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Background: Developmental and epileptic encephalopathies (DEE) encompass a group of rare diseases with hereditary and genetic causes as well as acquired causes such as brain injuries or metabolic abnormalities. The phosphofurin acidic cluster sorting protein 2 (PACS2) is a multifunctional protein with nuclear gene expression. The first cases of the recurrent c.625G>A pathogenic variant of PACS2 gene were reported in 2018 by Olson et al. Since then, several case reports and case series have been published. Methods: We performed a systematic review of the PUBMED and SCOPUS databases using Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines. Our search parameters included DEE66 with a pathogenic PACS2 gene p.Glu209Lys mutation published cases to which we added our own clinical experience regarding this pathology. Results: A total of 11 articles and 29 patients were included in this review, to which we added our own experience for a total of 30 patients. There was not a significant difference between sexes regarding the incidence of this pathology (M/F: 16/14). The most common neurological and psychiatric symptoms presented by the patients were: early onset epileptic seizures, delayed global development (including motor and speech delays), behavioral disturbances, limited intellectual capacity, nystagmus, hypotonia, and a wide-based gait. Facial dysmorphism and other organs' involvement were also frequently reported. Brain MRIs evidenced anomalies of the posterior cerebellar fossa, foliar distortion of the cerebellum, vermis hypoplasia, white matter reduction, and lateral ventricles enlargement. Genetic testing is more frequent in children. Only 4 cases have been reported in adults to date. Conclusions: It is important to maintain a high suspicion of new pathogenic gene variants in adult patients presenting with a characteristic clinical picture correlated with radiologic changes. The neurologist must gradually recognize the distinct evolving phenotype of DEE66 in adult patients, and genetic testing must become a scenario with which the neurologist attending adult patients should be familiar. Accurate diagnosis is required for adequate treatment, genetic counseling, and an improved long-term prognosis. [ABSTRACT FROM AUTHOR]

Background: The PACS gene family has been demonstrated to be related to intracellular vesicular trafficking. The phenotypic manifestations caused by the pathogenic variants of PACS include epilepsy, intellectual disability/developmental delay, and malformations, such as facial abnormalities. Methods: We identified seven new cases with pathogenic or likely pathogenic PACS variants using next-generation sequencing. Detailed information obtained from these patients was analyzed along with that obtained from previously reported patients. Results: With the inclusion of the newly diagnosed cases in this study, 103 cases with PACS gene family-related neurological diseases were reported, of which 43 were PACS2-related cases and the remaining were PACS1-related cases. Most patients had seizures, which have been reported to be effectively controlled by several types of anti-seizure medications (ASMs). The most efficacious and frequently prescribed ASMs included sodium valproate (43.3%, 13/30), oxcarbazepine/carbamazepine (26.7%, 8/30), and levetiracetam (20%, 6/30). Almost all patients had intellectual disability/developmental delay. The most common pathogenic missense variants were PACS1 p. Arg203Trp and PACS2 p.Glu209Lys. In addition, we report a patient carrying a likely pathogenic copy number variation (CNV) (de novo heterozygous deletion of chr14:105821380-106107443, 286 kilobase, destroyed part of the furin-binding region domain and the protein structure after it) with more severe and refractory late-onset epilepsy. Conclusions: The clinical phenotypes of the different PACS heterozygous missense variants were similar. The pathogenic variant sites of PACS1 and PACS2 were quite limited but located in different regions. A CNV destroying part of the PACS2 gene might also be pathogenic. These findings may provide an important clue for further functional studies on the pathogenic mechanism of neurological disorders related to the PACS gene family. BTtobEFtUtBmTfL76THaaU Video Abstract (MP4 65767 kb) [ABSTRACT FROM AUTHOR]

Phosphofurin Acidic Cluster Sorting Protein 2 (PACS2)-related early infantile developmental and epileptic encephalopathy (EIDEE) is a rare neurodevelopmental disorder. EIDEE is characterized by seizures that begin during the first three months of life and are accompanied by developmental impairment over time. In this article, we present three patients with EIDEE who experienced neonatal-onset seizures that developed into intractable seizures during infancy. Whole exome sequencing revealed a de novo heterozygous missense variant in all three patients in the p.Glu209Lys variant of the PACS2 gene. We conducted a literature review and found 29 cases to characterize the seizure patterns, neuroimaging features, the usage of anticonvulsants, and the clinical neurodevelopmental outcomes of PACS2-related EIDEE. The seizures were characterized by brief, recurring tonic seizures in the upper limbs, sometimes accompanied by autonomic features. Neuroimaging abnormalities were observed in the posterior fossa region, including mega cisterna magna, cerebellar dysplasia, and vermian hypoplasia. The long-term prognosis ranges from low–average intelligence to severe developmental retardation, emphasizing the importance of early recognition and accurate diagnosis by pediatric neurologists to provide personalized patient management. [ABSTRACT FROM AUTHOR]

