Etiology of Uric Acid Overproduction in Primary Gout

In an editorial that appeared elsewhere in I 960 23, the author ventured some speculations as to the nature and pathogenesis of primary gout, considered from the point of view of inborn errors of metabolism. Since then much relevant information has accumulated, and the Editorial Board of The Journal of Bone and Joint Surgery has asked me to bring the subject up to date and to summarize our views on the modern management of gout 84#{149} The concept of inborn errors of metabolism, defined as heritable disorders initi-ated by a gene mutation involving loss of activity of a specific enzyme, was intro-duced in I 908 by A. E. Garrod 16#{149}He cited as examples alkaptonuria, cystinosis, albinism, and pentosuria, but, significantly, did not include gout. The omission was not explained until I 93 1 when Garrod parenthetically remarked, without further comment, that gout “cannot be looked upon as due, like other such errors, to a rare mutation which occasionally occurs de novo, but rather as based upon an alternative and slightly divergent path of metabolism met with in a large part of the total popu-lation ” 17 We now know, thanks largely to the recent elegant studies of Seegmiller, Kelley and their associates, that gout occasionally is due to single gene mutations, and thus may be the expression of an inborn error of metabolism in Garrod’s original sense