Case Series: Impact of Diagnostic Testing on Medication choice
It is well known that diagnostic testing (e.g. chromosome microarray and whole exome sequencing) can impact the medical management of individuals with neurodevelopmental disorders (NDDs). Additionally, but perhaps less well known is the fact that diagnostic testing can also impact pharmacotherapy or medications used to treat symptoms associated with NDDs. This information can be very beneficial in improving symptoms as well as quality of life for all members of the family. Below are examples that highlight the value of diagnostic testing to guide pharmacotherapy in individuals with NDDs. Importantly, these pharmacotherapy guidelines are often not identified using pharmacogenetics testing panels.
CASE 1: Genetic diagnosis of HIVEP2 and medication improvement
A recent publication described a 15-year-old boy with autism spectrum disorder (ASD), far-sightedness, and short stature. He also had a decline in his adaptive and social functioning that was first noticed at 12 years of age (PMID: 30832905). While trialing multiple antipsychotic medications, he developed involuntary movements in his limbs and face. The medications were discontinued as they were thought to be causing these symptoms. Diagnostic genetic testing (specifically whole exome sequencing or WES) was pursued and a pathogenic variant in HIVEP2 was identified. This variant was de novo, meaning it was new in the child and not inherited from a parent. Pathogenic HIVEP2 variants are known to cause a variety of neurodevelopmental features including neurologic, behavioral, and cognitive impairments (PMID: 26153216). Importantly, HIVEP2-related intellectual disability is also associated with involuntary parkinsonian movements. With this new information, his medication history was reviewed again, leading to improvements in mood and behaviors. For example, his healthcare providers re-started medications he was previously taking since it was the genetic condition and NOT the medications themselves causing the involuntary movements. Also, healthcare providers added an anti-inflammatory medication (celecoxib) due to the possible role HIVEP2 plays in the inflammatory process. Overall, the child’s his mood, adherence to taking medications routinely, and quality of life all improved.
This story highlights the importance of identifying the underlying cause of a child’s change in emotional wellbeing and/or behavior in order to maximize the impact of medication and improve the family’s quality of life.
CASE 2: Genetic diagnosis of PPOX improves psychiatric and physical symptoms
Our laboratory recently performed diagnostic genetic testing in a 15-year-old boy with ASD, intellectual disability, and mild birth defects. At 13 to 14 years of age, he experienced behavior changes, increased clumsiness, reduced appetite, and worsening weakness. He felt as though he had a “sick brain”. These physical and psychiatric symptoms occurred rapidly over a short period of time, seemingly overnight according to his parents. He was evaluated by a psychiatrist who prescribed several medications with no apparent benefit. Additional evaluations included a brain MRI, EEG, and first tier diagnostic genetic testing (chromosomal microarray or CMA), which were all normal. WES was done next and a likely pathogenic variant in the PPOX gene was found, consistent with autosomal dominant variegate porphyria. This variant was inherited from his father who was healthy and had no symptoms.
Porphyria is a group of disorders characterized by psychiatric and physical symptoms (PMIDs: 30476629, 30385147). Psychiatric symptoms include anxiety, emotional lability, and hallucinations. Physical symptoms include skin findings, muscle weakness, respiratory distress, abdominal pain, vomiting, diarrhea, and constipation. Reduced penetrance is common, meaning not all individuals with a pathogenic variant will have symptoms (which could explain why the child’s father did not have symptoms). Alcohol consumption as well as certain medications can cause symptoms to appear or worsen in people with porphyria. This child was taking THREE medications known to induce porphyria-related symptoms. After the genetic diagnosis, medications were discontinued, and the child improved dramatically. The family was counseled about not only their child’s risk for these episodes to occur again but also the father’s increased risk to develop symptoms and to consider avoiding alcohol and specific medications.
This story highlights the importance of diagnostic genetic testing in identifying the underlying cause of psychiatric and physical symptoms rather than treating symptoms pharmacologically without knowing their root cause. Further, results from the diagnostic testing provided guidance about how to avoid these episodes in the future for other family members.
Known Genetic Disorders with Pharmacotherapy Benefit
As genetic testing becomes more common for people with NDDs, we are learning more about how to treat individual genetic conditions and how certain medications may help or harm them based on their genetic diagnosis. Many people with an NDD are given medication for co-occurring symptoms (e.g. anxiety, depression, ADHD, etc.) often without having an underlying genetic diagnosis. As the previous stories highlight, this is critical to understanding the best care, including medication choice for people with NDD (PMID: 31115059).
