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On the joys of combining pediatric clinical chemistry and research on inborn errors of metabolism.

One of the true joys of working as a clinical chemist in a children's hospital and doing research involving an inborn error of metabolism is that the clinical and research aspects of one's career are often complementary. I have found this to be especially true in the area of mitochondrial fatty acid [beta]-oxidation (FAO). This is a complex pathway whose proper functioning is critical to the energy metabolism of the human body. Errors in this pathway frequently present in infancy and childhood and may be fatal if not recognized and treated. In addition, new inborn errors of FAO are still being elucidated as more information is gathered about the intricacies of this system. Studying this pathway is a rewarding and occasionally frustrating blend of the clinical chemist's roles in providing clinical information to aid in patient diagnosis and therapeutic monitoring and in developing new methods to accomplish these tasks.

Sometimes a new assay is born in a research setting and then finds a clinical home. The assay measuring 3-hydroxy-fatty acids (30HFAs) is such an assay. Developed as a research tool, this assay was found to be clinically useful for helping to diagnose disorders in the t,-3hydroxyacyl-CoA dehydrogenases, which are involved in the third enzymatic step in mitochondrial FAO (1). Subsequently, we have found the assay to be useful not only as a diagnostic tool, but also for monitoring treatment and health status in long-chain 3-hydroxyacyl CoA dehydrogenase (LCHAD)-deficient patients. The assay continues to be an extremely useful research tool.

Since the assay's inception, we have added the quantification of 3-hydroxy-octadecanoic acid (3-OHC18) to the assay profile. This has given us quantitative assays for the 3-OH species with chain lengths from C6 to C18 and has added to the diagnostic usefulness and research capability of the assay (2). Research on the utilization and metabolism of stearate (C18 fatty acid) is ongoing.

Another research area that uses this assay involves the quantification of 30HFAs in culture media of skin fibroblasts from healthy and LCHAD-deficient individuals. The result of feeding the cultured cells with medium-chain triglycerides (MCTs), which is the treatment of choice for LCHAD-deficient patients, has provided information about the effectiveness and possible actions of this treatment in patients. We have shown that MCTs not only bypass the long-chain defect, but actually decrease the amount of accumulation of long-chain intermediates by an as yet unknown mechanism (3). Decanoate (C10 fatty acid) shows this effect to a greater extent than octanoate (C8). We have also shown that although odd-numbered MCTs (C7 and C9 fatty acids) also demonstrate this effect, they do so much less efficiently than even-numbered MCTs (4).

A particularly intriguing recent finding with the 30HFA assay has become the center of a new line of research. We are finding that normal fibroblasts, when fed intermediate-chain-length fatty acids, actually add two-carbon units to the molecule in the process of oxidizing it. Fig. 1 illustrates this completely unexpected finding. When C10 fatty acid is fed to the cells, they accumulate 3-OH-C12; feeding the cells C12 fatty acid leads to the accumulation of 3-OH-C14. The implication of this finding is that the FAO pathway is functioning in an unexpected and unknown way, involving steps that will have to be elucidated. This line of research beautifully illustrates the fun of performing research that may end up having wide-reaching implications in a clinical field.

[FIGURE 1 OMITTED]

As a clinical tool, this assay quickly established itself as an important part of the laboratory evaluation of patients suspected of having a FAO defect. We expect it to continue to provide us with new insights into the workings of this complex pathway.

This is only a small example of how clinical chemists work at the interface between basic research and clinical science, but it makes concrete for me the joy that comes from seeing one's scientific work applied for the benefit of patients.

References

(1.) Jones PM, Quinn R, Fennessey PV, Tjoa S, Goodman SI, Fiore S, et al. Improved stable isotope dilution-gas chromatography-mass spectrometry method for serum or plasma free 3-hydroxy-fatty acids and its utility for the study of disorders of mitochondrial fatty acid 0-oxidation. Clin Chem 2000;46:149-55.

(2.) Jones PM, Tjoa S, Fennessey PV, Goodman SI, Bennett MJ. Addition of quantitative 3-hydroxyoctadecanoic acid (3-0H-C18) to the stable isotope gas chromatography-mass spectrometry method for measuring 3-hydroxy-fatty acids. Clin Chem 2002;48:176-9.

(3.) Jones PM, Butt Y, Bennett MJ. Accumulation of 3-hydroxy-fatty acids in the culture medium of long-chain L-3-hydroxyacyl CoA dehydrogenase and mitochondrial trifunctional protein deficient skin fibroblasts: Implications for medium chain triglyceride dietary treatment of LCHAD deficiency. Pediatr Res 2003;53:783-7.

(4.) Jones PM, Butt YM, Bennett MJ. Effects of odd-numbered medium-chain fatty acids on the accumulation of long-chain 3-hydroxy-fatty acids in long-chain L-3-hydroxyacyl CoA dehydrogenase (LCHAD) and mitochondrial trifunctional protein (MTFP) deficient skin fibroblasts. Mol Genet Metab; in press (doi: 10.1016/j.ymgme.2003. 11.009).

Patricia M. Jones

Department of Pathology University of Texas Southwestern Medical Center and Children's Medical Center of Dallas Dallas, TX 75235

DOI: 10.1373/clinchem.2003.030668
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Title Annotation:The Clinical Chemist
Author:Jones, Patricia M.
Publication:Clinical Chemistry
Date:Mar 1, 2004
Words:846
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