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01.09.2015 | Original Article

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

verfasst von: Inga Harting, Nikolas Boy, Jana Heringer, Angelika Seitz, Martin Bendszus, Petra J.W. Pouwels, Stefan Kölker

Erschienen in: Journal of Inherited Metabolic Disease | Ausgabe 5/2015

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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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Titel: 1H-MRS in glutaric aciduria type 1: impact of biochemical phenotype and age on the cerebral accumulation of neurotoxic metabolites
verfasst von: Inga Harting
Nikolas Boy
Jana Heringer
Angelika Seitz
Martin Bendszus
Petra J.W. Pouwels
Stefan Kölker
Publikationsdatum: 01.09.2015
Verlag: Springer Netherlands
Erschienen in: Journal of Inherited Metabolic Disease / Ausgabe 5/2015
Print ISSN: 0141-8955
Elektronische ISSN: 1573-2665
DOI: https://doi.org/10.1007/s10545-015-9826-8

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