A teenage boy with Angelman syndrome, whose developmental differences were less substantial than those typically seen with the condition, was found to have genetic mosaicism — meaning some but not all of his cells harbored an Angelman-causing mutation — according to a case report.
The diagnosis followed detailed genetic analyzes done after the 16-year-old was referred to a developmental behavioral pediatrician for evaluation.
Like others found to have mosaic Angelman syndrome, this patient had been thought likely to have another rare genetic disorder, given that the phenotype, or disease characteristics, were not a typical match, the researchers noted.
“A broader phenotypic spectrum should be considered for [Angelman syndrome] as patients with atypical presentations may otherwise elude diagnosis,” the team wrote.
The study, “Atypical presentation of Angelman syndrome with intact expressive language due to low-level mosaicism,” was published in Molecular Genetics & Genomic Medicine.
The teen’s case was reported by a team of US researchers.
Atypical Angelman symptoms
As a newborn, the boy had exhibited low muscle tone, but he had not had any problems feeding and had hit motor milestones normally. His walking ability his remains normal now, though he continues to have low muscle tone and is “easily fatigued with physical activity” to the point that he is “not able to jump or run,” the researchers wrote.
The boy has never had a seizure, but he has a lifelong history of digestive upset and chronic diarrhea, which are Angelman symptoms. As a toddler he began exhibiting hyperphagia — an excessive hunger that is not eased by eating — and he was clinically classified as obese by age 7.
As he grew, the boy’s language development was markedly delayed, but not completely absent as is often the case in Angelman. While the boy never babbled like most babies do, he used sign language and a picture-based communication system to express himself in early childhood.
He first began speaking words at age seven, and currently communicates mainly through words. The researchers report that he usually speaks in short sentences just a few words long, and that he is able to ask and answer questions and follow short instructions.
Based on testing done early in childhood, the boy was broadly diagnosed with “intellectual disability and adaptive impairments.” He has also been diagnosed with anxiety, ADHD, and sleep difficulties. He is in school and receives special education services.
Overall, this clinical picture is not what is typical of Angelman syndrome. Indeed, most Angelman patients show much more pronounced developmental differences, with little to no verbal communication ability and usually seizures.
“Given his history of hypotonia in infancy, obesity, hyperphagia, mild–moderate intellectual disability, intelligible speech, normal gait, and lack of seizures, classic [Angelman syndrome] did not match the patient’s phenotype,” the researchers wrote.
The patient was initially suspected to have Prader-Willi syndrome (PWS), a genetic disorder usually characterized by hyperphagia and developmental differences.
PWS is caused by mutations in the paternal copy of the UBE3A gene — that is, the copy of this gene inherited from a person’s biological father. Angelman syndrome is also caused by UBE3A mutations, but specifically those affecting the copy inherited from the biological mother, called the maternal copy.
Genetic testing of the UBE3A gene showed no abnormalities in the paternal copy, but mutations indicating Angelman syndrome were identified for the maternal copy.
More detailed analyzes showed that genetic testing of the maternal copy yielded two results simultaneously: the strongest signal indicated a normal, non-mutated gene, while a weaker signal suggested absence of the maternal copy, indicative of either uniparental disomy or an imprinting error.
Based on this finding, the researchers concluded that the boy has genetic mosaicism — meaning that some cells in his body harbor the Angelman-causing mutation while other cells in his body don’t, making a “mosaic” of cells with and without the mutation throughout his body.
“Our patient fits the clinical characteristics of mosaic AS [Angelman syndrome] with his strong expressive language skills and mild–moderate intellectual disability, instead of the phenotype of classic AS,” the researchers wrote.
Noting that other cases of mosaic Angelman have been reported in the past, the team said that this case “highlights the importance of considering a broader phenotypic spectrum for AS during a genetic evaluation.”