Emerging role of complement system in the induction of neuroinflammation in adenylosuccinate lyase deficiency disorder
Adenylosuccinate lyase deficiency disorder (ADSLDD) is an ultra-rare autosomal recessive metabolic condition that leads to severe neurological impairment, with an estimated global prevalence of approximately 0.00125 cases per 100,000 individuals. Clinically, ADSLDD presents in three distinct phenoty...
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Elsevier
2025-10-01
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| Series: | Brain, Behavior, & Immunity - Health |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2666354625001498 |
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| author | Albert Frank Magnusen Robert James Hopkin Charles Vorhees Elizabeth Wilson Molly Moehlman Barbara Hallinan Craig Erickson Melissa P. DelBello Luca Marsili Nicole G. Coufal Manoj Kumar Pandey |
| author_facet | Albert Frank Magnusen Robert James Hopkin Charles Vorhees Elizabeth Wilson Molly Moehlman Barbara Hallinan Craig Erickson Melissa P. DelBello Luca Marsili Nicole G. Coufal Manoj Kumar Pandey |
| author_sort | Albert Frank Magnusen |
| collection | DOAJ |
| description | Adenylosuccinate lyase deficiency disorder (ADSLDD) is an ultra-rare autosomal recessive metabolic condition that leads to severe neurological impairment, with an estimated global prevalence of approximately 0.00125 cases per 100,000 individuals. Clinically, ADSLDD presents in three distinct phenotypes: the fatal neonatal form, the childhood form, and the more slowly progressive form, each characterized by varying degrees of developmental and neurological dysfunction. The disorder is caused by pathogenic variants in the ADSL gene, leading to impaired enzymatic activity and the accumulation of toxic substrates particularly succinyladenosine (S-Ado) and succinylaminoimidazole carboxamide riboside (SAICAr).The ratio of S-Ado to SAICAr in cerebrospinal fluid has been correlated with disease severity, where lower ratios are associated with more severe clinical outcomes. However, the precise mechanisms linking elevated SAICAr levels to neurological damage remain incompletely understood.This review summarizes current insights into the metabolic dysfunction and immune activation observed in ADSLDD, with a focus on the role of SAICAr in promoting neuroinflammation. We highlight emerging hypotheses implicating activation of the alternative complement pathway as a key driver of inflammation, blood-brain barrier disruption, and progressive neurodegeneration.By synthesizing recent findings, this review underscores the urgent need for mechanistic studies and therapeutic exploration, particularly targeting complement activation, as a promising strategy to mitigate inflammation and improve clinical outcomes in ADSLDD. |
| format | Article |
| id | doaj-art-cb810ccb988440939edea27ba27e64b4 |
| institution | Kabale University |
| issn | 2666-3546 |
| language | English |
| publishDate | 2025-10-01 |
| publisher | Elsevier |
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| series | Brain, Behavior, & Immunity - Health |
| spelling | doaj-art-cb810ccb988440939edea27ba27e64b42025-08-24T05:14:40ZengElsevierBrain, Behavior, & Immunity - Health2666-35462025-10-014810109110.1016/j.bbih.2025.101091Emerging role of complement system in the induction of neuroinflammation in adenylosuccinate lyase deficiency disorderAlbert Frank Magnusen0Robert James Hopkin1Charles Vorhees2Elizabeth Wilson3Molly Moehlman4Barbara Hallinan5Craig Erickson6Melissa P. DelBello7Luca Marsili8Nicole G. Coufal9Manoj Kumar Pandey10Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OHIO, USADivision of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OHIO, USA; Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH, USADivision of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH, USADivision of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH, USADivision of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH, USADivision of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH, USAThe Kelly O'Leary Center for Autism Spectrum Disorders, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH, USADepartment of Psychiatry, College of Medicine, University of Cincinnati, Cincinnati, OH, USAJames J. and Joan A. Gardner Center for Parkinson's Disease and Movement Disorders, University of Cincinnati, OH, USADepartment of Pediatrics, University of California San Diego and Rady Children's Hospital, University of California, San Diego, USADivision of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OHIO, USA; Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH, USA; Corresponding author. Division of Human Genetics, Cincinnati Children's Hospital Medical Center, MLC 7016S, Suite S4.206 (Office), Burnet Campus, 3333 Burnet Avenue, Cincinnati, OH, 45229-3026, USA.Adenylosuccinate lyase deficiency disorder (ADSLDD) is an ultra-rare autosomal recessive metabolic condition that leads to severe neurological impairment, with an estimated global prevalence of approximately 0.00125 cases per 100,000 individuals. Clinically, ADSLDD presents in three distinct phenotypes: the fatal neonatal form, the childhood form, and the more slowly progressive form, each characterized by varying degrees of developmental and neurological dysfunction. The disorder is caused by pathogenic variants in the ADSL gene, leading to impaired enzymatic activity and the accumulation of toxic substrates particularly succinyladenosine (S-Ado) and succinylaminoimidazole carboxamide riboside (SAICAr).The ratio of S-Ado to SAICAr in cerebrospinal fluid has been correlated with disease severity, where lower ratios are associated with more severe clinical outcomes. However, the precise mechanisms linking elevated SAICAr levels to neurological damage remain incompletely understood.This review summarizes current insights into the metabolic dysfunction and immune activation observed in ADSLDD, with a focus on the role of SAICAr in promoting neuroinflammation. We highlight emerging hypotheses implicating activation of the alternative complement pathway as a key driver of inflammation, blood-brain barrier disruption, and progressive neurodegeneration.By synthesizing recent findings, this review underscores the urgent need for mechanistic studies and therapeutic exploration, particularly targeting complement activation, as a promising strategy to mitigate inflammation and improve clinical outcomes in ADSLDD.http://www.sciencedirect.com/science/article/pii/S2666354625001498Genetic defectRare diseaseNeuroinflammationComplement activation |
| spellingShingle | Albert Frank Magnusen Robert James Hopkin Charles Vorhees Elizabeth Wilson Molly Moehlman Barbara Hallinan Craig Erickson Melissa P. DelBello Luca Marsili Nicole G. Coufal Manoj Kumar Pandey Emerging role of complement system in the induction of neuroinflammation in adenylosuccinate lyase deficiency disorder Brain, Behavior, & Immunity - Health Genetic defect Rare disease Neuroinflammation Complement activation |
| title | Emerging role of complement system in the induction of neuroinflammation in adenylosuccinate lyase deficiency disorder |
| title_full | Emerging role of complement system in the induction of neuroinflammation in adenylosuccinate lyase deficiency disorder |
| title_fullStr | Emerging role of complement system in the induction of neuroinflammation in adenylosuccinate lyase deficiency disorder |
| title_full_unstemmed | Emerging role of complement system in the induction of neuroinflammation in adenylosuccinate lyase deficiency disorder |
| title_short | Emerging role of complement system in the induction of neuroinflammation in adenylosuccinate lyase deficiency disorder |
| title_sort | emerging role of complement system in the induction of neuroinflammation in adenylosuccinate lyase deficiency disorder |
| topic | Genetic defect Rare disease Neuroinflammation Complement activation |
| url | http://www.sciencedirect.com/science/article/pii/S2666354625001498 |
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