Angelman Syndrome Flashcards
A 2-year-old girl is brought to the neurologist by her parents due to developmental delay and unprovoked, generalized tonic-clonic seizures. Over the past six months, the child has exhibited frequent bouts of uncontrollable laughter and hyperactive behavior. She struggles to speak and is nonverbal but consistently appears happy and sociable. Physical examination shows microcephaly, ataxic gait, and subtle facial dysmorphisms, including a wide mouth and prominent jaw. Genetic testing is performed. Which of the following is the most likely finding?
a. Trinucleotide repeat expansion in the FMR1 gene
b. Mutation in the MECP2 gene
c. Segmental deletion of the ubiquitin ligase coding gene on the maternal chromosome
d. Double paternal inheritance of chromosome 15q11-q13
e. Mutation in the extracellular matrix protein-coding gene
Answer:
c. Segmental deletion of the ubiquitin ligase coding gene on the maternal chromosome
Explanation:
This patient’s presentation, including developmental delay, ataxia, seizures, and a happy demeanor with frequent laughter, is classic for Angelman Syndrome. This syndrome is caused by a lack of expression of the UBE3A gene, most commonly due to a segmental deletion on the maternal chromosome 15q11-q13. UBE3A is normally imprinted, with the maternal allele being active in the brain. Deletions, mutations, or paternal uniparental disomy result in a lack of UBE3A expression, leading to the clinical manifestations observed in Angelman Syndrome.
What is an outdated term for Angelman Syndrome?
Happy puppet syndrome, referring to the happy demeanor and ataxic gait.
What are the hallmark clinical features of Angelman Syndrome?
Severe intellectual disability, minimal speech, ataxic gait, frequent laughter, microcephaly, and seizures.
What is the genetic cause of Angelman Syndrome?
Loss of maternal UBE3A expression on chromosome 15q11-q13.
What are the mechanisms of UBE3A loss in Angelman Syndrome?
Maternal deletion (most common), paternal uniparental disomy, or imprinting defects.
What protein does the UBE3A gene encode?
Ubiquitin ligase, critical for protein degradation in neuronal cells.
What behavioral traits are characteristic of Angelman Syndrome?
Excessive friendliness, excitability, and frequent inappropriate laughter.
Hyperexcitability, short attention span.
Fascination with water.
What diagnostic tests are used for Angelman Syndrome?
Chromosomal microarray, DNA methylation testing, and uniparental disomy studies.
Which syndrome shares the 15q11-q13 deletion but has opposite parent-of-origin effects?
Prader-Willi Syndrome.
What are the primary differential diagnoses for Angelman Syndrome?
Rett syndrome, Fragile X syndrome, Prader-Willi syndrome, and Autism Spectrum Disorder.
What are the key features of seizures in Angelman Syndrome?
Generalized tonic-clonic seizures, absence seizures, and myoclonic seizures.
What is the management for Angelman Syndrome?
Antiepileptic drugs, speech and occupational therapy, behavioral therapy, and multidisciplinary care.
What is the prognosis for Angelman Syndrome?
Lifelong disability requiring support; seizures may improve with age; normal life expectancy.
Mnemonic for Angelman Syndrome?
A: Ataxia
N: Nonverbal speech
G: Giggles
E: Epilepsy
L: Loss of maternal UBE3A (“No Mama”)
M: Microcephaly
A: Abnormal gait
N: Neurological impairments
What are diagnositic approaches for Angelman Syndrome?
Clinical features with Genetic testing.
