Dr. MILHORAT. At the present time a number of invesigators are studying the various chemical abnormalities that occur in the muscles of patients with muscular dystrophy and of animals in which the disease has been experimentally produced. Significant alterations in the metabolism of several substances already has been demonstrated, but what these alterations are, we do not know whether they are primary or secondary to the muscular-dystrophy process. Moreover, certain alterations in the liver have been demonstrated at least in the experimental animal, and the primary defect might well be in the liver. There is an important concept in biochemistry that now is being applied to the problem of muscular dystrophy and that is the one of dynamic equilibrium. What it means is that the structures in the body are not static; that they are constantly being broken down and rebuilt. Heretofore, we have always looked upon muscular wastage as a mere dissolution of the muscle and the loss of its protein, and yet, work being done in our laboratories indicates that the actual rate of breakdown of the muscle is diminished, which means that the rate of synthesis must be markedly diminishing. That brings us to the process of experiments by means of cortisone. Cortisone we know interferes with the synthesis of protein, so that our attention probably should be on the basis of rebuilding the tissue.

The CHAIRMAN. What I had in mind, Doctor, when I spoke was that I wanted you, as well as the other witnesses who appear here, to feel free to add to your testimony in a voluminous way, if you wish, by building to your statements or submitting reports of your organi

zations.

Dr. MILHORAT. I see.

The CHAIRMAN. We desire to have as complete a record as possible and more complete than it would be possible if we had to depend upon its being entirely submitted by oral testimony. So, feel perfectly free to do that, and that applies to the others as well to present any additional information that they wish for the record.

Dr. MILHORAT. Thank you very much, Mr. Chairman. My only regret is that I cannot show you a patient crippled with muscular dystrophy.

(The following statement was submitted by Dr. Milhorat :)

MUSCULAR DYSTROPHY

(Prepared for the hearings of the House Committee on Interstate and Foreign Commerce, October 7, 1953, by the Muscular Dystrophy Associations of America, Inc., New York, N. Y.)

Muscular dystrophy is a chronic, noncontagious, progressive disease, manifested by weakness and wasting of the voluntary muscles. Gradually, most of the voluntary muscles of the body are affected and the patient becomes so weak and helpless that he is first confined to a wheelchair and then to his bed, It affects persons of all ages, but more than two-thirds of the victims are children aged 3 to 12 years. There are estimated to be more than 200,000 cases of the disease in the United States, but there are doubtless many thousands more which have not been brought to medical attention since muscular dystrophy is not a reportable disease, and also, due to its very recent recognition by the medical world at large, it is often misdiagnosed as cerebral palsy, rickets, polio, or other more well-known crippling diseases.

The disease causes the death of all the younger patients before they reach maturity, and it is a great contributory factor to the death of the older patients. There is no known treatment to stop or even retard the progress of muscular dystrophy.

In terms of economic loss to the community and the country, although no exact figures have been compiled, the many considerations involved in muscular dystrophy would certainly point to the disease as a severe drain on American resources. Of the adults stricken by muscular dystrophy, only a few are able to maintain jobs which would make them self-supporting. Since the disease makes people progressively less active, those afflicted find themselves increasingly incapacitated as far as finding work they can do, and are increasingly dependent on aid from members of their families or outside people for their everyday needs. In the case of children, parents who might otherwise be more gainfully employed, often have to give up all or part of their work to take care of the needs of their helpless children. And, in families where more than one person is afflicted, the economic status often reaches complete destitution. Cost of wheelchairs, braces, physical therapy, and other measures are items of extreme cost to individuals and their families.

The only reason that costs to Government agencies have not been higher is that heretofore such agencies have not fully assumed obligations to these patients, preferring to use their limited means on diseases for which the prognosis was not so serious as with muscular dystrophy. For example, if muscular dystrophy patients were given adequate physical therapy, the minimum cost for 200,000 patients would be estimated at $2,080,000 per year.

There is a great need for medical research to seek means of alleviating the crippling and fatal effects of muscular dystrophy but limited funds have prohibited any extensive research program until very recently. Basic research has only been started in the last 3 years, as a result of the voluntary contributions to the Muscular Dystrophy Associations of America. Apart from a small number of Government-supported projects, through the National Institute for Neurological Diseases and Blindness, all major work in the study of muscular dystrophy is being supported by this association which has, in the 3 years of its existence, disbursed $682,370 for the establishment and maintenance of 35 separate research projects. (See appendixes A, list of research projects, B, financial report, for specific expenditures.)

Among the preliminary findings revealed so far as a result of patient-history studies, are the characteristics of transmission of muscular dystrophy by heredity. It has been found, for example, that the most common form of such transmission is from a healthy mother to her sons. Second most common is from an afflicted parent to a child of either sex. Most important is the finding that new "dystrophy bearing" families are constantly arising by mutation.

Basic studies on protein constituents and on the chemistry of muscle have yielded fundamental contributions to knowledge of normal muscle. These findings are now beginning to be applied to the study of diseased muscle in muscular dystrophy. Analysis of dystrophic muscle has already shown the presence of defects in important metabolic processes. Whether these are causes or effects of muscular dystrophy must still be investigated.

