The genetic error in each of the mitochondrial diseases is most often a single-point mutation that leads to the alteration of a single amino acid, but there are also single or multiple deletions or duplications of mitochondrial genes that do not conform to maternal inheritance because they are caused by nuclear DNA defects. It is important to note that approximately 85 percent of the protein components of the respiratory chain are coded in nuclear DNA and are then imported into the mitochondrion; as mentioned above, this allows for a mitochondrial disease with a mendelian pattern of inheritance rather than a maternal one. Another of the general rules of mitochondrial inheritance is exemplified by an infantile myopathy (cytochrome oxidase deficiency) that is usually fatal but may also occur in a less severe form and have a later onset. In cases of earlier onset, there is less of the normal mitochondrial DNA than in the cases of later onset.
Because the unique function of mitochondria is the production of ATP by oxidative phosphorylation, it is not surprising that many of the genes contained in mitochondria code for proteins in the respiratory chain. However, there is not always concordance between the error in the mitochondrial genome and the enzymatic defect that leads to disease. Of the five complexes that make up the respiratory chain, cytochrome-c oxidase (complex IV) is the one most often disordered, and its deficient function gives rise to lactic acidosis, a feature common to many of the mitochondrial disorders (see further on). In keeping with the mutable nature of this class of disorders, it is thought that some cases of complex IV defect are autosomally transmitted. Complex I defects, which originate in mitochondrial mutations, are seen, for example, in Leber optic atrophy. A more complete account of the disorders of the mitochondrial respiratory chain can be found in the review by Leonard and Schapira.
As one would expect, aberrant function of the ubiquitous energy-producing mitochondria results in disease of many organs besides skeletal muscle (e.g., diabetes and other endocrinopathies and minor dysmorphic features are seen in several mitochondrial disorders). Nevertheless, most of the mitochondrial disorders affect the nervous system prominently and at times exclusively. Two characteristics traceable to mitochondrial abnormalities are particularly common: one is a special change in muscle fibers termed ragged red fibers, a clumping of mitochondria in muscle fibers described in more detail further on, and the other is a systemic lactic acidosis. Other than these, each of the mitochondrial diseases has distinctive features and in their main elements they do not resemble each other. The main syndromes are MELAS and MERRF (acronyms defined further on), Leber hereditary optic atrophy, progressive external ophthalmoplegia, and the Leigh syndrome. These diseases are described in detail in the last part of this chapter.
Diagnostic Features of Hereditary Metabolic Diseases
In clinical practice, one should consider the possibility of a hereditary metabolic disease when presented with the following lines of evidence: 1. A neurologic disorder of similar type in a sibling or close relative 2. Recurrent nonconvulsive episodes of impaired consciousness or intractable seizures in infants or young children or infantile spasms and progressive myoclonic seizures in the absence of neonatal hypoxia-ischemia 3. Some combination of unexplained symmetrical or generalized spastic weakness, cerebellar ataxia, extrapyramidal disorder, deafness, or blindness 4. Progression of a neurologic disease measured in months, or a few years, sometimes identified by achieving and then losing developmental milestones, as outlined in Chap. 27 5. Developmental delay in an individual if there are no congenital somatic abnormalities or developmental delay in a sibling or close relative
In the face of such clinical information, one should obtain appropriate biochemical analyses of blood, urine, and cerebrospinal fluid (CSF); MRI of the brain; and genetic studies.