Researchers develop breath test for rare inherited disorder

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Methylmalonic acidemia (MMA) is a rare genomic condition that disrupts the normal metabolism of certain proteins and fats, resulting in a toxic accumulation of methylmalonic acid in the body. This build-up may lead to irreparable kidney impairment, metabolic liver dysfunction, pancreatitis, intellectual disability and eventually, without treatment, death. Researchers at the National Institutes of Health have now developed a breath test for MMA, based on safe (non-radioactive) stable isotope tracers, publishing their findings in Genetics in Medicine. The test could help physicians determine the severity of the disorder and the prospects for disease improvement following therapies.

One specific form of MMA is caused by mutations in the gene coding the methylmalonyl-CoA mutase (MMUT) enzyme in the liver, which is essential for metabolism of amino acids, fatty acids and cholesterol. As a result of the mutations, patients with MMA fail to effectively oxidize propionate (a metabolic by-product created by the breakdown of food) to carbon dioxide (CO2) during energy production. In milder cases, the mutation can result in a partial deficiency in enzyme activity; in more severe cases, it leads to a complete absence of activity that’s associated with high mortality.

 Metabolism complexity complicates evaluation

Currently, MMA remains incurable, so affected individuals control their symptoms with dietary restrictions, consisting of a special protein-managed diet and vitamin supplements. In severe cases, however, patients require liver or combined liver and kidney transplants to provide metabolic stability. Alternative therapeutic approaches, including gene therapy or genome editing, aim to restore enzyme activity.

“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,” explains senior authorCharles Venditti from the National Human Genome Research Institute (NHGRI). “Instead of looking at levels, we decided to measure metabolism itself.”

To achieve this, the multidisciplinary team – from the National Institute of Diabetes and Digestive and Kidney Diseasesthe National Institute of Mental Health and the NHGRI – investigated the rate of oxidation of propionate to CO2 in MMA patients to compare the MMUT functionality between individuals with and without treatment.

 Non-invasive breath testing assesses MMA

“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,” says co-author Irini Manoli from the NHGRI. “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.”….

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