Diagnosis and Treatment of Mitochondrial Myopathies

Abstract

Mitochondrial myopathies are progressive muscle conditions caused primarily by the impairment of oxidative phosphorylation (OXPHOS) in the mitochondria. This causes a deficit in energy production in the form of adenosine triphosphate (ATP), particularly in skeletal muscle. The diagnosis of mitochondrial myopathy is reliant on the combination of numerous techniques including traditional histochemical, immunohistochemical, and biochemical testing combined with the fast-emerging molecular genetic techniques, namely next-generation sequencing (NGS). This has allowed for the diagnosis to become more effective in terms of determining causative or novel genes. However, there are currently no effective or disease-modifying treatments available for the vast majority of patients with mitochondrial myopathies. Existing therapeutic options focus on the symptomatic management of disease manifestations. An increasing number of clinical trials have investigated the therapeutic effects of various vitamins, cofactors, and small molecules, though these trials have failed to show definitive outcome measures for clinical practice thus far. In addition, new molecular strategies, specifically mtZFNs and mtTALENs, that cause beneficial heteroplasmic shifts in cell lines harboring varying pathogenic mtDNA mutations offer hope for the future. Moreover, recent developments in the reproductive options for patients with mitochondrial myopathies mean that for some families, the possibility of preventing transmission of the mutation to the next generation is now possible.Electronic supplementary materialThe online version of this article (10.1007/s13311-018-00674-4) contains supplementary material, which is available to authorized users.

Mitochondrial dysfunctions and antihypoxants

“…Rational diet therapy (usually, ketogenic diet) with a reduced amount of easily digestible carbohydrates, high fat content and average protein content in combination with exercise therapy is recommended to be used [2,65].…”

“…The possibility of mitochondrial replacement therapy in 5 main areas is studied: 1 -xenotopic gene expression; 2 -allotopic gene expression [25]; 3 -the synthesis of artificially created in vivo mitochondrial tRNA and rRNA with their subsequent transfer to mutant mitochondria with damaged structures replacement; 4 -the creation of "vector" nucleic acids complementary to the mutated piece of mtDNA, which while binding to them, contribute to their inhibition and shutdown of the replication processes; 5 -the use of artificially created vesicles penetrating through the membranes of mitochondria and restoring lost functions. Besides, the mutation correction systems in mtDNA based on molecular genome editing technologies, for example, systems called "mitochondrial zinc fingers", mitoTALEN, mitoCRISPR/Cas9 are being developed [2,11]. The main disadvantage of these directions is that they do not eliminate the underlying mutation in the mitochondria genome, but only reduce the heteroplasmy level, resulting in partial restoration of the mitochondria function.…”

“…The direction determining the significance and role of energy exchange disorders in mitochondria in the pathogenesis of diseases is developing actively in medical science over past decades. Тhe conception "mitochondrial dysfunctions" (MD) is formed as а result of it [2,4,67].…”

Clinical Profile and Outcome of Pediatric Mitochondrial Myopathy in China

“…Mitochondrial myopathies (MMs), are an important group of muscle conditions characterized by isolated or predominant skeletal muscle involvement, caused primarily by the impairment of oxidative phosphorylation (OXPHOS) due to mutations of nuclear or mitochondrial DNA (1). Currently there are no available effective or disease-modifying treatments for majority of patients with mitochondrial myopathies (1). Myopathy is one of the most common manifestations of adult-onset mitochondrial disorders due to the high cellular energy demand of skeletal muscle.…”

Myopathy: Recent Progress, Current Therapies, and Future Directions

“…Mutations in nuclear DNA or mitochondrial DNA (mtDNA) can disrupt the function of mitochondrial proteins resulting in an impairment of oxidative phosphorylation that may cause damage not only to skeletal muscle, but to other organs as well. Although no curative therapies are yet available, Ahmed et al discuss strategies for the symptomatic management of these diseases [11]. A recent success in the field has been the availability of new reproductive options that may prevent the transmission of disease-causing mutations from mother to offspring.…”