Angelman Syndrome

Overview

Plain-Language Overview

Angelman Syndrome is a rare genetic disorder that primarily affects the nervous system. It causes developmental delays, problems with movement and balance, and speech difficulties. People with this condition often have a happy, excitable demeanor with frequent smiling and laughter. Seizures are common and usually begin in early childhood. The syndrome results from a loss of function of a specific gene on chromosome 15 inherited from the mother.

Clinical Definition

Angelman Syndrome is a neurogenetic disorder caused by the loss of function of the maternally inherited UBE3A gene on chromosome 15q11-q13. This loss leads to impaired ubiquitin-protein ligase activity, which disrupts normal neuronal function. Clinically, it is characterized by severe developmental delay, absent or minimal speech, and ataxia with a characteristic gait. Patients often exhibit a unique behavioral phenotype including frequent laughter, smiling, and excitability. Seizures typically begin before 3 years of age and are often difficult to control. Microcephaly and characteristic craniofacial features such as a prominent chin, wide mouth, and widely spaced teeth may be present. Diagnosis is confirmed through genetic testing including methylation analysis, deletion studies, or UBE3A mutation analysis. Differential diagnosis includes other causes of intellectual disability and movement disorders. Management is supportive and focuses on seizure control, physical therapy, and communication aids.

Inciting Event

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Latency Period

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Diagnostic Delay

Delayed diagnosis often occurs due to nonspecific early developmental delays and seizures.
Misdiagnosis as cerebral palsy or other neurodevelopmental disorders can delay recognition.
Lack of awareness of the syndrome and limited access to genetic testing contribute to delays.

Clinical Presentation

Signs & Symptoms

Severe developmental delay with absent speech.
Movement disorders including ataxia and tremulousness.
Frequent episodes of paroxysmal laughter and smiling.
Seizures beginning in early childhood.
Sleep disturbances with reduced need for sleep.

History of Present Illness

Developmental delay with severe speech impairment and motor dysfunction.
Frequent seizures beginning in early childhood.
Characteristic behavioral features including a happy demeanor, frequent laughter, and hyperactivity.
Ataxic gait and tremulous movements.

Past Medical History

History of early-onset seizures.
Delayed motor milestones such as sitting and walking.
Feeding difficulties and failure to thrive in infancy.

Family History

Usually no family history due to de novo mutations or imprinting errors.
Rare cases may have a family history of Angelman syndrome or related imprinting disorders.
Parental history of chromosomal abnormalities or imprinting defects may be relevant.

Physical Exam Findings

Patients often have a characteristic happy demeanor with frequent smiling and laughter.
There is notable microcephaly with a small head circumference.
Examination reveals ataxic gait and jerky movements.
There is often a protruding tongue and a wide mouth.
Hypopigmentation of the skin, hair, and eyes may be present due to genetic imprinting effects.

Diagnostic Workup

Diagnostic Criteria

Diagnosis of Angelman Syndrome requires clinical features including severe developmental delay, absent or minimal speech, ataxia or movement disorder, and a characteristic behavioral profile with frequent laughter and smiling. Genetic testing confirming loss of maternal UBE3A gene function through deletion, mutation, or imprinting defects on chromosome 15q11-q13 is essential. Seizures beginning in early childhood and characteristic EEG patterns support the diagnosis. Other causes of intellectual disability must be excluded.

Pathophysiology

Key Mechanisms

Angelman syndrome results from loss of function of the maternally inherited UBE3A gene on chromosome 15q11-q13.
The disorder is caused by impaired ubiquitin-protein ligase activity leading to abnormal protein degradation in neurons.
Genomic imprinting causes only the maternal allele of UBE3A to be expressed in the brain, so paternal deletions do not cause the syndrome.

Involvement	Details
Organs	Brain is the primary organ affected, leading to severe neurodevelopmental delay and seizures.
Organs	Muscle tissue may be hypotonic, contributing to motor difficulties.
Tissues	Brain tissue shows abnormal development and function in Angelman syndrome.
Tissues	Cerebellar tissue is often involved, contributing to ataxia and motor dysfunction.
Cells	Neurons are the primary cells affected in Angelman syndrome due to UBE3A gene dysfunction.
Cells	Glial cells support neuronal function and may contribute to neurological symptoms.
Chemical Mediators	Gamma-aminobutyric acid (GABA) is involved in inhibitory neurotransmission and may be dysregulated.
Chemical Mediators	Glutamate is the main excitatory neurotransmitter implicated in neuronal signaling abnormalities.

Treatment

Pharmacological Treatments

Antiepileptic drugs
- Mechanism: Control seizures by modulating neuronal excitability
- Side effects: Drowsiness, dizziness, rash
Melatonin
- Mechanism: Regulates sleep-wake cycles to improve sleep disturbances
- Side effects: Headache, dizziness, nausea

Non-pharmacological Treatments

Early intervention with physical therapy improves motor skills and coordination.
Speech therapy assists in developing communication abilities despite severe speech impairment.
Behavioral therapy helps manage hyperactivity and improve social interactions.
Occupational therapy supports daily living skills and sensory integration.

Prevention

Pharmacological Prevention

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Non-pharmacological Prevention

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Outcome & Complications

Complications

Recurrent seizures can lead to status epilepticus.
Aspiration pneumonia due to feeding difficulties.
Severe intellectual disability impacting quality of life.
Orthopedic deformities such as scoliosis.

Short-term Sequelae	Long-term Sequelae
Seizure episodes requiring acute management. Feeding intolerance and failure to thrive. Sleep disruption affecting daytime function.	Persistent severe intellectual disability with absent speech. Chronic motor impairment including ataxia and tremors. Behavioral issues such as hyperactivity and sleep disturbances. Orthopedic complications including scoliosis.

Differential Diagnoses

Angelman Syndrome versus Autism Spectrum Disorder (ASD)

Angelman Syndrome	Autism Spectrum Disorder (ASD)
Severe developmental delay with frequent laughter and a happy, excitable disposition.	Impairment in social communication and repetitive behaviors without characteristic happy demeanor.
Marked ataxia and jerky movements.	No consistent presence of ataxia or seizures.
Microcephaly and seizures common in early childhood.	Normal to above-average head circumference.

Angelman Syndrome versus Prader-Willi Syndrome

Angelman Syndrome	Prader-Willi Syndrome
Severe developmental delay with frequent laughter and smiling.	Neonatal hypotonia with poor feeding followed by hyperphagia leading to obesity.
Prominent ataxia and seizures common in early childhood.	Characteristic almond-shaped eyes and narrow forehead.
Microcephaly and protruding tongue often observed.	Mild to moderate intellectual disability without the characteristic happy demeanor.

Angelman Syndrome versus Rett Syndrome

Angelman Syndrome	Rett Syndrome
Severe developmental delay with prominent happy demeanor and frequent laughing episodes.	Primarily affects females with normal early development followed by loss of purposeful hand skills and development of hand-wringing movements.
Marked ataxia and puppet-like gait.	Presence of microcephaly developing after birth.
Absence of purposeful hand movements replaced by hand-flapping and jerky movements.	Characteristic breathing irregularities such as hyperventilation and apnea during wakefulness.