Muscular dystrophy has been produced in several species of animals by experimental means (by cortisone overdosage, and by vitamin-E deficiency), and investigations are now being made to determine the chemical abnormalities of these forms of the disease to devise effective methods of treatment and to determine in what way these findings may be applied to the disease in human patients.

While the Muscular Dystrophy Associations of America have been interested in every facet of the muscular dystrophy problem, limited means have made it necessary to restrict investigations to the field of chemical analysis of muscle, in which field trained technicians are available to work on a modest basis. Increased funds would be necessary not only to support work in related fields, but also to train personnel for investigation in other areas not yet studied, such as the role of the various hormones in growth functions and maintenance of muscle relation of liver to muscle structure through its synthesis of protein, role of the various elements in muscle integrity, the factors of metabolism of sugar in muscle, of contracture in muscle tendon units, and many other related problems which may hold at least a partial answer to the search for a cure for muscular dystrophy.

Although public contributions to muscular dystrophy research through the muscular dystrophy associations are answering some of the research needs, in the long run, research on a scope wide enough to make a conclusive contribution to the discovery of an effective treatment and cure for muscular dystrophy would be dependent on increased Government aid. Since the voluntary muscles constitute the largest organ in the body and since many of the chemical reactions which occur in muscle occur also in other tissues, it may reasonably be expected

that any fundamental knowledge of muscular dystrophy will lead to significant findings about other parts of the body-and to findings significant to other diseases. The effect of such information on the alleviation of human suffering and economic loss caused not only by muscular dystrophy, but by other conditions as well, is incalculable.

APPENDIX A

The following research programs are being financially supported by the Muscular Dystrophy Associations of America, Inc., as of August 1, 1953:

This is by far the most extensive research program and includes a metabolism ward, dietary kitchen, extensive laboratory facilities, psychiatrist, physical chemist, and a large staff of investigators and technicians.

Columbia University, New York.... Studies of Surface-spread Actomyesin Fibers....

Dr. Teru Hayashi.

Interaction Between Ions and Muscle Proteins..

Dr. David Machmansohn.

University of Rochester, New York. Structural and Metabolic Studies on Degeneration and

National Institute of Neurological
Diseases and Blindness, Washing-
ton, D. C.

Johns Hopkins Hospital, Baltimore,
Md.

Repair of Skeletal Muscle in Experimental Muscu-
lar Dystrophy.

Dr. Karl E. Mason.

Total funds allocated by MDAA since commencement of project

$4,860

9,330

8,316

3,240

12,474

16.135

The following projects, which received our financial support in the past, have now been completed:

APPENDIX B

Statement of income and disbursements for the fiscal years ended Mar. 31, 1952

Dr. BAILEY. May I interrupt a moment, Mr. Chairman, and include the work being done in muscular dystrophy at the National Institute of Neurological Diseases and Blindness? We have a rather large project in muscular dystrophy at the present time. Would you like for that to be included in the list for the record?

The CHAIRMAN. Yes, sir; we would be glad to have it. (The materials follow:)

NATIONAL INSTITUTE OF NEUROLOGICAL DISEASES AND BLINDNESS-STATEMENT ON RESEARCH PROGRAM IN MUSCULAR DYSTROPHY

The National Institute of Neurological Diseases and Blindness has concentrated its medical neurological research program during the fiscal year 1954 on that group of disorders generally known as neuromuscular. Such disorders are usually grouped together in neurologic research, inasmuch as a nerve cell in the spinal cord and its nerve, and the muscle fibers that are attached to this nerve are generally considered as a single structural and functional unit which carries the name "lower motor neuron." Thus, a disorder anywhere along this chain, whether in the nerve cell, the nerve, or the muscle, may cause a wasting or weakness of muscle, and it is only by understanding the functional anatomy of the entire unit that one can differentiate and investigate the various disorders. This group of neuromuscular disorders comprises muscular dystrophy, myositis and dermatomyositis, myotonia, myasthenia gravis and amyotrophic lateral sclerosis. The most promising research in these disorders lies in understanding the pathophysiological and chemical factors underlying the disease. This institute has approached this problem by organizing a clinical research team consisting of scientists qualified in neuromuscular chemistry, radioactive isotope techniques and personnel trained in electronic nerve and muscle conduction, and finally, personnel trained in the application of pharmacological agents. Chemical studies will be performed on the primary muscle proteins, and their formation, particularly myosin and actin, which, when reacting with a chemical called adenosine-triphosphate, forms one of the bases of neuromuscular contraction. Studies of the effect of potassium on such mechanisms will be analyzed by the use of radioactive potassium (K-42). All of these studies will be correlated with electrical responses, and the pathology of the disorder will be controlled by adequate examination of biopsied muscle.

Though many of the investigations outlined above may be done in basic laboratories, the clinical implication of the findings necessitates a research team in which clinical neurologists with laboratory training collaborate with laboratory researchers. It is only by such cross-fertilization that the importance of such findings as might be obtained can be correlated rapidly with the diseases of the neuromuscular system.