Is Muscular Dystrophy a Primary Myopathy?

BRIEF PROPOSALS IS MUSCULAR DYSTROPHY A PRIMARY MYOPATHY? RICHARD S. POPE* Approximately 100 years ago, Meryon in 1864, Duchenne in 1855 and especially 1861, and Erb in 1871 published a number of papers directed to descriptions of muscular dystrophy. Duchenne in 1868 was the first to describe pathologic findings where the material was obtained by biopsy [I]. He devised a "muscle harpoon" and thus was able to greatly increase the amount of material available for study. These studies served to begin a classification of muscular dystrophies and a differentiation of some types with and other types without effected enervation. Eventually, certain muscle diseases were classified as primary myopathies, with Duchenne's muscular dystrophy or pseudohypertrophic one of the most common and best described. The literature covering Duchenne's muscular dystrophy is now very large, with many contributions describing clinical and biochemical features, classifications, age of onset, progression, genetics, histology, and many other facets of the disease. Although the condition is now acknowledged to be genetic in nature, the basic cause is still unknown, and a specific treatment is not available. Because the cause of the disease is unknown, many hypotheses may be entertained . Obvious causes of disease such as bacteria can be ruled out because of the absence of cross infection and the conclusive evidence for inheritance. The possibility of a latent virus causing the disease and then being transmitted in germ plasma, such as the Bittner virus causing mouse mammary tumor, is also unlikely because of the success in crossbreeding experiments where the mouse gene for dystrophy has been placed in varying genetic backgrounds. Various possible toxic agents can also be ruled out for similar reasons. The nature of a genetic disease would suggest that a faulty or absent gene product is the primary defect. Gene products are considered to be proteins or polypeptides, such as enzymes or certain hormones. The most likely cause of muscular dystrophy, then, should be a defective enzyme or other protein molecule. In 1955, Ann Michelson, Elizabeth Russell, and P. J. Harman reported the occurrence of a mutation in the mouse (inbred strain 129) which appears to be a muscular dystrophy like Duchenne's dystrophy in the human [2]. Over 350 *Laboratory of Neurophysiology, Good Samaritan Hospital and Medical Center, Portland , Oregon 97210. Perspectives in Biology and Medicine · Winter 1975 I 287 articles have been published since that time using this mouse as the experimental model. The murine condition appears essentially analogous to the human except for its genetic pattern. Although the mouse has provided an extremely useful experimental animal and although many scientists have labored for many years, we still do not seem closer to a knowledge of the basic cause of the disease and thus still do not have an effective cure. Genetic studies are conclusive in the finding of an inherited pattern for muscular dystrophy. This is true both in the human [3] and in the mouse [2, 4]. Additional positive evidence for the causal relationship of inheritance is the routine transplantation of ovary from dystrophic to normal females for use in the production of dystrophic mice. The facts of genetic inheritance, however, do not provide evidence as to the causative substance except to suggest strongly that a protein substance is involved. This protein could be defective or absent, and it cannot be predicted from the genetic findings where the location of the protein might be. Thus, both enzymes and hormones are likely candidates. The site of malfunction on a clinical basis is obviously muscle. This, however, does not necessarily mean that the primary cause of malfunction is in muscle. Thus, there could be a metabolic error in some other organ which results in an effect in muscle. All of the clinical signs of muscle wasting, weakness, loss of use, contractures, etc., could be secondary results. The biochemical findings likewise could be secondary results of muscle wasting. Much effort has been expended toward finding evidence of a primary defect in muscle, but this has not been demonstrated so far. Nerve has been considered as a possible site of the primary defect; the evidence for nerve, however, is considered to indicate that nerve is not involved except indirectly [5, 6]. The only...