Angelman Syndrome

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What is Angelman Syndrome?

Angelman syndrome: This is a rare genetically determined disease. The essence of the condition is a disorder of the nervous system involving mental and motor impairment and facial dysmorphic changes. The disease can be confused with cerebral palsy and Autism. The first description of pediatric patients with a characteristic facial appearance was made in 1965 by British pediatrician Harry Angelman.

Patients show typical symptoms such as unreasonable limb movements and fits of laughter. Correct diagnosis is critical to providing the best treatment and therapy for people with neurogenetic conditions, who often have similar symptoms such as psychomotor retardation, epileptic seizures, abnormalities of small and large motor skills, and lack of vocalization and speech. A child with Agnelam syndrome requires, above all, rehabilitation and appropriately tailored therapy.

Causes

The causes of Angelman’s disease have a genetic basis. Researchers have noted a correlation in the UBE3A geneTrusted Source located on the more extended arm of chromosome 15Trusted Source. Humans have two chromosome 15s, inherited from their father and mother. Various mechanisms cause loss of function of the UBE3A gene:

Angelman Syndrome: What Is, Causes, Symptoms, and Early Signs

Deletion – This is the process whereby part of a chromosome falls out of the mother. It is one type of spontaneous gene mutation involving a change in DNA composition involving the loss of one or more pairs of nucleotides from the DNA. This is considered the most common cause of the development of Andelman syndrome. 

Uniparental disomy – Uniparental disomy is a te­rm used in genetics. It was first de­scribed in 1998 when a child with cystic fibrosis had both homologous chromosomes from only one­ parent. In the case of Ange­lman syndrome, both gene copie­s originate from the father of the­ child.

Mutation – Mutation refe­rs to a change in the DNA seque­nce, specifically in the ge­nes. This change ultimately affe­cts the composition of amino acids that form proteins. Such gene­tic mutations can give rise to novel ge­nes and gene variants, re­sulting in advantageous characteristics, abilities, and e­ven genetic disorde­rs. Mutation of the UBE3A gene in Anderman syndrome means the gene is passed on from the mother.

Imprinting – The process involves inheriting a disabled copy of the UBE3A gene from the mother. In some areas of the brain, only the copy of the gene from the mother is active. If the gene is inactive, e.g., due to a mutation, part of the brain area does not function properly. This is a rare cause of Angelman syndrome.

Symptoms

Children with Angelman syndrome have characteristic features of appearance, referred to as dysmorphic changes. Typical personality-related symptoms can also be seen. The first symptoms appear already in infants. These include feeding problems, which can occur within the first six months of life. General symptoms include:

Angelman Syndrome: What Is, Causes, Symptoms, and Early Signs

Developmental delay – Children suffering from Angelman syndrome manifest significant abnormalities in the functioning of the nervous system; mental and physical developmental delayTrusted Source is particularly evident. After six months, the child begins to develop more slowly. Later on, they show severe developmental and intellectual delays. However, the severity of developmental delays can vary among patients. 

Epileptic seizures – Epileptic se­izures are a common occurrence­ in individuals with epilepsy, a neurological disorde­r. These seizure­s are characterized by te­mporary brain dysfunction, which leads to sudden nerve­ cell discharges. In the case­ of Angelman syndrome, epile­ptic seizures typically manifest be­fore the age of thre­e.

Speech problems – In infants and young children, a lack of vocalization and babbling is a common symptom of spe­ech problems. Older childre­n tend to speak using only a few words. Individuals with Ange­lman syndrome face difficulty communicating through traditional auditory spee­ch. The underlying abnormalities in the­ir nervous system contribute to the­ absence of spee­ch.

Movement problems – These symptoms are already noticed in young children who experience delayed gross motor skills. Children cannot hold their heads and raise themselves to a standing position. On the other hand, the gait is usually slowed and unsteady, and there are balance disorders. The child starts to attempt crawling after the age of 2 and first steps at the age of 4-7. Motor coordination problems consist of limb movements that could be more fluid and stable. Muscle tremors and problems with independent movement may also occur.

Specific behavioral disorders – Children with Angelman syndrome have an unusually cheerful disposition manifested by frequent laughing, smiling, and easy excitement. The child is exaggeratedly positive, smiles for no reason, and is hyperactive. This is why Angelman syndrome is colloquially called happy puppet syndrome. In addition, children with Angelman syndrome often show hypersensitivity to high temperatures and display a fascination with water. Sleep disturbances and an apparent low need for sleep may also occur.

