Molecular Signature of PWS Linked to Episodes of Psychosis, Study Finds
Prader–Willi syndrome (PWS) is associated with a specific molecular signature — a set of genes that can be used as markers for a certain trait — in the brain that is linked to episodes of psychosis, or a loss of contact with reality, a mouse study found.
According to the researchers, “between 16% and 32% of [PWS] patients experience episodes of psychosis, including delusional ideation and hallucinations.”
These findings may help in understanding how genes contribute to such episodes of psychosis and break new ground in developing potential therapeutic interventions, the team suggested.
The study, “Comparison of mouse models reveals a molecular distinction between psychotic illness in PWS and schizophrenia,” was published in the journal Translational Psychiatry.
PWS is caused by a loss of or defects in the genes in a region of chromosome 15 known as the “PWS locus.” These genes are involved in how the brain develops and works, controlling sleep, metabolism, appetite, growth, intellectual skills, and social behavior.
Their deletion or defects also lead to psychiatric conditions such as psychosis — including hallucinations, in which patients see or sense things that seem real but are not.
The researchers noted that psychosis is more common, and usually worse, in patients whose disease is due to a gene defect inherited from the mother.
“Population studies of individuals with PWS report increased incidence and severity of psychosis in those with [maternally derived defects] compared to [paternally derived deletions], including a higher rate of diagnoses of schizoaffective and bipolar disorders,” they wrote.
Now, a team of researchers at Cardiff University, in the U.K., sought to better understand the mechanisms leading to these episodes. To learn more, the investigators used a mouse model that can mimic the behavior and cognitive symptoms of people with PWS.
The model, called PWS-IC, lacks the imprinting center in chromosome 15. An imprinting center is a sequence of DNA that regulates the turning off of either the maternal or the paternal copy of a gene.
Like people with PWS, these mice are less active than is normal, have a short attention span, and also have greater impulsivity.
Here, the team wanted to know if another mouse model of PWS also presents the same characteristic traits. The new model, which the researchers named PWS-cr, carries a deletion of a critical region in the PWS locus.
Both models are characterized by slower body growth and excessive eating. However, unlike PWS-IC mice, PWS-cr animals showed no impairments in their ability to move from one place to another, nor in their attention.
To know if these different traits could be explained by genetic variations, the researchers used a technique called RNA sequencing to read the sequences of RNA in brain tissue. RNA delivers the genetic instructions contained in DNA to the rest of the cell.
The researchers used brains of neonatal mice “as a genetic risk for psychiatric illness has been shown to manifest from early developmental stages,” they wrote.
The analysis revealed a greater number of differentially expressed genes — genes with greater or lower activity in a sample compared with another — between PWS-IC mice and their wild-type (healthy) littermates than between PWS-cr mice and their wild-type littermates. These included known PWS genes such as Snrpn, Necdin, Mkrn3, and Magel2, as well as genes outside the PWS cluster.
Next, the scientists did a genome-wide association study or GWAS, which scans markers across the genome to find genetic variations associated with a particular disease. They found that the differentially expressed genes in PWS-IC mice were linked to episodes of psychosis “but, interestingly, not schizophrenia.”
Schizophrenia is a mental disorder that affects how a person thinks, feels, and behaves. It is characterized by delusions, hallucinations, disorganized speech, trouble with thinking, and reduced motivation. It shares genetic links to psychosis.
Based on the findings of the study, the researchers suggest that the factors contributing to the development of schizophrenia are distinct from those of psychosis in PWS, and this “could have implications for therapeutic strategies used to treat psychosis in individuals with PWS.”
Ultimately, the findings could “shed light on a molecular basis of behavioural and cognitive problems seen in PWS,” the team wrote.
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