Efficacy and safety of cyclic pyranopterin monophosphate substitution in severe molybdenum cofactor deficiency type A: a prospective cohort study

Bernd C Schwahn, Francjan van Spronsen, Abdel Ali Belaidi, Stephen Bowhay, John Christodoulou, Terry G J Derks, Julia B Hennermann, Elisabeth Jameson, Kai Konig, Tracy McGregor, Esperanza Font-Montgomery, Jose Angel Santamaria-Araujo, Saikat Santra, Mamta Vaidya, Anne Vierzig, Evangeline Wassmer, Ilona Weis, Flora Yuen-Wait Wong, Alex Veldman, Guenter Schwarz

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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 mug/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.
Original languageEnglish
Pages (from-to)1955 - 1963
Number of pages9
JournalThe Lancet
Publication statusPublished - 2015

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