Efficacy and safety of cyclic pyranopterin monophosphate substitution in severe molybdenum cofactor deficiency type A: a prospective cohort study. Issue 10007 (14th November 2015)

• Record Type: Journal Article
• Authors: Schwahn, Bernd C; Van Spronsen, Francjan J; Belaidi, Abdel A; Bowhay, Stephen; Christodoulou, John; Derks, Terry G; Hennermann, Julia B; Jameson, Elisabeth; König, Kai; McGregor, Tracy L; Font-Montgomery, Esperanza; Santamaria-Araujo, José A; Santra, Saikat; Vaidya, Mamta; Vierzig, Anne; Wassmer, Evangeline; Weis, Ilona; Wong, Flora Y; Veldman, Alex; Schwarz, Günter
• Is Part Of: Lancet. Volume 386:Issue 10007(2015)
• Page Start: 1955
• Page End: 1963
• Publication Date: 2015-11-14
• Subjects: Medicine -- Periodicals; Medicine -- Periodicals; Medicine; Medicine; Electronic journals; Periodicals; 610.5
• DOI: 10.1016/S0140-6736(15)00124-5
• Languages: English
• ISSNs: 0140-6736

Abstract

Summary: Background: Molybdenum cofactor deficiency (MoCD) is characterised by early, rapidly progressive postnatal encephalopathy and intractable seizures, leading to severe disability and early death. Previous treatment attempts have been unsuccessful. After a pioneering single treatment we now report the outcome of the complete first cohort of patients receiving substitution treatment with cyclic pyranopterin monophosphate (cPMP), a biosynthetic precursor of the cofactor. Methods: In this observational prospective cohort study, newborn babies with clinical and biochemical evidence of MoCD were admitted to a compassionate-use programme at the request of their treating physicians. Intravenous cPMP (80–320 μg/kg per day) was started in neonates diagnosed with MoCD (type A and type B) following a standardised protocol. We prospectively monitored safety and efficacy in all patients exposed to cPMP. Findings: Between June 6, 2008, and Jan 9, 2013, intravenous cPMP was started in 16 neonates diagnosed with MoCD (11 type A and five type B) and continued in eight type A patients for up to 5 years. We observed no drug-related serious adverse events after more than 6000 doses. The disease biomarkers urinary S-sulphocysteine, xanthine, and urate returned to almost normal concentrations in all type A patients within 2 days, and remained normal for up to 5 years on continued cPMP substitution. Eight patients with type A disease rapidly improved under treatment and convulsions were either completely suppressed or substantially reduced. Three patients treated early remain seizure free and show near-normal long-term development. We detected no biochemical or clinical response in patients with type B disease. Interpretation: cPMP substitution is the first effective therapy for patients with MoCD type A and has a favourable safety profile. Restoration of molybdenum cofactor-dependent enzyme activities results in a greatly improved neurodevelopmental outcome when started sufficiently early. The possibility of MoCD type A needs to be urgently explored in every encephalopathic neonate to avoid any delay in appropriate cPMP substitution, and to maximise treatment benefit. Funding: German Ministry of Education and Research; Orphatec/Colbourne Pharmaceuticals.