Inborn errors of metabolism

Abstract

Dr. Frederick K. Heath: Inborn errors of metabolism may be considered to be the result of an alteration in a specific biochemical reaction or series of reactions. In the case of the mold Neurospora, it has been demonstrated that single genes may control individual biochemical reactions through specific enzymes; that this tendency to control is dominant; and that through gene mutation a recessive altered enzyme specificity may be transmitted under suitable genetic conditions, becoming apparent as an abnormal nutritional requirement.If this information be applied to man, estimated to have tens of thousands of distinct genes, it becomes probable that many inborn errors of metabolism remain to be recognized. Furthermore, a reasonable basis is given for certain features of these disorders, e.g., their relative infrequency, their familial character often associated with consanguinity and their appearance in early life.Although many diseases have been classified as belonging to the group of inborn errors, this clinic considered only four of the better understood examples. Alcaptonuria, characterized by the excretion of homogentisic acid in the urine proportional to the protein intake, is regarded as resulting from a defect in the metabolism of 2,5-hydroxybenzene compounds, particularly phenylalanine and tyrosine. Such urine when acid is normal in color but on standing turns black at the air surface or becomes brown or black when alkaline; it reduces Benedict's solution and turns blue with ferric chloride. Individuals so affected develop ochronosis in later life due to the deposition in fibrous tissues, cartilage and atheromas of a black pigment thought to be a polymer of homogentisic acid. Hence gray, brown or blue pigmentation may be noted in skin and sclerae, and in the aural, nasal and joint cartilages. Osteoarthritis of the intervertebral and larger joints is common. No therapy is known.Congenital galactosemia becomes manifest in infants, who exhibit vomiting, failure to grow or gain weight, hepatomegaly sometimes with positive cephalin-flocculation tests, cataracts, a no galactose an albumin in their urine. On a galactose-free diet all manifestations of the disorder disappear. The nature of the defect responsible for the inability to metabolize galactose is unknown.The Fanconi syndrome is presented as a renal tubular defect characterized by impairment in the reabsorption of glucose, amino acids, inorganic phosphate and possible bicarbonate. The urine tends to be alkaline. Depletion of liver glycogen follows from the loss of urinary glucose. Acidosis, to which the ketosis, amino acid excretion and loss of base all contribute, leads to a negative calcium balance. Replacement therapy is advised.In congenital methemoglobinemia a specific red blood cell enzyme defect in diaphorase, a flavoprotein, has been described which may be responsible for the failure of these individuals to reduce naturally occurring methemoglobin to the ferrous form. Ascorbic acid directly and methylene blue indirectly may aid in this reduction and so modify the severity of the disease.The clinic thus emphasizes the role of genetic factors in determining the enzymic constitution of cells and thereby the metabolic behavior of the whole organism, whether mold or man. It also brings out the need of modification of Garrod's original concept of the relatively benign and non-progressive character of inborn errors of metabolism, since it is now clear that accumulation of even normal metabolic intermediates may have deleterious effects. Finally, the growing significance of the clinical implications of our expanding knowledge of the role of enzyme systems is brought out.