Recognition, investigation and management of mitochondrial disease

Abstract

Mitochondria are dynamic organelles present in virtually all human cells that are needed for a multitude of cellular functions, including energy production, control of cell apoptosis and numerous biochemical catabolic and synthetic pathways that are critical for cellular health. Primary mitochondrial disorders are a group of greater than 200 single gene defects arising from two genomes (nuclear and mitochondrial) leading to mitochondrial dysfunction, and are associated with extremely heterogeneous phenotypes. Neuromuscular features predominate, but often with multisystem involvement. Clinical suspicion of a mitochondrial disorder should prompt multipronged investigation with biochemical and molecular genetic studies. Recent wide-scale adoption of next-generation sequencing approaches has led to a rapid increase in the number of disease genes. The advances in unravelling the genetic landscape of mitochondrial diseases have not yet been matched by progress in developing effective therapies, and the mainstay of care remains supportive therapies in a multidisciplinary team setting.

Mitochondrial medicine in the omics era

“…Mitochondrial diseases display heterogeneous phenotypic and biochemical presentations. 2,5,6 This variation, together with an incomplete understanding of mitochondrial pathophysiology, besets mitochondrial diseases with diagnostic challenges and a lack of curative therapies. In recent years, however, highthroughput omics techniques, that is, high-throughput technologies capable of detecting differences in a multitude of molecular constituents in organisms (including genomics, transcriptomics, proteomics, metabolomics, and epigenomics) accompanied by sophisticated bioinformatics tools, have revealed new detail about mitochondrial functionalities and how they contribute to cellular health and disease.…”

Functional Assessment of Lipoyltransferase-1 Deficiency in Cells, Mice, and Humans

“…Here, we describe a familial form of lactic acidosis, epilepsy, developmental delay, and early death. These symptoms occur in many IEMs and thus do not point to a specific defect (Davison and Rahman, 2017). Metabolomics suggested a defect in multiple 2-ketoacid dehydrogenase (2KDH) enzymes, and WES identified variants in LIPT1, the gene encoding lipoyltransferase-1 (LIPT1), which catalyzes transfer of lipoic acid from the H-protein of the glycine cleavage system to E2 subunits of 2KDHs.…”

Oxygen consumption in platelets as an adjunct diagnostic method for pediatric mitochondrial disease

“…sequencing or in some settings whole-genome sequencing, are currently gaining traction (2,26). Interestingly, as one recent review pointed out, improved genetic testing may actually place greater emphasis on less invasive tests and methods to confirm pathogenicity (26). Blood cell respirometry may potentially be a part of the first-line screening arsenal, and as such it would not likely be replaced by large-scale genetic testing any time soon.…”