New UBE3A Mutation Linked to Severe Angelman in 2 Chinese Sisters

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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UBE3A gene mutation | Angelman Syndrome News | illustration of DNA strand

A newly identified mutation in the UBE3A gene that causes an inherited, severe form of Angelman syndrome was found in two sisters in China, scientists report.

While UBE3A mutations are typically associated with milder forms of Angelman, these cases highlight a link between this new mutation and early-onset seizures, significant intellectual disability, and microcephaly, or a smaller head and brain size.

Such features usually are seen in cases caused by large deletions of a DNA region containing UBE3A and other genes, according to researchers.

These findings expand the genetic spectrum of Angelman syndrome and support genetic testing for those affected. Testing could help speed both diagnosis and treatment — at least for epilepsy — as well as genetic counseling for patients’ families, the team noted.

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Spotting Rare UBE3A Mutations Can Require Comprehensive Gene Testing

The case study, “Two siblings suffering from Angelman Syndrome with a novel c.1146T>G mutation in UBE3A: A case report,” was published in the journal Biomedical Reports.

Angelman syndrome is characterized by developmental delays, motor problems, seizures, and sleep problems. It also is known for characteristic facial features and speech impairment, as well as unique behaviors such as frequent laughing.

Identifying UBE3A gene mutations in Angelman

Most cases are caused by a de novo deletion of a region of the maternally inherited chromosome 15 that contains UBE3A. De novo genetic changes are mutations not inherited from a person’s parents, but instead developed for the first time during embryonic development. Some 10% of cases are associated with de novo mutations, or alterations, in the maternal UBE3A gene.

Since the maternally inherited copy of UBE3A is the only active copy in specific regions of the brain, mutations or the complete loss of this copy result in UBE3A deficiency in nerve cells and the neurodevelopmental symptoms seen in patients.

Typically, mutations in the maternal UBE3A gene are associated with a milder disease relative to chromosome 15 deletions affecting other genes besides UBE3A. And given their rarity, UBE3A variants are typically not covered by most commonly used and standard genetic tests for Angelman syndrome.

As such, despite Angelman’s well-characterized features, “genetic diagnosis may be hindered by the change in disease presentation and the presence of different molecular mechanisms,” the researchers wrote.

That means that about “10-15% of patients, [who] are suspected to have AS [Angelman syndrome], are not diagnosed at an early stage of the disease.”

Now, a team of researchers at the Affiliated Hospital of Jining Medical University, in China, described the cases of two Chinese sisters with a severe form of Angelman that was caused by a previously unknown inherited UBE3A mutation.

The younger sister, an 8-year-old girl, was first treated at the hospital for frequent seizures. She was the second child of healthy parents — but had a 15-year-old sister with similar clinical manifestations.

Both births were uneventful, and developmental issues were detected when each girl was about 8 months old. At that age, each was diagnosed with either impaired growth or developmental delays.

The siblings showed typical facial features of Angelman, with substantial drooling, and also had walking and movement coordination difficulties, low muscle tone in the legs, and microcephaly. The two tended to laugh easily, had an excited mood, and experienced sleep problems.

Both girls showed significant intellectual impairment, were only able to understand simple sentences, and had difficulty pronouncing even simple words like “mama” and “baba” for mother and father.

Seizures, in the absence of fever, started when the younger sister was 15 months old and the older sister was 1.5 years old. When first treated, the girls were having seizures more than 10 times a day.

These seizures were slightly more severe in the younger girl, who was more introverted. According to the researchers, “the stress associated with contact with a stranger could trigger an epileptic attack.”

The results of electroencephalograms, or EEGs — a test of brain waves — showed abnormal brain activity suggestive of Angelman syndrome in each of the siblings.

Neither girl’s seizures were well-controlled with standard anti-seizure medication. A slight reduction in seizure frequency was associated with the use of lamotrigine when also given with sodium valproate. But the researchers said there was no direct effect observed with the use of this combination.

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UBE3A variant | Angelman Syndrome News | illustration of DNA

New Disease-causing UBE3A Variant Identified in 6 Members of Family

More genetic testing needed, researchers say

Genetic testing revealed a new UBE3A mutation — c.1146T>G (p.Asn382Lys) — in both girls and in the healthy mother, supporting an inherited form of Angelman.

The girls’ grandmother did not carry the mutation and their grandfather had died. Thus, it was impossible for the team to assess whether the mutation was inherited from him or whether it developed as a de novo mutation in the mother.

The genetic variant was found to lead to a modification in a single amino acid — a  building block of proteins — in the resulting UBE3A protein, which reduced protein production. The mutation was deemed likely disease-causing.

No other genetic abnormalities were detected, further supporting the newly identified UBE3A mutation as the cause of Angelman syndrome in these girls.

Overall, despite being caused by a single UBE3A mutation, clinical manifestations in both sisters were severe, and similar to those seen in cases of Angelman caused by large chromosome 15 deletions.

The researchers said this case highlights the need for genetic testing to enable the early diagnosis of Angelman and other disorders caused by gene mutations.

“The identification of specific [disease-causing] genes can aid genetic counseling and prenatal testing for families and may be used for early diagnosis of [Angelman in pediatric patients],” the team wrote.

Early diagnosis “can improve the control of epilepsy in children and reduce the incidence of brain injury,” they added, also noting that identifying Angelman at an younger age can allow for “specialized education at an early stage in order to improve [patients’] quality of life.”