Researchers also used the test to assess the severity of the disease in people and help determine if they would benefit from surgical or experimental genomic therapies that target the liver. The study results were published in Genetics in Medicine. Scientists at the National Human Genome Research Institute (NHGRI) led the project team, with collaborators from the National Institute of Diabetes and Digestive and Kidney Diseases and the National Institute of Mental Health.
MMA is a rare genomic disease that impairs the body’s ability to metabolize certain proteins and fats. This causes toxic substances to build up, which may result in kidney disease, pancreatitis, movement disorders, intellectual impairments, complications in many organs, and, in severe cases, death. One in 80,000 children born in the United States are diagnosed with MMA during newborn screenings. Currently, MMA is incurable, but people with MMA manage their symptoms through dietary restrictions and vitamin supplements. In extreme cases, patients receive liver or combined liver and kidney transplants, which help restore normal levels of metabolic proteins.
“Vast fluctuations in metabolic substances in the bodies of patients make it difficult for us to tell if treatments like genome editing and transplants are likely to be successful,” said Charles P. Venditti, M.D., Ph.D., senior author and senior investigator in the NHGRI Medical Genomics and Metabolic Genetics Branch. “Instead of looking at levels, we decided to measure metabolism itself.”
One form of MMA is caused by mutations in the methylmalonyl-CoA mutase gene (MMUT), which encodes for the MMUT protein. People with this form of MMA have a deficiency in the MMUT protein, which plays a pivotal part in metabolism. The protein is involved in the biological steps that help break down food, fats, cholesterol and amino acids.
MMUT helps break down food into a chemical byproduct called propionate, which is followed by an integral process involved in metabolism called oxidation. Through oxidation, a healthy body converts propionate into energy and carbon dioxide, which is exhaled, but that process is faulty for people with MMA.
Because MMUT protein function is compromised in people with MMA, Venditti and his team chose to assess how well the MMUT protein helped break down propionate in both patients who did and not did not receive treatment. The researchers believed this would act as a proxy for how much oxidation was happening in a patient’s body.
“We wanted to measure exhaled carbon dioxide because we planned to use a breath test to track oxidation of propionate in a non-invasive way,” said Irini Manoli, M.D., Ph.D., co-author and associate investigator in the NHGRI Medical Genomics and Metabolic Genetics Branch. “The trick was to somehow ‘mark’ the carbon dioxide so we could see which patients are unable to oxidize propionate because of a faulty MMUT protein.”
Usually, the carbon dioxide we exhale as a result of propionate breaking down in the body contains a lighter, more common form of carbon, carbon 12. But because carbon dioxide that contains carbon 12 is released by several metabolic processes in the human body, simply measuring carbon dioxide exhaled by MMA patients would not show how well MMUT helped oxidize propionate.