Angelman Syndrome

Characteristics of Angelman Syndrome

Angelman syndrome (AS) is a neurodevelopmental disorder caused by the loss of function of the maternal UBE3A gene, which is characterized by severe cognitive disability, motor dysfunction, speech impairment, hyperactivity, frequent seizures, and autism spectrum disorder (ASD) as common comorbidity. The characteristic behaviors of AS include mouthing of objects, happy demeanor with easily provoked laughter, attraction to water, hyperactivity, short attention span, and decreased sleeping. These features of AS can be seen in other neurodevelopmental disorders, leading to a broad differential diagnosis.

Causes of Angelman Syndrome

Human genetic studies revealed that AS is caused by 4 molecular mechanisms: denovo maternal deletions of chromosome 15q11-q13 (70-80%); intragenic mutations in the maternally inherited UBE3A within chromosome 15q11-q13 (10-20%); paternal uniparental disomy (UPD) for chromosome 15q11-q13 (3-5%); or imprinting defects within chromosome 15q11-q13 that alter the expression of maternally inherited UBE3A (3-5%). In addition, UBE3A expression leads to the cognitive and language impairment underlying AS. The hippocampus is one of the most prominently affected brain regions in AS model mice, manifesting in severe hippocampal-dependent memory and plasticity deficits. Studies implicate Ube3a in experience-dependent visual cortical plasticity, other studies have found that deletion of Ube3a also leads to changes in inhibitory synapse function. These findings suggest that AS may result from a fundamental defect in excitatory synapse development leading to lower numbers of functional excitatory and inhibitory synapses in the brain.

PKA and UBE3A Play a Major Regulatory Role in Angelman Syndrome

The lack of Ube3a-mediated ubiquitination of the Ca²⁺-activated small conductance potassium channel, SK2, contributes to impairment of synaptic plasticity and learning in AS mice. Synaptic SK2 levels are also regulated by protein kinase A (PKA), which phosphorylates SK2 in its C-terminal domain, facilitating its endocytosis, and that PKA activation promotes long-term potentiation (LTP) in hippocampal slices from AS mice. In addition, Ube3a-mediated SK2 ubiquitination inhibits its recycling to synaptic membranes after endocytosis. Finally, PKA-mediated SK2 phosphorylation increases Ube3a-mediated ubiquitination, and these two enzymes collaboratively maintain optimal synaptic SK2 levels. The complex interactions between PKA and Ube3a in the regulation of SK2 synaptic levels might provide new platforms for developing treatments for AS and various forms of autism.

Treatment Methods of Angelman Syndrome

Recent work has identified multiple approaches with preclinical therapeutic potential for AS:

• Antisense oligonucleotides and topoisomerase inhibitors have the potential to unsilence paternal UBE3A and re-express UBE3A protein.
• Gene therapy provides a direct method of expressing UBE3A.
• Mechanism-based approaches downstream of UBE3A include GABAA agonists (THIP/gaboxadol) and modulation of αCaMKII.
• Other approaches include altering diet.

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