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1H-MRS in glutaric aciduria type 1: impact of biochemical phenotype and age on the cerebral accumulation of neurotoxic metabolites

  • Original Article
  • Published:
Journal of Inherited Metabolic Disease

Abstract

Background

In glutaric aciduria type 1 (GA1) the neurotoxic metabolites glutaric acid (GA) and 3-hydroxyglutaric acid (3-OH-GA) accumulate within the brain. Due to limited efflux across the blood–brain-barrier biochemical monitoring of intracerebrally accumulating toxic metabolites is as yet not possible.

Aims

To investigate brain metabolic patterns in glutaric aciduria type 1 using 1H magnetic resonance spectroscopy (1H-MRS) with focus on detecting the disease-related neurotoxic metabolites GA and 3-OH-GA.

Patients and methods

Short echo time 1H-MRS was performed in 13 treated metabolically stable patients. Twenty-one white matter and 16 basal ganglia spectra from 12 patients (age range 7 months - 22 years) were included. Subgroups based on age, biochemical phenotype and/or associated MRI changes were compared with control spectra.

Results

GA was elevated in white matter of patients. 3-OH-GA was elevated in white matter of older patients with associated signal changes on MRI, which was structurally characterized by decreased creatine and phosphocreatine (tCr) and elevated choline (Cho). Metabolite changes differed with biochemical phenotype and disease duration: Low excretors with up to 30 % residual enzyme activity had only mildly, non-significantly elevated GA and mildly subnormal N-acetylaspartate (tNAA). High excretors with complete lack of enzyme activity had significantly increased GA, tNAA was mildly subnormal in younger and decreased in older high excretors.

Conclusions

GA and 3-OH-GA are detectable by in vivo 1H-MRS, which might finally allow biochemical follow-up monitoring of intracerebrally accumulating neurotoxic metabolites in GA1. A high excreting phenotype appears to be a risk factor for cerebral GA accumulation and progressive neuroaxonal compromise despite a similar clinical course in younger high and low excreting patients. This might have consequences for long-term outcome.

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Acknowledgments

We thank the patients with GA1 and their parents for participation in this study. The study was supported by a grant from the Kindness for Kids Foundation, Munich, Germany, to IH.

Conflict of Interest

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Authors and Affiliations

  1. Department of Neuroradiology, University of Heidelberg Medical Center, Im Neuenheimer Feld 400, D-69120, Heidelberg, Germany

    Inga Harting, Angelika Seitz & Martin Bendszus

  2. Department of General Pediatrics, Division of Inherited Metabolic Disease, University Children’s Hospital, Heidelberg, Germany

    Nikolas Boy, Jana Heringer & Stefan Kölker

  3. Department of Physics and Medical Technology, VU University Medical Center, Amsterdam, Netherlands

    Petra J.W. Pouwels

Authors
  1. Inga Harting
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  2. Nikolas Boy
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  4. Angelika Seitz
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  6. Petra J.W. Pouwels
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  7. Stefan Kölker
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Corresponding author

Correspondence to Inga Harting.

Additional information

Communicated by: Jutta Gaertner

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Suppl.Table 1

Previously reported 1H-MRS of cerebral white matter and basal ganglia. (n: number of patients with MRS; AEC: acute encephalopathic crisis; bgl: basal ganglia; d: day(s); mo: months; yrs: years; TE: echo time) (DOCX 66 kb)

Suppl. Fig. 1

Concentration differences of tNAA and MMLip20 due to inclusion of GA in the basis set (std&GA -std basis sets) plotted against corresponding GA values together with results of linear fitting (tNAA: y=0.16*x+0.023; MMLip20: y=-1.09*x+-0.08). (GIF 7 kb)

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Harting, I., Boy, N., Heringer, J. et al. 1H-MRS in glutaric aciduria type 1: impact of biochemical phenotype and age on the cerebral accumulation of neurotoxic metabolites. J Inherit Metab Dis 38, 829–838 (2015). https://doi.org/10.1007/s10545-015-9826-8

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  • DOI: https://doi.org/10.1007/s10545-015-9826-8

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