Since the initial discovery of mitochondrial DNA mutations in 1988, our understanding of the mitochondrial encephalomyopathies has advanced at an astoundingly rapid pace. Numerous scientific and clinical reports have documented the discoveries, while review articles^19,23 and even several books^20,104 have summarized much of this progress. The purpose of this chapter is not to describe the mitochondrial encephalomyopathies comprehensively, but rather, to illustrate some of the fundamental clinical and scientific themes in these diverse disorders that often manifest epilepsy.

Mitochondria are vital organelles, because they (a) produce energy in the form of adenosine triphosphate (ATP) through oxidative-phosphorylation of carbohydrates, fats, and amino acids,^57,70,128 (b) are essential for intracellular calcium homeostasis,²⁸ (c) contribute to the synthesis of important metabolic precursors [e.g., uridine,⁵⁴ amino acids, and iron-sulfur (Fe-S) clusters³⁴], and (d) finally, participate in cell death pathways.³⁹ Much has been learned about the functions of these organelles, and defects of specific processes provide an elegant and rational biochemical classification system of the mitochondrial diseases (Table 1). A prime example of a specific biochemical defect of mitochondria is carnitine palmityl transferase (CPT) II deficiency.²¹ Transport of fatty acids through the mitochondrial membranes is impaired by specific mutations in CPT II. By contrast, mitochondrial respiratory chain disorders often do not conform to single-enzyme defects because multiple enzymes can be affected; therefore, this biochemical classification scheme has limitations.

Molecular genetics provides an alternative perspective of mitochondrial diseases. One can gain a better understanding of mitochondrial disorders by considering the several unique genetic characteristics of mitochondria. Mitochondria are unique mammalian organelles because they possess their own genetic material, mitochondrial DNA (mtDNA), which is a small (16.5 kilobases) circular molecule encoding 13 polypeptides, 22 transfer RNAs (tRNA), and two ribosomal RNAs (rRNA).⁴ The mtDNA-encoded polypeptides are vital subunits of the respiratory chain. In addition, more than 1,000 mitochondrial proteins are encoded in the nuclear DNA (nDNA). Because mitochondria are the products of two genomes, defects in either genome can cause mitochondrial dysfunction. To date, most of the respiratory chain defects that have been characterized at the molecular genetic level are due to mtDNA mutations.^19,20,23

An important principle of mtDNA genetics is heteroplasmy. Each mitochondrion contains two to ten copies of mtDNA and, in turn, each cell contains multiple mitochondria; therefore, there are hundreds to thousands of mtDNA molecules in each cell. Alterations of mtDNA may be present in some of the mtDNAs (heteroplasmy) or in all of the molecules (homoplasmy). As a consequence of heteroplasmy, the proportion of a deleterious mtDNA mutation can vary widely. An individual who harbors a large proportion of mutant mtDNA will be more severely afflicted by the mitochondrial dysfunction than a person with a low percentage of the same mutation. As a consequence, a given mtDNA mutation can produce a diverse spectrum of clinical severity among patients.

A second factor that can influence the expression of a mtDNA mutation in a person is the tissue distribution of that mutation. The best example of tissue distribution variation is offered by large-scale mtDNA deletions. Infants with a high proportion of deleted mtDNA in their blood can develop Pearson syndrome, a sideroblastic anemia often accompanied by exocrine pancreatic dysfunction.^68,92 Presumably, these infants have a high proportion of deleted mtDNA in the bone marrow stem cells. Some children survive the anemia with blood transfusions and subsequently recover, because the stem cells with a high proportion of deleted mtDNA are eliminated through a negative selection bias. Later in life, however, those children may develop the multisystem mitochondrial disorder Kearns-Sayre syndrome (KSS), characterized by ophthalmoplegia, pigmentary retinopathy, and cardiac conduction block.^53,93 Thus, variable tissue distribution broadens the clinical spectrum of pathogenic mtDNA mutations.

The third factor that determines clinical expression of a mtDNA mutation is tissue threshold effect. Cells with high metabolic activities are more severely affected by relatively lower levels of mtDNA mutations; therefore, these disorders tend to affect disproportionately the brain and muscles (encephalomyopathies).

A fourth unusual characteristic of mtDNA is maternal inheritance. During the formation of the zygote, the mtDNA is derived exclusively from the oocyte. Thus, mtDNA is transmitted vertically in a nonmendelian fashion from the mother to both male and female progeny. A single exception to this rule has been described; a man with exercise intolerance and two base-pair deletions in the mitochondrial-encoded gene for subunit 2 of complex I (nicotinamide adenine dinucleotide [NAD] dehydrogenase 2 [ND2]) showed paternal inheritance of mtDNA in skeletal muscle.^56,108 Because paternal inheritance of mtDNA appears to be exceedingly rare,^29,109,122 maternal inheritance is important to recognize in determining whether a family is likely to harbor a mtDNA mutation. A caveat to this principle is the fact that maternal relatives who have lower percentages of a mtDNA mutation may have fewer symptoms (oligosymptomatic) than the proband, or they may even be asymptomatic. Therefore, in taking the family history, it is important to ask about the presence of subtle symptoms or signs in maternally related family members who might be oligosymptomatic.

These peculiar features of “mitochondrial genetics” contribute to the clinical complexity of human mitochondrial
disorders. Variable heteroplasmy of mtDNA mutations produces an extensive range of disease severity, whereas tissue distribution and tissue threshold of mtDNA mutations explain the frequent but variable involvement of multiple organ systems.

In addition to mtDNA mutations, nuclear DNA (nDNA) defects can also cause mitochondrial dysfunction. In fact, nDNA encodes most of the components of the respiratory chain and, since 1995, many nDNA mutations associated with defects in oxidative-phosphorylation have been identified.^19,20 In this chapter, we review the major mitochondrial encephalomyopathy syndromes associated with seizures. We will not quote or summarize the vast literature on mitochondrial encephalomyopathies; rather, we will try to convey some of the principles of evaluation, diagnosis, and treatment of these disorders with emphasis on epilepsy.

The mitochondrial encephalomyopathies comprise a heterogenous group of multisystem disorders that typically affect infants, children, or young adults. Among these diverse conditions, specific clinical syndromes were recognized. Because clinicians are confronted with patients, the clinical classification of the mitochondrial disorders is of pragmatic significance in guiding the diagnostic evaluation, determining prognosis, and in directing therapy. The discovery of distinct mtDNA and nDNA mutations has demonstrated that, in general, clinical phenotypes have specific genotypes; however, some patients do not fit into any clinical syndrome, or they have an atypical presentation for a particular mutation.

Common to all mitochondrial disorders with prominent epilepsy is involvement of the central nervous system (CNS), particularly the cortex. Imaging techniques have confirmed that gray matter involvement is an early feature of myoclonus epilepsy with ragged-red fibers (MERRF) and of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS); white matter abnormalities are also seen at later stages, but usually not in isolation.¹⁵ Maternal inheritance is pathognomonic of mtDNA point mutations, whereas patients with single large-scale rearrangements tend to be sporadic. In addition, phenotypic variability in families is the general rule rather than the exception with pathogenic mtDNA point mutations.