Organic acid profile of isovaleric acidemia: a comprehensive metabolomics approach
Date
2013Author
Dercksen, Marli
Koekemoer, Gerhard
Mienie, Lodewyk J.
Reinecke, Carolus J.
Duran, Marinus
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Show full item recordAbstract
Isovaleric acidemia (IVA, MIM 248600) can be
a severe and potentially life-threatening disease in affected
neonates, but with a positive prognosis on treatment for
some phenotypes. This study presents the first application
of metabolomics to evaluate the metabolite profiles derived
from urine samples of untreated and treated IVA patients as
well as of obligate heterozygotes. All IVA patients carried
the same homozygous c.367 G[A nucleotide change in
exon 4 of the IVD gene but manifested phenotypic diversity.
Concurrent class analysis (CONCA) was used to
compare all the metabolites from the original complete
data set obtained from the three case and two control
groups used in this investigation. This application of
CONCA has not been reported previously, and is used here
to compare four different modes of scaling of all metabolites.
The variables important in discrimination from the
CONCA thus enabled the recognition of different metabolic
patterns encapsulated within the data sets that would
not have been revealed by using only one mode of scaling.
Application of multivariate and univariate analyses
disclosed 11 important metabolites that distinguished
untreated IVA from controls. These included well-established
diagnostic biomarkers of IVA, endogenous
detoxification markers, and 3-hydroxycaproic acid, an
indicator of ketosis, but not reported previously for this
disease. Nine metabolites were identified that reflected the
effect of treatment of IVA. They included detoxification
products and indicators related to the high carbohydrate
and low protein diet which formed the hallmark of the
treatment. This investigation also provides the first comparative
metabolite profile for heterozygotes of this inherited
metabolic disorder. The detection of informative
metabolites in even very low concentrations in all three
experimental groups highlights the potential advantage of
the holistic mode of analysis of inherited metabolic diseases
in a metabolomics investigation.
URI
http://hdl.handle.net/10394/14679https://doi.org/10.1007/s11306-013-0501-5
https://link.springer.com/article/10.1007/s11306-013-0501-5