Mitochondrial Disorders: Clinical, Pathologic and Genetic Classification

Abstract

Mitochondrial disorders are a wide spectrum and heterogeneous disorders that are first described in the early 1960s. It can be said that mitochondrial disorders are the most common Neurometabolic diseases of childhood. Thesedisordersnot only present with nonspecific symptoms, but also there is not a reliable biomarker specific for the screening of them. However increased plasma level of lactate or pyruvate can be considered an important marker of mitochondrial disease. As a general rule, the involvement of 3 or more organ symptoms without a unifying diagnosis should raise suspicion of mitochondrial disease. Mitochondria are the main source of energy for all human tissues and contain many metabolic pathways, including the pyruvate dehydrogenase complex [PDHC], the carnitine cycle, the β-oxidation system, and the Krebs cycle. Defects in any of these pathways cause mitochondrial disorders. The reducing agents produced in the Krebs cycle and in the β-oxidation systems are transferred along the electron transport chain that in turn consists of four multimeric enzyme complexes (I to IV) plus two small electron carriers, coenzyme Q and cytochrome c. The energy produced by these reactions is used to pump protons from the mitochondrial matrix into the space between the inner and outer mitochondrial membranes.This “proton pumping” generates an electrochemical proton gradient, which is utilized by the last enzyme complex (complex V or ATP synthase) to produce ATP in a process known as oxidation/phosphorylation coupling. Electron transport chain and oxidative phosphorylation together are called “respiratory chain”, or oxidative phosphorylation (OXPHOS) system. This system is controlled by both nuclear and mitochondrial DNA (nDNA and mDNA) and is the only metabolic pathway under dual control of both nuclear and mitochondrial genomes. Indeed,complexes I, III, IV, and V contain some subunits encoded by mtDNA and all subunits of complex II, most subunits of the other four complexes, as well as CoQ10 and cytochrome c are encode by nDNA. The term “primary mitochondrial disease” or “mitochondrial encephalomyopathy” refers specifically to mitochondrial dysfunction caused by genetic mutations, directly impacting the composition and function of the electron transport chain. Other Metabolic disorders that are associated with lactic acidosis are include: amino acid disorders, organic acidemias, urea cycle defects, pyruvate metabolism defects, Krebs cycle defects, mitochondrial OXPHOS disorders, disorders of liver glycogen metabolism, disorders of liver gluconeogenesis and biotidinase deficiency. Therefore, when mitochondrial dysfunction is confirmed by sophisticated biochemical testing, it can be challenging to distinguish whether the cause for this dysfunction is a gene that directly impacts the electrontransport chain or is secondary to an unrelated genetic or environmental cause. Mahmoud Reza ASHRAFI MD1, Alireza TAVASOLI MD1