Pharmacogenetic Testing of Cytochrome P450 Drug Metabolizing Enzymes in a Case Series of Patients with Prader-Willi Syndrome

Janice Forster,Jessica Duis,Merlin G Butler

doi:10.3390/genes12020152

Abstract

Prader-Willi syndrome (PWS) is associated with co-morbid psychiatric symptoms (disruptive behavior, anxiety, mood disorders, and psychosis) often requiring psychotropic medications. In this clinical case series of 35 patients with PWS, pharmacogenetic testing was obtained to determine allele frequencies predicting variations in activity of cytochrome (CYP) P450 drug metabolizing enzymes 2D6, 2B6, 2C19, 2C9, 3A4, and 1A2. Results were deidentified, collated, and analyzed by PWS genetic subtype: 14 deletion (DEL), 16 maternal uniparental disomy (UPD) and 5 DNA-methylation positive unspecified molecular subtype (PWS Unspec). Literature review informed comparative population frequencies of CYP polymorphisms, phenotypes, and substrate specificity. Among the total PWS cohort, extensive metabolizer (EM) activity prevailed across all cytochromes except CYP1A2, which showed greater ultra-rapid metabolizer (UM) status (p < 0.05), especially among UPD. Among PWS genetic subtypes, there were statistically significant differences in metabolizing status for cytochromes 2D6, 2C19, 2C9, 3A4 and 1A2 acting on substrates such as fluoxetine, risperidone, sertraline, modafinil, aripiprazole, citalopram, and escitalopram. Gonadal steroid therapy may further impact metabolism of 2C19, 2C9, 3A4 and 1A2 substrates. The status of growth hormone treatment may affect CYP3A4 activity with gender specificity. Pharmacogenetic testing together with PWS genetic subtyping may inform psychotropic medication dosing parameters and risk for adverse events.

Highlights

There were differences between the molecular classes of Prader-Willi Syndrome (PWS) with the deletion subtype having fewer extensive metabolizers and more intermediate metabolizers; both DEL and uniparental disomy (UPD) subtypes had more poor metabolizers compared to the normative American population
These results suggest that increased vigilance is required by clinicians for dose selection and speed of titration of psychotropic medications used in patients with PWS that are substrates for CYP2D6, such as aripiprazole, bupropion, chlorpromazine, citalopram, clonidine, doxepin, escitalopram, fluoxetine, haloperidol, imipramine, mirtazapine, olanzapine, quetiapine, risperidone, sertraline, trazadone, venlafaxine and ziprasidone
The increased frequency of ultra-rapid metabolizing status of CYP1A2 in PWS, especially among those with UPD, suggests that careful selection of drug dose is indicated for agents that are substrates, such as acetaminophen, benztropine, chlorpromazine, clomipramine, clozapine, duloxetine, estradiol, fluvoxamine, haloperidol, imipramine, mirtazapine, and olanzapine [32]

Summary

Introduction

15 translocations or inversions are seen in the remaining patients [2]. This multi-system disorder is characterized by severe infantile hypotonia with a poor suck, weak cry, failure to thrive and feeding difficulties. Hypothalamic dysfunction causes growth and other hormone deficiencies, as well as dysregulation of body temperature, sleep and wakefulness, hunger, thirst, and stress response. Growth hormone, usually started in the first year of life, is the only medication indicated for PWS to manage short stature, small hands and feet, global developmental delay and abnormalities of body composition consisting of excessive fat mass to lean body weight [3]

Methods

Results

Discussion

Conclusion