Abstract
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.