HAIFA, Israel, 20 May 2025 – In a comprehensive Genomic Press Invited Expert Review, researchers from the University of Haifa have synthesized cutting-edge findings on Prader-Willi syndrome (PWS), revealing how this complex neurodevelopmental disorder serves as a critical model for understanding the interplay between autism spectrum disorder (ASD) and psychotic spectrum disorders (PSD).
A Window into Neuropsychiatric Conditions
PWS occurs equally in males and females across all ethnic groups, with prevalence estimates ranging from 1 in 16,062 to 1 in 76,574 births. What makes this condition particularly valuable to researchers is how its genetic subtypes correlate with distinct psychiatric outcomes. The review, led by Professor Shani Stern and Professor Ahmad Abu-Akel, examines how PWS provides insights into the relationship between genetics and psychiatric vulnerabilities.
"Approximately 12-40% of individuals with PWS meet criteria for autism spectrum disorder, while a smaller subset, around 10-30%, may develop psychotic spectrum disorders in late adolescence or adulthood," explains Professor Stern. "This co-occurrence creates a unique opportunity to study how genetic variations can lead to different psychiatric outcomes."
Genetic Mechanisms Underlying the Syndrome
The review outlines how PWS results from the absence of paternal gene expression within the critical 15q11-q13 region on chromosome 15. This absence stems from three distinct genetic mechanisms: deletion (DEL) of the paternal chromosome region (65-75% of cases), maternal uniparental disomy (mUPD) where both chromosome 15 copies come from the mother (20-30% of cases), or imprinting center defects (ICD) affecting gene regulation (1-4% of cases).
"What's particularly fascinating is how these different genetic subtypes influence psychiatric risk," notes Professor Abu-Akel. "Patients with deletions tend to exhibit more autism-like traits, while those with maternal uniparental disomy show increased vulnerability to psychosis. This genotype-phenotype correlation offers invaluable insights into how specific genetic pathways might contribute to different psychiatric outcomes."
Key Genes Shaping Brain Development
The review identifies several crucial genes within the PWS region that influence neurodevelopment and psychiatric vulnerability. The MAGEL2 gene, involved in hypothalamic function and neuronal connectivity, strongly influences cognitive impairments and metabolic dysregulation when disrupted. Similarly, the NDN gene regulates neuronal survival and hypothalamic development, with its loss linked to breathing irregularities and cognitive deficits characteristic of PWS.
Perhaps most intriguing is the role of CYFIP1, located in the 15q11.2 BP1-BP2 region. This gene has been linked to both ASD and schizophrenia through its role in regulating the balance between neuronal excitation and inhibition. Could this excitation/inhibition imbalance represent a common pathway between seemingly distinct psychiatric conditions? The review suggests this possibility warrants further investigation.
Neuroimaging Reveals Structural Differences
The authors extensively analyze neuroimaging studies that have uncovered significant brain structure and function differences in PWS patients. Structural MRI studies consistently show gray matter reductions, particularly in regions involved in reward processing and inhibitory control, such as the orbitofrontal cortex, caudate nucleus, and hypothalamus.
These brain alterations differ based on genetic subtype. Individuals with the deletion subtype show more pronounced structural atrophy, particularly in the prefrontal cortex and cerebellum. In contrast, those with maternal uniparental disomy display more widespread disruptions in functional connectivity, especially within the prefrontal-limbic circuit, resembling patterns seen in schizophrenia.
"The neuroimaging findings provide a biological basis for understanding how genetics shapes brain development and ultimately influences psychiatric vulnerability," says Professor Stern. "This raises important questions about whether we might be able to identify early biomarkers that could predict psychiatric risk before symptoms emerge."
Emerging Potential of Stem Cell Models
A particularly promising direction highlighted in the review is the use of induced pluripotent stem cells (iPSCs) to study the cellular and molecular mechanisms underlying PWS. These patient-derived neuronal models allow researchers to observe how genetic variations affect neural development in real-time.
Recent studies using iPSC-derived neurons have revealed that autism and schizophrenia exhibit contrasting phenotypes during early development but converge toward similar synaptic deficits at later stages. This temporal dimension adds complexity to our understanding of these conditions but also offers potential therapeutic windows for intervention.
"The ability to generate neurons from patients with different genetic subtypes of PWS opens exciting possibilities for personalized medicine approaches," explains Professor Abu-Akel. "We can potentially test how different medications affect neurons with specific genetic variations, moving us closer to precision treatments."
Future Treatment Directions
The review outlines several promising therapeutic directions. Current treatments focus on symptom management through hormone therapies, dietary interventions, and medications targeting specific behavioral challenges. However, emerging approaches, including gene editing technologies, epigenetic therapies, and regenerative medicine strategies, aim to address the underlying genetic mechanisms.
Could treatments targeting the excitation/inhibition balance in neurons benefit both autism and psychosis symptoms in PWS? What role might artificial intelligence play in predicting individual responses to different therapeutic approaches? These questions represent critical avenues for future research.
The review also emphasizes the importance of early intervention and comprehensive care strategies that address both physical and psychiatric aspects of PWS. This multidisciplinary approach requires coordinated efforts among geneticists, endocrinologists, psychiatrists, and therapists to optimize outcomes for individuals with this complex condition.
Implications Beyond Prader-Willi Syndrome
The insights gained from studying PWS extend far beyond this rare condition. By illuminating the shared and distinct mechanisms underlying autism and psychosis, this research contributes to a broader understanding of neurodevelopmental and psychiatric disorders affecting millions worldwide.
"What makes PWS so valuable is that it provides a controlled genetic model where we can observe how specific genetic variations influence neurobiological outcomes," notes Professor Stern. "The lessons we learn from PWS could potentially transform our approach to more common psychiatric conditions."
As research technologies continue to advance, the integration of genetic, neuroimaging, and cellular approaches promises to unlock new insights into how genes shape brain development and function. Could this integrated approach eventually lead to predictive models that identify psychiatric vulnerability early in development? Might it enable tailored interventions that modify neurodevelopmental trajectories before symptoms emerge?
The review presents PWS as a critical model for precision psychiatry, where treatments are tailored to individual genetic profiles rather than broad diagnostic categories. This paradigm shift could revolutionize psychiatric care, not only for those with rare genetic syndromes but potentially for all individuals with neurodevelopmental and psychiatric conditions.
The article in Genomic Psychiatry titled "Prader-Willi syndrome: Genetics, clinical symptoms, and model systems," is freely available via Open Access on 20 May 2025 in Genomic Psychiatry at the following hyperlink: https://doi.org/10.61373/gp025i.0044 .
About Genomic Psychiatry: Genomic Psychiatry: Advancing Science from Genes to Society (ISSN: 2997-2388, online and 2997-254X, print) represents a paradigm shift in genetics journals by interweaving advances in genomics and genetics with progress in all other areas of contemporary psychiatry. Genomic Psychiatry publishes peer-reviewed medical research articles of the highest quality from any area within the continuum that goes from genes and molecules to neuroscience, clinical psychiatry, and public health.
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