Allopurinol Treatment Improves Cognitive Skills, Adaptive Behavior, and Biochemical Markers in Young Patients With Adenylosuccinate Lyase Deficiency

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.