Prenatal-Onset Lethal Adenylosuccinate Lyase Deficiency Diagnosed by Rapid Whole Genome Sequencing: A Case Report

Adenylosuccinate lyase deficiency (ADSLD) is an ultra-rare autosomal recessive disorder of purine metabolism. The most severe neonatal phenotype presents with profound encephalopathy from birth, hypotonia, respiratory insufficiency, and early seizures. A preterm infant was delivered at 34+0 weeks with antenatal progressive microcephaly and mild polyhydramnios. At birth, the neonate exhibited absent spontaneous respiration and marked hypotonia, necessitating ventilation and intubation. Respiratory distress syndrome (RDS) was managed with surfactant, but two extubation attempts with non-invasive continuous positive airway pressure/biphasic positive airway pressure (nCPAP/DuoPAP) were unsuccessful. Neurologically, the infant demonstrated profound central hypotonia, stimulus-induced myoclonus, and a burst-suppression pattern on amplitude-integrated electroencephalography (aEEG). Antiseizure therapy with phenobarbital and levetiracetam was initiated. Brain magnetic resonance imaging (MRI) revealed microcephaly with simplified gyrification, bilateral intraventricular hemorrhage (IVH) with additional posterior fossa hemorrhage, delayed myelination, and evolving post-hemorrhagic hydrocephalus. Targeted biochemical testing identified markedly elevated succinylpurines (succinyladenosine (S-Ado) and SAICA-riboside (SAICAr)) in urine and serum. Rapid whole-genome sequencing (WGS) confirmed autosomal recessive ADSLD. In the absence of disease-modifying therapy and given the extremely poor prognosis, care was transitioned to comfort-focused palliation. ADSLD should be considered in neonates presenting with severe microcephaly, profound hypotonia, and early epileptic encephalopathy. Rapid genomic testing, when available and clinically appropriate, may enable timely etiologic diagnosis, supporting prognostication and shared decision-making.