Coupled brain and urine spectroscopy - in vivo metabolomic characterization of HMG-CoA lyase deficiency in 5 patients

Mol Genet Metab. 2017 Jun;121(2):111-118. doi: 10.1016/j.ymgme.2017.03.006. Epub 2017 Mar 30.


Background: 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.

Methods: Urine samples, brain MRI and 1H-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 reference 1H 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.

Results: 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.

Conclusion: 3-Methylglutaric, 3-hydroxyisovaleric and 3-hydroxy-3-methylglutaric acids identified on urine 1H-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.

Keywords: 3-hydroxy-3-methylglutaric aciduria; Brain spectroscopy; Cerebellum; HMG-CoA lyase deficiency; Urine spectroscopy; White matter.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetyl-CoA C-Acetyltransferase / chemistry
  • Acetyl-CoA C-Acetyltransferase / deficiency*
  • Acetyl-CoA C-Acetyltransferase / metabolism
  • Acetyl-CoA C-Acetyltransferase / urine
  • Amino Acid Metabolism, Inborn Errors / diagnostic imaging
  • Amino Acid Metabolism, Inborn Errors / metabolism*
  • Amino Acid Metabolism, Inborn Errors / urine*
  • Brain / diagnostic imaging*
  • Brain / metabolism*
  • Brain Chemistry*
  • Cerebellum / metabolism
  • Child
  • Child, Preschool
  • Female
  • Humans
  • Hydrogen-Ion Concentration
  • Infant
  • Infant, Newborn
  • Magnetic Resonance Imaging
  • Male
  • Meglutol / analogs & derivatives
  • Meglutol / metabolism
  • Meglutol / urine*
  • Metabolomics / methods*
  • Proton Magnetic Resonance Spectroscopy
  • Urine / chemistry
  • Valerates / metabolism
  • White Matter / metabolism


  • Valerates
  • beta-hydroxyisovaleric acid
  • 3-methylglutaric acid
  • Meglutol
  • Acetyl-CoA C-Acetyltransferase

Supplementary concepts

  • 3-Hydroxy-3-Methylglutaryl-CoA Lyase Deficiency