The mitochondrial disorders are a heterogenous group of disorders in which biochemical or genetic analysis, inheritance pattern, histopathology, or clinical presentation suggests a primary dysfunction of the mitochondria.^5,8,20,28 Mitochondria are tiny intracellular organelles that are essential for oxidative phosphorylation and play a role in other metabolic processes. They are responsible for generating much of the energy needed by the cell, in the form of adenosine triphosphate (ATP). The central nervous system, including the ocular tissues such as retina and optic nerve, are particularly reliant on mitochondrial energy production.

Every human cell contains hundreds of mitochondria. Each mitochondrion contains its own DNA and all the elements necessary for local transcription, translation, and replication. Like nuclear DNA, mitochondrial DNA (mtDNA) is read onto messenger RNAs that are then translated into proteins. These processes take place within the mitochondrion. Unlike nuclear DNA, which is organized in chromosomes, mtDNA exists in the form of circular molecules that are similar to the DNA found in bacteria. Each circle of mtDNA consists of a pair of complementary chains of DNA, totaling approximately 16,500 base pairs. Each mitochondrion contains between two and ten such circles of mtDNA. Mitochondrial DNA replicates at random within the mitochondria, and the mitochondria themselves divide by a budding process, unlike the elaborate cell cycle and mitosis of eukaryotic cells. During cellular mitosis, intracytoplasmic organelles, including mitochondria, are randomly partitioned into each daughter cell. If a new mutation in mtDNA occurs, intracellular populations of both mutant and normal mtDNA coexist, a condition known as heteroplasmy.

However, not all of the proteins found within the mitochondria are encoded by mtDNA. In fact, most of the proteins found in mitochondria are encoded by nuclear genes, synthesized in the usual way in the cytoplasm on cytoplasmic ribosomes, and subsequently transported into the mitochondria. Hence, primary mitochondrial dysfunction can result from different origins, with different inheritance patterns. Mutations can arise involving mtDNA, including single-nucleotide substitutions, such as in Leber's hereditary optic neuropathy (see chapter 76), which will be inherited maternally. Other mutations resulting in disease include segmental deletions and rearrangements involving entire regions of mtDNA.¹⁴ Other mutations can arise involving nuclear genes that participate in mitochondrial function. These genes may code for mitochondrial proteins or may otherwise be involved in the normal functioning of mitochondria and even mtDNA. Diseases resulting from abnormalities in these genes will be transmitted in classic Mendelian fashion.

The criteria required to label a disease as mitochondrial has evolved over time. Initially, diseases were considered mitochondrial myopathies if somatic muscle biopsy showed morphological evidence of abnormalities involving the mitochondria, usually by using the modified Gomori trichrome stain to produce the so-called ragged red appearance.³⁰ Later, abnormalities of muscle mtDNA were found in such patients.^14,15,26,51 Therefore, the label of mitochondrial disease was expanded to include diseases that had genetic evidence to suggest mitochondrial abnormalities, even if the muscle fibers were morphologically normal. Several clinical syndromes were designated as mitochondrial diseases, include Leber's hereditary optic neuropathy,⁴⁹ MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes),³³ MERRF (myoclonic epilepsy with ragged red fibers),¹⁰ and KSS (Kearns-Sayre syndrome).²¹

Clinically, the mitochondrial diseases manifest with a surprising amount of heterogeneity. There is poor correlation among the genetic defect, the biochemical abnormality, and the clinical presentation.^5,28 Thus, a single genetic defect can give rise to a range of clinical presentations. Similarly, a single clinical syndrome can arise from a number of different genetic defects. In general, however, the most common ophthalmologic manifestations of mitochondrial disease can be grouped into syndromes of bilateral optic neuropathy, progressive external ophthalmoplegia (PEO), pigmentary retinopathy, and retrochiasmal visual loss, although there is frequently overlap among these categories.⁵ For example, KSS encompasses both ophthalmoplegia and pigmentary retinopathy and may rarely include optic atrophy.^26,51

The literature on electrophysiological studies of the visual pathways in mitochondrial diseases is difficult to interpret, both because of the evolving definition of mitochondrial disease and because of the use of different electrophysiological techniques in the various reports. Older articles, prior to modern molecular genetic diagnosis, include information collected on patients with “mitochondrial myopathy,” a diagnosis that was usually established by the presence of ragged red fibers on muscle biopsy. These studies typically included patients with varying clinical presentations but with common histopathological findings. Newer articles focus primarily on patients or pedigrees with either a defined clinical presentation or, more frequently, a specific genetic defect. Because of the range of presentation, some of the patients who were reported, although genetically carriers, were clinically unaffected. In addition, many of these reports focus on other issues, and information on the electrophysiological findings may be sparse.

The electrophysiological investigations described in both the earlier and more recent studies include primarily various forms of the electroretinogram (ERG) and the visual evoked potential (VEP). Data from the electro-oculogram (EOG) are reported in a few studies. Results are variably reported as either normal or subnormal, without further details or, less commonly, with more detailed descriptions of photopic or scotopic abnormalities. Studies in the English-language literature that provide electrophysiological data are summarized in the tables and detailed below.