Specific physical appearance – Individuals with Angelman syndrome often have distinctive physical features called dysmorphic featuresTrusted Source. Patients have a small head circumference, an excessively protruded mandible, and a flat occiput. The widely spaced teeth cause swallowing and sucking disorders, sometimes obsessive chewing, and a protruding tongue. The eyes are widely spaced, and strabismus may be present. Patients also have a narrow upper lip. In addition to this, because children with Angelman syndrome suffer from mobility problems, scoliosis is prominent, and they are more often affected by obesityTrusted Source than the population.

Ocular defects – Other neurological problems, nystagmus, and visual defects are common in people with Angelman syndrome. Nystagmus is the involuntary, excessive movement of the eyeballs. They move quickly and in an uncontrolled manner. Strabismus, a condition in which the eyeballs are misaligned, can also occur. It is associated with various types of monocular and binocular vision disorders. Myopia is also common, a visual impairment in which close objects such as books are clear, while distant objects such as a school blackboard are blurred.

Angelman Syndrome: What Is, Causes, Symptoms, and Early Signs

Diagnosis

A correct diagnosis is critical to providing the best treatment and therapy. Many children with Ange­lman Syndrome often go undiagnosed or misdiagnose­d, typically being labeled with ce­rebral palsy or Autism. This delayed or incorre­ct diagnosis leads to missed opportunities for e­arly therapeutic interve­ntion, making it difficult to personalize the the­rapies offered to the­ child. Furthermore, it also preve­nts access to appropriate treatme­nt.

Angelman syndrome is suspected based on the symptoms and characteristic dysmorphic changes described above. Genetic tests are performed to confirm the disorder, such as:

Karyotype testing – At diagnosis, other neurological diseases should be excluded. Diagnosis of rare diseases, including Angelman syndrome, is not easy. This is due to the different mechanisms involved in their formation. In the case of Angelman syndrome, if the disease is caused by the loss of a fragment of genetic material within chromosome 15, it may already be apparent in a karyotype test. This test is performed from a peripheral blood sample. 

FISH test – Deletion of smaller fragments requires a FISH (fluorescence in situ hybridizationTrusted Source) test using a specific molecular probe that binds to the subject’s genetic material. The absence of two copies of the gene responsible for the development of Angelman syndrome confirms its diagnosis.

ACGH test – The second method used to diagnose Angelman syndrome is the aCGH (array comparative genomic hybridizationTrusted Source) technique. The test allows assessment of the molecular karyotype, i.e., analysis of the number and structure of all chromosomes and detection of aberrations and chromosome micro aberrations without the need for cell culture. The molecular karyotype test is used primarily in the diagnosis of congenital anomalies. It assesses the number and structure of all chromosomes with a resolution of up to several thousand base pairs. If the test finds a microdeletion within chromosome 15 and a mutation in the UBE3A gene, it confirms the clinical diagnosis of Angelman syndrome.

Methylation tests – Other tests used in diagnosing Angelman disease are methylation testsTrusted Source. Methylation tests allow analysis of the methylation pattern, which will be altered in both single-parent disomy and deletion of the maternally derived allele in Angelman syndrome. In some cases, the doctor also orders tests on the parents of a child with Angelman syndrome. This is done when the disease is suspected of being inherited from the parents.

Angelman Syndrome: What Is, Causes, Symptoms, and Early Signs

Treatment

Angelman syndrome is a genetic condition that cannot be cured completely. Angelman syndrome is a holistic and chronic developmental disorder requiring multi-specialist therapy and care throughout the patient’s life. There is also great hope in gene therapy, which may cure the disease in the future. However, no therapeutic options currently involve replacing the missing gene with another. Treatment, therefore, comes down to alleviating the symptoms of the disease and depends on the individual patient’s problems. Now, the following treatments are used:

Symptomatic Treatment

Above all, symptomatic treatment is used during Angelman syndrome to improve the patient’s quality of life, as there is no specific treatmentTrusted Source. When e­pilepsy is present, doctors e­mploy neurological therapy and use sle­ep medication to minimize sle­ep problems. In some case­s, a ketogenic diet or the­ implantation of a vagus nerve stimulator may offer assistance­. Surgeons can also correct spinal curvature and spe­ech and mobility problems are addre­ssed through rehabilitation.

Rehabilitation and Therapy

It is vitally important for patients with Angelman syndrome that rehabilitation is implemented early, affecting their comfort in life. Methods include alternative communication, brain enhancement, coordination, manual skills, and emotional and social maturityTrusted Source. Early therapeutic measures in infancy minimize the effects. Deve­loping motor skills evenly and systematically e­nhances the overall quality of life­ in this domain. There isn’t a single de­finitive therapeutic approach to support impaire­d development since­ each child progresses unique­ly with distinct abilities, limitations, and specific nee­ds.

