Original articleNeurological aspects of the Angelman syndrome☆
Introduction
Initially described in 1965 [1], Angelman syndrome (AS) is familiar to most child neurologists as a recognizable syndrome associated with infantile seizures. Several general reviews have recently appeared in the genetic literature [2], [3], [4] and this article reviews the salient neurological and diagnostic aspects of the condition.
Section snippets
Incidence
It appears that AS occurs worldwide without geographic clustering. Studies on school age children, age 6–13 years, show a minimum prevalence of AS of 1/12,000 in Sweden [5] and 1/10,000 in Denmark [6]. Several reports address the prevalence among individuals with established developmental delay, showing rates of 0% [7], 1.3% [8], 1.4% [9], and 4.8% [10]. The latter study extrapolated data in order to compare it to the population of the Washington state (using 1997 US Census Bureau figures) and
Clinical presentation
Clinical consensus criteria for the diagnosis have been published is illustrated in Table 1 [11]. Severe speech deficit (usually absent speech), severe mental retardation, behavioral abnormalities and movement problems are ubiquitous in AS. Other features, such as microcephaly or seizures may be absent. The AS clinical gestalt is heavily dependent on the combination of the behaviors of excessive laughter and apparent happiness combined with tremulous movements and gait ataxia.
The neurologist
Genetic etiology
It was not until the 1980s that chromosome 15 was implicated in its causation. The first clue to this was the discovery that the majority of individuals with AS had microdeletion of 15q11.2–15q13. Initially confusing was the observation that the Prader-Willi syndrome (PWS) could also be caused by the same microdeletion. It soon became evident that deletions on the paternally derived 15 caused PWS and ones on the maternally derived 15 caused AS. The two syndromes are, however, caused by
Genetic diagnostic testing
DNA methylation testing of blood is a sensitive and specific screening for three of the four known genetic mechanisms. There are several methods available for this testing and all rely on the observation that the AS DNA methylation pattern in the IC control region is easily distinguishable from normal when AS is caused by chromosome deletions, UPD or IC defects. The diagnosis of AS is thus confirmed if this methylation result is abnormal but it does not distinguish which of the three above
UBE3A and neuronal development in AS
The UBE3A gene has at least 16 exons that span about 100 kb and produces an mRNA of 5–8 kb size, spliced into five different mRNA types [32], [33]. UBE3A produces a protein called the E6-associated protein (E6AP) which acts as a cellular ubiquitin ligase enzyme. It is termed ‘E6-associated’ because it was first discovered as the protein able to associate with p53 in the presence of the E6 oncoprotein of the human papilloma virus, type 16 [34]. The E6AP enzyme's function is to create a covalent
Acknowledgements
Funding for this work was supported in part by the Raymond C. Philips Research and Education Unit, Department of Children and Family Services, State of Florida.
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The paper is based on the lecture given at the 6th annual meeting of the Infantile Seizure Society, Tokyo, March 15–16, 2003.