Children with Angelman syndrome have diminished bone health — which continues to decline with age — compared with their peers in the general population, according to a study by researchers in the Netherlands.
Deletions in the UBE3A gene as the cause of disease, as well as immobility, late onset of puberty, and a history of bone fractures, were all found to be risk factors for poor bone health.
“Monitoring and guidance of bone health should become a regular part of clinical follow-up in [Angelman syndrome],” the researchers wrote, noting that future work should further explore the mechanisms underlying bone issues in Angelman, as well as possible interventions to prevent bone loss over time.
The study, “Bone health in children with Angelman syndrome at the ENCORE Expertise Center,” was published in the European Journal of Pediatrics.
Researchers develop scale, dubbed BHI-SDS, to assess bone health
Angelman syndrome is caused by various defects in the UBE3A gene, which lead to severe neurological symptoms such as developmental delay, epilepsy, and movement disorders. The most common — and most severe — genetic subtype of the disease occurs when a part of chromosome 15, where UBE3A resides, is deleted.
In recent years, researchers at the ENCORE Expertise Center for Neurological Disorders, in Rotterdam, noticed that many of their patients were coming into the clinic with bone fractures. While evidence suggests that children with neurological disabilities may have compromised bone health, there have not been many studies on the topic specifically in the context of Angelman syndrome, the team noted.
To learn more, the scientists examined data from 91 children with Angelman who visited their center between 2010 and 2021. Their goal was to identify long-term patterns of bone problems among Angelman patients and to determine possible risk factors for low bone quality.
A specialized type of X-ray of the hand was used to look at bone thickness, and the data were used to generate a bone health index standard deviation score — dubbed the BHI-SDS — reflective of bone quality relative to the average seen in the general population.
Essentially, a BHI-SDS score of zero would mean a person’s bone health is about exactly average compared to what would be seen in the general population. Scores between -2 and 2 would fall within the normal range, while lower scores, specifically negative numbers, would indicate worse such health.
At the most recent assessment done with their patients, children with Angelman had a relatively low mean BHI-SDS of -1.77. Patients with a genetic deletion were found to have significantly lower BHI-SDS, of -2.22, than did children with other genetic causes of disease, whose scores averaged -1.02. The scores for children with a genetic deletion dropped below the normal reference range, the researchers noted.
A few other factors in addition to genetic deletion were also significantly linked to lower bone health in the children. These included an inability to walk and late onset of puberty.
Of 82 children with available data, 22% — 18 patients, equally split among boys and girls — had a history of one or more fractures, and these children had significantly lower bone health scores than those without a history of bone fractures.
Ability to walk, genetic disease type ID’d as key risk factors
The scientists also looked at long-term changes in bone health. The results showed a significant effect of age on BHI-SDS, with scores significantly decreasing over time. Again, genetic disease type and a patient’s ability to walk were significantly associated with bone health.
“As BHI-SDS is already lower in childhood and even decreases with age, we hypothesize that young adults with [Angelman] will have a lower peak bone mass than their neurotypical peers,” the researchers wrote, noting that studying bone health in Angelman patients older than 18 should be a focus of future research.
It is not clear from this study what drives poorer bone health in Angelman patients. However, the scientists noted that factors known to be associated with such issues, like immobility and the use of antiseizure medications, are common in Angelman. Still, it is also possible that Angelman’s disease mechanisms and changes in the UBE3A gene are directly responsible for affecting bone health, the team notes.
“Further research is needed to unravel a possible primary AS-specific mechanism for low bone health,” the researchers wrote.
As BHI-SDS is already lower in childhood and even decreases with age, we hypothesize that young adults with [Angelman] will have a lower peak bone mass than their neurotypical peers. … Further research is needed to unravel a possible primary AS-specific mechanism for low bone health.
Based on their findings, the scientists propose that bone health be routinely measured in young Angelman patients, especially if they’re experiencing fractures from nonsignificant injuries or if they have unexplained discomfort.
In turn, such data can inform treatment and management decisions related to antiseizure medications, puberty induction, and exercise, where bone health is an important consideration.
The researchers noted that “an important strength of this study” is that its patient population of 91 children with Angelman, is the largest described to date. Further, the center’s records included more than 10 years of follow-up for many patients, allowing for longitudinal analyses.
“Our findings contribute to optimization of follow-up and treatment and thereby quality of life of children and adults with [Angelman],” the team wrote.