New UBE3A Mutation Linked to Milder Form of Angelman in Case Report

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by Alice Melão |

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Sarepta Therapeutics

A new mutation in the UBE3A gene, which was linked to a more mild form of Angelman syndrome, was found in three children from two unrelated families, according to a case report.

The study, “Two Angelman families with unusually advanced neurodevelopment carry a start codon variant in the most highly expressed UBE3A isoform,” was published in the American Journal of Medical Genetics.

Angelman syndrome is a genetic disorder caused by mutations in the UBE3A gene, which provides instructions for making three different versions of the ubiquitin protein ligase E3A enzyme — a protein required for normal cell function.

The three coded protein versions differ in length, with the most common form — isoform 1 — present in about 50 tissue types throughout the body, including the cerebral cortex and cerebellum, two areas of the brain that play key roles in speech, awareness, and movement control.

The broad distribution of these enzymes helps explain the characteristic manifestations of Angelman syndrome, which include global developmental delay, intellectual disability, movement impairment, seizures, and very limited or complete absence of speech.

During the Angelman syndrome Natural History Study (NCT00296764) — a study aimed at better understanding disease progression and clinical features in Angelman children over time — researchers identified two siblings and one unrelated child who were carriers of a UBE3A mutation, Met1Thr, which was linked to an unexpected presentation of the disease.

All children had “motor and language skills that were more advanced than expected,” and were able to use “spontaneous phrases to express themselves, which has never been reported in Angelman syndrome,” the researchers wrote.

The two siblings, an 11 year-old boy and a 9-year-old girl, showed early signs of developmental delay that was linked to an amino acid substitution in the first position of the UBE3A gene sequence, a mutation found to be inherited from the mother.

The boy exhibited behavior characterized by a happy disposition, being easily excitable, easily provoked laughter and hand-flapping, and hyperactivity with a short attention span. In contrast to Angelman’s classical manifestations, he had no reports of seizures, had normal walking ability, and was able to use more complex speech to communicate.

“While his speech was more than 75% intelligible to familiar listeners when the context of the conversation was known, it was no more than 25% intelligible to unfamiliar listeners when the context was unknown,” the researchers reported.

The girl showed slightly different behavior than her brother. She had a happy disposition, a short attention span and a tendency to mouth (but not eat) non-food objects, but had no other behavioral issues.

Similar to her sibling, she was able to communicate verbally and was easier to understand. About 90% of her speech was understandable to an unfamiliar adult with previous knowledge of the topic, and approximately 75% if they had no knowledge of the topic.

The third case reported in the study was an 8 year-old boy who had global developmental delays, particularly in expressive language, but was only diagnosed with Angelman at 5 years old. He also carried the Met1Thr UBE3A variant.

In contrast to the siblings, this boy had experienced several types of seizures since he was a year old. He also showed characteristic Angelman behavior, and could communicate verbally with complex phrases and sentences in an intelligible form to unfamiliar listeners.

The newly identified UBE3A mutation is thought to change the production of the common isoform 1-coded enzyme. However, its impact on the other two enzyme variants remains unclear.

Researchers could not explain why this particular mutation would give rise to a milder form of Alngelman syndrome, but hypothesize that it is probably due to the roles the different enzyme isoforms play in the brain, which is still not fully understood.

“Further investigations into the expression of the different wild-type UBE3A isoforms in different brain regions and the level of expression of each isoform in the neurons of these three children, perhaps through the use of … stem cells, could potentially inform our understanding of the importance of the different UBE3A isoforms in the brain,” they wrote.

“Some of the therapeutic strategies that are currently being developed for AS involve reactivation of the normally silenced … paternal UBE3A allele, but the level of UBE3A expression that would result in a clinically meaningful outcome is unknown. As such, knowing the minimum amount of UBE3A that needs to be expressed for an AS individual to have spontaneous syntactic speech would be important,” they concluded.