Genetics of PANS/PANDAS
Herbert M. Lachman, Jennifer Frankovich, Peter J. van der Spek, Janet L. Cunningham
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Introduction
Pediatric Acute-Onset Neuropsychiatry Syndrome (PANS) is an enigmatic condition characterized by the abrupt onset of obsessive-compulsive disorder (OCD) and/or restricted eating, with two or more secondary symptoms: anxiety, mood lability, rage, cognitive regression, autonomic instability, sensory dysregulation, movement abnormalities, dysuria/enuresis.
PANS is believed to be an autoimmune/autoinflammatory disorder that primarily affects basal ganglia. Flares are typically induced by infections, especially group A beta-hemolytic Streptococcus.
Methods
To understand the pathogenesis of PANS, we carried out two genetic studies. In the first, 391 cases were analyzed by whole exome sequencing (WES), focusing on ultrarare variants (minor allele frequency < 0.0001) in immune and neurodevelopmental disorder (NDD) genes.
In the second study, an additional 14 patients had whole WES, and immune and NDD panels were analyzed in 50. We focused primarily on pathogenic ultrarare variants in immune and NDD genes, DNA repair genes, and nuclear genes that affect mitochondrial function.
Results
In the first study, we identified 11 genes (in 21 patients) that code for immune regulators (PPM1D, CHK2, NLRC4, RAG1, and PLCG2) and neuronal function (SHANK3, SYNGAP1, GRIN2A, GABRG2, CACNA1B, and SGCE).
Among the immune genes, PPM1D and CHK2 encode proteins that regulate DNA repair through the p53 DNA damage response (DDR) pathway. NLRC4 codes for an inflammasome component.
In the second study, we identified 9 genes in 17 PANS patients. In children with an underlying neurodevelopmental disorder, some flares were more consistent with acute neuropsychiatric regression and seronegative autoimmune encephalitis. The 9 genes clustered around the p53 DDR pathway (PPM1D, ATR, ATM, 53BP1), and members of the Fanconi Anemia Complex (FANCE, FANCI, FANCP, FANCA, FANCC), which also regulate DDR.
We also found pathogenic variants in genes that affect mitochondrial function (8 patients; SLC25A5, SLC13A5, TRAK1, MTO1, POLG, PRKN, SPG7, UBR4), and similar to NLRC4, pathogenic variants were found in genes that regulate the innate immune system (13 patients; SAMHD1, LILRA2, OASL, ABL2, DUOX2, RNF215, TNFRSF13B, TLR10).
Finally, 10 patients with autism spectrum disorder (ASD) were found to have pathogenic variants in GABBR2, TANC2, ADNP, GRIN2A, and GRIP2. These patients developed acute regression or PANS symptoms similar to our original findings of in patients with SHANK3 and SYNGAP1 mutations.
Discussion/conclusion
These genetic studies show that PANS and regression in ASD are genetically heterogeneous. Yet, our findings suggest convergence on distinct pathways such as inflammasome, toll-like receptor, and NF-kappaB signaling that could impact immunological function if disrupted.
The set of genes related to DDR leads to the hypothesis of potential involvement of cGAS-STING, an inducer of type 1 interferons and AIM2 inflammasomes typically activated by viral and bacterial DNA, and damaged nuclear and mitochondrial DNA.
We hypothesize that mutations in genes that code for regulators of these pathways increase the risk maladaptive immunological responses and/or neuroinflammation following infections that activate the same pathways. Our findings also suggest that specific genetic subgroups of ASD cases are at increased risk of developing neuropsychiatric decompensation following infections.
Confirmations and further characterization of these findings may have translational consequences in PANS and ASD regression in some cases.
Link | PDF (Comprehensive Psychiatry) [Symposium presentation, abstract only]
Herbert M. Lachman, Jennifer Frankovich, Peter J. van der Spek, Janet L. Cunningham
[Line breaks added]
Introduction
Pediatric Acute-Onset Neuropsychiatry Syndrome (PANS) is an enigmatic condition characterized by the abrupt onset of obsessive-compulsive disorder (OCD) and/or restricted eating, with two or more secondary symptoms: anxiety, mood lability, rage, cognitive regression, autonomic instability, sensory dysregulation, movement abnormalities, dysuria/enuresis.
PANS is believed to be an autoimmune/autoinflammatory disorder that primarily affects basal ganglia. Flares are typically induced by infections, especially group A beta-hemolytic Streptococcus.
Methods
To understand the pathogenesis of PANS, we carried out two genetic studies. In the first, 391 cases were analyzed by whole exome sequencing (WES), focusing on ultrarare variants (minor allele frequency < 0.0001) in immune and neurodevelopmental disorder (NDD) genes.
In the second study, an additional 14 patients had whole WES, and immune and NDD panels were analyzed in 50. We focused primarily on pathogenic ultrarare variants in immune and NDD genes, DNA repair genes, and nuclear genes that affect mitochondrial function.
Results
In the first study, we identified 11 genes (in 21 patients) that code for immune regulators (PPM1D, CHK2, NLRC4, RAG1, and PLCG2) and neuronal function (SHANK3, SYNGAP1, GRIN2A, GABRG2, CACNA1B, and SGCE).
Among the immune genes, PPM1D and CHK2 encode proteins that regulate DNA repair through the p53 DNA damage response (DDR) pathway. NLRC4 codes for an inflammasome component.
In the second study, we identified 9 genes in 17 PANS patients. In children with an underlying neurodevelopmental disorder, some flares were more consistent with acute neuropsychiatric regression and seronegative autoimmune encephalitis. The 9 genes clustered around the p53 DDR pathway (PPM1D, ATR, ATM, 53BP1), and members of the Fanconi Anemia Complex (FANCE, FANCI, FANCP, FANCA, FANCC), which also regulate DDR.
We also found pathogenic variants in genes that affect mitochondrial function (8 patients; SLC25A5, SLC13A5, TRAK1, MTO1, POLG, PRKN, SPG7, UBR4), and similar to NLRC4, pathogenic variants were found in genes that regulate the innate immune system (13 patients; SAMHD1, LILRA2, OASL, ABL2, DUOX2, RNF215, TNFRSF13B, TLR10).
Finally, 10 patients with autism spectrum disorder (ASD) were found to have pathogenic variants in GABBR2, TANC2, ADNP, GRIN2A, and GRIP2. These patients developed acute regression or PANS symptoms similar to our original findings of in patients with SHANK3 and SYNGAP1 mutations.
Discussion/conclusion
These genetic studies show that PANS and regression in ASD are genetically heterogeneous. Yet, our findings suggest convergence on distinct pathways such as inflammasome, toll-like receptor, and NF-kappaB signaling that could impact immunological function if disrupted.
The set of genes related to DDR leads to the hypothesis of potential involvement of cGAS-STING, an inducer of type 1 interferons and AIM2 inflammasomes typically activated by viral and bacterial DNA, and damaged nuclear and mitochondrial DNA.
We hypothesize that mutations in genes that code for regulators of these pathways increase the risk maladaptive immunological responses and/or neuroinflammation following infections that activate the same pathways. Our findings also suggest that specific genetic subgroups of ASD cases are at increased risk of developing neuropsychiatric decompensation following infections.
Confirmations and further characterization of these findings may have translational consequences in PANS and ASD regression in some cases.
Link | PDF (Comprehensive Psychiatry) [Symposium presentation, abstract only]