Metilmalonik asidüride, vücutta belirli bir metabolit birikir. Bu genellikle yoğun tıbbi bakım gerektiren hastalara yol açar. Kredi: Üniversite Çocuk Hastanesi Zürih / Valérie Jaquet
Metilmalonik asidüri (MMA), yaklaşık 90.000 yenidoğandan birini etkileyen nadir bir metabolik bozukluktur. Hastalığın ortaya çıkması için her iki ebeveynin de genetik yatkınlığı taşıması gerekir. Sonuçlar da ağırdır: Bu genç hastaların enerji metabolizması için ihtiyaç duyduğu bir enzim kusurlu kalır.
Arızalı enzim nedeniyle, belirli bir metabolit vücutta birikir ve enerji için parçalanmak yerine zarar verir. MMA şu anda tedavi edilemez olarak kabul edilir.
Doktorlar belirli bir dereceye kadar yardım sunabilirken, hastalar büyüme geriliği, böbrek yetmezliği ve ciddi nörolojik bozukluk yaşayabilir. Etkilenen çocuklar ve ergenler genellikle tekerlekli sandalye kullanırlar ve yetişkinliğe ulaşmak için her zaman hayatta kalamazlar.
Ağ başarı getirir
Üniversite Çocuk Hastanesi Zürih, bu hastalığın teşhis ve tedavisinde önde gelen küresel merkezlerden biridir. Dünyanın her yerinden hasta numuneleri teşhis için Zürih’e gönderiliyor. Disiplinler arası büyük bir projede, çeşitli İsviçre araştırma kurumlarından bilim adamları 210 biyopsiyi ayrıntılı olarak incelediler. Sadece tüm genleri incelemediler ([{” attribute=””>DNA) in the patient’s cells but also the RNA transcripts of these genes and many of the proteins.
This is the first 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 Children’s Hospital Zurich, ETH Zurich, EPFL, the University of Zurich, and the Health 2030 Genome Center in Geneva. The molecular analysis 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. However, this approach has led to repeated instances of the correct diagnosis being overlooked, reports Sean Froese, research group leader at the University Children’s Hospital Zurich and co-senior author of the study. 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,” says Bernd Wollscheid, professor at 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 also its consequences in terms of RNA, proteins, and protein function. This enabled the consortium, as part of this study, to develop a diagnostic strategy that correctly diagnosed 84 percent of the patients examined. “Moving forward, our new method will drastically increase the chances for patients to receive a correct diagnosis,” says Patrick Forny, senior physician at the University Children’s Hospital Zurich and co-lead author of the study. “This will allow the provision of the correct treatment at a much earlier stage.”
A new approach to therapy
The multi-omics data also showed that MMA patients use an alternative energy source to help deal with the fact that a vital enzyme is defective. However, in patients, this alternative energy source usually is not able 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 alternative energy source.
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 multi-omics approach to other genetic diseases.
Reference: “Integrated multi-omics reveals anaplerotic rewiring in methylmalonyl-CoA mutase deficiency” by Patrick Forny, Ximena Bonilla, David Lamparter, Wenguang Shao, Tanja Plessl, Caroline Frei, Anna Bingisser, Sandra Goetze, Audrey van Drogen, Keith Harshman, Patrick G. A. Pedrioli, Cedric Howald, Martin Poms, Florian Traversi, Céline Bürer, Sarah Cherkaoui, Raphael J. Morscher, Luke Simmons, Merima Forny, Ioannis Xenarios, Ruedi Aebersold, Nicola Zamboni, Gunnar Rätsch, Emmanouil T. Dermitzakis, Bernd Wollscheid, Matthias R. Baumgartner and D. Sean Froese, 26 January 2023, Nature Metabolism.
DOI: 10.1038/s42255-022-00720-8