Mitochondrial defects of brain and muscle.

The brain and muscle are particularly vulnerable to mitochondrial defects as are the heart, kidney and liver. This hierarchy of organ involvement is reflected in the clinical signs and symptoms associated with these diverse encephalomyopathic syndromes. The biochemical correlates involve pyruvate metabolism, the citric acid cycle and the respiratory chain. Lactic acidosis is the metabolic signature in these diseases although not present in all syndromes, witness Leber hereditary optic neuropathy. Ragged-red fibers are equally distinctive in biopsied skeletal muscle but are present only with biochemical defects involving the respiratory chain. Defects of pyruvate metabolism and the citric acid cycle are inherited as autosomal or x-linked Mendelian traits. Respiratory chain defects may be inherited as Mendelian or maternal (non-Mendelian) traits. All mitochondria of the progeny are inherited from the mother; and all 13 polypeptides encoded by the mitochondrial genome are located in the respiratory chain (complexes I, III, IV and V). These biological principles are helpful in understanding the clinical syndromes and patterns of inheritance associated with the mitochondrial myopathies and encephalomyopathies.