(or inborn errors of metabolism), diseases caused by hereditary disturbances in metabolism. The term “molecular disease” was proposed by the American chemist L. Pauling. At the beginning of the 20th century, the British physician A. E. Garrod, while studying a number of hereditary diseases, conjectured that they arise as a result of the decreased activity or complete absence of the enzyme that controls a certain stage in metabolism. Thus, the appearance of homogentisic acid in the urine of patients with alkaptonuria is caused by the absence of the enzyme that normally oxidizes it. (It was subsequently revealed that in this case the inactive form of the enzyme is formed.) Albinism is produced by an enzymatic block in the formation of melanin pigments as a result of a deficiency of one of the necessary enzymes, tyrosinase. Garrod’s ideas received general recognition and concrete chemical interpretation several decades later.
Investigations of the changes in biosynthesis observed in the microorganisms after gene mutation have proved decisive in understanding the mechanisms of the origin of molecular diseases. As a rule, each normal gene determines (encodes) the biosynthesis of a strictly determined enzyme, that is, of a normal enzyme. The study of biochemical mutants (mainly the work of the American geneticists G. Beadle and E. Tatum, 1941) has shown that gene mutation leads to absence of an enzyme or change in its activity; that is, the protein is either not synthesized at all, or it is synthesized with an altered primary structure (a different sequence of amino acids in the polypeptide chain). Alteration of the primary structure of a protein (enzyme, structural protein, serum proteins) apparently does not influence its properties (“silent” mutations). However, in a number of cases (such as change in the active center of an enzyme) changes in the properties and consequently in the functions of the protein do occur. Thus, all molecular diseases are associated either with the loss of some normal enzyme or with a change in its enzymatic or physicochemical properties.
Inasmuch as every enzyme controls a definite metabolic reaction, the enzyme’s absence or inability to perform its function leads to an arrest in the normal metabolic pathway at the stage of the biosynthesis of the substance that is the substrate of that enzyme. Disease develops either as a result of deficiency in the body of the end product whose synthesis is blocked or as a result of the accumulation of the precursor of the blocked reaction, an excess of which disrupts metabolic processes.
Molecular diseases include disorders of amino-acid metabolism (aminoaciduria), carbohydrate metabolism (glycosuria), lipide metabolism (lipidoses and leukodystrophies), purine metabolism, and pyrimidine metabolism. More than 1,000 molecular diseases are known. The frequency of each molecular disease is relatively small; one of the most common ones, phenylketonuria, is encountered with an average frequency of 1:10,000. Some hereditary metabolic disorders do not entail clinical sequelae (for example, the inability to perceive the flavor or odor of certain substances), while others have very serious consequences. A number of molecular diseases are manifested only under the challenge of the environment.
With timely diagnosis, some molecular diseases can be prevented and effectively treated. Since the gene mutation affects a very specific step in the biosynthetic pathway, establishing the hereditary nature of a disease by various methods of biochemical analysis reveals its influence on the whole chain of reactions involved in the biochemical and physiological anomalies. Replacement therapy is used with hormonal diseases. (Diabetes mellitus is treated with insulin; hereditary forms of hypothyroidism, with thyroid hormone.) Restricted diets, that is, those from which the substance that is accumulating in the body is eliminated (an amino acid, a carbohydrate), prove to be effective in treating a number of molecular diseases.
The prevention of molecular diseases is being carried out through medical-genetic consultations for families in which carriers of molecular diseases have been discovered. For a number of molecular diseases, methods of early (including intrauterine) diagnosis have been developed. Some molecular diseases, such as erythrocytopathies, are widespread in African and Mediterranean countries, because the transformed abnormal erythrocyte becomes resistant to the malarial Plasmodium.
REFERENCESZucherkandl, E., and L. Pauling.“Molekuliarnye bolezni, evoliutsiia i gennaia raznorodnost’.” In the collection Gorizonty biokhimii. Moscow, 1964. (Translated from English.)
Efroimson, V. P. Vvedenie v meditsinskuiu genetiku, 2nd ed. Moscow, 1968.
Zhurnal Vsesoiuznogo khimicheskogo obshchestva imeni D. I. Mendeleeva, 1970, vol. 15, no. 6. (Deals with the biochemistry of hereditary diseases in humans.)
Problemy meditsinskoi genetiki. Moscow, 1970.
Garrod, A. E. Inborn Errors of Metabolism. London, 1963.
The Metabolic Basis of Inherited Disease, 2nd ed. New York, 1966.
K. D. KRASNOPOL’SKAIA