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Angelman syndrome (AS) is a neurogenic disorder with a symptom complex that includes, but is not limited to, severe developmental delay, profound cognitive disruption, motor coordination defects, increased propensity for seizure with a characteristic abnormal EEG, sleep disruption, behavioral difficulties, a lack of speech and an overall happy demeanor. The disorder was first described in 1965 by British pediatrician Dr. Harry Angelman: however, AS is clinically characterized by a wide constellation of symptoms with varying degrees of severity it is not readily diagnosed by clinical presentation alone and misdiagnosis is common.
In the past few years AS has begun to show an increasing presence in the scientific literature and as a result is more recognizable in the clinic. Typical of rare disorders, the initial basic science investigation of AS took place within only a handful of laboratories. This small community of physicians and scientists achieved the initial identification and characterization of the gene responsible for giving rise to the disorder and the subsequent production of an animal model to examine the molecular underpinnings of the symptom complex. Findings from these early studies formed the generalities of AS still referenced today and established the current dogma concerning its genetics and etiology. The molecular and biochemical signature of AS has slowly gained research attention and as more multidisciplinary teams apply their insights, our knowledge of the disorder continues to grow and the general perception of AS as a brain region-specific developmental disorder has evolved. Recent published studies support the idea that while AS has a simple genetic origin, the genetic disruption results in a complex biochemical signature and subsequent variable symptomatic expression.
The prevalence of AS is 1/10-20,000 births. AS can arise from a variety of genetic disturbances within a localized region on chromosome 15 that contains imprinted genes. The information contained in certain genes in this region is modified through differential methylation patterns according to whether it is passed to a child through the egg or the sperm. This modification is referred to as genetic imprinting and determines whether the information contained in the gene copy is expressed or not. The imprinting pattern for UBE3A results in gene expression of the maternal copy and silencing of the paternal copy. Nearly 70% of AS cases involve a de novo deletion of an approximate 4 Mb span of genetic material containing the UBE3A gene on the maternal chromosome 15q11-13 (Class I) (1, 2). 7-9% of AS cases are the result of imprinting mutations in which both the maternal and paternal copies undergo paternal-like DNA methylation (Class III) and subsequent silencing (3, 4), and 2-3% show uniparental disomy (UPD) whereby the individual inherits two copies of the paternal chromosome region with no maternal copies present (Class II) (5, 6). The remaining individuals with clinically diagnosed AS do not show any of the above mutations or any other discernable changes in 15q11-13.
Current NLML AS Research Projects
UBE3A Gene Function
Model Systems of Angelman Syndrome
Molecular Changes in the AS Mouse Model
Parents Area
1. R. E. Magenis et al., Am J Med Genet 35, 333 (1990).
2. L. C. Kaplan et al., Am J Med Genet 28, 45 (1987).
3. K. Buiting et al., Nat Genet 9, 395 (1995).
4. J. M. Gabriel et al., Proc Natl Acad Sci U S A 96, 9258 (1999).
5. J. H. Knoll et al., Am J Med Genet 32, 285 (1989).
6. S. Malcolm et al., Lancet 337, 694 (1991).
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