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

Abstract

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.

• Authors: Bernd C Schwahn, Francjan J Van Spronsen, Abdel A Belaidi, Stephen Bowhay, John Christodoulou, Terry G Derks, Julia B Hennermann, Elisabeth Jameson, Kai König, Tracy L McGregor, Esperanza Font-Montgomery, José A Santamaria-Araujo, Saikat Santra, Mamta Vaidya, Anne Vierzig, Evangeline Wassmer, Ilona Weis, Flora Y Wong, Alex Veldman, Günter Schwarz
• Journal: Lancet (London, England) (Lancet) Vol. 386 Issue 10007 Pg. 1955-1963 (Nov 14 2015) ISSN: 1474-547X [Electronic] England
• PMID: 26343839 (Publication Type: Journal Article, Observational Study, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.

Chemical References

• Organophosphorus Compounds
• Pterins
• nulibry

Topics

• Cohort Studies
• Compassionate Use Trials
• Drug Administration Schedule
• Female
• Humans
• Infant, Newborn
• Male
• Metal Metabolism, Inborn Errors (diagnosis, drug therapy)
• Organophosphorus Compounds (therapeutic use)
• Pterins (therapeutic use)
• Treatment Outcome