Organic acidurias : proceedings of the ninth symposium of the Society for the Study of Inborn Errors of Metabolism / edited by J. Stern and C. Toothill.

  • Society for the Study of Inborn Errors of Metabolism.
Date:
1972
Catalogue details

Licence: Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)

Credit: Organic acidurias : proceedings of the ninth symposium of the Society for the Study of Inborn Errors of Metabolism / edited by J. Stern and C. Toothill. Source: Wellcome Collection.

    33/202 (page 17)
    METHYLMALONIC ACIDURIA 17 patient with ketotic hyperglycinaemia, the metabolism of the second carbon atom of glycine to the third carbon atom of serine is perfectly normal. Metabolically, these are two quite different conditions. Eldjarn (Oslo). In Professor Nyhan's presentation hydroxypropionic acid and methyl citrate figure prominently. Have you done any experiments to ensure that hydroxypropionic acid is not an artefact? In our systems hydroxypropionic acid is produced from traces of water, methanol, hydrochloric acid and diazomethane. The formation of homocitrate reminds me of the work of Sir Rudolph Peters {Biochemical Lesions and Lethal Synthesis, 1963, Oxford, Pergamon) on fluoroacetate poisoning via the formation of fluorocitrate. Could it be that homocitrate similarly interferes with the citric acid cycle and that some of the symptoms could be explained in this way? Nyhan {LaJolla). Thank you very much for your comment and for remind¬ ing me about fluoroacetate and its condensation. One of the earliest things I worked with in the laboratory was fluoroacetate, and I learned a con¬ siderable respect for it. As you know, it is extremely toxic. It has been used in Africa as a rat poison; it is, as documented by Peters, condensed to fluorocitrate and acts as inhibitor of the citric acid cycle. We have told you this morning the sum total of our information up to a week or so ago, so that the experiment you suggest has not been carried out. However, it certainly will be. We have been puzzled, from the time we saw the first patient with the ketotic hyperglycinaemia syndrome, with the mechanism of ketosis in these children. I think that whether you look at methylcitrate or homo¬ citrate, if you will, as a way of draining of four carbon acids and thus depleting the citric acid cycle of the material with which to condense acetylCoA, or whether you look at it as a toxic compound like fluoro¬ citrate, it would provide a good way of explaining the ketosis which is central to all these conditions. This is a very exciting aspect of this new observation. Gerritsen {Madison). In the infant at risk from hyperglycinaemia it is the glycine/alanine ratio in the plasma which must be watched. This is less than 1 in normal infants. In the early stages of ketotic hyperglycinaemia the serum glycine level may be barely increased but the glycine/alanine ratio is greater than 1. Nyhan. I certainly would second that comment. We have had experience with at least two patients in whom we have found normal glycine levels on more than one occasion and for relatively prolonged periods of time. This was particularly exemplified by George Donnell's case in which they knew that the patient was a sibling of a known patient with ketotic hyper¬ glycinaemia who had died of the disease. It was approximately six weeks before that patient developed consistent elevations of the serum glycine.