Affiliations: Nijmegen Center for Mitochondrial Disorders,
Department of Pediatrics, 774 Laboratory of Genetic, Endocrine and Metabolic
Disease, Radboud University Nijmegen Medical Center, Nijmegen, The
Netherlands
Note: [] Corresponding author: Richard J.T. Rodenburg, Nijmegen Center
for Mitochondrial Disorders, Department of Pediatrics, 774 Laboratory of
Genetic, Endocrine and Metabolic Disease, Radboud University Nijmegen Medical
Center, Nijmegen, The Netherlands. Tel.: +31 24 361 48 18; Fax: +31 24 361 89
00; E-mail: [email protected]
Abstract: The clinical heterogeneity of mitochondrial disorders often makes it
a challenge to establish a diagnosis in suspected mitochondrial patients. The
classical approach to the diagnostic examination usually involves a muscle
biopsy to evaluate mitochondrial function by measuring enzyme activities of the
OXPHOS enzymes complex I to V, and to determine flux parameters such as oxygen
consumption, the oxidation of various substrates, and ATP production. Based on
the combination of clinical features and biochemical parameters, candidate
genes are selected for subsequent molecular genetic studies in the conventional
diagnostic work-flow. The procedures for diagnostic molecular genetic analysis
of mitochondrial patients are rapidly evolving, due to the introduction of next
generation sequencing (NGS) technologies in diagnostic laboratories. In
addition to the application to mtDNA sequence analysis, NGS is used for the
sequence analysis of multiple nuclear genes. The new technological
possibilities for molecular genetic testing will result in a change in the
diagnostic work-up of suspected mitochondrial patients. Because of the often
poor genotype-phenotype correlation in mitochondrial disease, NGS analysis will
often require functional follow up testing to confirm pathogenicity of genetic
variants. This will create a demand for more specific diagnostic functional
tests; not only for mitochondrial oxidative phosphorylation, but also for other
mitochondrial processes like substrate transport, nucleotide homeostasis, mtDNA
transcription/translation, and so on. The development of a collection of
sophisticated and preferably non-invasive diagnostic tests for functional
follow-up of NGS molecular genetics results is the next challenge in the
diagnostic examination of suspected mitochondrial patients.
