Angelman syndrome is a complex genetic disorder, estimated to affect about 1 in 15,000 children worldwide. It can result in serious physical and mental disabilities, most of which do not ease as the patient ages. No cure currently exists for Angelman syndrome.
The disorder is caused by genetic alterations present well before birth, although it is often diagnosed between the ages of 9 months and 6 years old. Angelman syndrome is generally believed to be random and not hereditary (inherited), but researchers report a small rate of recurrence (about a 1% greater risk than the general population) within families.
Angelman syndrome is caused by the absence or malfunction of the ubiquitin protein ligase E3A (UBE3A) gene, also known as the Angelman gene, located on chromosome 15.
All babies receive two pairs of the UBE3A gene, one inherited from each biological parent. Most cells use both copies of inherited genes. However, in specific regions of the brain, only the copy of UBE3A — that inherited from the mother, and called the maternal UBE3A gene — is active. The copy a child inherits from the father (the paternal UBE3A gene) is turned off through a process called imprinting, and cannot be used by cells.
When the maternal UBE3A gene is dysfunctional, brain cells lack the instructions typically provided by the gene, leading to a number of serious neurological symptoms and associated illnesses. There are several known reasons for problems in the maternal UBE3A gene, including chromosome deletions, imprinting errors, paternal uniparental disomy (when both gene copies come from the father), and mutations in the UBE3A gene. In roughly 10% of cases, no specific cause for Angelman in a child can be identified.
About 70% of Angelman syndrome cases can be attributed to the microdeletion of a region of the maternal chromosome 15, where the UBE3A gene resides — meaning this small part of the chromosome is lost. Genetic microdeletions are typically irregular processes and are not hereditary.
In around 1% of microdeletion incidences, the deleted chromosome segment may be rearranged. In the case of Angelman syndrome, a segment of the maternal chromosome 15 containing the UBE3A gene breaks off and reattaches to a different chromosome location, disrupting the function of other genes and potentially causing other diseases.
Genomic imprinting is the process by which one copy of the same gene (either the maternal or paternal copy) is preferentially silenced, or turned off. This could either be the maternal or the paternal copy of the gene. Genomic imprinting is essential for healthy development overall, but causes problems in the case of Angelman.
Erroneous imprinting can lead to Angelman syndrome by inactivating part of the maternal chromosome 15 where the UBE3A gene resides. Imprinting errors are reported to cause between 3% and 5% of Angelman syndrome cases. The causes of imprinting defects are not well understood.
Paternal uniparental disomy
About 2% to 4% of Angelman cases are due to uniparental disomy, or when a child inherits both copies of chromosome 15 from the father, and there is no maternal copy of chromosome 15. While this phenomenon can occur with any chromosome, paternal uniparental disomy of chromosome 15 causes Angelman syndrome.
UBE3A gene mutations
Mutations in the maternal UBE3A gene are the cause of about 10% of Angelman syndrome cases. In these cases, the UBE3A gene has abnormal changes in its genetic code that prevent the gene from working effectively.
Last updated: April 28, 2021
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