Topic: Mitochondrial Disorders: Molecular Mechanisms, Biomarkers and Emerging Therapies

Mitochondrial disorders are genetic conditions in which the the mitochondrial respiratory chain (MRC) fails to produce sufficient energy in the form of ATP to main cellular functions, and which if severe enough can result in cellular morbidity and demise.  Organs with high energy demands such as the central nervous system and skeletal muscle are very vulnerable to mitochondrial dysfunction, but any organ can be affected by this disorder and many patients with these conditions have a multisystem presentation. Mitochondrial disorders are a phenotypically and genetically diverse group of diseases which have an estimated incidence of at least 1 in 5000. MRC dysfunction can present at any age and result from mutations in either mitochondrial (mtDNA) or nuclear DNA (nDNA), and therefore both matrilineal and Mendelian inheritance patterns are exhibited by families with these conditions, although as yet, no bona fide genotype phenotype relationship has been established. Diseases such as Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes (MELAS), Myoclonic Epilepsy with Ragged-Red Fibers (MERRF), Leber Hereditary Optic Neuropathy (LOHN) have been associated with mutations in mtDNA, whereas the severe neurological disorder, Leigh syndrome can be caused by both mutations in mtDNA or nDNA .In addition to primary genetic causes, MRC dysfunction can also occur as a secondary consequence of disease pathophysiology such as by increased oxidative stress. Secondary impairment of MRC function has been reported in a number of disorders including lysosomal storage disorders and Parkinson`s disease. At present there is no definitive biomarker available for the diagnosis of mitochondrial disorders, and therefore, patients with these conditions cannot be diagnosed in the early stages of the disease using Newborn screening with diagnosis generally occurring once the clinical presentation has begun using biochemical, histological and genetic investigations. The clinical heterogeneity and unpredictable clinical course of mitochondrial disorders have not been conducive to the development of effective therapeutic strategies for these diseases, and treatment is generally supportive, focusing on managing symptoms, enhancing mitochondrial and improving quality of life, but curative treatment is the object of active research.

The focus of this special issue of the Rare Disease and Orphan Drugs Journal is to highlight new developments in the diagnosis, treatment and pathophysiology of both primary and secondary mitochondrial disorders.