Latest research offers potential advantages for those affected by the hereditary metabolic disease methylmalonic aciduria. By combining the outcomes of multiple molecular analyses, scientists can higher diagnose this rare and severe disease. In the long run, an improved understanding of the disease may also improve treatment options.

Methylmalonic aciduria (MMA) is a metabolic disorder that affects roughly one in 90,000 newborns; each parents must carry a genetic predisposition to the disease. This implies the disease is rare. The results are also severe: an enzyme these young patients need for energy metabolism is left defective. Consequently, a selected metabolite, which will likely be broken right down to create energy, as an alternative accumulates within the body doing damage. MMA is taken into account incurable. 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 don’t at all times survive to achieve maturity.

Network brings success

The University Kid’s Hospital Zurich is one in all the leading global centers for diagnosing and treating this disease. Patient samples from everywhere in the world are sent to Zurich for diagnosis. In a big interdisciplinary project, scientist from various Swiss research institutions studied 210 biopsies intimately. They examined not only the entire genes (DNA) within the patient’s cells but in addition the RNA transcripts of those genes and most of the proteins.

That is the primary time that MMA has been studied using a multi-omics approach (genomics, transcriptomics, proteomics, metabolomics). The work was initiated and funded by the ETH domain strategic focus area Personalized Health and Related Technologies (PHRT) and involved researchers from the University Kid’s Hospital Zurich, ETH Zurich, EPFL, the University of Zurich, and the Health 2030 Genome Center in Geneva. The molecular evaluation was carried out at PHRT’s Swiss Multi-Omics Center (SMOC) in Zurich.

Increased diagnosis accuracy

Until now, physicians have relied mainly on DNA sequencing for genetic diagnosis of MMA. Nevertheless, this approach has led to repeated instances of the right diagnosis being ignored, reports Sean Froese, research group leader on the University Kid’s Hospital Zurich and co-senior creator of the study. Previous efforts have reported that only one-third to one-half of all cases might be appropriately diagnosed in this manner. “The rationale is that everybody, even healthy individuals, has many naturally occurring genetic mutations that don’t have any apparent impact on human health, so it’s tough to seek out the one or two that truly cause disease,” says Bernd Wollscheid, professor on the Department of Health Sciences and Technology at ETH Zurich, head of the Executive Committee of PHRT and co-author of the study.

By opting to expand significantly their molecular investigation, the researchers considered not only the disease’s genetic cause but in addition its consequences when it comes to RNA, proteins, and protein function. This enabled the consortium, as a part of this study, to develop a diagnostic strategy that appropriately diagnosed 84 percent of the patients examined.

Moving forward, our latest method will drastically increase the possibilities for patients to receive an accurate diagnosis. It will allow the supply of the right treatment at a much earlier stage.”

Patrick Forny, senior physician on the University Kid’s Hospital Zurich and co-lead creator of the study

Latest approach to therapy

The multi-omics data also showed that MMA patients use an alternate energy source to assist take care of the proven fact that a significant enzyme is flawed. Nevertheless, in patients, this alternative energy source often shouldn’t be in a position to sufficiently compensate for energy production lost. In in vitro experiments with patient cells, the researchers succeeded in boosting energy production to near-normal levels by supplying such an alternate energy source.

Future investigations will show if such an approach may have the identical effect in animal models and may end up in a feasible therapy for patients. As well as, the researchers launched a latest national interdisciplinary and interinstitutional project called SwissPedHealth, co-funded by PHRT and the Swiss Personalized Health Network (SPHN), to extend the diagnostic effectiveness further and to increase the multi-omics approach to other genetic diseases.

Source:

Journal reference:

Forny, P., et al. (2023) Integrated multi-omics reveals anaplerotic rewiring in methylmalonyl-CoA mutase deficiency. Nature Metabolism. doi.org/10.1038/s42255-022-00720-8.