A GC/MS-based metabolomic approach for diagnosing citrin deficiency |
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Authors: | Tomiko Kuhara Morimasa Ohse Yoshito Inoue Arthur J L Cooper |
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Institution: | (1) Department of Biochemistry, Division of Human Genetics, Medical Research Institute, Kanazawa Medical University, Uchinada, Kahoku-gun Ishikawa, 920-0293, Japan;(2) Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595, USA |
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Abstract: | Citrin is the hepatic mitochondrial aspartate–glutamate carrier that is encoded by the gene SLC25A13. Citrin deficiency often leads to hyperammonemia, for which the current treatment concept is different from that for primary
hyperammonemias. Metabolite level diagnosis, often referred to as chemical diagnosis, is not always successful in identifying
citrin deficiency immediately or in a timely fashion. We previously made the chemical diagnosis of citrin deficiency in ten
patients from nine families. In order to devise a more rapid and more accurate chemical diagnosis of this disorder than is
currently available, we reinvestigated the gas chromatography/mass spectrometry-based urine metabolome in these patients.
In patients aged 2 to 5 months, prominent biomarkers detected included one or more of the following metabolites: tyrosine,
p-hydroxyphenyllactate, p-hydroxyphenylpyruvate, and N-acetyltyrosine, galactose, galactitol and galactonate, glucose, glucitol, and cystathionine. These biomarkers are less prominent
in older patients, but are not increased in argininosuccinate synthetase deficiency or other hyperammonemias. α-Ketoglutaramate
(KGM), a recently recognized urinary biomarker of primary hyperammonemias associated with defects of the urea cycle, was increased
in most patients with citrin deficiency studied here in spite of normal urinary levels of glutamine (the immediate precursor
of KGM), 5-oxoproline, glutamate, aspartate, and asparagine. Other important urinary biomarkers that should be measured for
differential diagnosis of hyperammonemias, including orotate, uracil, and β-ureidopropionate, were not increased. The presence
of citrulline and citrulline-derived metabolites was noted in all cases. The present study shows that noninvasive urine metabolomics,
together with an analysis of selected metabolites or groups of metabolites, provides a more reliable and rapid chemical diagnosis
of citrin deficiency than was previously available and more readily differentiates this disorder from other hyperammonemic
syndromes. |
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