Treatable Neonatal Molybdenum Cofactor Deficiency: Rapid Demise Despite Rapid Biochemical Diagnosis

Molybdenum cofactor deficiency (MoCD) is an inborn error of metabolism included in the differential for refractory neonatal seizures. The prognosis is guarded, with a median reported age of death between 2.4 and 3.0 years. Mortality is primarily due to seizures and lower respiratory tract infections. MoCD has a distinct biochemical profile, characterized by elevated urinary <i>S</i>-sulfocysteine, xanthine, and hypoxanthine, and low or undetectable serum and urine uric acid levels. A disease-altering treatment is available for MoCD Type A; however, due to the rarity of the condition, its natural history remains poorly understood. We present a patient with neonatal-onset refractory seizures, whose biochemical testing, performed within 24 h of specimen receipt in the laboratory, revealed a pattern consistent with MoCD. Before the genetics team could disclose the preliminary diagnosis, the patient demised, without evidence of worsening seizures or respiratory infection. Results of genome sequencing, guided by biochemical findings, identified double homozygous pathogenic variants in <i>MOCS1</i> (associated with MoCD Type A). Although the biochemical genetics laboratory's protocol for analyzing and reporting <i>S</i>-sulfocysteine levels within 48 h enabled a rapid preliminary diagnosis, the patient's condition deteriorated too quickly to initiate disease-altering treatment, progressing more rapidly than described in the literature. We discuss potential hypotheses for his rapid decline and the broader implications for the field of biochemical genetics.