What is Angelman Syndrome? Causes and Diagnosis

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What is Angelman Syndrome?

Angelman Syndrome (AS) is a rare neurogenetic disorder that primarily affects the nervous system. It is characterized by developmental delays, intellectual disabilities, speech impairments, and a distinct behavioral phenotype. 

The syndrome was first described by British pediatrician Harry Angelman in 1965.

Key features of Angelman Syndrome include:

• Developmental Delays: Individuals with Angelman Syndrome typically experience delays in reaching developmental milestones such as sitting, crawling, and walking.
• Intellectual Disabilities: Most individuals with Angelman Syndrome have moderate to severe intellectual disabilities. They may have difficulty with tasks that involve reasoning and problem-solving.
• Speech Impairments: Individuals with Angelman Syndrome often have limited or absent speech. They may communicate using gestures, vocalizations, and other non-verbal means.
• Movement and Balance Issues: People with Angelman Syndrome may exhibit a stiff, jerky gait and have balance issues. Some individuals may also have seizures.
• Happy and Excitable Demeanor: A characteristic behavioral trait of Angelman Syndrome is a generally happy and excitable demeanor. Frequent smiling, laughter, and an easily excitable personality are often observed.
• Hyperactivity: Hyperactivity is a common feature of Angelman Syndrome, and individuals may display a short attention span.
• Sleep Disturbances: Sleep problems, such as difficulty falling asleep and frequent waking during the night, are common in individuals with Angelman Syndrome.
• Distinct Facial Features: While not always present, some individuals with Angelman Syndrome may have distinct facial features, such as a wide mouth, wide-spaced teeth, and a prominent chin.

Angelman Syndrome is typically caused by the loss of function of a specific gene called UBE3A (ubiquitin protein ligase E3A), which is located on chromosome 15. This loss of function can occur through a variety of genetic mechanisms, including deletions, mutations, or uniparental disomy (both copies of chromosome 15 inherited from one parent).

Although there is no cure for Angelman condition, individuals with the condition can benefit from supportive therapies, such as physical therapy, speech therapy, and educational interventions, to maximize their potential and improve their quality of life.

Management may also include medications to address specific symptoms, such as seizures or sleep disturbances. Early intervention and a multidisciplinary approach involving healthcare professionals, educators, and families are crucial for the well-being of individuals with Angelman condition. ( Know more about- What is Kallmann Syndrome? )

What are the causes of Angelman Condition ?

Angelman Syndrome is primarily caused by genetic abnormalities that result in the loss of function of the UBE3A gene, located on chromosome 15. There are several ways in which this loss of function can occur, and the genetic mechanisms underlying Angelman condition include:

• Deletion: The most common cause of Angelman Syndrome is a deletion of the maternal allele of the UBE3A gene on chromosome 15q11.2-q13. If a child inherits a deletion in this chromosomal region from the mother, the UBE3A gene on the maternal chromosome is lost, leading to the absence of its function in the affected individual.
• Mutation: In some cases, individuals may have Angelman Syndrome due to a mutation in the UBE3A gene. This mutation can occur on the maternal allele or, less commonly, on the paternal allele. Mutations can disrupt the normal function of the UBE3A gene, leading to the characteristic features of Angelman Syndrome.
• Uniparental Disomy (UPD): Uniparental disomy occurs when an individual inherits both copies of a chromosome from one parent and none from the other. In Angelman Syndrome, if both copies of chromosome 15 are inherited from the father and none from the mother, the UBE3A gene on the maternal chromosome is absent, resulting in the loss of its function.
• Imprinting Defects: Angelman condition can also occur due to imprinting defects, where the UBE3A gene on the maternal allele is present, but its expression is silenced. This can happen if there are abnormalities in the imprinting process, preventing the normal activation of the UBE3A gene on the maternal chromosome.
• Mosaic Angelman Syndrome: In rare cases, individuals may have a mixture of cells with a normal chromosome 15 and cells with a deletion or mutation in the UBE3A gene. This is known as mosaic Angelman Syndrome and can result in a milder phenotype. ( Know more about- What is Alpers syndrome ? )

How is Angelman condition diagnosed?

Diagnosing Angelman condition typically involves a combination of clinical evaluation, developmental assessments, and genetic testing. 

Here are the key steps in the diagnostic process:

• Clinical Evaluation: Medical History and Physical Examination: A thorough medical history is obtained, and a physical examination is conducted to assess developmental milestones, behavioral characteristics, and any physical features associated with Angelman Syndrome.

• • • Developmental and Behavioral Assessment: The healthcare provider evaluates the individual’s developmental progress, intellectual abilities, speech and language skills, motor function, and behavioral traits, such as the characteristic happy demeanor and hyperactivity often seen in Angelman condition.

• Genetic Testing: Chromosomal Microarray Analysis (CMA): CMA is often the first-line genetic test for individuals suspected of having Angelman Syndrome. It can detect chromosomal abnormalities, including deletions or duplications in the chromosomal region 15q11.2-q13, where the UBE3A gene is located.

• • • DNA Methylation Analysis: DNA methylation studies can help identify abnormalities in the imprinting of the UBE3A gene. This test distinguishes between Angelman Syndrome (maternal deletion or mutation) and Prader-Willi Syndrome (paternal deletion or mutation), as both conditions involve the same chromosomal region.
    • UBE3A Gene Sequencing: Direct sequencing of the UBE3A gene may be performed to identify specific mutations in the gene. This test is particularly relevant when there is suspicion of a UBE3A mutation in the absence of detectable chromosomal abnormalities.

• Parental Testing: Parental Genetic Testing: To further characterize the genetic mechanism causing Angelman condition, genetic testing may be performed on both parents. This helps determine if the genetic abnormality is inherited or if it occurred de novo (new mutation).

• Additional Testing: Electroencephalogram (EEG): EEG may be recommended to assess for abnormal brain wave patterns, as individuals with Angelman condition have an increased risk of seizures.

• Genetic Counseling: Genetic Counseling: Genetic counseling is an integral part of the diagnostic process. It provides individuals and families with information about the genetic basis of Angelman condition, the risk of recurrence in future pregnancies, and guidance on managing the condition.

The combination of clinical evaluation and genetic testing helps establish a definitive diagnosis of Angelman condition. 

Early diagnosis is crucial for initiating appropriate interventions and support services to address the developmental and medical needs of individuals with Angelman condition. 

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