title: Hyperprolinemia in Type 2 Glutaric Aciduria and MADD-Like Profiles.
abstract: Classical neonatal-onset glutaric aciduria type 2 (MAD deficiency) is a severe disorder of mitochondrial fatty acid oxidation associated with poor survival. Secondary dysfunction of acyl-CoA dehydrogenases may result from deficiency for riboflavin transporters, leading to severe disorders that, nevertheless, are treatable by riboflavin supplementation. In the last 10 years, we identified nine newborns with biochemical features consistent with MAD deficiency, only four of whom survived past the neonatal period. A likely iatrogenic cause of riboflavin deficiency was found in two premature newborns having parenteral nutrition, one of whom recovered upon multivitamin supplementation, whereas the other died before diagnosis. Four other patients had demonstrated mutations involving ETF or ETF-DH flavoproteins, whereas the remaining three patients presumably had secondary deficiencies of unknown mechanism. Interestingly, six newborns among the seven tested for plasma amino acids had pronounced hyperprolinemia. In one case, because the initial diagnostic workup did not include organic acids and acylcarnitine profiling, clinical presentation and hyperprolinemia suggested the diagnosis. Analysis of our full cohort of >50,000 samples from >30,000 patients suggests that the proline/alanine ratio may be a good marker of MAD deficiency and could contribute to a more effective management of the treatable forms.
authors.affiliation: Centre de Référence des Maladies Héréditaires du Métabolisme, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, University of Paris Descartes, Institut Imagine, Paris, France. clement.pontoizeau@aphp.fr.|Service de Biochimie Métabolomique et Protéomique, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, 149 rue de Sèvres, 75015, Paris, France. clement.pontoizeau@aphp.fr.
authors.forename: Clément
authors.initials: C
authors.lastname: Pontoizeau
authors.affiliation: Centre de Référence des Maladies Héréditaires du Métabolisme, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, University of Paris Descartes, Institut Imagine, Paris, France.|Service de Biochimie Métabolomique et Protéomique, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, 149 rue de Sèvres, 75015, Paris, France.|INSERM UMR-S 1124, University of Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Habarou
authors.affiliation: Centre de Référence des Maladies Héréditaires du Métabolisme, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, University of Paris Descartes, Institut Imagine, Paris, France.
authors.forename: Anaïs
authors.initials: A
authors.lastname: Brassier
authors.affiliation: Service Maladies Héréditaires du Métabolisme et Dépistage Néonatal, Centre de Biologie et Pathologie Est, CHU Lyon, Bron, France.
authors.forename: Alice
authors.initials: A
authors.lastname: Veauville-Merllié
authors.affiliation: Centre de Référence des Maladies Héréditaires du Métabolisme, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, University of Paris Descartes, Institut Imagine, Paris, France.
authors.forename: Coraline
authors.initials: C
authors.lastname: Grisel
authors.affiliation: Centre de Référence des Maladies Héréditaires du Métabolisme, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, University of Paris Descartes, Institut Imagine, Paris, France.
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Arnoux
authors.affiliation: Service Maladies Héréditaires du Métabolisme et Dépistage Néonatal, Centre de Biologie et Pathologie Est, CHU Lyon, Bron, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Vianey-Saban
authors.affiliation: Centre de Référence des Maladies Héréditaires du Métabolisme, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, University of Paris Descartes, Institut Imagine, Paris, France.|Service de Biochimie Métabolomique et Protéomique, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, 149 rue de Sèvres, 75015, Paris, France.|INSERM UMR-S 1124, University of Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Robert
authors.initials: R
authors.lastname: Barouki
authors.affiliation: Centre de Référence des Maladies Héréditaires du Métabolisme, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, University of Paris Descartes, Institut Imagine, Paris, France.|Service de Biochimie Métabolomique et Protéomique, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, 149 rue de Sèvres, 75015, Paris, France.|INSERM UMR-S 1124, University of Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Bernadette
authors.initials: B
authors.lastname: Chadefaux-Vekemans
authors.affiliation: Service Maladies Héréditaires du Métabolisme et Dépistage Néonatal, Centre de Biologie et Pathologie Est, CHU Lyon, Bron, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Acquaviva
authors.affiliation: Centre de Référence des Maladies Héréditaires du Métabolisme, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, University of Paris Descartes, Institut Imagine, Paris, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: de Lonlay
authors.affiliation: Centre de Référence des Maladies Héréditaires du Métabolisme, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, University of Paris Descartes, Institut Imagine, Paris, France.|Service de Biochimie Métabolomique et Protéomique, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, 149 rue de Sèvres, 75015, Paris, France.|INSERM UMR-S 1124, University of Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Chris
authors.initials: C
authors.lastname: Ottolenghi