Clinical Information

The mitochondrion occupies a unique position in eukaryotic biology. It is the site of energy metabolism, and it is the sole subcellular organelle that is composed of proteins derived from 2 genomes, mitochondrial and nuclear. A group of hereditary disorders due to variants in either the mitochondrial genome or nuclear mitochondrial genes have been well characterized.

The diagnosis of mitochondrial disease can be particularly challenging as the presentation can occur at any age, involve virtually any organ system, and be associated with widely varying severities. Due to the considerable overlap in the clinical phenotypes of various mitochondrial disorders, it is often difficult to distinguish these specific inherited disorders without genetic testing. This test utilizes massively parallel sequencing, also termed next-generation sequencing (NGS), to analyze 221 nuclear-encoded genes implicated in mitochondrial disease and to determine the exact sequence of the entire 16,569 base-pair mitochondrial genome.

The utility of this test is to assist in the diagnosis of mitochondrial diseases that result from variants in both nuclear encoded genes and in the mitochondrial genome. Those diseases involving nuclear genes include disorders of mitochondrial protein synthesis, coenzyme Q10 biosynthesis, respiratory chain complexes, and mitochondrial DNA (mtDNA) maintenance (ie, mtDNA depletion disorders). Disorders of the mitochondrial genome include those caused by point alterations, such as mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes (MELAS), myoclonic epilepsy with ragged red fibers (MERRF), mitochondrial myopathy (MM), neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP), Leigh syndrome, Leber hereditary optic neuropathy (LHON), and chronic progressive external ophthalmoplegia (CPEO). In addition to the detection of single base changes with these disorders, large deletions, such as those associated with Kearns-Sayre or Pearson syndromes, are also detected. In contrast to variants in nuclear genes, which are present in either 0, 1, or 2 copies, mitochondrial variants can be present in any fraction of the total organelles, a phenomenon known as heteroplasmy. Typically, the severity of disease presentation is a function of the degree of heteroplasmy. Individuals with a higher fraction of altered mitochondria present with more severe disease than those with lower percentages of altered alleles. The sensitivity for the detection of altered alleles in a background of wild-type (or normal) mitochondrial sequences by NGS is approximately 10%.