PWS Subtypes May Respond Differently to Psychotropic Treatments

A small study exploring gene alterations related to Prader-Willi syndrome (PWS) suggests that subtypes of the disorder have different genetic profiles that may affect response to psychotropic treatments and potential side effects.

Due to its small size, only trends rather than statistically significant differences were observed. Still, obsessive behaviors and mood disorders mark some PWS subtypes, and study findings indicate that “gene testing should be considered before initiating pharmacotherapy in PWS,” the scientists wrote.

The study, “Pharmacodynamic Gene Testing in Prader-Willi Syndrome,” appeared in the journal Frontiers in Genetics.

PWS is characterized by obesity, short stature, and intellectual disability. About 60% of PWS cases are caused by a deletion in chromosome 15 (DEL) while a further 35% are due to uniparental disomy (UPD), the inheritance of two copies of chromosome 15 from one parent — in this case, the mother — rather than one from each parent.

People with PWS may have co-existent neuropsychiatric disorders, and its treatment focuses on managing weight, monitoring growth, and addressing associated conditions such as sleep apnea and skin picking.

Clinical practice suggests that PWS patients are more sensitive to psychotropic medications than the general public. Researchers in the U.S. explored the pharmacodynamics — the effects of drugs on the body — of structural gene changes, such as chromosomal deletions, in PWS patients.

Pharmacodynamic testing was used to assess how commonly studied genes that are directly targeted by therapies vary between the PWS subtypes, and how that genetic variation could impact how the treatment works. The genes explored include two serotonin receptors (HRT2A and HRT2C), the serotonin transporter SLC6A4, the adrenergic receptor 2A (ADRA2A), the COMT enzyme, and another enzyme known as MTHFR. 

Notably, serotonin is a chemical messenger that regulates mood, cognition and happiness, among other functions; ADRA2A plays a role in metabolism and obesity; COMT may affect processes such as cognitive flexibility, impulse control, and the ability to follow instructions; and MTHFR processes amino acids, the building blocks of proteins.

A group of 33 people diagnosed with PWS (14 due to DEL, 14 with UPD, and five with unknown genetic subtype) were recruited from clinics at the University of Kansas Medical Center, Vanderbilt University Medical Center, and Pittsburgh Partnership. In all of the tested genes, differences in genetic variations were observed between the two PWS subtypes.

In the UPD subtype population, a SLC6A4 variant (L/L) associated with high gene activity had a frequency of 53.8%, compared with 18.2% in DEL and 36% in the general population. According to the scientists, the increased frequency of the variant in UPD patients may indicate increased sensitivity to selective serotonin reuptake inhibitors (SSRIs), common antidepressants that work by increasing serotonin levels in the brain.

One variant of COMT (VAL/VAL), associated with a high level of activity in the enzyme it encodes and a typical response to psychostimulants was also more frequent in UPD than DEL patients.

As for the serotonin receptors HTR2A and HTR2C, an increased frequency of the HTR2C variant, which increases the risk for side effects related to antipsychotics, was observed in PWS patients. In the DEL subtype, a higher frequency of the HRT2A variant was seen to associate with a greater risk of treatment side effects. 

In turn, the adrenergic receptor ADRA2A serves as a direct target of guanfacine, which has shown efficacy in treating behavioral problems in PWS patients. But this treatment is not effective at easing the severe psychological symptoms more commonly found in patients with the UPD subtype.

In the present study, the ADRA2A variant linked to stress-induced changes in blood pressure was more frequent in DEL subtype patients, while the variant associated with lesser efficacy was more frequent in the UPD subtype. Weight gain and metabolic syndrome are common side effects of antipsychotics, and may be mediated by ADRA2A and other adrenergic receptors.  

MTHFR variants have been linked to a variety of neurodevelopmental and neuropsychiatric disorders, as well as disease severity, symptom duration, treatment response, and risk of side effects. In both PWS subtypes, an increased frequency of the MTHFR variants associated with diminished gene function and greater psychosis risk were observed. 

“Although limited by a small number in this clinical case series, polymorphisms [variants] of pharmacodynamic genes associated with PWS genetic subtype may contribute to disparities in treatment response and emergence of adverse effects. Further investigation of pharmacodynamic gene-gene interactions in the PWS population is recommended in a larger [group],” the research team wrote.