Improving the treatment and diagnosis of methylmalonic aciduria

Improving the treatment and diagnosis of methylmalonic aciduria
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A combined research team from Switzerland is developing new tools for the diagnosis and treatment of the rare disease, methylmalonic aciduria.

Methylmalonic aciduria is a metabolic disease that affects approximately one in 90,000 new-borns. The disease causes an enzyme, needed for young patients to metabolise energy, to become defective. This means a specific metabolite, which is meant to break down and create energy, accumulates in the body, damaging the patient’s health.

Patients with methylmalonic aciduria are likely to experience delayed growth, kidney failure, and severe neurological impairment. Patients will often need to use wheelchairs and do not always survive to adulthood.

The University Children’s Hospital Zurich is one of the leading centres for diagnosing and treating methylmalonic aciduria and samples from all over the world are sent to Zurich for diagnosis. As part of a large interdisciplinary study, researchers from various Swiss research institutions analysed 210 biopsies in detail. The researchers examined all of the genes in the patient’s cells, as well as RNA transcripts of these genes and many of the proteins. The project is the first to study methylmalonic aciduria using a multi-omics approach.

Methylmalonic aciduria is often misdiagnosed

Prior to this research, physicians have relied on DNA sequencing for the genetic diagnosis of methylmalonic aciduria. This approach has led to numerous cases of misdiagnosis. Previously, only one-third to one-half of all cases of methylmalonic aciduria have been correctly diagnosed with DNA sequencing.

“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, professor at the Department of Health Sciences and Technology at ETH Zurich.

The researchers opted to expand their molecular investigation, allowing the researchers to not only examine the disease’s genetic cause but also the consequences in terms of RNA, proteins, and protein function. This enabled the researchers to develop a diagnostic strategy that correctly diagnosed 84% of all patients examined.

Creating new treatment methods

“Moving forward, our new method will drastically increase the chances for patients to receive a correct diagnosis. This will allow the provision of the correct treatment at a much earlier stage,” said Patrick Forny, senior physician at the University Children’s Hospital Zurich and co-lead author of the study.

The researchers also found that methylmalonic aciduria patients use an alternative energy source to help deal with the defective enzyme. However, this alternative energy source is not usually able to sufficiently compensate for energy production lost. Through In vitro experiments with patient cells, the researchers were able to boost energy production to near-normal levels by supplying patients with an alternative energy source.

Next, the researchers will investigate whether this approach will have the same effect in animal models and if it could lead to therapy for patients. Additionally, the researchers will launch a new national interdisciplinary and interinstitutional project to further improve diagnostics for methylmalonic aciduria.

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