Severe adenylosuccinate lyase deficiency with early autonomic dysfunction: functional characterization of a novel...

Adenylosuccinate lyase (ADSL) deficiency (MIM# 103050) is a rare inherited disorder of purine metabolism characterized by neurodevelopmental impairment, epilepsy, and accumulation of succinylpurines. The clinical spectrum ranges from severe prenatal manifestations with congenital anomalies to mild intellectual disability. We report a child with a severe form of ADSL deficiency presenting with early autonomic dysfunction, including recurrent apnea and bradycardia beginning in the neonatal period, followed by pharmacoresistant epilepsy and profound developmental delay. Exome sequencing identified compound heterozygous variants in the ADSL gene: a known variant (NM_000026.4): c.340 T > C (p.Tyr114His), and a novel variant, c.363G > T (p.Leu121Phe). Urinary metabolite analysis showed highly elevated levels of succinylaminoimidazolecarboxamide riboside (SAICAr) and succinyladenosine (SAdo). Functional studies in patient fibroblasts demonstrated severely reduced ADSL activity (1 to 4% of control values) and absence of purinosome assembly. Enzymatic activity in parental fibroblasts was reduced to less than 30% of control values, while purinosome formation remained preserved. Recombinant ADSL proteins carrying the p.(Tyr114His) and p.(Leu121Phe) variants retained less than 6% and 17% of wild-type catalytic activity, respectively, supporting the pathogenicity of the novel variant. In the absence of disease-specific therapy, off-label treatment with disulfiram was initiated to reduce succinylpurine accumulation. Disulfiram treatment was associated with a decrease in SAICAr and an increase in the upstream metabolite aminoimidazole ribotide (Air), suggesting a possible effect on de novo purine synthesis. This study expands the clinical spectrum of ADSL deficiency, functionally validates a novel ADSL variant, and illustrates a potential metabolic intervention targeting succinylpurine accumulation.