A process known as “mosaic imprinting” may be responsible for milder symptoms observed in patients with atypical Angelman syndrome, according to a case series on three young patients.
The study, “Atypical Angelman Syndrome Due to a Mosaic Imprinting Defect: Case Reports and Review of the Literature” was published in the American Journal of Medical Genetics.
Every person has two copies of each gene, called alleles, one from the mother and one from the father. However, in specific regions of the brain, only the maternal UBE3A gene is active, and the paternal gene is turned off and cannot be used.
In these regions of the brain, when the maternal UBE3A gene is dysfunctional, brain cells do not get the instructions typically provided by the gene, resulting in a number of serious neurological symptoms and associated illnesses.
There are several known reasons for the maternal UBE3A gene to be dysfunctional, including chromosome deletions, genetic imprinting errors, mutations in the UBE3A gene, and cases where chromosomes come from a single parent. By far the most common cause of Angelman is gene deletion, which occurs in 80 percent of cases. Imprinting defects occur in only about 3 percent of cases.
Mosaic imprinting is a combination of two different genetic phenomenons: genetic imprinting and genetic mosaicism.
Genomic imprinting is a process by which either the maternal or paternal copy of a gene is silenced. It does not affect the genetic code, but instead, affects how genes are expressed, e.g., the process by which information in a gene is synthesized to create a working product, such as a protein.
Genetic mosaicism, as the name implies, indicates the person is a mosaic — that is, composed of more than one genotype (the genetic constitution of an organism), even though they have developed from a single fertilized egg.
Normally, humans are derived from the product of a fusion of egg and sperm, and all cells that descend from that original founding cell should contain an identical nuclear genome — our personal DNA signature.
Mosaic imprinting can occur through a process known as methylation, where a methyl molecule is added to DNA controlling its expression. This means that in mosaic imprinting, the code that instructs the DNA on how to express genes is altered. Usually, imprinting errors occur after an egg has been fertilized and following initial cell division. This causes the subsequent daughter cells to lose their initial (maternal) methylation pattern.
Atypical Angelman is characterized by a milder phenotype, unlike the classical form of the disease. These patients often exhibit excessive hunger and obesity or non-specific intellectual disability, have a larger vocabulary of up to 100 words, and can speak in small sentences.
The three young patients, 11, 16, and 17 years old, presented in this case series had mild symptoms and the ability to form simple sentences. Genetic analysis showed that all three patients had cellular mosaicism for an imprinting defect.
Unlike classical Angelman, where there is almost a complete absence of methylation, where mean methylation is 0.8% versus 45-47.4% in healthy individuals, due to the absence of a maternal allele, these atypical Angelman cases only had reduced levels of methylation, ranging from 6.5% to 10.9%. This indicates the presence of a mixture of normal cells and cells containing an Angelman imprinting defect on the maternal allele.
Although the symptoms associated with Angelman can be quite broad, the authors suggest that the type of mutation can dictate symptom severity. For example, patients with gene deletions are more likely to have classical Angelman, whereas those with a mutation in the UBE3A gene are more likely to have intermediate symptoms. Patients with an imprinting defect or mosaic Angelman tend to have milder symptoms.
“Importantly, the phenotype of individuals with mosaic AS may not be entirely consistent with the diagnostic features recommended by the 2005 Consensus Statement of the United States AS Foundation,” the authors wrote, adding that these individuals have greater speaking ability. In fact, one patient had a vocabulary of more than 100 words, “which is more than any other previously reported individual in the literature,” according to the researchers.
All patients could walk unassisted by age 5, and one patient learned to ride a bicycle. Moreover, these patients had a lower incidence of typical Angelman behavioral features, seizures, and microcephaly — abnormal smallness of the head — which may delay diagnosis.
“Significantly greater receptive communication skills in comparison to the level of verbal skills in a child with developmental delay should prompt SNRPN DNA methylation testing for a potential Angelman imprinting defect mosaicism,” the authors concluded.