Mitochondrial disorders: challenges in diagnosis & treatment

Nahid Akhtar Khan, Periyasamy Govindaraj, Angamuthu Kannan Meena, Kumarasamy Thangaraj, Nahid Akhtar Khan, Periyasamy Govindaraj, Angamuthu Kannan Meena, Kumarasamy Thangaraj

Abstract

Mitochondrial dysfunctions are known to be responsible for a number of heterogenous clinical presentations with multi-systemic involvement. Impaired oxidative phosphorylation leading to a decrease in cellular energy (ATP) production is the most important cause underlying these disorders. Despite significant progress made in the field of mitochondrial medicine during the last two decades, the molecular mechanisms underlying these disorders are not fully understood. Since the identification of first mitochondrial DNA (mtDNA) mutation in 1988, there has been an exponential rise in the identification of mtDNA and nuclear DNA mutations that are responsible for mitochondrial dysfunction and disease. Genetic complexity together with ever widening clinical spectrum associated with mitochondrial dysfunction poses a major challenge in diagnosis and treatment. Effective therapy has remained elusive till date and is mostly efficient in relieving symptoms. In this review, we discuss the important clinical and genetic features of mitochondrials disorders with special emphasis on diagnosis and treatment.

Figures

Fig. 1
Fig. 1
Schematic picture showing the mitochondrial genetic bottleneck. Selected number of mtDNA molecules are transferred to each cell during the production of primary oocyte. The rapid replication of mtDNA in mature oocyte causes random shift of mutation load between generations and is responsible for the variable levels of mutant mtDNA in affected offspring.
Fig. 2
Fig. 2
Schematic picture showing the clinical features and the organs affected by mitochondrial diseases. Additional information is also given in the Table.
Fig. 3
Fig. 3
(A) T2-weighted magnetic resonance (MR) images of a normal child, and (B) Axial T1, and (C) T2- weighted MR images of the patient showing bilateral basal ganglionic lesions, highly characteristic of Leigh disease (shown by arrows), and (D) Axial T1. Source: Ref. 77.
Fig. 4
Fig. 4
Tissue section showing the pathological abnormalities of mitochondrial disorders. (A) Hematoxylin and Eosin (HE) stain; (B) Red ragged fibers appear on modified gomorie trichome (MGT) stain suggesting abnormal subsarcolemmal accumulation of mitochondria; (C) Blue red fibers on succinate dehydrogenase (SDH) staining, suggesting an increased number of mitochondria; (D) COX staining shows absence of enzymes of respiratory chain. (E & F) Electron micrograph showing low and high magnification of mitochondria with paracrystalline inclusions (E x10000, F x40000).

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