Fatal neonatal-onset isolated sulfite oxidase deficiency associated with a homozygous SUOX frameshift variant: a case report

Background: Isolated sulfite oxidase deficiency (ISOD) is a rare autosomal recessive neurometabolic disorder that may mimic hypoxic-ischemic or infectious encephalopathy in neonates. We describe a fatal neonatal presentation associated with a homozygous SUOX frameshift variant and highlight the diagnostic value and limitations of genomic testing when disease-specific biochemical assays are unavailable.

Case Description: A male Uyghur neonate born at 37+5 weeks developed poor responsiveness, hypotonia, impaired sucking and swallowing, and recurrent clinically observed seizure-like events beginning approximately 33 hours after birth. The events were characterized by tonic and clonic movements with bilateral staring, lasted approximately 3-4 minutes, and occurred up to 12 times/day during the first admission, with a reported increase to approximately 20 episodes/day before readmission. Electroencephalography was not performed. Brain magnetic resonance imaging (MRI) performed on day 3 demonstrated extensive bilateral symmetric diffusion restriction involving the frontal, parietal, temporal, and occipital cortices, with corresponding low apparent diffusion coefficient values and symmetric involvement of the bilateral basal ganglia. Total serum calcium increased from 1.44 to 1.98 mmol/L after calcium supplementation, while the clinically observed seizure-like events persisted. Blood and cerebrospinal fluid cultures were negative, and inflammatory markers subsequently decreased. Blood for whole-exome sequencing (WES) was collected on day 3; WES subsequently identified a homozygous SUOX NM_001032386.2:c.663del (p.Val222Tyrfs*13) variant, and both parents were confirmed to be heterozygous carriers. The formal WES report was issued after the infant had died at 16 days of age following readmission with respiratory failure and frequent clinically observed seizure-like events. Urinary sulfite, thiosulfate, S-sulfocysteine, plasma total homocysteine, plasma uric acid, and urinary purine metabolites were not measured.

Conclusions: The clinical phenotype, segregation pattern, and predicted truncating effect of c.663del provide genetic support for probable SUOX-related ISOD, although disease-specific biochemical and functional confirmation was unavailable. In critically ill neonates with otherwise unexplained progressive encephalopathy, parallel targeted metabolic testing and rapid genomic testing may shorten the time to molecular diagnosis when specialized metabolic assays are not readily available.