As with the metabolic disorders of the nervous system, the diseases included under this heading are so varied and may involve so many parts of the nervous system that the clinical entities by which they are identified cannot be easily addressed in any one part of this book. In their overlapping relationships, however, they are unlike the more discrete clinical entities caused by nuclear genetic mutations. Their diversity is evident not only in the details of their clinical presentations but also in the age at which symptoms first become apparent and, what is most intriguing, sometimes in the abrupt onset of their neurologic manifestations. Most of this variability in presentation is understandable from the principles of mitochondrial genetics outlined in the introductory section of this chapter. Of particular importance is the mosaicism of the mitochondria within cells and from cell to cell and the crucial role the organelles play in the oxidative energy metabolism that supports the function of cells in all organs. Although a ubiquitous metabolic derangement would seemingly offer an explanation for the dysfunction of several disparate tissues in the mitochondrial disorders, such clarification is not available.
Fortunately for the clinician, the most important of these diseases are expressed in several recognizable core syndromes and in a few variants thereof and they are each monogenic disorders. A number of acronyms derived from the initial letters of the main clinical features are used to designate the major mitochondrial syndromes: MERRF, MELAS, PEO, NARP, etc., as summarized in Table 36-9. The addition of certain subtle dysmorphic features including short stature; endocrinopathies, particularly diabetes; and a number of other systemic abnormalities such as lactic acidosis (discussed further on) aids in diagnosis of this class of disorder.
These diseases are the result of mutations in the mitochondrial genome, a ringed DNA of 16,569 base pairs and 37 genes contained within the organelle, or of mutations in a few nuclear genes that code for a component of the mitochondrion. To date, more than 100 point mutations and 200 deletions, insertions, and rearrangements have been identified. It is estimated that two-thirds of the point mutations affect the transfer RNA of the mitochondrion, one-third affect polypeptide units of the respiratory chain, and a small number affect mitochondrial ribosomal RNA. This corresponds approximately to the proportion of genes devoted to each of these functions. DiMauro and Schon, and Koopman and colleagues have written reviews of mitochondrial genomics and the most relevant diseases, which may be consulted by interested readers.
The first described and best-characterized member of this group of diseases is a symmetrical proximal myopathy that occurs as an isolated illness or in combination with any of the major mitochondrial syndromes. In 1966, Shy and coworkers described the histochemical and electron-microscopic abnormalities of the muscle mitochondria in a childhood myopathy, which they called megaconial (meaning marked enlargement of the mitochondria) or pleoconial (referring to an excessive number of mitochondria). Later this change came to be known as “ragged red fibers,” so named because of the subsarcolemmal and intermyofibrillar collections of membranous (mitochondrial) material in the type 1 (red) muscle fibers as visualized by the Gomori trichrome stain in sections of frozen muscle. This morphologic change may be an asymptomatic accompaniment of the mitochondrial disorders or, conversely, a mitochondrial disease of the CNS may exist without histologic or ultrastructural abnormalities in the muscle.