Children with Angelman syndrome have weakened bone health – which continues to decline with age – compared to their peers in the general population, according to a study by researchers in the Netherlands.
Deletions in UBE3A the disease-causing gene, 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 [Angelman syndrome],” the researchers wrote, noting that future work should further explore the mechanisms underlying the 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 Center of Expertise”, was published in European Journal of Pediatrics.
Researchers develop scales, called BHI-SDS, to assess bone health
Angelman syndrome is caused by various defects in UBE3A gene, which leads 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 part of chromosome 15, where UBE3A stays, hides.
In recent years, researchers at the ENCORE Expertise Center for Neurological Disorders, in Rotterdam, noticed that many of their patients were coming to 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 this topic specifically in the context of Angelman syndrome, the team noted.
To learn more, 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 in Angelman patients and determine potential risk factors for quality low bone density.
A specialized type of X-ray of the hand was used to look at bone thickness, and the data was used to generate a standard deviation score of the Bone Health Index – called the BHI-SDS – reflective of bone quality in relation to with the average seen in the general population.
Basically, a BHI-SDS score of zero means that a person’s bone health is about 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, especially negative numbers, would indicate poorer health.
In the most recent assessment done with their patients, the children with Angelman had a relatively low mean BHI-SDS of -1.77. Patients with a genetic deletion were found to have a significantly lower BHI-SDS, of -2.22, than children with other genetic causes of the disease, whose scores averaged -1.02. Results for children with a genetic deletion fell below the normal reference range, the researchers noted.
Several factors other than genetic deletion were also significantly associated with poor bone health in children. These included the inability to walk and the late onset of puberty.
Of the 82 children with available data, 22%—18 patients, equally divided between boys and girls—had a history of one or more fractures, and these children had significantly lower bone health scores than those no history of bone fractures.
Ability to walk, type of genetic disease ID’d as major risk factors
The scientists also looked at long-term changes in bone health. Results showed a significant effect of age on the BHI-SDS, with scores decreasing significantly over time. Again, the type of genetic disease and the patient’s ability to walk were significantly related to bone health.
“Since BHI-SDS is already lower in childhood and even decreases with age, we hypothesize that youth with [Angelman] will have a lower bone mass than their neurotypical peers,” the researchers wrote, noting that studying bone health in Angelman patients older than 18 years should be a focus of future research.
It is not clear from this study what drives the poorer bone health in Angelman patients. However, the scientists noted that factors known to be associated with such issues, such as immobility and use of anti-seizure medications, are common in Angelman. However, it is also possible that the mechanisms of Angelman disease and changes in UBE3A genes are directly responsible for influencing bone health, the team notes.
“Further research is needed to uncover a possible primary AS-specific mechanism for poor bone health,” the researchers wrote.
Since the BHI-SDS is already lower in childhood and even decreases with age, we assume that young people with [Angelman] will have a lower peak bone mass than their neurotypical peers. … Further research is required to uncover 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 are experiencing fractures from minor injuries or if they have unexplained discomfort.
In turn, such data can inform treatment and management decisions regarding anticonvulsant 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 data included more than 10 years of follow-up for many patients, allowing for longitudinal analyses.
“Our findings contribute to optimizing the follow-up and treatment and thus the quality of life of children and adults with [Angelman]”, the team writes.
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