A second unifying feature of these diseases is an elevation of lactate concentration or of the lactate-to-pyruvate ratio in the blood and CSF; this is the result of the respiratory chain abnormalities. These elevations are most prominent after exercise, infection, fever, or alcohol ingestion and in some conditions are capable of inducing recurrent ketoacidotic coma, which may be the presenting manifestation of a mitochondrial disease. Leigh syndrome and MELAS particularly have a tendency to exhibit elevations of lactate; however, the diagnosis of either cannot be excluded in the presence of normal levels of this substance, even after provocation by exercise (see further on for a description of testing for elevated lactate). Using phosphorus MRI scans, one can compare levels of inorganic phosphate to phosphocreatine levels in muscle; in genetic muscle diseases of several types, this ratio increases, but it is highest in those of mitochondrial origin.
Although the mitochondrial diseases are considered here as a group, individual ones are of necessity mentioned in other chapters because of their outstanding characteristics. Thus the syndrome that combines epilepsy, deafness, and developmental delay with ragged red muscle fibers (myoclonic epilepsy with ragged red fibers, or MERRF) was discussed in Chap. 15, on epilepsy. The syndrome of progressive external ophthalmoplegia (PEO) has been included with other abnormalities of eye movements due to muscular disorders (see Chap. 45); lactic acidosis and stroke-like episodes (MELAS) were considered in Chap. 33, with the cerebrovascular diseases; and Leber hereditary optic neuropathy, with other causes of visual loss (see Chaps. 13 and 38). Leigh syndrome, a symmetrical subacute necrotizing encephalomyelopathy, usually with lactic acidosis, also has a number of complex presentations and is mentioned in the differential diagnosis of several diseases. For each of the aforementioned processes, wide clinical experience will bring to light an individual or a family in whom some odd syndrome has been linked to a mitochondrial disorder. Furthermore, two major syndromes may coexist in one individual and fragmentary subsyndromes are known to occur, having an onset any time from childhood to early adult life. Consequently, it serves little purpose to catalogue all of these associations. Only the best-characterized entities, listed in Table 36-9, are described here. The most common combinations of mitochondrial syndromes have been of Kearns-Sayre syndrome with MELAS or with MERRF, progressive ophthalmoplegia with MERRF, and MERRF with MELAS.
We prefer to avoid the issue of what defines a “mitochondrial disorder”—its genetic defect, the biochemical disorder, or the clinical syndrome. The clinician assigns this term to the combination of a mutation of mitochondrial DNA and certain clinical features that constitute a recognizable syndrome; the biochemical changes are taken as markers of the disordered energy-producing mechanisms of the mitochondrial machinery. Mitochondrial failure has also become a focus of interest in various degenerative neurologic conditions, such as Alzheimer and Parkinson diseases but none of the currently understood mutations of the mitochondrial genome is clearly implicated in these conditions.