The broadening spectrum of mitochondrial disease: shifts in the diagnostic paradigm.
BACKGROUND
The diagnosis of mitochondrial disease requires a complex synthesis of clinical, biochemical, histological, and genetic investigations. An expanding number of mitochondrial diseases are being recognized, despite their phenotypic diversity, largely due to improvements in methods to detect mutations in affected individuals and the discovery of genes contributing to mitochondrial function. Improved understanding of the investigational pitfalls and the development of new laboratory methodologies that lead to a molecular diagnosis have necessitated the field to rapidly adopt changes to its diagnostic approach.


METHODS
We review the clinical, investigational and genetic challenges that have resulted in shifts to the way we define and diagnose mitochondrial disease. Incorporation of changes, including the use of fibroblast growth factor 21 (FGF-21) and next generation sequencing techniques, may allow affected patients access to earlier molecular diagnosis and management.


CONCLUSIONS
There have been important shifts in the diagnostic paradigm for mitochondrial disease. Diagnosis of mitochondrial disease is no longer reliant on muscle biopsy alone, but should include clinical assessment accompanied by the use of serological biomarkers and genetic analysis. Because affected patients will be defined on a molecular basis, oligosymptomatic mutation carriers should be included in the spectrum of mitochondrial disease. Use of new techniques such as the measurement of serum FGF-21 levels and next-generation-sequencing protocols should simplify the diagnosis of mitochondrial disease.


CONCLUSIONS
Improvements in the diagnostic pathway for mitochondrial disease will result in earlier, cheaper and more accurate methods to identify patients with mitochondrial disease. This article is part of a Special Issue entitled Frontiers of Mitochondrial Research.
Department of Neurology, Royal North Shore Hospital, St. Leonards, New South Wales 2065, Australia.
Christina
C
Liang
Department of Neurology, Royal North Shore Hospital, St. Leonards, New South Wales 2065, Australia.
Kate
K
Ahmad
Department of Neurology, Royal North Shore Hospital, St. Leonards, New South Wales 2065, Australia; Department of Neurogenetics, Kolling Institute of Medical Research, Royal North Shore Hospital and the University of Sydney, St. Leonards, New South Wales 2065, Australia. Electronic address: carolyn.sue@sydney.edu.au.
Carolyn M
CM
Sue
D004252:DNA Mutational Analysis / Q000379:methods; D005787:Gene Frequency; D006580:Genetic Carrier Screening / Q000379:methods; D018740:Genetic Heterogeneity; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D028361:Mitochondrial Diseases / Q000175:diagnosis* / Q000235:genetics* / Q000473:pathology; D025202:Molecular Diagnostic Techniques; D018482:Muscle, Skeletal / Q000473:pathology; D009154:Mutation; D010641:Phenotype
FGF21; Mitochondrial disease; Next-generation-sequencing