Original article
Neurological aspects of the Angelman syndrome

https://doi.org/10.1016/j.braindev.2003.09.014Get rights and content

Abstract

Angelman syndrome (AS) has emerged as an important neurogenetic syndrome due to its relatively high prevalence and easier confirmation of the diagnosis by improved genetic testing. In infancy, nonspecific clinical features of AS pose diagnostic challenges to the neurologist and these include any combination of microcephaly, seizure disorder, global developmental delay or an ataxic/hypotonic cerebral palsy-like picture. In later childhood, however, absent speech, excessively happy behavior, ataxia and jerky movements usually present as a recognizable clinical syndrome. Brain MRI shows nonspecific or normal findings but occasionally the characteristic EEG patterns alone can lead to the correct diagnosis. The physical, clinical and behavioral aspects appear to be attributable to localized CNS dysfunction of the ubiquitin ligase gene, UBE3A, located at 15q11.2. In certain brain regions, UBE3A normally has mono-allelic expression from the maternally derived chromosome 15. Several distinct genetic mechanisms can inactivate or disrupt the maternally derived UBE3A: chromosome microdeletions, paternal uniparental disomy, imprinting defects and intragenic UBE3A mutations. Those with the deletion type of AS are the most prevalent (about 70% of cases) and appear to have a more severe clinical phenotype. The unique epileptic patterns and distinct behavioral features may be related to multiple actions of UBE3A, possibly occurring during, as well as after, the time of neuronal development.

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.

References (48)

  • S. Kumar et al.

    Identification of HHR23A as a substrate for E6-associated protein-mediated ubiquitination

    J Biol Chem

    (1999)
  • Y.H. Jiang et al.

    Mutation of the Angelman ubiquitin ligase in mice causes increased cytoplasmic p53 and deficits of contextual learning and long-term potentiation [see comments]

    Neuron

    (1998)
  • R.K. Murphey et al.

    New roles for ubiquitin in the assembly and function of neuronal circuits

    Neuron

    (2002)
  • H. Angelman

    Puppet children: a report on three cases

    Dev Med Child Neurol

    (1965)
  • M.R. Mann et al.

    Towards a molecular understanding of Prader-Willi and Angelman syndromes

    Hum Mol Genet

    (1999)
  • J. Clayton-Smith et al.

    Angelman syndrome: a review of the clinical and genetic aspects

    J Med Genet

    (2003)
  • M.B. Petersen et al.

    Clinical, cytogenetic, and molecular diagnosis of Angelman syndrome: estimated prevalence rate in a Danish county

    Am J Med Genet

    (1995)
  • A.M. Vercesi et al.

    Prevalence of Prader-Willi and Angelman syndromes among mentally retarded boys in Brazil

    J Med Genet

    (1999)
  • N.H. Aquino et al.

    Angelman syndrome methylation screening of 15q11–q13 in institutionalized individuals with severe mental retardation

    Genet Test

    (2002)
  • J. Jacobsen et al.

    Molecular screening for proximal 15q abnormalities in a mentally retarded population

    J Med Genet

    (1998)
  • R.H. Buckley et al.

    Angelman syndrome: are the estimates too low?

    Am J Med Genet

    (1998)
  • C.A. Williams et al.

    Angelman syndrome: consensus for diagnostic criteria. Angelman syndrome foundation

    Am J Med Genet

    (1995)
  • J.S. Fryburg et al.

    Diagnosis of Angelman syndrome in infants

    Am J Med Genet

    (1991)
  • R.A. King et al.

    Hypopigmentation in Angelman syndrome

    Am J Med Genet

    (1993)
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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.

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