 of the maternal set, but its nature and mode of occurrence may vary. Sometimes the disease debuts as a result of the transmission of altered genetic information from the parent, sometimes it is a consequence of spontaneous disorders in the genome. Chromosomal abnormalities can be detected in approximately 85-88% of patients. The cause of the syndrome may be:
- Deletion. With this defect, part of the genetic material is lost or inactivated. In 70% of patients, extensive deletions of the 15q12 region of the chromosome, in which the activator of the gene is localized, are diagnosed.
- Homogenous dysomy. HGD is determined in 2-3% of cases of the disease. There are two copies of the father’s chromosome 15 in the chromosome set. There is no maternal chromosome, the gene is also missing.
- The defect of imprinting. The essence of the anomaly lies in the fact that the imprinting center, which regulates the activity of the UBE3A locus, turns out to be non-functional, “turned off”. The gene remains structurally intact, but does not perform its functions. The prevalence of DI is 3-5%.
- Mutation of UBE3A. In 5-10% of patients, mutational gene changes are the cause of the disease. They are represented by inversions, microdeletions, translocations and duplications.
Pathogenesis
The basis of Angelman syndrome is a violation of the functions of the UBE3A gene located on the fifteenth maternal chromosome. This gene encodes the production of protein E6AR, which is an enzyme component of a complex protein degradation reaction. E6AR is involved in the formation of ubiquitin, a protein of the proteasome system that stimulates the proteolysis of defective protein molecules in brain neurons. Normally, ubiquitin marks unnecessary (inactive, non-functional) proteins in order to initiate their destruction. E6AR ensures the fixation of ubiquitin on the surface of the target protein molecule. Then the proteasomes break it down into peptide residues and amino acids. In Angelman syndrome, ubiquitin is not fixed on defective proteins, they accumulate in the nervous tissue of the brain, the process of synaptic transmission is disrupted. Deviations, delays in mental and motor development are formed.
Symptoms
Clinically, the disease manifests itself at the age of 6 to 12 months. The delay in development is gradually increasing, previously mastered skills are preserved, but the acquisition of new ones is slow. Children can sit, crawl, take objects and shift them from hand to hand, maintain visual contact, hum and babble. Walking is difficult, the sense of balance is disturbed, there are frequent falls, bruises on furniture. Tremor and chaotic movements of the limbs, especially the hands, are detected. Speech disorders are represented by both delays and a complete absence of expressive speech. Children either do not speak at all, or use babble, simple syllables and words with a total volume of no more than 10 units. The understanding of the reversed speech, the desire for communication, the use of non-verbal means of communication: gestures, facial expressions, indirect signs are preserved.
The main behavioral disorder is hyperactivity. Children often have fun and laugh for no objective reason, are motor disinhibited, restless, purposeless. Many people have a pathological attachment to a certain toy or household item, with the appearance of which the mood immediately rises, moodiness and crying are replaced by laughter. Concentration of attention is reduced, switching is fast and non-directional. There are learning difficulties, persistent decline in intellectual functions. Stereotypes are easily fixed: swinging the body, waving the arms. 80% of patients have microcephaly, insufficient cranial volume, and epileptic brain activity. Rarely there is a decrease in the control of tongue movements, which is manifested by difficulties sucking the breast or nipple, followed by a lack of body weight.
Characteristic features of the appearance of children are strabismus, scoliotic curvature of the spine, enlargement of teeth and lips, dilution of the dentition, flattening of the back of the head, protrusion of the chin. The tongue is often stuck out, the mouth is slightly open in a smile. Muscular dystonia develops, the severity of tendon reflexes increases, forming the specificity of motor skills: patients walk on straight unbending legs, shoulders are lifted, arms are bent at the elbows. A peculiar symptom is a craving for water. Most children feel calmer in the aquatic environment, they like to splash in the bathroom, play with boats in the basin.
Complications
Angelman syndrome is a rare little–known disease. In this regard, the diagnosis and the provision of medical, psychological and pedagogical assistance are often carried out untimely, by the age of 6-8, which causes a low success rate of correctional and therapeutic measures. Without physiotherapy, disorders of the musculoskeletal system are aggravated – patients suffer from severe forms of scoliosis, they move with difficulty independently. The peculiarity of appearance and behavior becomes the cause of deterioration of the already difficult social adaptation. All of the above entails the aggravation of the disability of patients.
Diagnostics
Neurologists, psychiatrists and geneticists are engaged in the examination of children with suspected Angelman syndrome. Parents complain about the lack of speech, motor stereotypes, difficulties in forming walking and other motor skills, hyperactivity. Differential diagnosis is carried out, during which more common diseases such as mental retardation, autism spectrum disorders, dementia, mutism, non-symptomatic forms of epilepsy should be excluded. A comprehensive study includes the following procedures:
- General inspection. The presence of the syndrome is often indicated by specific features of the appearance of patients: protruding tongue, drooling, large mouth, wide rare teeth, protruding lower jaw, flat shape of the back of the head. A light shade of skin, eyes and hair is characteristic. The gait of children resembles the movements of a puppet doll due to the strengthening of tendon reflexes and a decrease in muscle tone.
- Examination by a psychiatrist. In 100% of cases of Angelman syndrome, a pronounced delay in the development of the psyche, lack of independent speech or a very poor vocabulary is diagnosed. Communication is carried out with the help of facial expressions, gestures, drawings. Hyperactivity, stereotypical hand movements, unreasonable laughter are noted in the behavior.
- Neurological examination. Ataxia and tremor of the extremities are detected in all patients. 80% of patients have postnatal microcephaly – the circumference of the newborn’s head is less than 32 cm, by 12 months – about 42 cm. According to the EEG data, symptomatic epilepsy is detected (high-amplitude discharges of slow complex waves), convulsive seizures are clinically possible. Some children have strabismus, diffuse decrease in muscle tone, increased tendon reflexes, hyperkinesis.
- Genetic research. Laboratory diagnostics is aimed at detecting mutations and deletions in the UBE3A gene. A set of procedures is consistently carried out, including fluorescent hybridization in situ, analysis of the mutation of the imprinting center, methylation of CA DNA/PVS of the region, the diagnosis of deletion by micromatrix analysis, the search for mutational changes in the UBE3A locus.
Treatment
The chromosomal abnormalities underlying the syndrome cannot be eliminated. Patients are prescribed symptomatic treatment, psychological and pedagogical correction, rehabilitation measures. Anticonvulsants are used to reduce the frequency of epileptic seizures, melatonin is used to normalize sleep. Physical therapy classes and massage sessions are aimed at developing fine motor skills and coordinated gait, eliminating scoliosis. To improve their communication skills, children are taught sign language, involved in group classes, and conduct behavioral therapy sessions that allow them to master the rules of interaction in society.
The search for ways to effectively treat the syndrome continues. A test application of the drugs on genetically modified mice is being carried out. The results prove that topoisomerase inhibitors are able to activate the maternal UBE3A gene. At this stage, control studies are being carried out, the safety and risks of therapy are being determined, but there is not enough information yet to transfer experiments to groups of people.
Prognosis and prevention
The severity of symptoms of Angelman syndrome can vary greatly. Patients with mild forms of the disease have a favorable prognosis: their speech becomes more detailed, self-control skills improve with some disorders of the motor sphere. With any degree of severity, early initiation and regular medical and psychological care improves the quality of life of patients. Prevention is reduced to a genetic examination of couples whose families have a child with this syndrome. The nature of the chromosomal defect (sporadic or hereditary) makes it possible to determine the risk of having a second sick child.
