Angelman syndrome: current understanding and research prospects.
Angelman syndrome is a neurogenetic disorder characterized by developmental delay, severe intellectual disability, absent speech, exuberant behavior with happy demeanor, motor impairment, and epilepsy, due to deficient UBE3A gene expression that may be caused by various abnormalities of chromosome 15. Recent findings in animal models demonstrated altered dendritic spine formation as well as both synaptic [including gamma-aminobutyric acid (GABA)(A) and N-methyl-D-aspartate (NMDA) transmission] and nonsynaptic (including gap junction) influences in various brain regions, including hippocampus and cerebellar cortex. Reversal of selected abnormalities in rescue genetically engineered animal models is encouraging, although it should not be misinterpreted as promising "cure" for affected patients. Much research is still required to fully understand the functional links between lack of UBE3A expression and clinical manifestations of Angelman syndrome. Studies of regulation of UBE3A expression, including imprinting-related methylation, may point to possibilities of therapeutic upregulation. Understanding relevant roles of the gene product might lead to targeted intervention. Further documentation of brain network dynamics, with particular emphasis on hippocampus, thalamocortical, and cerebellar networks is needed, including in a developmental perspective. There is also a need for further clinical research for improving management of problems such as epilepsy, behavior, communication, learning, motor impairment, and sleep disturbances.
Dan
Bernard
B
Department of Neurology, Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de Bruxelles, Brussels, Belgium. bernard.dan@ulb.ac.be
D017204:Angelman Syndrome / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology*; D000818:Animals; D001921:Brain / Q000254:growth & development / Q000378:metabolism / Q000503:physiopathology*; D002531:Cerebellum / Q000378:metabolism / Q000503:physiopathology; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics / Q000378:metabolism; D026603:D-Aspartic Acid / Q000502:physiology; D049229:Dendritic Spines / Q000235:genetics / Q000502:physiology; D004195:Disease Models, Animal; D054351:Electrical Synapses / Q000235:genetics / Q000502:physiology; D015870:Gene Expression; D006624:Hippocampus / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D008297:Male; D016202:N-Methylaspartate / Q000235:genetics / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics; D005680:gamma-Aminobutyric Acid / Q000502:physiology
D026603:D-Aspartic Acid; D005680:gamma-Aminobutyric Acid; D016202:N-Methylaspartate; C471639:UBE3A protein, human; D044767:Ubiquitin-Protein Ligases