ROUND TABLE DISCUSSION 519 
ScHREIER: A cystine-free diet will help the patient with FANcoNnI’s syndrome only if cystine 
is the toxic substance responsible for the changes. If there is something else, an inborn error of 
a different type, and cystine deposition is only a secondary effect, one would not obtain very 
satisfactory results, don’t you think? 
WESTALL: I agree absolutely. The cystine effect in this cystinosis is so gross that I think you 
would have to eliminate, if possible, this effect before you can make further studies to see whether 
or not the cystine deposition was a secondary effect only. 
May I change the subject slightly, to alter the drift of the discussion. There are just two things 
that I would like to put to the meeting here for some consideration. One is the general type of 
findings in phenylketonuria and in argininosuccinic aciduria, that it appears that brain damage 
in these cases occurs at a very early age. This, I think, pertains to the possibility that it might 
be due to amino acid imbalance, inasmuch as during that time, when there is a good deal of 
brain growth and myelinization takes place, it is more than likely that the nutrient medium from 
which these substances are synthesized may be considerably out of balance. A further note may 
be made, possibly, that particularly in these two diseases that I have just mentioned, it appeais 
that they are not usually lethal, and that after the period of growth has finished, the disease 
doesn’t seem to get any worse. Such patients learn to live with their defect and survive to a 
reasonable age. 
The second point is this; the idea of amino acid imbalance has been much to the fore with 
nutritionists for a good number of years, particularly in view of the low protein diets which are 
used in underprivileged countries. Leucine and isoleucine are two amino acids that have been 
studied a good deal but these types of studies tend to be rather long term. We have had some 
sort of evidence recently, particularly in maple-syrup disease, where the effects of imbalance of 
leucine and isoleucine are more acute. Two years ago we picked up a patient in England, the 
first one that we had found, with maple-syrup urine disease. I might, perhaps, say to those who 
are not so familiar with the disease that the blood plasma amino acids in the condition are in a 
tremendous state of imbalance. The most obvious thing is that leucine, isoleucine and valine are 
up to 10 to 20 times their normal value. There seems to be an imbalance of the two sulfur amino 
acids, although the fact that the methionine is high and the cystine is low is not quite so unusual, 
now that we know a little more about the plasma levels of younger babies. The other thing is that 
the KreEBs’ cycle amino acids, the non-essential ones, are very low. The obvious course of treatment 
here is to try and correct this imbalance. We devised a diet containing only the minimum amounts 
of leucine, isoleucine and valine which were needed for growth. The amounts were calculated 
from information from RoseE’s work and from some studies done by SNYDERMAN in New York. 
The response was quick. These particular amino acids in the blood fell to more reasonable levels, 
although not quite back to normal; the large urinary excretions of the keto acid analogs of 
these amino acids disappeared, as did the characteristic smell. 
We then thought we would go a little further, because from the point of view of the genetics of 
this disease we like, if we can, to pinpoint the defect at one site, and we couldn’t at that time live 
with the idea that three of the essential amino acids could be in a way affected by just one enzyme 
deficiency. So we decided that perhaps only one of the metabolic pathways was in error, and that 
the other two were involved by some sort of amino acid transport inhibition, so we started to 
put these amino acids back into the diet one at a time and to watch the effect. The first one we 
put back was valine because we felt at that time that it might possibly be least important. But 
as soon as the valine was put back into the diet the blood valine rose to a high level, and the blood 
a-ketoisovaleric acid came out in the urine, though not as high as it was before. We withdrew the 
valine, stabilized the child with the basal diet, and gave additional isoleucine. The same sort of 
thing happened. The isoleucine rose to an abnormally high level in the blood. Finally we put 
back the leucine to a normal dietary level and once more the leucine level in the blood rose, the 
other two amino acids tended to rise also, a high amount of the a-ketoisocaprylic acid came out in 
the urine, and the characteristic maple-syrup smell returned. Although we had the idea the leucine 
was probably doing more damage than the other two, we couldn’t escape from the fact that all 
three were causing trouble. 
There is just one other thing I would like to cite, and that is that we ran out of synthetic amino 
acids at that time, so I took a casein hydrolyzate, fractionated it on ion exchange columns, 
withdrew the fractions containing the leucine, isoleucine, and part of the valine, and fed the others 
plus a little bit of supplemental tryptophane and cystine. Once again the smell disappeared from 
the urine and the blood levels came down; in this case the blood level of leucine and isoleucine were 
just about normal. We tended to overdo the withdrawal. We were giving only about half the 
essential amount of these amino acids. But with regard to valine, which was only reduced by 
about a third of what it was in the original diet, the blood level rose to a phenomenal figure of 
77 mg%. Our general conclusion here correlates with other ideas that have come about, that there 
is not only a sort of general balance of amino acids of this group, but that the withdrawal of one 
does have an effect on the others. 
References p. 524 
