Discussion on Some Clinical, Genetic and Biochemical Aspects of Metabolic Disorders of the Nervous System

It is not possible to discuss clinical aspects of inborn errors of metabolism without a brief incursion into biochemistry and genetics. Dent (1957a) has stated that if we believe in the genetic theory of inheritance it is not permissible to speak of inborn errors of metabolism of the nervous system, or of the renal tubule or of any other organ. The abnormal gene is universally distributed in the somatic cells. For the clinician this emphasizes the importance of recording associated abnormalities in inherited nervous disease. Numerous examples come to mind; it was pigmentation of the skin that first led to the suspicion of metallic poisoning in Wilson's disease. The recent report on the association of ichthyosis, mental defect and spastic paralysis (Sjogren and Larsson, 1957) shows that clinical observation may still have much to contribute. There is general agreement that metabolic errors are the expression of defective or abnormal enzyme action. Much of the basis for this belief rests on elegant experiments on unicellular organisms. As far as I am able to understand this work it seems to contain certain valuable ideas for the clinician. It is probable that although the abnormal gene may be present in every cell the resulting metabolic error is only potentially present. It has been shown that in certain instances not only the action, but even the production of a genetically-induced enzyme may be controlled by the environment. A second significant findihg is that enzyme abnormalities are not necessarily absolute; an enzyme may be reduced in quantity but not completely absent (Davis, 1954). If these findings can be applied to human disease they are of some importance as, at first sight, a disease due to an intracellular enzyme defect is not a promising therapeutic subject. It is through the environment that we can hope to exert any influence and there is strong evidence that in many instances it is environmental factors that are responsible for the production of symptoms. A puzzling feature of certain of these diseases is that, in spite of a presumably constant metabolic defect, symptoms are often episodic and sometimes very acute. Another feature is the great variation of clinical response to an apparently stereotyped biochemical disorder. Even in a single family great variation may occur and between families there are often wide differences in the age of onset and severity of symptoms. The interaction of the genetic defect, which may itself perhaps vary in degree from case to case, and the environment, is of vital importance. It may one day be possible to classify inborn errors according to the enzyme at fault and to describe the manner in which the nervous system is affected. We are very far from this at present and even in apparently simple examples there is no agreement. In the condition of congenital methemoglobineemia a varying proportion of the hiemoglobin is unable to transport oxygen. The disease is characterized by fluctuating cyanosis and, in some instances, by mental defect and motor retardation. It is tempting to attribute the mental defect to anoxia, but here we meet a recurring theme in writing on hereditary disease, as it has been suggested that the cerebral damage is not causally connected with the metabolic defect but is separately inherited (Worster-Drought et al., 1953). There is recent evidence that this may not be so. Dine (1956) reported a family in which the elder child was diagnosed