When medications behave differently: exploring pharmacogenetic testing in ASXL-related disorders

Families caring for individuals with ASXL-related disorders often become very familiar with the process of managing complex medical needs. One area that can sometimes be unexpectedly challenging is medication. With limited condition-specific medical guidance available for ASXL-related disorders, managing medication involves a degree of guesswork particularly because many individuals are nonverbal or have limited communication abilities. This makes it difficult to understand what they may be feeling or experiencing as a side effect.

Compounding this medication management challenge are reports from the ASXL family and medical community that some medications sometimes cause paradoxical or atypical responses in someone with an ASXL-related disorder. For example, diphenhydramine, commonly known by the brand name Benadryl, usually makes people drowsy. Yet some ASXL families report that their child becoming restless and alert after taking it. These responses are paradoxical reactions, meaning the effect is the opposite of what is expected.

For many families, these paradoxical or atypical reactions to some medications are more than just surprising. They can lead to difficult behaviors, disrupted sleep, and side effects that are hard to interpret or manage. This can place additional stress on both the individual and their caregivers, particularly when it is unclear whether a medication is helping, causing harm, or doing both at the same time.

While these patterns have not yet been formally studied in large research trials, they are familiar to some clinicians who care for individuals with ASXL-related disorders, and to many parents. For one father in our community, unexpected reactions to medications were a recurring problem. Bob Walsh, whose daughter Amelia has Bainbridge-Ropers Syndrome (ASXL3), remembers how confusing medication responses could sometimes be.

“Over time we started noticing that some medications just didn’t behave the way we expected,” Bob said. “Sometimes they didn’t seem to work at all, and other times the reaction was the opposite of what the doctors anticipated.”

“At times, it could lead to behaviors that were really hard to manage, and we didn’t always know if it was the medication itself or something else going on,” he added. “That uncertainty was one of the hardest parts.”

Bob and Amelia’s care team wanted to better understand why these reactions were happening. That search eventually led them to explore pharmacogenetic testing as a possible way to gather more information.

Pharmacogenetic testing looks at how a person’s genes influence the way their body processes medications. Certain genes control enzymes that help the body break down drugs, particularly in the liver. Variations in these drug-metabolizing genes can affect how quickly a medication is metabolized, which in turn may influence how effective the drug is or whether it is more likely to cause side effects.

Testing does not evaluate every medication or every possible drug response, but can be used to provide insight into specific groups of medications, including some that are often prescribed to support mood, behavior, and attention. For many ASXL families, this is where the testing may have the most practical value.

The test does not diagnose a condition, and it does not determine which medications a person should or should not take. It is also important to note that, while the test will provide validated information on specific drug metabolizing genes and how they process drugs at the genetic sequence level, the test does not measure the amount of enzymes produced by the drug metabolizing genes, which can vary from person to person, and which can also affect how drugs are metabolized. Despite this limitation, pharmacogenetic testing has been shown to provide information that doctors can use alongside clinical judgment when making medication decisions. In some cases, the results may suggest that a person processes certain drugs more slowly or more quickly than average, which can help guide dosing or medication selection.

For Bob, the goal of testing was to give Amelia’s medical team another piece of information to work with.

“We weren’t expecting the test to solve everything,” he explained. “But if it could give Amelia’s doctors a little more insight before trying a new medication, that felt valuable. Anything that could help reduce the guesswork was worth looking into.”

Families who are interested in learning more about pharmacogenetic testing may wish to speak with their physician or genetic specialist. The results should always be interpreted by a qualified medical professional who understands the individual’s full clinical picture. However, for some families, it can offer an additional piece of information that may help guide conversations with their care team. As Bob so perfectly put it, “If our experience helps another family start a conversation with their doctor or avoid some of the uncertainty we faced, then it’s worth it.”