Differentiating sulfite intoxication and mitochondrial-related encephalopathy in neonates: a review

Abstract Introduction Molybdenum cofactor deficiency (MoCD), isolated sulfite oxidase deficiency (ISOD), and primary mitochondrial disorders (MDs) are rare conditions that can cause life-threatening seizures and rapidly progressive encephalopathy in the neonatal period. Overlapping clinical presentations, biochemical abnormalities, and imaging findings can make differentiation challenging. Main body We highlight both the shared and distinct aspects of the pathogenesis, clinical features, and diagnostic evaluation of MoCD, ISOD, and MDs. All three can present with neonatal encephalopathy, intractable seizures, and hypotonia, due to impaired energy metabolism and mitochondrial function. However, their underlying molecular etiologies lead to differences in their metabolic signatures, neuroimaging patterns, and disease trajectories. Primary MDs result from over 400 pathogenic variants in nuclear or mitochondrial DNA that lead to respiratory chain deficiencies. In contrast, MoCD and ISOD disrupt sulfite oxidase activity through pathogenic variants in the molybdenum cofactor synthesis or sulfite oxidase genes, respectively. MoCD and ISOD typically manifest in the first days of life with severe seizures and rapid neurological decline, while MDs show a more variable age of onset, with cases presenting in the neonatal period associated with poor prognosis. Other frequent manifestations among these disorders include feeding difficulties and neuroimaging patterns. MoCD and ISOD predominantly affect the central nervous system and eyes, whereas MDs often involve multiple organ systems. A definitive diagnosis relies on a combination of neuroimaging, metabolic testing, and confirmatory genomic analysis. Conclusions Prompt diagnostic evaluation in suspected cases of MoCD, ISOD, or MDs is essential to guide early therapeutic interventions or supportive care, which are associated with prolonged patient survival and improvements in neurological outcomes.