Diabetes is a chronic metabolic disorder that can cause many microvascular and microvascular complications, including diabetic nephropathy. Endothelial cells exhibit phenotypic and metabolic diversity and are affected by metabolic disorders. Whether changes in endothelial cell metabolism affect vascular endothelial function in diabetic nephropathy remains unclear. In diabetic mice, increased renal microvascular permeability and fibrosis, as well as increased MAMs and PACS2 in renal endothelial cells, were observed. Mice lacking PACS2 improved vascular leakage and glomerulosclerosis under high fat diet. In vitro, PACS2 expression, VE-cadherin internalization, fibronectin production, and Smad-2 phosphorylation increased in HUVECs treated with high glucose and palmitic acid (HGHF). Pharmacological inhibition of AKT significantly reduced HGHF-induced upregulation of PACS2 and p-Smad2 expression. Blocking fatty acid β-oxidation (FAO) ameliorated the impaired barrier function mediated by HGHF. Further studies observed that HGHF induced decreased FAO, CPT1a expression, ATP production, and NADPH/NADP+ ratio in endothelial cells. However, these changes in fatty acid metabolism were rescued by silencing PACS2. In conclusion, PACS2 participates in renal vascular hyperpermeability and glomerulosclerosis by regulating the FAO of diabetic mice. Targeting PACS2 is potential new strategy for the treatment of diabetic nephropathy. [ABSTRACT FROM AUTHOR]

The PACS2 gene encodes a multifunctional sorting protein involved in nuclear gene expression and pathway traffic regulation that has been shown to be highly expressed during human prenatal brain development. Pathogenic variants in PACS2 have been recently shown to be implicated in a phenotype with global developmental delay/intellectual disability, seizures, autistic traits, facial dysmorphic features, and cerebellar dysgenesis. Here, we report a 25‐year‐old male with intellectual disability, epileptic encephalopathy, cerebellar dysgenesis, facial dysmorphism, and a previously reported pathogenic variant in PACS2. To our knowledge, this is the oldest patient reported who, in addition to the known phenotype described in PACS2 patients, presented with a vein of Galen malformation and dilated cardiomyopathy as previously unreported findings. [ABSTRACT FROM AUTHOR]

Phosphofurin Acidic Cluster Sorting Protein 2 (PACS2)-related early infantile developmental and epileptic encephalopathy (EIDEE) is a rare neurodevelopmental disorder. EIDEE is characterized by seizures that begin during the first three months of life and are accompanied by developmental impairment over time. In this article, we present three patients with EIDEE who experienced neonatal-onset seizures that developed into intractable seizures during infancy. Whole exome sequencing revealed a de novo heterozygous missense variant in all three patients in the p.Glu209Lys variant of the PACS2 gene. We conducted a literature review and found 29 cases to characterize the seizure patterns, neuroimaging features, the usage of anticonvulsants, and the clinical neurodevelopmental outcomes of PACS2-related EIDEE. The seizures were characterized by brief, recurring tonic seizures in the upper limbs, sometimes accompanied by autonomic features. Neuroimaging abnormalities were observed in the posterior fossa region, including mega cisterna magna, cerebellar dysplasia, and vermian hypoplasia. The long-term prognosis ranges from low–average intelligence to severe developmental retardation, emphasizing the importance of early recognition and accurate diagnosis by pediatric neurologists to provide personalized patient management.

PACS2 pathogenic variants are associated with an autosomal dominant syndrome (OMIM DEE66), associating developmental and epileptic encephalopathy, facial dysmorphism, and cerebellar dysgenesis. However, no malformation of cortical development has been reported yet. We report here a seven-year-old child with a history of infantile epileptic spasm syndrome and a right insular polymicrogyria and pachygyria due to de novo PACS2 recurrent mutation c.625G>A (p.Glu209Lys). Our observation raises the question of the role of PACS2 in the cortical development. It also reminds the importance of cerebellar anomalies in the recognition of PACS-related DEE., (© 2023 International League Against Epilepsy.)

