Adenylosuccinate lyase deficiency

Adenylosuccinate lyase deficiency (ADSL deficiency), also known as adenylosuccinase deficiency or succinylpurinemic autism, is a rare autosomal recessive inborn error of purine metabolism caused by mutations in the ADSL gene located on chromosome 22q13.1. The enzyme adenylosuccinate lyase catalyzes two steps in the de novo purine synthesis pathway, and its deficiency leads to the accumulation of two substrates—succinyladenosine (S-Ado) and succinylaminoimidazole carboxamide riboside (SAICAr)—in body fluids including cerebrospinal fluid and urine. These succinylpurines are thought to be neurotoxic and are responsible for the predominantly neurological manifestations of the disease. The condition primarily affects the central nervous system. Clinical presentation is variable and has been classified into three forms based on severity: a severe neonatal form with encephalopathy, seizures, and often fatal outcome in early life; a moderate form (type I) presenting in infancy or early childhood with psychomotor retardation, seizures, autistic features, and hypotonia; and a milder form (type II) characterized by mild to moderate intellectual disability with or without autistic behavior. Additional features may include growth retardation, muscle wasting, and microcephaly. The ratio of SAICAr to S-Ado in cerebrospinal fluid has been proposed as a prognostic marker, with higher ratios correlating with more severe disease. Diagnosis is established by detecting elevated succinylpurines in urine using the modified Bratton-Marshall test or HPLC analysis, confirmed by enzyme activity assay and molecular genetic testing of the ADSL gene. Currently, there is no curative treatment for ADSL deficiency. Management is primarily supportive and symptomatic, including antiepileptic medications for seizure control, physical therapy, and educational support. Trials of oral supplementation with adenine, allopurinol, and D-ribose have been attempted with limited or no consistent benefit. Research into potential therapeutic strategies is ongoing.

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