Mitochondrial disease: genetics and management

Abstract

Mitochondrial disease is one of the most common groups of genetic diseases with a minimum prevalence of greater than 1 in 5000 in adults. Whilst multi-system involvement is often evident, neurological manifestation is the principal presentation in most cases. The multiple clinical phenotypes and the involvement of both the mitochondrial and nuclear genome make mitochondrial disease particularly challenging for the clinician. In this review article we cover mitochondrial genetics and common neurological presentations associated with adult mitochondrial disease. In addition, specific and supportive treatments are discussed.

Metabolic Alterations in Inherited Cardiomyopathies

“…In this context, disorders of the oxidative phosphorylation system (OXPHOSDs) are a heterogeneous group of diseases determined by mutations affecting the mitochondrial ETC and ATP synthase. Altogether, their prevalence is higher than 1 in 5000 in adults [110]. The OXPHOS consists of five multimeric enzyme complexes: complexes I-IV form the ETC, while complex V (F1Fo ATP synthase) catalyzes ADP phosphorylation ( Figure 2).…”

Roles of the mitochondrial replisome in mitochondrial DNA deletion formation

“…The primary, single large-scale deletions were the first mtDNA defects described (Holt et al, 1988) and remain the most common sporadic mutations on mtDNA, accounting for approximately a quarter of all mitochondrial disorders in the human population (Schaefer et al, 2008;Pitceathly et al, 2012;Grady et al, 2014;Gorman et al, 2015). In contrast to point mutations, pathogenic mtDNA deletions typically arise de novo and, with rare exceptions (Chinnery et al, 2004), are not inherited by the offspring (Ng and Turnbull, 2016;Kauppila et al, 2017). Phenotypically, primary deletions manifest as the often-fatal Pearson syndrome in infancy, Kearns-Sayre syndrome (KSS) in childhood and adolescence, or late onset progressive external ophthalmoplegia (PEO) (Rocha et al, 2018;Russell et al, 2018).…”

“…Secondary mtDNA diseases result from mutations in nuclear genes and their inheritance follows the Mendelian pattern, often in an autosomal dominant fashion (Ng and Turnbull, 2016;Alston et al, 2017). The major causes of secondary mtDNA diseases identified to date involve defects in the mitochondrial replisome: mutations in the POLG1 and TWNK genes, which encode respectively Pol g-a and Twinkle (Van Goethem et al, 2001;Copeland, 2014;Nurminen et al, 2017;Rahman and Copeland, 2019).…”

Targeted Reduction of Pathogenic Heteroplasmy Through Binding of G-Quadruplex DNA

“…Mitochondrial diseases pose formidable challenges in diagnosis and treatment (1). The diseases are bigenomic, caused by pathogenic variants in either the maternally inherited mitochondrial genome (mtDNA) or the nuclear genome (nDNA) that affect mitochondrial respiratory complex function.…”