Toward Broader Inclusion of Liquid Chromatography-Mass Spectrometry in the Clinical Laboratory

Mass spectrometry is widely appreciated as a powerful analytical method, characterized by high sensitivity and high information content, that can be used for both the qualitative and quantitative analysis of nearly all types of molecules. In light of this power, I would propose that mass spectrometry is ready for a substantially larger role in routine clinical analyses.In this issue of Clinical Chemistry , Muddiman and coworkers from the Mayo Clinic present reports in which two levels of mass spectrometry experiments are used to detect and characterize transthyretin variants by accurately measuring the molecular mass of the intact protein isolated from human serum (1)(2). As described by the authors, transthyretin variants can form amyloid in tissues that may ultimately damage those tissues. Currently, diagnosis is generally made after symptoms appear by detecting the amyloid in biopsies of the affected tissue.The report by Nepomuceno et al. (1) uses a sophisticated dual-source electrospray ionization-Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometry system to make the transthyretin molecular mass measurement and detect the variant protein. These FT-ICR instruments are the current pinnacle of mass spectrometry performance, vastly exceeding any other instrument type in all relevant issues of merit, including resolution, sensitivity, and mass range. The power of the FT-ICR instrument, and the unique dual-ion source designed and developed by this group (3), is used to carry out an experiment in which the molecular mass of the intact transthyretin protein is measured with an extraordinary mass accuracy of <3 parts per million (i.e., mass accuracy to within 0.05 Da for the 13 761-Da protein). The result of this mass accuracy is illustrated by both the proper detection of several known transthyretin variants and the detection and characterization of a novel double-mutant based on a 2-Da mass difference relative to the wild-type …