Breath Test Determines Severity of Methylmalonic Acidemia Disease

Methylmalonic acidemia is a disorder in which the body cannot break down certain proteins and fats. The result is a buildup of a substance called methylmalonic acid in the blood. This condition is passed down through families and is one of several conditions called an "inborn error of metabolism."

Methylmalonic acidemia affects about 1 in 80,000 newborns and can lead to the buildup of proteins and fats by affecting their metabolism, and cause kidney, liver, and other disease. Methylmalonic acidemia is a genomic disorder that can be caused by mutations in the methylmalonyl-CoA mutase (MMUT) gene.


A large team of medical genomic scientists at the National Human Genome Research Institute (Bethesda, MD, USA) developed a non-invasive test that gauges disease severity by measuring patients' metabolism though the levels of 1-¹³C-propionate in their breath. The team administered their test to 57 methylmalonic acidemia (MMA) patients and 16 healthy volunteers to find patients with severe subtypes of the disease had low propionate oxidation levels, while those with less severe disease or who had been treated with liver transplants had near-normal propionate oxidation levels.

Isotopomer enrichment (¹³CO₂/¹²CO₂) was measured in exhaled breath after an enteral bolus of sodium-1-¹³C-propionate, and normalized for CO₂ production. 1-¹³C-propionate oxidation was then correlated with clinical, laboratory, and imaging parameters collected via a dedicated natural history protocol. Breath samples were collected via disposable breath collection kits (EasySampler Breath Test Kit, QuinTron, Santa Maria, CA, USA) prior to isotope administration, and at specified time points over two hours. A second method, utilizing the BreathID Exalenz device (Meridian Bioscience, Cincinnati, OH, USA) was also employed.

The scientists reported that Lower propionate oxidation was observed in patients with the severe mut⁰ and cblB subtypes of MMA, but was near normal in those with the cblA and mut⁻ forms of the disorder. Liver transplant recipients demonstrated complete restoration of 1-¹³C-propionate oxidation to control levels. 1-¹³C-propionate oxidation correlated with cognitive test result, growth indices, bone mineral density, renal function, and serum biomarkers. Test repeatability was robust in controls and in MMA subjects (mean coefficient of variation 6.9% and 12.8%, respectively), despite widely variable serum methylmalonic acid concentrations in the patients.

Charles P. Venditti, MD, PhD, the principal investigator and senior author of the study, said, “Our next goal is to see if this specialized breath test can detect increase in carbon 13 propionate oxidation after gene, mRNA, or genome editing therapies. This way, we can also use this test to measure how effective these treatments are in restoring MMUT function.”

The authors concluded that propionate oxidative capacity, as measured with 1-¹³C-propionate breath testing, predicts disease severity and clinical outcomes, and could be used to assess the therapeutic effects of liver-targeted genomic therapies for MMA and related disorders of propionate metabolism. The study was published on April 5, 2021 in the journal Genetics in Medicine.

Related Links:
National Human Genome Research Institute
QuinTron
Meridian Bioscience