Breath biopsy in inborn errors of metabolism: A proof-of-principle study in propionic acidemia

Background: Impaired oxidation of branched chain amino acids may give rise to volatile organic compounds (VOCs). We hypothesized that VOCs will be present in exhaled breath of participants with propionic acidemia (PA), and their relative abundance would correlate with clinical and biochemical characteristics of the disease.

Methods: We enrolled 5 affected participants from a natural history study of PA (ClinicalTrials.gov ID NCT02890342) plus five age- and sex-matched unaffected controls. We collected exhaled breath using a non-invasive breath sampling platform paired with thermal desorption-gas chromatography-mass spectrometry. Clinical and biochemical parameters were correlated with the relative abundance of VOCs.

Results: Unbiased screening identified several candidate VOC biomarkers of PA. One candidate putatively identified as 3-pentanone was the most abundant (45-fold higher in cases vs. controls, p-value <0.05). 3-Pentanone abundance positively correlated with plasma propionylcarnitine (p = 0.01), plasma 2-methylcitrate (p < 0.05), 3-OH-propionate (p < 0.01), full scale IQ (p < 0.01), and showed a statistical trend with height z-scores (p = 0.08). It inversely correlated with the whole-body in vivo oxidation of 1-¹³C-propionate (p < 0.05). In a participant who received an orthotopic liver transplant, 3-pentanone levels were lower and segregated with "mild" PA.

Conclusion: Non-invasive breath sampling is a promising method to identify and quantitate VOCs that correlate with the clinical and biochemical parameters of PA. Our proof-of-principle findings may have wide implications for the diagnosis and severity stratification of inborn errors of metabolism affecting oxidation of amino acids which might be monitored in a similar fashion.

Synopsis: A proof-of-principle study putatively identifies 3-pentanone in exhaled breath as a correlate of the clinical and biochemical outcomes in propionic acidemia.