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


RESULTS
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.


CONCLUSIONS
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.


BACKGROUND
German Ministry of Education and Research; Orphatec/Colbourne Pharmaceuticals.
Royal Hospital for Sick Children, NHS Greater Glasgow and Clyde, Glasgow, UK; Willink Biochemical Genetics Unit, Saint Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK. Electronic address: bernd.schwahn@cmft.nhs.uk.
Bernd C
BC
Schwahn
Beatrix Children's Hospital, University Medical Center of Groningen, University of Groningen, Groningen, Netherlands.
Francjan J
FJ
Van Spronsen
Institute of Biochemistry, Department of Chemistry, Center for Molecular Medicine Cologne, CECAD Cologne, University of Cologne, Cologne, Germany; Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, VIC, Australia.
Abdel A
AA
Belaidi
Royal Hospital for Sick Children, NHS Greater Glasgow and Clyde, Glasgow, UK.
Stephen
S
Bowhay
Western Sydney Genetics Program, Children's Hospital at Westmead, and Disciplines of Paediatrics & Child Health and Genetic Medicine, University of Sydney, Sydney, NSW, Australia.
John
J
Christodoulou
Beatrix Children's Hospital, University Medical Center of Groningen, University of Groningen, Groningen, Netherlands.
Terry G
TG
Derks
Villa Metabolica, Center for Pediatric and Adolescent Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
Julia B
JB
Hennermann
Willink Biochemical Genetics Unit, Saint Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
Elisabeth
E
Jameson
Department of Pediatrics, Mercy Hospital for Women, Melbourne, VIC, Australia.
Kai
K
König
Department of Pediatrics, Vanderbilt University School of Medicine and Monroe Carell Jr Children's Hospital at Vanderbilt, Nashville, TN, USA.
Tracy L
TL
McGregor
Children's Hospital of Wisconsin, Milwaukee, WI, USA.
Esperanza
E
Font-Montgomery
Orphatec/Colbourne Pharmaceuticals, Niederkassel, Germany.
José A
JA
Santamaria-Araujo
Birmingham Children's Hospital, Birmingham, UK.
Saikat
S
Santra
Paediatric Intensive Care, Bart's Health NHS Trust, Royal London Hospital, London, UK.
Mamta
M
Vaidya
Paediatric Intensive Care, University Children's Hospital, University of Cologne, Cologne, Germany.
Anne
A
Vierzig
Birmingham Children's Hospital, Birmingham, UK.
Evangeline
E
Wassmer
Children's Hospital, Gemeinschaftsklinikum Koblenz-Mayen, Kemperhof, Koblenz, Germany.
Ilona
I
Weis
Monash Newborn, Monash Medical Centre, The Ritchie Centre, Hudson Institute of Medical Research, and The Department of Paediatrics, Monash University, Melbourne, VIC, Australia.
Flora Y
FY
Wong
Orphatec/Colbourne Pharmaceuticals, Niederkassel, Germany; Monash Newborn, Monash Medical Centre, The Ritchie Centre, Hudson Institute of Medical Research, and The Department of Paediatrics, Monash University, Melbourne, VIC, Australia.
Alex
A
Veldman
Institute of Biochemistry, Department of Chemistry, Center for Molecular Medicine Cologne, CECAD Cologne, University of Cologne, Cologne, Germany; Orphatec/Colbourne Pharmaceuticals, Niederkassel, Germany.
Günter
G
Schwarz
D015331:Cohort Studies; D057176:Compassionate Use Trials; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008664:Metal Metabolism, Inborn Errors / Q000175:diagnosis / Q000188:drug therapy*; D009943:Organophosphorus Compounds / Q000627:therapeutic use*; D011622:Pterins / Q000627:therapeutic use*; D016896:Treatment Outcome
D009943:Organophosphorus Compounds; D011622:Pterins; C549445:nulibry