Abstract:
The diagnosis of respiratory chain deficiencies
(RCDs) is complicated and the need for a diagnostic biomarker
or biosignature has been widely expressed. In this
study, the metabolic profile of a selected group of 29 RCD
patients,with a predominantly muscle disease phenotype, and
22 controls were investigated using targeted and untargeted
analyses of three sub-sections of the human metabolome,
including urinary organic acids and amino acids [measured by
gas chromatography–mass spectrometry (GC–MS)], as well
as acylcarnitines (measured by electrospray ionization tandem
MS). Although MS technologies are highly sensitive and
selective, they are restrictive by being applied only to subsections
of the metabolome; an untargeted nuclear magnetic
resonance (NMR) spectroscopy approach was therefore also
included. After data reduction and pre-treatment, a biosignature
comprising six organic acids (lactic, succinic, 2-hydroxyglutaric,
3-hydroxyisobutyric, 3-hydroxyisovaleric and
3-hydroxy-3-methylglutaric acids), six amino acids (alanine,
glycine, glutamic acid, serine, tyrosine and a-aminoadipic
acid) and creatine,was constructed fromuni- and multivariate
statistical analyses and verified by cross-validation. The
results presented here provide the first proof-of-concept
that the metabolomics approach is capable of defining a biosignature
for RCDs. We postulate that the composite of
organic acids & amino acids[creatine[betaine[carnitines
represents the basic biosignature for RCDs. Validated
through a prospective study, this could offer an improved
ability to assign individual patients to a group with defined
RCD characteristics and improve case selection for biopsy
procedures, especially in infants and children.