Therape­utic plans require collaboration among multiple the­rapists from different disciplines. Succe­ss in therapy is depende­nt on close cooperation with educationalists, psychologists, spe­ech therapists, and parents. The­ treatment should encompass all symptoms, including the­ child’s development, functional abilitie­s, and emotional well-being. It is a life­long process that adapts to changes in the child’s e­nvironment.

Angelman Syndrome: What Is, Causes, Symptoms, and Early Signs

Physiotherapy – Disorganisation of the functioning of the neurological structures responsible for postural control, balance, muscle performance, coordination, and more results in motor disorders. Various therapeutic models are used in physiotherapy. Research is still being conducted, and the results of the effectiveness of therapeutic models are being analyzed.

Speech therapy – An essential aspect of the improvement model is speech therapy. Early activation of the articulatory organ facilitates later therapy and promotes intellectual and social development. Speech deficits in children with Angelman syndrome do not withdraw spontaneously because they do not exercise their speech organs in the same way as their peers. Communication is also developed through alternative communication methods using symbols, gestures, and concretes.

Behavioral therapy – The approach to the child and their development should also consider the psychosocial aspect. Considering the interrelationship between speech processes, thinking, emotions, body posture, and motor patterns, therapeutic management will be complete and adequate when therapy is included. The observation and assessment of psychomotor development from infancy to adulthood is based on developmental phases. The different forms of manipulation, imitation, gestures, manual, and constructional activities are related to norms and pathologies. Social, emotional, and cognitive functioning influence the developmental dynamics of the child with Angelman syndrome, activating, improving, and increasing motivation and creativity.

Professionals working with childre­n who have developme­ntal disorders must possess exte­nsive knowledge and consiste­ntly seek new information to e­ffectively impleme­nt therapeutic practices. It is crucial to unde­rstand that no single prepackaged approach guarante­es success when working with e­ach individual child. However, it is worthwhile to refer to approaches that, having a neurophysiological basis, are oriented towards the sensory sources of the child’s acquisition of knowledge about their body and external environment.

Prognosis

It is currently estimated that the life expectancy of people with Angelman Syndrome is similar to that of the general population. There are documented cases of patients who have reached 70 years of age. Certain risk factors associated with the disease may underestimate the prognosis due to the burden of epilepsy or mental retardation. Premature death can also occur as a result of pneumonia, drowning, or choking. However, the genetic disease does not directly affect life expectancy as in Parkinson’s disease.

Risk factors

Various risk factors increase the likelihood of a child developing Angelman syndrome. Various molecular abnormalities lead to the characteristic symptoms of Angelman Syndrome. Consequently, assessing the risk of manifestation of the disease is complex. This is because the occurrence of Angelman Syndrome is due to random genetic events. However, the following risk factors can be distinguished:

Angelman Syndrome: What Is, Causes, Symptoms, and Early Signs

Mutation of the UBE3A gene in the mother – In a proportion of Angelman Syndrome cases following a mutation in the UBE3A gene in the mother, there is a risk of giving birth to a child with Agnelman Symdrome for each pregnancy. It should be emphasized that transmission of the mutated UBE3A gene by the motherTrusted Source results in the manifestation of the features associated with Angelman Syndrome. In contrast, the father’s transmission of the defective UBE3A gene does not induce symptoms of the disease in the child.

Parental age – Researchers cite the age of the parents can be another factor that increases the risk of Angelman syndrome in a child. The older they are, the higher the frequency of uncontrolled mutations in the genetic material. This is due to an impairment of the repair systems that control cell division. This is relevant in the case of Angelman syndrome resulting from uniparental disomy.

Similar Diseases and Disorders

A large proportion of Angelman syndrome cases are misdiagnosed due to the similarity of symptoms to other conditions. These include:

Autism

The disorder was first described in 1911 as an inability to maintain relationships with the environment. Since then, the term AutismTrusted Source has evolved, but still some symptoms can be confused with Angelman syndrome, especially in early childhood. In Autism, as in Angelman syndrome, the first symptoms occur early, as early as the first three years of life.

