What is already known about this topic? ◦. ADSL deficiency is a rare metabolic disorder, typically diagnosed postnatally with variable severity. ◦. ADSL activity is known to be reduced in affected patients. ◦. Pathogenic variants in ADSL are predominantly missense or truncating; no pathogenic synonymous variants have been reported. What does this study add? ◦. The first functionally confirmed case of severe prenatal‐onset ADSL deficiency is described. ◦. The first pathogenic synonymous ADSL variant causing aberrant splicing is identified. ◦. Reduced ADSL activity in PBMCs of unaffected parents is demonstrated for the first time.

Adenylosuccinate lyase deficiency (ADSLD) is a rare neurological disorder characterized by psychomotor retardation, autistic behaviors, and seizures, with no specific treatment available. ADSL catalyzes the transformation of succinylaminoimidazole carboxamide ribotide (SAICAr) to AICAR, and succinyl-AMP (S-AMP) to AMP. The pathogenesis of the disease is primarily attributed to the toxicity of elevated SAICAr concentrations. Allopurinol, used primarily for hyperuricemia, inhibits purine synthesis and may reduce SAICAr levels. We hypothesized that administering allopurinol could decrease SAICAr levels and lead to clinical improvement. A Phase II, prospective trial evaluated the efficacy of allopurinol in patients with ADSLD over 12 months. Eight participants (four children, four young adults) with developmental delay and high SAICAr levels received Zyloric (10-20 mg/kg/day, maximum 400 mg/day for children and 900 mg/day for adults). The study assessed changes in adaptive and cognitive functioning, behavior, and urinary levels of SAICAr and succinyl-adenosine (S-Ado). Results showed clinical improvements in younger, less cognitively impaired patients, indicated by better Vineland Adaptive Behavior Scale (VABS II) scores and reduced hyperactivity on the Aberrant Behavior Checklist (ABC) and Conners Rating Scale-Revised (CRSR). These improvements correlated with significant decreases in urinary SAICAr levels and an increased S-Ado/SAICAr ratio. No changes were observed in older or noncompliant patients. Allopurinol had no effect on epilepsy but was well tolerated. Allopurinol showed behavioral and developmental benefits in younger ADSLD patients, suggesting that it may be a viable treatment option.

Adenylosuccinate lyase deficiency (ADSLd) is a rare autosomal recessive purine metabolism disorder with several clinical manifestations. While toxic substrate accumulation is a known hallmark, no additional molecular mechanisms have been established. Here, we show that ADSLd is associated with mitochondrial dysfunction, including increased fragmentation, impaired respiration, and reduced ATP production. The severity of mitochondrial impairment correlates with ADSLd pathology, especially in mitochondria-dependent tissues. We also identify defects in mitochondrial dynamics and transport linked to ERK2 and AKT suppression. Notably, overexpressing constitutively active ERK2 or supplementing purine intermediates partially rescues the mitochondrial phenotype. These findings suggest an alternative disease mechanism and highlight mitochondrial metabolism as a potential therapeutic target in ADSLd.

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.

Adenylosuccinate lyase deficiency (ALD) is a rare neurometabolic disorder caused by biallelic loss-of-function variants in the ADSL gene. We report a severe type I ALD case involving a 2-year-old boy presenting with early-onset polymorphic seizures (clonic/myoclonic), developmental delay, and progressive neurological deterioration. Seizures were temporarily controlled with ethosuximide and vigabatrin, though neurodegeneration progressed. Analysis of whole-exome sequencing data revealed compound-heterozygous variants in the ADSL gene: the known pathogenic missense variant c.340T>C (p.Tyr114His) and a novel variant c.859A>G (p.Ile287Val). Although p.Ile287Val is predicted to be benign at the protein level, RNA analysis demonstrated that c.859A>G activates a cryptic splice site in exon 8, resulting in aberrant transcripts (64%, 4-bp deletion, targeted by nonsense-mediated decay) and a smaller proportion of normal transcripts (36%) encoding the p.Ile287Val protein. This case highlights splicing disruption as a novel pathogenic mechanism in ALD and expands the mutational spectrum associated with the disease. This case also underscores the importance of integrating RNA analysis with genomic data to uncover cryptic splicing defects, especially when protein-level predictions suggest benignity.