Study IDs genetic subtype as possible psychosis risk factor in PWS
A person's mutation type may influence brain processing, increasing 'vulnerability'
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People with Prader-Willi syndrome (PWS) that’s caused by a certain type of genetic mutation may experience abnormalities in how the brain processes information that make them more vulnerable to psychosis — which is more common among PWS patients than in the general population.
That’s according to a new study from the U.K. that found that patients with this mutation, called maternal uniparental disomy or mUDP, tend to show slower cognitive processing and reduced cognitive flexibility compared with individuals whose PWS is due to other causes. Specifically, the data showed that these cognitive issues were more likely to manifest in those with mUDP relative to people with PWS caused by a genetic deletion, which is the most common PWS-causing mutation.
These cognitive and behavioral alterations “may represent trait-like characteristics associated with increased vulnerability to psychosis,” the researchers noted.
The findings “indicate that mUPD [maternal uniparental disomy] is associated with a distinct neurocognitive profile that may increase psychosis liability,” the team wrote. Further, “although preliminary, the study supports using predictive processing frameworks to understand [mutation]-specific risks,” the scientists wrote.
The study, “Cognitive and behavioural correlates of psychosis in genetic subtypes of Prader-Willi syndrome,” was published in the Journal of Psychiatric Research. The work was funded by the Foundation for Prader-Willi Research and Sam’s PW Research Foundation.
Every person has 23 pairs of chromosomes, which are rodlike structures where genes are located, with one chromosome inherited from the mother and one from the father. PWS is a complex disorder caused by mutations that affect a specific region, called the PWS locus, in the paternal copy of chromosome 15. The paternal copy is activated in most body tissues, while the maternal copy is silenced.
Fewer PWS patients have the mutation identified
In most PWS patients, the disease arises due to a paternal genetic deletion, meaning the PWS locus inherited from the father is missing. In a smaller number of PWS patients, the disease is caused by maternal uniparental disomy, meaning the individual inherits two chromosome 15 from the mother and none from the father.
Regardless of the specific type of underlying mutation, people with PWS tend to experience many of the same symptoms, such as uncontrolled hunger and mild to moderate intellectual disability.
While mental health problems, such as anxiety and depression, are also common across genetic subtypes of PWS, psychosis appears to be more frequent in patients with mUPD.
A mental health problem, psychosis is characterized by paranoia, hallucinations, or seeing or hearing things that aren’t there, and/or delusions, which are fixed beliefs that are not based in observable reality.
Reports have indicated that psychosis affects as many as 60% of PWS patients with mUPD, compared with about 11% of those with paternal deletions.
One potential explanation for this difference is the so-called two-hit hypothesis. The idea is that, in all PWS patients, the lack of a functional paternal PWS locus leads to changes in neurological function — the first hit. But in those with mUPD, activity of extra maternally inherited genes may lead to further neurological abnormalities, creating a second hit.
If that’s true, then it would be expected that PWS patients with mUPD would have detectable differences in measures of neurological function that are more pronounced than those seen in other PWS patients, according to researchers.
Investigating the ‘two-hit’ hypothesis
Now, two scientists in the U.K. put that idea to the test. In a first set of experiments, 29 people with PWS — 16 with deletions and 13 with mUPD — completed in-person assessments of intellectual ability, executive functioning, and processing speed. Executive functioning is the set of cognitive skills that helps in planning, focusing attention, switching gears, and juggling tasks.
Among the participants, 13 completed additional online behavioral assessments measuring reaction time, reasoning skills, and perception. Six of these individuals had deletions and seven had mUPD. Another 10 people without PWS, serving as controls, also underwent these online assessments.
Using all these data, the researchers compared cognitive and behavioral performance between PWS patients and healthy controls. The duo also assessed whether observed differences were more pronounced in patients with mUPD, which could help explain the higher susceptibility to psychosis.
“This framework distinguishes general cognitive alterations [in PWS] from those specifically linked to increased vulnerability in the mUPD subtype,” the researchers wrote.
The results showed that, compared with controls, PWS patients had worse performance on measures of executive functioning, processing speed, and perceptual abilities.
“Across the full PWS [group], widespread inefficiencies were present in processing speed, executive functioning, probabilistic reasoning, and perceptual inference. These global alterations support the first part of the ‘two-hit’ hypothesis,” the researchers wrote.
Among those with PWS, the individuals with mUPD tended to have slower processing speed than those with paternal deletions. The mUPD patients also had reduced cognitive flexibility and belief updating, which is the ability to revise one’s thinking when presented with new information.
“Exploratory subtype patterns found in the study further suggested that the mUPD group may exhibit an additional layer of cognitive inefficiency, constituting the second part of the ‘two hit’ hypothesis,” the scientists wrote.
The researchers stressed that their analysis was limited to a small number of patients, so further work to validate and expand on these findings will be vital.
“Replication in larger, multi-site [patient groups] will be essential to determine whether the patterns observed here reflect stable [mutation-specific] mechanisms or sampling variability,” the team wrote.
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