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January 1967

The Pathogenesis of Homocystinuria: Implications for Treatment

Am J Dis Child. 1967;113(1):103-108. doi:10.1001/archpedi.1967.02090160153024

IN THE GROUP of diseases under discussion, it is considered axiomatic that compounds proximal to a defective enzyme accumulate to toxic concentrations, while distal to the block there is a relative deficiency that is not physiologically significant because the substance is freely available in the diet. The hunt for these toxic metabolites, only recently begun in homocystinuria, is in its 36th year in the case of phenylketonuria (PKU), without any agreement about which metabolite causes the disease—to say nothing of how.

Fortunately there are characteristic pathological changes in homocystinuria that make it possible to decide whether we have reproduced the disease in animals. Klavins' experiments with excess homocystine in the diet1 and Stekol and Szaran's experiments with excess methionine2 show that "toxic" concentrations of these compounds, while deleterious, are not sufficient to reproduce the disease. Clearly, we must also look at the other, more neglected, side of the