Introduction: PACS1 -related neurodevelopmental disorder ( PACS1- related NDD) is caused by pathogenic variants in the PACS1 gene and is characterized by a distinctive facial appearance, intellectual disability, speech delay, seizures, feeding difficulties, cryptorchidism, hernias, and structural anomalies of the brain, heart, eye, and kidney. There is a marked facial resemblance and a common multisystem affectation with patients carrying pathogenic variants in the WDR37 and PACS2 genes, although they vary in terms of severity and eye involvement., Case Presentation: Here, we describe 4 individuals with PACS1 -related NDD from Mexico, all of them carrying a de novo PACS1 variant c.607C>T; p.(Arg203Trp) identified by exome sequencing. In addition to eye colobomata, this report identified corneal leukoma, cataracts, and tortuosity of retinal vessels as ophthalmic manifestations not previously reported in patients with PACS1 -related NDD., Discussion: We reviewed the ocular phenotypes reported in 74 individuals with PACS1 -related NDD and the overlaps with WDR37- and PACS2 -related syndromes. We found that the 3 syndromes have in common the presence of colobomata, ptosis, nystagmus, strabismus, and refractive errors, whereas microphthalmia, microcornea, and Peters anomaly are found only among individuals with PACS1 -related NDD and WDR37 syndrome, being more severe in the latter. This supports the previous statement that the so-called WDR37 - PACS1 - PACS2 axis might have an important role in ocular development and also that the specific ocular findings could be useful in the clinical differentiation between these related syndromes., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2022 by S. Karger AG, Basel.)

Objectives: Atherosclerosis is one of the most common cardiovascular diseases. The functional roles of circular (circ) RNAs have been discovered in atherosclerosis. Our goal was to explore the regulation and mechanism of circ_0002194 in oxidized low-density lipoprotein-induced human vascular endothelial cells., Methods: Circ_0002194, microRNA-637 (miR-637) and phosphofurin acidic cluster sorting protein 2 (PACS2) levels were determined through the reverse transcription-quantitative polymerase chain reaction. Cell viability was detected using the Cell Counting Kit-8 assay, and angiogenetic ability was analysed via the tube formation assay. Flow cytometry was used to measure cell apoptosis. Western blot was performed to examine protein expression. Oxidative stress was assessed using commercial kits. The RNA immunoprecipitation assay and dual-luciferase reporter assay were conducted for target analysis., Results: Treatment with oxidized low-density lipoprotein induced the upregulation of circ_0002194 in endothelial cells. Cell viability and angiogenesis were promoted while cell apoptosis and oxidative stress were reduced by the downregulation of circ_0002194 in the cell model. Furthermore, miR-637 was identified as an miRNA target of circ_0002194, and the regulatory role of circ_0002194 was associated with the sponge effect on miR-637. Moreover, circ_0002194 could regulate PACS2 by affecting miR-637. Additionally, miR-637 suppressed endothelial cell damage by partly mediating the expression of PACS2., Conclusions: The results demonstrated that circ_0002194 facilitated endothelial cell dysfunction in atherosclerosis partly through upregulating PACS2 by targeting miR-637., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

Background: The identification of novel therapeutic candidates from natural products for the development of chemoresistant glioblastoma multiforme (GBM) treatment has been a highly significant and effective strategy.Purpose: Sesquiterpenes are a class of naturally occurring 15-carbon isoprenoid compounds, and several types of sesquiterpenes have the ability to induce growth inhibition and apoptosis in a variety of cancer cell lines. In the present study, 56 sesquiterpenes of five types, namely, eudesmane-type (I) (1-24), eremophilane-type (II) (25-32), cadinane-type (III) (33-41), guaiane-type (IV) (42-49), and oplopanone-type (V) (50-56), were screened for their antiglioma activity, structure-activity relationship analysis (SAR), and underlying mechanism based on patient-derived recurrent GBM strains, patient-derived GBM cell sphere, GBM organoid (GBO) models, and temozolomide (TMZ)-resistant GBM cell lines.Results: We found that compound 12 (oxyphyllanene B, OLB) showed the most potent antiglioma activity, and we confirmed that OLB could induce apoptosis in a time- and dose-dependent manner in TMZ-resistant GBM cells and GBOs. SAR announced that the presence of an α, β-unsaturated carbonyl moiety was likely to enhance cytotoxic activities. Mechanistic studies demonstrated that OLB induced abnormal changes in ER and mitochondria-associated membrane (MAM) networks, which triggered ER stress, mitochondrial dysfunction, and apoptosis. Furthermore, our findings suggested that OLB-triggered PACS2 activation might form a committed step to disrupt ER-mitochondria communication and showed for the first time that the expression levels of PACS2 might positively correlate with the progression and chemotherapy resistance of glioma.Conclusion: Our results indicated that OLB might be a promising candidate for treating TMZ-resistant GBM cells by activating PACS2, which triggered a crucial event to promote the disruption of ER-mitochondria communication and overcome chemotherapy resistance of GBM. [ABSTRACT FROM AUTHOR]