Mosaic Angelman Should be Included in the Differential Diagnosis of People With Milder AS Symptoms, Study Suggests

Clinicians should consider mosaic Angelman syndrome in the differential diagnosis of people who show milder symptoms of the disorder, a study suggests.

The study, “Preserved expressive language as a phenotypic determinant of Mosaic Angelman Syndrome,” was published in Molecular Genetics & Genomic Medicine.

Angelman syndrome (AS) is a genetic neurodevelopmental disorder usually associated with severe intellectual disability, difficulty speaking, loss of movement control (ataxia), and epileptic seizures. It is normally caused by the loss or malfunction of the maternal copy of the ubiquitin protein ligase E3A (UBE3A) gene in neurons from specific regions of the brain.

However, in some people, these genetic defects that affect the normal function of the UBE3A gene are only present in a handful of their cells. This phenomenon, known as mosaicism, can happen if one of the first cells of an embryo acquires a mutation in the UBE3A gene which is then passed on to their daughter cells as the embryo grows.

People with mosaic Angelman syndrome (mAS) typically have milder symptoms than those with Angelman syndrome. For instance, they experience milder expressive language delay with greater ability to attain meaningful words than typical Angelman patients.

In this study, researchers from the Vanderbilt University Medical Center and their collaborators set out to describe the clinical symptoms of mAS in a larger group of individuals to help clinicians with the differential diagnosis of Angelman syndrome.

The study included data from 22 people with mAS, whose caregivers filled out surveys at the medical center. Data from four additional patients was obtained from the Angelman Natural History Study, an observational study that followed the course of the disease in 302 Angelman patients over more than eight years. Clinical data from people with mAS was then compared to historical data from individuals with Angelman.

Findings revealed that nearly all mAS patients (90%) had some form of developmental delay. However, unlike those with Angelman, less than 15% of survey respondents said that mAS children showed signs of severe developmental delays before reaching the age of 1.

Compared with the significant language impairments seen in children with Angelman, 59% of the children with mAS retained the ability to articulate more than 20 words, with a fifth (20%) of them able to speak more than 1,000 words.

Other core features of Angelman, including ataxia, gait abnormalities, and limb tremulousness, were found in less than 33% of mAS children.

Additional clinical features of Angelman syndrome were also evident in patients with mAS: “The three most prominent findings included abnormal sleep/wake cycles and decreased sleep in 73% of patients, followed by obesity in 64% of patients and heat sensitivity in 45% of patients,” the researchers wrote. “Constipation, a common problem in [Angelman syndrome] patients was also noted in the mAS cohort, with 72% of patients endorsing constipation.”

Although children with mAS had milder speech impairments and were better able to engage in daily activities, they still faced many behavioral challenges that were typical in Angelman syndrome.

“Anxiety was the most frequently endorsed behavior reported in our cohort, present to some degree in 95% of mAS patients and rated as severe in 43% of patients. Hyperactivity was commonly endorsed, reported in 59% of patients,” the researchers wrote.

“Overall these data encourage specialists to broaden the clinical features of [Angelman syndrome],” said the researchers, who added that clinicians should consider tests to rule out mAS in individuals with “developmental delay, hyperactivity, anxiety, and an uncharacteristically happy demeanor.”