title: Coupled brain and urine spectroscopy - in vivo metabolomic characterization of HMG-CoA lyase deficiency in 5 patients.
abstract: 3-Hydroxy-3-Methylglutaryl-Coenzyme A (HMG-CoA) lyase deficiency is a rare inborn error of leucine metabolism and ketogenesis. Despite recurrent hypoglycemia and metabolic decompensations, most patients have a good clinical and neurological outcome contrasting with abnormal brain magnetic resonance imaging (MRI) signals and consistent abnormal brain proton magnetic resonance spectroscopy (1H-MRS) metabolite peaks. Identifying these metabolites could provide surrogate markers of the disease and improve understanding of MRI-clinical discrepancy and follow-up of affected patients.
  
  
  
  Urine samples, brain MRI and1H-MRS in 5 patients with HMG-CoA lyase deficiency (4 boys and 1 girl aged from 25days to 10years) were, for each patient, obtained on the same day. Brain and urine spectroscopy were performed at the same pH by studying urine at pH 7.4. Due to pH-induced modifications in chemical shifts and because reference1H NMR spectra are obtained at pH 2.5, spectroscopy of normal urine added with the suspected metabolite was further performed at this pH to validate the correct identification of compounds.
  
  
  
  Mild to extended abnormal white matter MRI signals were observed in all cases. Brain spectroscopy abnormal peaks at 0.8-1.1ppm, 1.2-1.4ppm and 2.4ppm were also detected by urine spectroscopy at pH 7.4. Taking into account pH-induced changes in chemical shifts, brain abnormal peaks in patients were formally identified to be those of 3-hydroxyisovaleric, 3-methylglutaconic, 3-methylglutaric and 3-hydroxy-3-methylglutaric acids.
  
  
  
  3-Methylglutaric, 3-hydroxyisovaleric and 3-hydroxy-3-methylglutaric acids identified on urine1H-NMR spectra of 5 patients with HMG-CoA lyase deficiency are responsible for the cerebral spectroscopy signature seen in these patients, validating their local involvement in brain and putative contribution to brain neuropathology.
authors.affiliation: Centre Agréé des Maladies Héréditaires du Métabolisme, Centre de Génétique Humaine, Institute of Pathology and Genetics, Gosselies (Charleroi), Belgium. Electronic address: dominique.roland@ipg.be.
authors.forename: Dominique
authors.initials: D
authors.lastname: Roland
authors.affiliation: Department of Neuroradiology, Roger Salengro Hospital, CHRU Lille, France.
authors.forename: Patrice
authors.initials: P
authors.lastname: Jissendi-Tchofo
authors.affiliation: Department of Biochemistry and Molecular Biology, Laboratory of Endocrinology, Metabolism-Nutrition, Oncology, Pathology Center, CHRU Lille, France.
authors.forename: Gilbert
authors.initials: G
authors.lastname: Briand
authors.affiliation: Inserm, Biochemistry and Molecular Biology, HMNO, Center of Biology and Pathology Pierre Marie Degand, CHRU Lille, France.
authors.forename: Joseph
authors.initials: J
authors.lastname: Vamecq
authors.affiliation: Biochemistry and Molecular Biology, HMNO, Center of Biology and Pathology Pierre Marie Degand, CHRU Lille, France.
authors.forename: Monique
authors.initials: M
authors.lastname: Fontaine
authors.affiliation: UDSL, Laboratoire de RMN, UFR Pharmacie, CHRU Lille, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Ultré
authors.affiliation: Hereditary Metabolic Diseases Service, East Center for Biology and Pathology, Lyon Civil Hospices 69677 Bron cedex, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Acquaviva-Bourdain
authors.affiliation: Centre de Référence Maladies Héréditaires du Métabolisme de l'Enfant et de l'Adulte, Jeanne de Flandre Hospital, CHRU Lille, and RADEME EA 7364, Faculty of Medicine, University Lille 2, Lille 59037, France.
authors.forename: Karine
authors.initials: K
authors.lastname: Mention
authors.affiliation: Centre de Référence Maladies Héréditaires du Métabolisme de l'Enfant et de l'Adulte, Jeanne de Flandre Hospital, CHRU Lille, and RADEME EA 7364, Faculty of Medicine, University Lille 2, Lille 59037, France. Electronic address: dries.dobbelaere@chru-lille.fr.
authors.forename: Dries
authors.initials: D
authors.lastname: Dobbelaere
mesh_terms: D000101:Acetyl-CoA C-Acetyltransferase / Q000737:chemistry / Q000172:deficiency* / Q000378:metabolism / Q000652:urine; D000592:Amino Acid Metabolism, Inborn Errors / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000652:urine*; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D001923:Brain Chemistry; D002531:Cerebellum / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007223:Infant; D007231:Infant, Newborn; D008279:Magnetic Resonance Imaging; D008297:Male; D015093:Meglutol / Q000031:analogs & derivatives / Q000378:metabolism / Q000652:urine*; D055432:Metabolomics / Q000379:methods*; D066244:Proton Magnetic Resonance Spectroscopy; D014556:Urine / Q000737:chemistry; D014631:Valerates / Q000378:metabolism; D066127:White Matter / Q000378:metabolism
chemical_list: D014631:Valerates; C004961:beta-hydroxyisovaleric acid; C033686:3-methylglutaric acid; D015093:Meglutol; D000101:Acetyl-CoA C-Acetyltransferase
keywords: 3-hydroxy-3-methylglutaric aciduria; Brain spectroscopy; Cerebellum; HMG-CoA lyase deficiency; Urine spectroscopy; White matter