The aim of the project is to optimise efficient and accurate diagnosis throughout the EU and thereby establish best practice for the clinical investigation and management of patients and families with inherited mitochondrial disease. Genetic studies are hampered by the extreme heterogeneity of these disease with a possible defect in the mtDNA or in one of the several hundreds of nuclear genes. Therefore we invested in high-throughput CHIP-based resequencing technology to screen the entire mtDNA and we were able to solve 25% of the paediatric patients with mitochondrial disease (1). Using this technology we were also able to explain the heterogenic clinical expression of patients with Leber Hereditary Optic Neuropathy (LHON) by linking extraocular clinical features to mtDNA mutations, present in addition to the primary LHON mutations (2). Linkage analysis in LHON families revealed a nuclear locus on the X-chromosome, which could be involved in the reduced penetrance of the disease. Linkage analysis using 50k SNP-CHIPs were also performed in a number of autosomal recessive OXPHOS families and new genetic loci, containing genes involved in OXPHOS disease were identified. Gene expression profiling was performed in affected tissue (muscle) of subgroups of patients to identify pathogenic molecular pathways. Processes related to ROS damage protein turnover and complement mediated regeneration of muscle were identified. As these disorders can be very severe and no cure is available we concentrated on preventing the transmission of mitochondrial disease by prenatal diagnosis (PND) or preimplantation genetic diagnosis (PGD). For mtDNA mutations this is not straightforward and specific problems occur at the technical, interpretational and ethical level. Methods to determine the mutation level at single cell have been established, but interpretation of the results on single blastomeres to predict the future phenotype largely depend on the specific mutation and the knowledge obtained so far in literature (3). This uncertainty is of ethical concern and ethical and practical guidelines are being formulated based on empirical studies and qualitative research by means of semi-structured interviews. The major aim of these interviews is to offer a complete picture of the stakeholders' ethical considerations concerning the prevention of mitochondrial disease, in other words, to collect as much and diverse ethical considerations as possible regarding reproductive options for carriers of mitochondrial disorders.

Selected publications

Van Eijsden RG, Gerards M, Eijssen LM, Hendrickx AT, Jongbloed RJ, Wokke JH, Hintzen RQ, Rubio-Gozalbo ME, De Coo IF, Briem E, Tiranti V, Smeets HJ.
Chip-based mtDNA mutation screening enables fast and reliable genetic diagnosis of OXPHOS patients.
Genet Med. 2006 Oct;8(10):620-7. 

Spruijt L, Hoogendijk JE, Hendrickx AT, de Coo IF, Doevendans PA, de Jong PT, Spliet WG, Kroes H, Smeets HJ.
Additional mitochondrial DNA mutations may explain extra-ocular involvement in LHON.
Am J Med Genet A. 2006 Jul 1;140(13):1478-81. 

Jacobs LJ, de Wert G, Geraedts JP, de Coo IF, Smeets HJ.
The transmission of OXPHOS disease and methods to prevent this.
Hum Reprod Update. 2006 Mar-Apr;12(2):119-36.

Research group
Dr. H.J.M. Smeets, project leader
Prof.dr. G. de Wert (ethics)
Dr. P.J. Lindsey
Dr. C.E.M. de Die-Smulders
Prof.dr. J.P.M. Geraedts 

Post-doctoral fellows
Dr. B.J.C. van den Bosch 

PhD students
L.J.A.M. Jacobs
R.G.E. van Eijsden
L. Spruijt
A. Bredenoord 

Technicians
C.M.M van den Burg
M. Gerards 

Undergraduates
C. Calis