Volatile organic compounds (VOCs) in the breath of people with ALS may differ from those with cervical spondylotic myelopathy (CSM), according to findings published May 23 in Scientific Reports. The results suggest that breath VOCs may merit investigation diagnostic biomarkers for ALS, as explored for some forms of lung cancer (Phillips et al., 2009, Horvath et al., 2009) , but future work will be required to determine their clinical utility and potential as a progression biomarker.
The study, led by Enyou Li of Harbin Medical University in Harbin, China, compared breath samples from 28 ALS patients and 13 CSM patients, using gas chromatography/mass spectrometry. Out of 242 features found in the breath samples, 4 metabolites stood out as potential biomarkers: monoammonium carbamic acid, (S)-l-alanine ethylamide, N,N-dimethyl guanidine, and (p-hydroxyphenyl)-phosphonic acid, each of which was elevated in CSM patients versus ALS patients. Combined, the four compounds gave a high sensitivity and specificity for distinguishing the two diagnoses. The biological pathways accounting for the differences in the two diseases have not been determined.
Several questions remain unanswered. The time since diagnosis was not reported in the study, and it is unclear whether the samples were obtained shortly after diagnosis, when the distinction between the two conditions is most difficult to determine on clinical grounds alone. Reference values in healthy controls were also not reported, which may be useful in determining whether the higher values in CSM or the lower ones in ALS represents the metabolically unusual condition, and thus might provide insight into pathogenesis.
“CSM of sufficient severity to result in clinical impairment would most certainly be visualized by routine MRI,” Erik Pioro of the Cleveland Clinic in Ohio, wrote to the ALS Research Forum. Analysis of volatile compounds in breath, with the requisite gas chromatography-mass spec analysis, may be “overkill,” he said. Nonetheless, “because CSM is not such an infrequent confounding diagnosis, and one that may coexist with ALS, comparative analysis of VOCs in exhaled breath could serve to identify whether the patient does, in fact, have ALS as well as CSM.”
Robert Bowser of Barrow Neurological Institute in Phoenix commented that, “A breath test would obviously be a very easy and non-invasive method to collect samples from patients for diagnostic purposes,” but the challenge of standardizing collection methods is not trivial. “There is value in further validation of this approach to develop diagnostic biomarkers for ALS,” he added. “However in the current study, few total samples were used, and the clinical characteristics of the ALS patients were not well-defined. A much larger study is required to validate these initial findings. In addition, a longitudinal study would be very interesting to determine if changes in the VOCs occur over time and disease progression.”
As for whether such a test, if shown to be valid in larger samples, might serve a clinical purpose beyond research studies, Bowser said, “Many challenges remain in moving this method to the clinic. The sample collection and analysis must occur in a short time frame, due to stability of the VOCs (some of the VOCs may be lost during the time-consuming procedures required for the testing). Standardized measures to accurately quantify each VOC are still in development. Relatively inexpensive and portable instrumentation that provide accurate analysis of breath samples are needed to move this towards the clinic. Larger studies including additional disease mimics are required to determine the diagnostic accuracy of the test. Variability of the method is also unknown, which could dramatically impact results and ultimately the predicted diagnosis. Overall, I would not predict that this approach would get to the ALS clinic for a number of years.”
Wang C, Li M, Jiang H, Tong H, Feng Y, Wang Y, Pi X, Guo L, Nie M, Feng H, Li E. Comparative Analysis of VOCs in Exhaled Breath of Amyotrophic Lateral Sclerosis and Cervical Spondylotic Myelopathy Patients. Sci Rep. 2016 May 23;6:26120. [Pubmed].