Angelman Syndrome is a rare genetic condition that bears the name of the British paediatrician who described three children who presented with characteristic features in the 1960s. Affected individuals show developmental delay, intellectual disability, have (practically) no spoken words and an exuberant, contagiously happy temperament, smiling nearly all the time and laughing a lot, tending to stick out their tongue, and loving to play with water with wanton enjoyment. They may also have epilepsy, as well as various problems with coordinating their movements, and their EEG (brainwave recording) often shows recognisable patterns. Angelman Syndrome is due to lack of expression of a gene called UBE3A in brain cells. Although the condition is genetic in origin, it usually occurs in unrelated individuals rather, than in several members of a family. The UBE3A gene was known before scientists suspected its implication in Angelman Syndrome. A few of its functions have been described, but more remain to be discovered. It is not well understood how the genetic defect leads to abnormalities in brain maturation, control of movements, organisation of intelligence, problems of speech or of sleep, epilepsy and the peculiar behaviour. Current hypotheses relate to various processes underlying the way brain cells communicate with each other.
The medical genetics of Angelman Syndrome is particularly complex. In all our cells, we have two copies of the UBE3A gene: one is passed on to us from our mother and the other one from our father. In brain cells, the UBE3A gene is normally expressed only from the copy inherited from the mother, while the copy from the father remains (virtually) silent. This is because just next to UBE3A, there is a control centre which acts as a DO NOT READ! signal. On the maternal chromosome, this control centre is deactivated (by a chemical process called methylation). As a result, the DO NOT READ! signal is not produced and UBE3A can be effectively expressed.
Different mechanisms may prevent normal expression of the UBE3A gene and thus cause Angelman Syndrome, as illustrated in the cartoon by Christyan Fox, who is the father of a boy with Angelman Syndrome. There may be a deletion or a mutation of the maternal copy of UBE3A. More rarely, the problem is the absence of the imprinting that marks the chromosome inherited from the mother, as such. This is called ‘imprinting defect’: the methylation pattern that should block the DO NOT READ! signal of the control centre is not there, so the UBE3A gene cannot be read. Or the whole chromosome that should be inherited from the mother is absent and the individual has two copies of this chromosome from the father, both with silenced UBE3A: this is referred to as paternal ‘uniparental disomy’. All these mechanisms prevent expression of the UBE3A gene, either because the gene itself is abnormal (deletion or mutation), or because it cannot be read because there is no methylation inactivating the DO NOT READ! signal (imprinting defect or uniparental disomy). Thus, they all result in Angelman Syndrome, but the severity of the manifestations may vary according to the underlying mechanism. For example, intellectual disability, speech problems and epilepsy tend to be less severe in individuals with imprinting defect or uniparental disomy, than in those with a deletion of a mutation. Seeing these variations in severity according to the genetic mechanism, some scientists have thought that there may actually be a very weak expression of the intact copy of the UBE3A gene, despite the presence of the silencing DO NOT READ! signal.
Thanks to genetic engineering approaches, labs can ‘produce’ mice with the genetic defect and study selected aspects of their functioning, hoping that it is representative enough of that of humans with Angelman Syndrome. In fact, mice tolerate the genetic abnormality much better than people, and it is not easy (if at all possible) to tell the genetically modified mice from the normal ones with the naked eye. These mouse models of Angelman Syndrome have helped us understand fine neurological abnormalities, using mouse.adapted tests for Problem-solving, for movement coordination and recordings of various parts of the brain. They have also allowed much progress in the understanding of interaction between genes and the effect of the gene defect at many microscopic levels. A number of teams worldwide (including our own) are involved in various aspects of this research. In the last few years, there have been more and more encouraging results. Recently, the team led by Ed Weeber found improvements in the electrical functioning of the brain and in motor performance of a mouse model, following administration of a specific antibiotic. These results still need to be confirmed and it is currently not clear how the drug works. Still, a study is currently being carried out in humans with Angelman Syndrome.
Since 2000, several teams of researchers have attempted to find ways to promote the expression of the copy of UBE3A which is intact, but non-functional because of this silencing signal without much success until a recent breakthrough. A team led by Ben Philpot and Marky Zylka tested more than 2000 drugs in mice in order to see if some of them could activate the paternal copy of UBE3A. They found that selected anticancer drugs and, in particular, one called topotecan, can unsilence this copy of the gene in the mice they studied by disrupting the DO NOT READ! signal. In human medical practice, topotecan is used for its toxicity, in order to kill cancer cells. This may have great implications for developing new strategies of pharmacological management of Angelman Syndrome, alhough a lot of questions need to be answered before we know if and how these early results in animal experiments can impact individuals with Angelman Syndrome. This process, which has brought about great successes in many fields, is typical of medical science: with due respect for ethics, and in the patients’ best interest, it must follow a sound, stepwise road. And results obtained in Angelman Syndrome may prove useful for a wide range of neurodevelopmental genetic disorders.
Current understanding which founds developmental medicine and much of child neurology emphasises the importance of maturational factors, experience.driven brain plasticity and the notion of critical periods that occur sequentially in a hierarchical order in embryonic, fetal and early postnatal life. Plasticity can imply windows of opportunity for optimising developmental trajectories as aimed for in ‘early intervention’ programmes, but it is constrained by these critical periods to a large extent. Therefore, there is currently no indication that neurodevelopmental genetic disorders might be cured by restoring normal gene expression, replacing or otherwise interfering with gene product, or bypassing the mutation altogether, as we do not know (yet) how we could allow unconstrained brain plasticity to take place. The perspective might change when we gain better understanding of the role the concerned genes on brain development and function.
The diagnosis of Angelman Syndrome is often made late in the history of brain development: at the earliest in infants and in most individuals in older children. It must also be borne in mind that it wouldn’t be correct to interpret as a cure the improvement or even normalisation of selected, specific aspects of the neurological functioning of animal models of Angelman Syndrome. Nevertheless, results from animal studies are likely to lead to the development of treatments that aim to improve how individuals with Angelman Syndrome use their own potential. Meanwhile, efforts into improving management need to rest very largely on improving physiological or adaptive functioning, with a view to symptomatic relief and on individually.tailored habilitation programmes aimed at optimising development, quality of life and participation. Validated guidelines for clinical management of individuals with Angelman Syndrome, developed by an international, multidisciplinary groups (including the mum of young man with Angelman Syndrome), are available from the Dyscerne website (http://www.dyscerne.org/dysc/digitalAssets/0/263_Angelman _Guidelines.pdf ).
Left: Cartoon illustrating the molecular classes that underlie Angelman Syndrome. ((c) Christyan Fox 2012). Chromosome 15 inherited from the mother is represented by a woman, the one inherited from the father by a man. One Way sign indicates expression of UBE3A allele. Dead End sign indicates allele inactivation. Roadworks sign indicates gene deletion or mutation. Right turn sign indicates activation of silent allele. (1) In the typical situation, the chromosome 15 inherited from the mother carries an epigenetic signal enabling UBE3A gene expression whereas the paternal allele is inactive. (2) In case of deletion or mutation of the maternal copy, this cannot be expressed while the paternal allele is inactive as in the typical situation. (3) In case of imprinting defect, both alleles are inactive. (5) Promoting the expression of the paternal allele might be a promising therapeutic avenue.