Disturbance of skeletal muscle is even less prominent in type IV glycogenosis (branching enzyme deficiency, or Andersen disease, which is also implicated in the polyglucosan disease that causes a special neuropathy discussed in Chap. 43, a motor system disease with flaccid bladder, or a leukoencephalopathy with dementia). This is a progressive disease of infancy and early childhood, characterized by cirrhosis and chronic hepatic failure, usually with death in the second or third year. Hepatomegaly as a result of accumulation of an abnormal polysaccharide is a universal finding. Muscle weakness and atrophy, hypotonia, and contractures occur less regularly and are overshadowed by the liver disease. The diagnostic hallmark of the myopathy is the presence of basophilic, intensely PAS-positive polysaccharide granules in skin and muscle.
The remaining nonlysosomal glycogenoses (types VIII through XI) need only be mentioned briefly. They are all rare and clinically heterogeneous, and a myopathy— characterized by intolerance to exercise, cramps, myoglobinuria, elevated CK, and, sometimes, renal failure—has been observed in a small proportion of them. Phosphoglycerate kinase deficiency (type IX glycogenosis, PGK1 mutation) differs in that it is inherited as a sex-linked recessive trait localized to chromosome Xq13. Hemolytic anemia—becoming evident soon after birth—mental retardation, seizures, and tremor are other features that set this glycogenosis apart from the others. The myopathic features of the lysosomal and nonlysosomal glycogenoses are listed in Table 45-5 and detailed accounts can be found in the monographs by Griggs and associates and of Engel and Franzini-Armstrong.
Disorders of Lipid Metabolism Affecting Muscle (Lipid Myopathies)
Although it has long been known that lipids are an important source of energy in muscle metabolism (along with glucose), it was only in 1970 that W.K. Engel and associates reported the abnormal storage of lipid in muscle fibers attributable to a defect in the oxidation of long-chain fatty acids. The subjects of their report were twin sisters who had experienced intermittent cramping of muscles associated with myoglobinuria after vigorous exercise. In 1973, A.G. Engel and Angelini described a young woman with progressive myopathy, lipid storage predominantly in type 1 muscle fibers, and a deficiency of muscle carnitine, a cofactor required for the oxidation of fatty acids. Since that time, highly sophisticated biochemical techniques have greatly expanded the study of fatty acid metabolism and the identification of many of the primary defects.
Carnitine (b-hydroxy-gamma-N-trimethylamino-butyrate), derived from lysine and methionine, plays a central role in the metabolism of fatty acids. Approximately 75 percent of carnitine comes from dietary sources (red meat and dairy products); the remainder is synthesized in the liver and kidneys. Practically all of the body carnitine is stored in muscle, where it has two main functions: (1) transporting long-chain fatty acylcoenzyme As (CoAs) from the cytosol compartment of the muscle fiber into the mitochondria, where they undergo beta-oxidation, and (2) preventing the intramitochondrial accumulation of acyl-CoAs, thus protecting the muscle cell from the membrane-destabilizing effects of these substances.