Angelman Syndrome

Angelman Syndrome

Background:

Angelman Syndrome, first described only forty years ago, continues to both expand and challenge the limits of genetic research. The disorder affects all major racial groups at an incidence of between 1 in 15,000 and 1 in 30,000, though precise numbers are difficult to gauge because the diagnosis can require extensive genetic testing to confirm. The symptoms are consistent with a neurological disorder, including an inappropriately happy demeanor, difficulty in walking, and an inability to form words. There are several genetic bases for the disorder, but all involve the loss of genetic material on the maternally inherited copy of chromosome 15. Since genomic imprinting inactivates that region of the paternal copy of chromosome 15, carrying an intact paternal copy of the chromosome does not prevent the disease, meaning that inheritance is not typically Mendelian (Glenn C. et al., 1997).

Symptoms:
The symptoms of Angelman Syndrome often manifest themselves in developmental delays within the first year of life. With time, the profound developmental delays characteristic of AS become readily apparent. As learning and coordination are impaired, two of the most typical AS symptoms appear: an unbalanced gait and lack of verbal communication. The severity of these symptoms is variable, but they are noted to some degree in nearly all cases. Most children do, in time, learn to walk with an unsteady gait, though few ever develop the ability to speak. Learning in general, though not stopped by the disease, proceeds at a very slow pace, with basic life skills such as feeding taking many years to learn. Some things do still come naturally to those with AS, though, particularly the ability to enjoy music and an often inappropriately happy demeanor. Though both of these can pose challenges as the child with AS constantly makes noises or laughs at situations others do not find particularly amusing, they do show that these individuals retain the ability to enjoy their lives despite what appears to those on the outside a stifling existence.

Further information:

• The Special Child provides general information on symptoms and typical trends of development with AS, written from the perspective of the parents.
• The Angelman Syndrome Foundation provides extensive information also geared towards parents, outlining many particular challenges common to the disorder along with some genetic background.
• NCBI's The Online Mendelian Inheritance in Man site provides extensive information in the form of many case studies, shedding some light on patterns of inheritance and suggesting that a significant portion of cases are linked to germ line mutations in the mother.

Genetic Origin:
Though the symptoms of AS are relatively easy to identify, the molecular basis for these symptoms has proved more elusive. Large deletions in the maternal copy of chromosome 15 have long been linked to the symptoms of AS, but until recently the precise gene responsible for the disorder has been difficult to identify. After extensive analysis of the common deleted regions of many patients, the location of the gene was narrowed down substantially until Matsuura et al. (1997) described patients showing typical AS symptoms but loss-of-function mutations in UBE3A gene instead of large deletions, suggesting a causative role of UBE3A in AS. Further research has supported this theory, as the genetic imprinting of UBE3A matches non-Mendelian inheritance pattern of AS. Since only the maternal copy of UBE3A is expressed in the brain, the maternal allele exclusively determines phenotype in the brain. Elsewhere, however, biallelic expression rescues the diseased phenotype, explaining why the disorder selectively affects the brain (Vu and Hoffman, 1997; Rougeulle et al., 1997). Though loss-of-function of UBE3A appears to cause the symptoms of AS, the precise mechanism is still unclear. UBE3A is known to interact with a number of proteins, including the tumor suppressor gene p53. It is thought that, by ligating ubiquitin to p53, UBE3A marks it for the protein degradation pathway, a finding consistent with the elevated p53 levels in the brains of mice carrying UBE3A knockouts. The reason why elevated levels of p53 would lead to the observed symptoms, though, is still unknown.

UBE3A Functional Homologues:

• Caenorhabditis elegans, wwp-1, accession number AAN73850.
• Canis familiaris, Predicted protein (derived from the genomic sequence and mRNA evidence), accession number XP_863724.
• Mus musculus, Herc2, accession number NP_034548. Mice are the primary model organism for this disorder, and those lacking this gene suffer from neuromuscular and spermiogenic disorders. Though this does not precisely mimic the human pattern of the disease, mice have been a helpful model system for the disorder and analyzing the brains of sacrificed mutant mice has provided evidence that p53 levels are elevated brains of knockout strains, which supports the role of UBE3A in protein degradation via the ubiquitin pathway.