Mitochondriopathy - Network for diagnostics and therapy (GENOMIT)

Mitochondria are the major source of ATP, which is synthesized by the mitochondrial respiratory chain through the process of oxidative phosphorylation (OXPHOS). OXPHOS is a complex biochemical process, carried out under the control of two different genomes, nuclear and mitochondrial and involves hundreds of genes. ATP deficiency leads to cellular dysfunction and ultimately cell death, especially in tissues with high energy demand. This explains the vast heterogeneity of mitochondrial disorders, a challenge to both diagnosis and clinical management. The prevalence of mitochondrial disorders estimated in Europe is about 1-2 in 10,000 live births. In an attempt to address the challenges of diagnosing and treating the heterogeneous group of patients with OXPHOS disorders, local and national networks are currently being established with the aim to provide specialized care centres for patients with mitochondrial disorders. Furthermore research in an European concerted action is necessary to concentrate expertise and to collect patients and patient samples from several competence centers in order to increase the number in each subgroup of the heterogenous mitochondrial diseases. Therefore a network of specialized centres in Germany, Italy, France, Israel, Austria and Belgium (GENOMIT) was created to apply for an e-rare grant with the aim to improve diagnosis, molecular understanding and treatment of patients with mitochondrial disorders in Europe. This goal will be accomplished with four workpackages: First, establishment of a European catalogue of databases and a collection of biomaterials from patients with mitochondrial diseases. Second, development of new diagnostic protocols based on next generation sequencing techniques that will be applied to shared sample collections. Third, extention of functional studies of genes and pathways involved in the pathophysiology of mitochondrial disorders. Fourth, testing of new therapeutic options by improving the range of and the access to animal disease models. GENOMIT partners are active as national centers for the diagnosis and care of patients with mitochondrial diseases. In addition, each of them has developed unique expertise that will be shared synergistically within the network. Our Department of Pediatrics at the Paracelsus Medical University is a national center for the diagnosis of patients with mitochondrial disorders in a close cooperation with the Department of Pediatrics (Munich-Schwabing) and the Institute of Human Genetics, Technical University Munich (www.mito-center.org) and furthermore already a part of the German network for mitochondrial disorders (MITONET) (www.mitonet.org). Our focus is laid on the functional investigation of unfrozen samples which led to the detection of novel disorders in the mitochondrial pyruvate oxidation and ATP synthesis. Furthermore the patient samples are investigated with various other biochemical, histological and genetic techniques to unravel the underlying molecular defects. Several of these methods have been optimized for the use of small tissue samples from pediatric patients. Our part in the e-rare project is mainly focused on the third working package of GENOMIT, using especially the expertise of the functional and biochemical characterization of OXPHOS for the understanding of key molecular and biochemical mechanisms responsible for mitochondrial diseases. This is also a prerequisite for the identification of new drug targets and the development of novel treatments. Defined respiratory chain complex defects will be evaluated using existing cellular models. Our part in the project covers an optimal use of the wide spectrum of established assays and makes them available to consortium members and has the objectives i) to validate newly identified disease gene candidates, ii) to delineate pathways involved in the pathogenesis of mitochondrial disorders and iii) to validate therapeutic approaches in in-vitro models.

Disorders of the mitochondrial energy metabolism are a group of rare inherited diseases with numerous clinical manifestations. In these diseases the oxygen dependent cells of the body have a lack of energy. The nervous system, the heart and skeletal muscles are most frequently affected by disorders of the mitochondrial energy metabolism. In the recent years the search for the genetic causes of theses disease was the main focus of research. Up to now, more than 250 genes have been associated with disorders in the mitochondrial energy metabolism.The GENOMIT project was raised as a multicentric international initiative aiming at the improvement of diagnostics and therapy of disorders of the mitochondrial energy metabolism. In our collective of patients we could identify a number of new disease-causing genes (COQ4, ELAC2, FBXL4, GTPBP3) by exome sequencing. In a number of further patients we could identify and publish new mutations in recently reported disease genes (AGK, BOLA3, ECHS1, FBXL4, HIBCH, MT-TW, MTFMT, NFU1, TTC19, TPK1), thereby expanding the spectrum of clinical phenotypes and further characterization of the involved cellular pathways. In addition, we published several review articles in order to put the newly identified disorders in a larger context. All together 19 peer-reviewed papers have been published.The GENOMIT project was the basis for collecting a relatively large number of patients with the same genetic defect. The identification and collection of these rare disorders is a big challenge and the prerequisite for the development of therapeutic options. Therefore, the work of this project is the basis for further studies. In order to continue the work, we are applying for another funding period within the ERA-Net at the moment. The present application takes over most of the aims of the finished GENOMIT project but has an additional focus on novel therapeutic approaches.