Genomic methods, specifically whole exome and whole genome sequencing, have been at the center of diagnosing rare, genetic diseases. For example, diagnosing the inborn errors of metabolism (IEM) disease, Methylmalonic aciduria (MMA), has relied largely on the detection of genomic mutations.

However, the current approach is limiting. MMA can be caused by defects in approximately 20 genes. The DNA-based approach has led to repeated instances of the correct diagnosis being overlooked, and previous efforts have reported that only one-third to one-half of all cases can be correctly diagnosed in this way.

“The reason is that everyone, even healthy individuals, has many naturally occurring genetic mutations that have no apparent impact on human health, so it’s tough to find the one or two that actually cause disease,” said Bernd Wollscheid, PhD, professor at the department of health sciences and technology at ETH Zurich.

MMA is an incurable metabolic disorder that affects approximately one in 90,000 newborns. Patients cannot metabolize methymalonyl-coenzyme A, resulting in a buildup of methylmalonic acid in the body. The result is excessive tiredness, vomiting, dehydration, weak muscle tone, acid-base imbalance, and in some patients, high levels of ammonia. While doctors can offer a certain degree of help, patients may experience delayed growth, kidney failure, and severe neurological impairment. Affected children and adolescents often use wheelchairs and do not always survive to reach adulthood.

Now, a team of researchers took a multi-layered omics profiling approach to diagnosing MMA and combined it with biochemical and clinical features of individuals with MMA. The result was a molecular diagnosis for 177 out of 210 (84%) cases.

This work is published in Nature Metabolism in the article, “Integrated multi-omics reveals anaplerotic rewiring in methylmalonyl-CoA mutase deficiency.”

The University Children’s Hospital Zurich is one of the leading global centers for diagnosing and treating MMA. Patient samples from all over the world are sent to Zurich for diagnosis. In this large, interdisciplinary project, scientists studied 210 biopsies in detail, combining a multi-layered, omics approach with the clinical findings.

The novel diagnostic strategy correctly diagnosed 84% of the patients examined, the majority (148) of whom display pathogenic variants in methylmalonyl-CoA mutase (MMUT).

“Moving forward, our new method will drastically increase the chances for patients to receive a correct diagnosis,” said Patrick Forny, MD, PhD, a former physician in pediatric metabolic medicine at University Children’s Hospital in Zurich who is now a post-doctoral researcher at Washington University School of Medicine in St. Louis. “This will allow the provision of the correct treatment at a much earlier stage.”

Lastly, the multi-omics data revealed the dysregulation of the tricarboxylic acid cycle—a finding that was further explored through multi-organ metabolomics of a hemizygous Mmut mouse model. Additional experiments found that treatment with dimethyl-oxoglutarate restored tricarboxylic acid cycling—suggesting glutamine replenishment as a potential therapeutic for MMA.

Future investigations will show if such an approach will have the same effect in animal models and can result in a feasible therapy for patients. In addition, the researchers launched a new national interdisciplinary and interinstitutional project called SwissPedHealth, co-funded by PHRT and the Swiss Personalized Health Network (SPHN), to increase the diagnostic effectiveness further and to extend the multiomics approach to other genetic diseases.

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