Molybdenum cofactor deficiency: A natural history

Molybdenum cofactor deficiency (MoCD) includes three ultrarare autosomal recessive inborn errors of metabolism (MoCD type A [MoCD‐A], MoCD‐B, and MoCD‐C) that cause sulfite intoxication disorders. This natural history study analyzed retrospective data for 58 living or deceased patients (MoCD‐A, n = 41; MoCD‐B, n = 17). MoCD genotype, survival, neuroimaging, and medical history were assessed retrospectively. Prospective biomarker data were collected for 21 living MoCD patients. The primary endpoint was survival to 1 year of age in MoCD‐A patients. Of the 58 MoCD patients, 49 (MoCD‐A, n = 36; MoCD‐B, n = 13) had first presenting symptoms by Day 28 (neonatal onset; median: 2 and 4 days, respectively). One‐year survival rates were 77.4% (overall), 71.8% (neonatal onset MoCD‐A), and 76.9% (neonatal onset MoCD‐B); median ages at death were 2.4, 2.4, and 2.2 years, respectively. The most common presenting symptoms in the overall population were seizures (60.3%) and feeding difficulties (53.4%). Sequelae included profound developmental delay, truncal hypotonia, limb hypertonia that evolved to spastic quadriplegia or diplegia, dysmorphic features, and acquired microcephaly. In MoCD‐A and MoCD‐B, plasma and urinary xanthine and S‐sulfocysteine concentrations were high; urate remained below the normal reference range. MOCS1 mutation homozygosity was common. Six novel mutations were identified. MoCD is a severe neurodegenerative disorder that often manifests during the neonatal period with intractable seizures and feeding difficulties, with rapidly progressive significant neurologic disabilities and high 1‐year mortality rates. Delineation of MoCD natural history supports evaluations of emerging replacement therapy with cPMP for MoCD‐A, which may modify disease course for affected individuals.