What Genes May Be Involved in PANS, a Sudden-Onset Childhood Neuropsychiatric Disorder?

What you need to know

• Researchers identified rare genetic mutations in 11 genes that may increase risk for PANS, a childhood disorder involving sudden onset of obsessive-compulsive symptoms and other neuropsychiatric issues.
• The genes affect either immune system function or brain development and communication between neurons.
• The findings suggest PANS may involve both immune system problems and brain differences, helping explain its complex symptoms.
• This research provides new insights into potential biological mechanisms underlying PANS, which could lead to improved diagnosis and treatment approaches.

What is PANS?

Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) is a complex disorder that involves the sudden onset of obsessive-compulsive symptoms and other neuropsychiatric problems in children. Symptoms can include anxiety, mood swings, irritability, restrictive eating, and behavioral regression. PANS often appears to be triggered by infections, leading researchers to suspect it may involve abnormal immune responses affecting the brain. However, the exact causes have remained unclear.

New genetic insights into PANS

To better understand the biological mechanisms that may underlie PANS, researchers conducted a genetic study of nearly 400 patients diagnosed with the condition. They used advanced DNA sequencing techniques to search for rare genetic mutations that might increase susceptibility to developing PANS.

The study identified ultra-rare mutations in 11 different genes among 21 patients with PANS. Interestingly, these genes fell into two main categories:

1. Genes affecting immune system function
2. Genes involved in brain development and communication between neurons

This suggests that both immune system abnormalities and differences in brain structure or function may play a role in PANS, helping explain its complex mix of symptoms.

Immune system genes

Several of the identified genes are known to affect various aspects of immune function:

• NLRC4: Helps activate inflammatory responses
• PPM1D: Regulates immune cell development and function
• RAG1: Involved in antibody production and immune cell development
• CHK2: Affects immune cell function and development
• PLCG2: Regulates immune cell activation

Mutations in these genes could potentially lead to abnormal inflammatory responses or other immune system problems that may somehow affect the brain in PANS.

Brain development and function genes

Other identified genes are primarily involved in brain development and the functioning of synapses, the connections between neurons:

• SHANK3: Helps organize proteins at synapses
• GRIN2A: Part of receptors for the neurotransmitter glutamate
• SYNGAP1: Regulates signaling at synapses
• CACNA1B: Involved in release of neurotransmitters
• GABRG2: Part of receptors for the neurotransmitter GABA
• SGCE: Affects synapse formation

Mutations affecting these genes could potentially alter brain development or function in ways that increase vulnerability to PANS symptoms.

Connections between immune system and brain

Interestingly, the researchers found that many of the “immune system” genes are also active in microglia, the brain’s resident immune cells. Similarly, some of the “brain” genes showed altered activity in certain immune cells during infections.

This highlights the complex interactions between the immune system and brain, suggesting PANS may involve disruptions to this delicate balance. The identified genes are also active in other relevant areas like the gut nervous system and the blood-brain barrier, which controls what substances can enter the brain.

Implications for understanding PANS

These genetic findings provide several important insights into PANS:

1. Both immune system problems and brain differences likely contribute to the disorder, explaining its complex symptoms.

2. There may be different subtypes of PANS with varying underlying causes, which could explain why symptoms and treatment responses can vary between patients.

3. Some patients may have genetic vulnerabilities that only lead to PANS when triggered by infections or other stressors.

4. PANS appears to share some genetic risk factors with other neurodevelopmental disorders like autism, which may explain why they sometimes occur together.

What this means for patients and families

While this research doesn’t provide immediate changes to PANS diagnosis or treatment, it offers several reasons for optimism:

1. It provides strong evidence that PANS has biological causes, validating patients’ experiences.

2. Understanding the genes and pathways involved could eventually lead to more targeted treatments.

3. Genetic testing might someday help identify children at higher risk for PANS, allowing for earlier intervention.

4. The findings may explain why some patients respond well to treatments targeting the immune system.

It’s important to note that having mutations in these genes doesn’t guarantee someone will develop PANS. The disorder likely involves a complex interplay of genetic and environmental factors.

Conclusions

• PANS appears to involve both immune system abnormalities and differences in brain development/function.
• There are likely multiple biological pathways that can lead to PANS symptoms.
• This research provides a foundation for developing better diagnostic tools and more targeted treatments in the future.
• Further studies are needed to fully understand how these genetic differences contribute to PANS and to translate these findings into clinical applications.

While many questions remain, this study represents an important step forward in unraveling the biology of PANS and offers hope for improved understanding and treatment of this challenging disorder.