Universität zu Köln

Schwahn, Bernd C., Van Spronsen, Francjan J., Belaidi, Abdel A., Bowhay, Stephen, Christodoulou, John ORCID: 0000-0002-8431-0641, Derks, Terry G., Hennermann, Julia B., Jameson, Elisabeth, Koenig, Kai, McGregor, Tracy L., Font-Montgomery, Esperanza, Santamaria-Araujo, Jose A., Santra, Saikat ORCID: 0000-0002-7497-3556, Vaidya, Mamta, Vierzig, Anne, Wassmer, Evangeline, Weis, Ilona, Wong, Flora Y., Veldman, Alex and Schwarz, Guenter ORCID: 0000-0002-2118-9338 (2015). Efficacy and safety of cyclic pyranopterin monophosphate substitution in severe molybdenum cofactor deficiency type A: a prospective cohort study. Lancet, 386 (10007). S. 1955 - 1964. NEW YORK: ELSEVIER SCIENCE INC. ISSN 1474-547X

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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 mu g/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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Schwahn, Bernd C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Van Spronsen, Francjan J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Belaidi, Abdel A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Bowhay, Stephen UNSPECIFIED UNSPECIFIED UNSPECIFIED Christodoulou, John UNSPECIFIED orcid.org/0000-0002-8431-0641 UNSPECIFIED Derks, Terry G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hennermann, Julia B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Jameson, Elisabeth UNSPECIFIED UNSPECIFIED UNSPECIFIED Koenig, Kai UNSPECIFIED UNSPECIFIED UNSPECIFIED McGregor, Tracy L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Font-Montgomery, Esperanza UNSPECIFIED UNSPECIFIED UNSPECIFIED Santamaria-Araujo, Jose A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Santra, Saikat UNSPECIFIED orcid.org/0000-0002-7497-3556 UNSPECIFIED Vaidya, Mamta UNSPECIFIED UNSPECIFIED UNSPECIFIED Vierzig, Anne UNSPECIFIED UNSPECIFIED UNSPECIFIED Wassmer, Evangeline UNSPECIFIED UNSPECIFIED UNSPECIFIED Weis, Ilona UNSPECIFIED UNSPECIFIED UNSPECIFIED Wong, Flora Y. UNSPECIFIED UNSPECIFIED UNSPECIFIED Veldman, Alex UNSPECIFIED UNSPECIFIED UNSPECIFIED Schwarz, Guenter UNSPECIFIED orcid.org/0000-0002-2118-9338 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-387040
DOI:	10.1016/S0140-6736(15)00124-5
Journal or Publication Title:	Lancet
Volume:	386
Number:	10007
Page Range:	S. 1955 - 1964
Date:	2015
Publisher:	ELSEVIER SCIENCE INC
Place of Publication:	NEW YORK
ISSN:	1474-547X
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Chemistry > Institute of Biochemistry
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language GENOMIC STRUCTURE; GENES MOCS1; MUTATIONS; BIOSYNTHESIS; FEATURES; URINE Multiple languages Medicine, General & Internal Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/38704