Here are a few more genetic conditions that provide important information about medication choice:
Duplication 15q syndrome is associated with a variety of symptoms that range from mild to severe and include hypotonia or low muscle tone, developmental delay and/or ID, seizures, absent or poor speech, ASD, and minor unique facial features (PMIDs: 27308687, 11803514, 27158270, 24502430, 23495136, 25573720, 26773682). Seizures occur in more than half of individuals with duplication 15q syndrome and they can be complex and difficult to control. There is some suggestion that certain anti-epileptic medications (AEMs) may be better at seizure management in individuals with duplication 15q syndrome which can lead to improved neurodevelopmental outcomes and reduce the risk of seizure-related side effects (PMIDs: 27158270, 24502430). One report even described a person whose seizures worsened when a specific AEM was prescribed (PMID: 23663378).
Wolf-Hirschhorn syndrome (WHS) or 4p- is a complex genetic disorder characterized by multiple birth defects, ID, and seizures (PMIDs: 18932224, 20301362, 26239400). Over 90% of children with WHS develop seizures which can vary in severity and type. Often seizures are poorly controlled and lead to neurodevelopmental decline and poor quality of life. A recent report identified specific AEMs that may provide better seizure management leading to improved neurodevelopmental outcomes and reduce the risk of seizure-related injuries (PMID: 29477837).
There are also multiple seizure-related genes with specific AEM guidance available. So, if someone is found to have a genetic variant in one of these genes that explains the person’s seizures, there would be specific information available to the healthcare provider for prescription information. Importantly, none of these can be identified through pharmacogenetics testing panels (Table 1 in PMID: 28331464):
SCN1A: Avoidance of phenytoin and lamotrigine (generally)
SCN2A: High-dose phenytoin beneficial
SCN8A: High-dose phenytoin beneficial
SLC2A1: Ketogenic diet helpful
PRRT2: Carbamazepine helpful
PLCB1: Inositol helpful
PNPO- Pyridoxal-5-phosphate responsive
KCNQ2: Consider ezogabine for loss-of-function variants
TSC: Consider everolimus (mTOR kinase inhibitor)
KCNT1: Consider quinidine for gain-of-function variants (emerging evidence)
GRIN2A: Consider memantine and/or dextromethorphan for gain-of-function variants (emerging evidence)
As more NDDs are better characterized and their genetic pathways are understood, the more pharmacologic treatments can be tailored to each individual. There are several published studies demonstrating the importance of certain pharmacologic treatments in individuals with specific genetic conditions, including the seizure-related conditions described above, as well as 22q11.2 deletion, fragile X, and Rett syndrome (PMIDs: 29331595, 26044111, 25897255, 30905360). It is possible for this trend to continue and expand to other NDDs. This means identifying the underlying cause for a child’s NDD as early as possible is important to unlock the maximum benefit from treatment.
References and PubMed identification (PMID) numbers
Wigby K, et al. 2018. PMID: 30832905
Srivastava S, et al. 2016. PMID: 26153216
Borrero Corte MJ, et al. 2018. PMID: 30476629
Loskove Y, et al. 2018. PMID: 30385147
DeVane CL. 2019. PMID: 31115059
Finucane BM, et al. 2018.PMID: 27308687
Bolton PF, et al. 2001. PMID: 11803514
DiStefano C, et al. 2016.PMID: 27158270
Conant KD, et al. 2014.PMID: 24502430
Urraca N, et al. 2013.PMID: 23495136
Shaaya EA, et al. 2015. PMID: 25573720
Luchsinger K, et al. 2016.PMID: 26773682
DiStefano C, et al. 2016. PMID: 27158270
Conant KD, et al. 2014. PMID: 24502430
DiRocco A, et al. 2013. PMID: 23663378
Poduri A. 2017. PMID: 28331464
Battaglia A, et al. 2008. PMID: 18932224
Battaglia A, et al. 2015. PMID: 20301362
Battaglia A, et al. 2015. PMID: 26239400
Ho KS, et al. 2018. PMID: 29477837
Weinberger R, et al. 2018. PMID: 29331595
Mariano MA, et al. 2015. PMID: 26044111
Schaefer TL, et al. 2015. PMID: 25897255
Gogliotti RG and Niswender CM. 2019. PMID: 30905360