Efficacy and safety of cyclic pyranopterin monophosphate substitution in severe molybdenum cofactor deficiency type A: a prospective cohort study.
Lancet
; 386(10007): 1955-1963, 2015 Nov 14.
Article
em En
| MEDLINE
| ID: mdl-26343839
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.
Texto completo:
1
Coleções:
01-internacional
Contexto em Saúde:
2_ODS3
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6_ODS3_enfermedades_notrasmisibles
Base de dados:
MEDLINE
Assunto principal:
Compostos Organofosforados
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Pterinas
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Erros Inatos do Metabolismo dos Metais
Tipo de estudo:
Diagnostic_studies
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Etiology_studies
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Guideline
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Incidence_studies
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Observational_studies
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Risk_factors_studies
Limite:
Female
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Humans
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Male
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Newborn
Idioma:
En
Revista:
Lancet
Ano de publicação:
2015
Tipo de documento:
Article