It follows from these observations that the efficiency and endurance of muscular contraction depend on a constant supply of glycogen, glucose, and fatty acids, and on the adequacy of the enzymes committed to their metabolism. Biochemical derangements in the storage, breakdown, or utilization of these substrates give rise to a large number of muscle disorders, the most important of which are elaborated in the following pages.
An abnormal accumulation of glycogen in the liver and kidneys was described by von Gierke in 1929; shortly thereafter, Pompe (1932) reported a similar disorder involving cardiac and skeletal muscle. Major contributions to our understanding of glycogen metabolism were made by McArdle, by Cori and Cori, and by Hers, who discovered the deficiency of acid maltase in Pompe disease and enunciated the concept of inborn lysosomal diseases (see
Chap. 36). Since then, many nonlysosomal enzyme deficiencies of muscle and other organs have been identified and have become the basis of the classification presented in Table 48-5. These enzymatic deficiencies alter the metabolism of many cells, but most strikingly those of the liver, heart, and skeletal muscle. In about half of affected individuals, a chronically progressive or intermittent myopathic syndrome is the major manifestation of the disease. It is a curious fact, that with the exception of the rare phosphoglycerate kinase deficiency (X-linked recessive inheritance), all the glycogenoses are inherited as autosomal recessive traits. The most impressive and common of these glycogen storage diseases from the standpoint of the clinical neurologist are 1,4-glucosidase (acid maltase) and myophosphorylase deficiencies.
Acid Maltase Deficiency (Glycogenosis Type II; Pompe Disease and Related Disorders, GAA Mutation)
A deficiency of the enzyme acid maltase (also called acid alpha-glucosidase and due to mutations in the GAA gene) takes three clinical forms, of which the first (Pompe disease) is the most serious. Pompe disease typically develops in infancy, between 2 and 6 months; dyspnea and cyanosis call attention to enlargement of the heart, and the liver may be enlarged as well. The skeletal muscles are weak and hypotonic, although their bulk may be increased. The tongue may be enlarged, giving the infant a cretinoid appearance. Hepatomegaly, while often present, is not pronounced. Exceptionally, the heart is normal in size and the CNS and muscles bear the brunt of the disorder. The clinical picture then resembles infantile spinal muscular atrophy (Werdnig-Hoffmann disease) and, to add to difficulty in differential diagnosis, there may be fasciculations. The infantile disease is rapidly progressive and ends fatally in a few months. The EMG shows myopathic changes, but there are, in addition, fibrillation potentials, heightened insertional activity, and pseudomyotonia. Large amounts of glycogen accumulate in muscle, heart, liver, and neurons of the spinal cord and brain. All tissues lack acid maltase (also called alpha-glucosidase) because of a mutation in its gene.
In the second (childhood) form, onset is during the second year, with delay in walking and slowly progressive weakness of shoulder, pelvic girdle, and trunk muscles. The toe walking, waddling gait, enlargement of calf muscles, and lumbar lordosis resemble those of Duchenne dystrophy. Cardiomyopathy is exceptional, hepatomegaly is less frequent than in the infantile form, and developmental delay is present in a minority. Death occurs between 3 and 24 years of age, usually from ventilatory failure and recurrent pulmonary infections.