While children with Angelman syndrome typically show happy, excitable behavior, they also are prone to hyperactivity and irritability, and tend to have short attention spans and aggressive outbursts — all of which have a negative impact on parents’ stress levels and quality of life, a study shows.
The study found that the maladaptive behaviors varied with the type of genetic defect that caused the disease. But it also showed a general trend toward greater irritability and hyperactivity as the patients aged. Researchers said the results provided useful information to be used as reference in upcoming clinical trials, and would help guide the selection of behaviors to be targeted by future therapies.
The findings were discussed in a study, “Maladaptive Behaviors in Individuals with Angelman Syndrome,” published in the American Journal of Medical Genetics.
Angelman syndrome is a rare genetic disorder that primarily affects the nervous system, causing intellectual disability and developmental delays. It is caused by reduced activity of the protein-making UBE3A gene, normally inherited from the child’s mother.
The majority of patients with Angelman syndrome (70-75%) have a deletion of the maternal copy of the gene. The remaining cases are due to paternal uniparental disomy (UPD) — in which two copies of the gene are inherited from the father — gene silencing, or a mutation at the maternal UBE3A gene.
People with Angelman syndrome typically are happy and excitable, displaying frequent laughter, mouthing of objects, and hand-flapping movements. But they also can exhibit more challenging behaviors, including restlessness, hyperactivity, noncompliance, irritability, temper outbursts, and stereotypy (repetitive movements). The behaviors interfere with their social abilities and pose a burden to parents and caregivers.
It remains unclear how these behaviors change over time. Available data provide inconsistent results, with some studies suggesting that the behaviors stabilize during childhood, and others noting an easing of irritability and hyperactivity as patients get older.
Recognizing the lack of studies on this issue, researchers examined the behaviors considered the most troublesome by caregivers, and evaluated how they varied with the type of genetic mutation, developmental level, age, or sex.
The team surveyed parents of 301 Angelman patients about their child’s behavior, using a structured interview and a standardized questionnaire, the Aberrant Behavior Checklist – Community version (ABC-C). Four scales of this questionnaire were evaluated: irritability, hyperactivity, lethargy (a state of drowsiness), and stereotypy, with higher scores indicative of more intense behaviors.
Developmental disability, parenting stress, and quality of life of the families also were evaluated by other distinct and validated scales.
Participants were recruited as part of the Angelman Syndrome Natural History Study, (NCT00296764), sponsored by the Rare Diseases Clinical Research Network at the National Institutes of Health, which followed patients between January 2006 and July 2014 at multiple U.S. clinical centers.
Nearly all patients (95%) were younger than 20 at first study visit. Approximately 70% had the disease due to maternal chromosome deletion, while 19% had parental UPD or gene silencing errors, and 11% were carriers of a UBE3A mutation.
In the questionnaire, caregivers frequently mentioned easy excitability, mouthing behaviors, and fascination with water, as common behaviors of their children, regardless of their genetic defect. The majority of them (87%) also worried about their children’s short attention span.
Taken together, patients had low ABC-C scores for irritability, lethargy, and stereotypy, meaning the behaviors were noticeable but not extreme. However, the magnitude of some of these behaviors significantly changed with the type of genetic mutation involved.
Individuals with a genetic deletion had lower irritability compared with those with paternal UPD or gene silencing defects, or compared with carriers of UBE3A mutations. But higher lethargy and stereotypy was seen in those with UPD or gene silencing defects, compared with those with a deletion.
Patients’ gender also seemed to have an influence, with females scoring as more lethargic than males.
The results showed that children with greater cognitive capacity also showed the worst hyperactivity and irritability. Researchers believe that this was linked to these children’s stronger self-awareness and subsequently, their increased frustration in not being able to fully express themselves and interact socially.
Overall, there was a general trend toward greater irritability, hyperactivity, lethargy, and stereotypy, as the children aged. Parents also reported that, as their children got older, aggressive behaviors, hand flapping, and anxiety were getting worse.
“[A]ll participants experienced an increase in irritability and hyperactivity with advancing age,” the researchers said.
However, irritability seemed to become markedly worse over time among those with UBE3A mutations, in contrast with patients with a deletion, where changes were less pronounced. Lethargy remained low over time, becoming only slightly worse in patients with a deletion or a UBE3A mutation. Stereotypy also increased with age for carriers of UBE3A mutations, but remained relatively stable for the other patients.
“[Sh]ort attention span emerged as an area of significant concern across the different genotypes, which over time increased for males and decreased for females,” the investigators said.
Hyperactivity and irritability seemed to be the most disturbing to parents, as they strongly correlated this behavior to parental stress. Accordingly, many aspects of the family’s quality of life were affected if a child was more hyperactive or irritable.
Supported by these findings, the team believes that these maladaptive behaviors in Angelman patients “should be ongoing targets for both behavioral and pharmacological treatments.”
“Treatments that alleviate some of these challenging behaviors would be expected to reduce parental stress and improve quality of life,” the investigators said.
Still, given the relatively young age of participants in this study, researchers note these findings should be interpreted with caution for adult patients.
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