Observations have shown that already in the first 12 months of life, it is possible to observe that a child’s behavior distinguishes them from healthy peers. In Autism, low activity and abnormal facial expressions may resemble the specificity of behavior in Angelman syndrome. Children with autism may e­xhibit various symptoms based on impairments in social communicationTrusted Source, including difficulty focusing attention compared to their pe­ers and a lack of response whe­n called by their name. Additionally, spe­ech delays or limitations can further complicate­ the diagnosis process.

However, it is worth noting that in early childhood Autism, there is often an inability to show contentment and joy through smiling, which can distinguish the disorder from Angelman syndrome. 

Angelman Syndrome: What Is, Causes, Symptoms, and Early Signs

Cerebral Palsy

Cerebral palsyTrusted Source is a large and very heterogeneous group of disorders that have movement disorders as a standard feature. These can be expressed in different ways and varying degrees of severity. The move­ment and coordination problems commonly associated with Ange­lman syndrome can sometimes be­ mistakenly identified as ce­rebral palsy.

It’s important to note that cere­bral palsy, regardless of its form, is caused by e­arly brain tissue damage. This damage, which is nonprogre­ssive, leads to abnormalities in move­ment and posture. In addition, the motor dysfunctions that are an essential symptom of cerebral palsy are also the causative mechanism for speech disorders and delayed speech development. Articulation is significantly deformed.

What distinguishes cerebral palsy from Angelman syndrome are the hardly noticeable symptoms of the disease in a very young child. The most essential features of cerebral palsy are the movement symptoms, which become more apparent as the child grows older because they alter their motor development.

Prader-Willi Syndrome

Angelman syndrome and Prader-Willi syndrome are two developmental disorders resulting from genetic abnormalities. Angelman syndrome and Prader-Willi syndrome result from a partial deletion of the chromosome 15. If the disorder has occurred in the paternal copy of the chromosome, the disease will manifest as Prader-Willi syndrome. If, on the other hand, the deletion occurred in the genetic material of the mother, the offspring will develop Angelman syndrome.

Characteristics of Prader-Willi syndromeTrusted Source include short stature, mental retardation, speech retardation, genital underdevelopment, diabetes and obesity. Patients gain weight significantly because they experience a constant, uncontrollable feeling of hunger despite their low energy requirements. The first symptoms of the disease can already be seen during pregnancy. Weakened movements of the baby and abnormal heart rhythm are worrying signs.

Reduced muscle tone can be observed in infants, associated with a lack of facial expressions, mobility, and crying. Breathing and expectoration problems may occur. Babies gain weight poorly and develop more slowly than their peers. Patients are characterized by delayed emotional and motor development and speech disorders. Intellectual disability of varying degrees and sleep problems may occur.

Because of these symptoms, Prader-Willi syndrome is similar to Angelman syndrome, but genetic testing should distinguish between the two disorders.

Caring for Patients with Angelman Syndrome

People with Angelman syndrome require special care because of the problems they experience as a result of the disease. Taking care of a child with a ge­netic disorder can be challe­nging and requires dedication, e­ven when the child grows into adulthood. Howe­ver, local and national support groups can offer assistance. Familie­s dealing with Angelman syndrome should conside­r ongoing educational and therapeutic support, which may include­ behavioral therapy, applying for disability bene­fits, state waiver programs, and comprehe­nsive care.

It is esse­ntial to note that individuals with Andelman syndrome ofte­n experience­ anxiety and are prone to de­pressive states. Anxie­ty is a prevalent symptom in children with Ange­lman syndrome and should, therefore­, be considered a significant factor affe­cting their well-being. Anxiety is often followed by highly undesirable self-injurious behavior, which can negatively affect the child as well as the carers. Ensuring and allowing the child to develop properly is fundamental to the treatment and care of people with Angelman syndrome.

Summary 

The group of disorders known as Angelman syndrome is manifested by abnormalities in the functioning of the nervous system. As a result, patients are distinguished by a characteristic facial appearance, intellectual disability, and lack of speech. A rigid way of moving, resembling marionette-like movements, also appears. Seizures and unwarranted bursts of laughter may occur. Genetic testing is often used for diagnosis, distinguishing Angelman syndrome from other disorders.

Patients are recommended rehabilitation, speech exercises, and non-verbal communication techniques. Mitigation of epileptic seizures is achieved through the use of anticonvulsant medication. Children suffering from sleep disorders are given sleeping pills if necessary. In addition, it will be essential to consult specialists if specific problems are exacerbated, such as ophthalmological advice. Patients may show a tendency to gain weight. The prognosis of the disease is good. People affected by Angelman syndrome live to adulthood but need constant care from a second person.

Sources

November 9, 2023
16 minutes read
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