2026-08-11 | A novel homozygous variant causing fatal neonatal adenylosuccinate lyase (ADSL) deficiency presenting with respiratory failure and encephalopathy.
Neonatal adenylosuccinate lyase (ADSL) deficiency is a rare neurodegenerative disorder that is associated with epileptic encephalopathy, diffuse hypotonia, and respiratory failure. Loss of enzymatic function of ADSL leads to toxic buildup of succinylaminoimidazole carboxamide riboside (SAICAr) and succinyladenosine (S-Ado). We describe a female term neonate who presented with respiratory failure and encephalopathy. Neuroimaging revealed microencephaly, a simplified gyral pattern, and diffuse white matter edema. Genetic testing showed novel homozygous loss of function mutations of ADSL, the adenylosuccinate lyase gene, consistent with fatal neonatal ADSL deficiency. We find this to be one of less than a dozen cases reported of the fatal neonatal phenotype of ADSL deficiency. The case highlights ADSL deficiency as a rare cause of neonatal encephalopathy and respiratory failure. Clinical recognition of epileptic encephalopathy, pertinent findings on MRI, and testing for S-Ado can confirm the diagnosis and support discussions about goals of care.
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2026-07-10 | Severe adenylosuccinate lyase deficiency with early autonomic dysfunction: functional characterization of a novel ADSL variant and exploratory treatment with disulfiram.
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.
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2026-04-28 | Creatine-ribose combination therapy for cellular energy restoration
Creatine enhances phosphocreatine-mediated ATP buffering while D-ribose provides substrate for enhanced PRPP synthesis via ribokinase, creating dual pathway support for energy metabolism disrupted by ADSL deficiency
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2026-04-28 | Folate pathway modulation targeting ATIC enzyme enhancement
High-dose folinic acid increases 10-formyl-THF availability to enhance ATIC enzyme activity in the final step of de novo purine synthesis, potentially compensating for upstream disruptions caused by ADSL deficiency
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2026-04-28 | Ayurvedic Rasayana compounds for purine salvage pathway enhancement in ADSL deficiency
Ashwagandha (Withania somnifera) withanolides and Brahmi (Bacopa monnieri) bacosides upregulate HPRT1 and APRT expression through Nrf2-mediated transcriptional activation, enhancing alternative purine salvage pathways to compensate for deficient ADSL activity
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