Mental Retardation in Trisomy 21[1]

Jérôme Lejeune

Paediatrician 6: 331-335 (1977)


Abstract. Analysis of karyotypes from patients with partial 21 trisomy indicates that only a portion of the chromosome is responsible for the characteristic phenotype. Biochemical models suggest that children with this condition may have unusual drug sensitivities which might be exploited eventually for early treatment to prevent the current universal mental retardation.

The discrepancy between our power to predict a difficult life and our miserable impotency to help suffering people has produced a crisis in genetics. The discussion of whether genetic disease should be discarded or whether the people affected by genetic diseases should be discarded has curiously arisen in recent years in a straightforward contradiction with the whole history of Hippocratic medicine which was to fight against diseases, but never against the patient. I would like to discuss with you the reason why we should find another way, which would be to help the disabled, not to discard them. This discussion will be limited to trisomy 21, and mainly about its primary difficulty, which is mental deficiency.

Supposedly, after the diagnosis of an extra chromosome of the 21 type, no matter how old the person is, age 5 months in utero or 10 years out of the uterus, the diagnosis is the same, mental deficiency is obvious and certain. But we have no idea why this extra chromosome, carrying normal genes, can produce this mental deficiency. We can perhaps use a different approach to try to understand that problem and maybe to solve it, not today, but in the future. The first tool we can use is the cytogenetic tool; that is, to look at the chromosome and to look especially at rare instances of trisomy 21 in which chromosomes are split in small pieces so that we can detect what kind of action is associated with a certain piece of chromosome 21.

We encountered an example of this when we analyzed the chromosomes of a mother who had a trisomic child. She had a normal 21 chromosome and another which had lost a terminal segment which had been transferred to the short arm of chromosome 18. The child was typically trisomic, but his extra chromosome, so to speak, was cut into two parts, the proximal portion of the 21, and the distal one, which was transferred to No. 18. In such a case the child has all the features of trisomy 21 and mental retardation. Several other cases have been described where the split of the long arm of chromosome 21 was at the same point as in this family, but was transferred onto No. 15. In those cases there was no particular position effect, and none was apparent in this case either. In this family we could find 3 children, 1 with the translocation like the mother with a normal phenotype, 1 with trisomy 21 phenotype with the No. 15 with the extra piece, and 1 translocation with a tiny proximal piece extra, so that we had all three of the possibilities.

The child who had just the distal part of No. 21 extra carried by the No. 15 had a typical trisomy 21 syndrome, and he died from severe cardiopathy at 1 year of age. The child who was a carrier of the balanced translocation was perfectly normal. The other child was a carrier of the extra piece of the proximal part of the long arm of chromosome 21. While she had no stigmata of trisomy 21, she did have some trouble, being a little shy, a little retarded in school, but with no comparison whatsoever to the mental retardation of the typical trisomy 21.

The second approach, because I will come back to cytogenetics to mix it with the second one, is a biochemical one. It has been demonstrated by hybridization of cells that the super-oxide dismutase is located on chromosome 21. There are two super-oxide dismutase, SOD-1, which is located on chromosome 21, and SOD-2, which is located on chromosome 6. They also differ, not only by their chromosome location, but by their location inside the cells; that is, SOD-1 is cytoplasmic and found in the red cells and SOD-2 is mitochondrial and can be detected in platelets, so they are different enzymes. What it does is to reduce O2- which is a molecule of oxygen with an extra electron and is very reactive. This is in fact the way molecular oxygen is transformed before being used in oxidation and especially in oxidization of the benzene ring to produce some mediators in the brain.

It has been demonstrated that SOD-1 is increased among trisomics, multiplied by a factor of 1.5, which is roughly what is expected if you suppose an additive effect of the three genes they have compared to the two genes of normal persons. Surprisingly, SOD-2, which is not on the No. 21, is decreased among trisomics. Its efficiency is 0.67 as a mean among our trisomic children. This proves that there is a regulation mechanism. These children have, because of the constitution of their chromosomes, an increased level of SOD-1, but then they have replaced partially the other type so that they still have an even concentration of superoxide ions, otherwise they could not oxidize anything.

Let us try to correlate this biochemical information with the cytogenetics. Examination of a map of chromosome 21 demonstrates that the long arm has one band which can be split again in two bands, two dark and one grey. Reviewing our own laboratory cases, we could find trisomy for end segment alone, for the whole chromosome, which is classical, and for a special translocation in which a proximal segment was excluded, and the child was trisomic only for that. We found that children who were trisomic only for the distal part are similar clinically and for SOD-1 to general trisomy, but trisomy for the terminal portion is not related to the phenotype and has normal SOD-1. We could not find any monosomy for the end part, but did locate 3 different cases of trisomy for the proximal part, varying slightly in their breakage point, but none have the phenotype of trisomy 21, and they have no abnormality of SOD-1. This substantiates the notion that the syndrome is related to a specific band and that SOD-1 is located on that band called 92.21.

Why, even if we can locate more precisely the causes the genetic causes of the disease, are they feeble-minded? Well, to try to tackle that question, we have to go to another way of looking at children, which is more physiological, more clinical, let us say more medical, than laboratory investigation. That is, I mean just looking at the patients, especially looking at the eyes. There is no medical man who cannot recognize, looking at the eyes of a feeble-minded child, that the child has a particular disease. Now, why should ore be able to look at them, and why should we not be able to use it as a research tool? We decided to make a very simple model of the structure of the iris, remembering that the iris is moved by two kinds of muscle, the orbicular one, which closes it, and the radial one, which opens it. The orbicular muscle of the iris is moved by the cholinergic system and the radial one, the one which will open the iris, is operated by the epinephrine system. When children with Down's syndrome were tested with a variety of stimulating drugs, no significant differences were noted on their dilating response. But the difference is very great if you use a cholinergic drug with Down's syndrome patients showing a greater response. The same is true if you use drugs which block cholinesterase so that it is only what they produce as acetylcholine which is used as a stimulant. Again they are much more sensitive than normal. We chose, for normals, their brothers and sisters as controls. It is a rather easy task to put one drop in one eye, to have the child in the room in a controlled light and take a picture of the iris every 15 min, and then to make enlargements of them, calculate their opening, and so on. It is very simple for the child, because they look at the machine like they would look at puppets at play, but for the experimenter it is rather long, so that it takes quite a bit of time to investigate only one drug. This demonstration, which is very simple, can be extended to the area of mental deficiency and we are now doing that. But in fact, in the very peculiar case of trisomy 21, they are suffering a constitutional abnormality which is related to the cholinergic system.

This is the first way in which a very precise chemical trouble can be detected in man with very simple tricks like eye drops put in one of the eyes. One of the reasons why we consider that this should be extended to other diseases is that it seems that in other chromosomal diseases with mental retardation there are all types of abnormal sensitivity to drugs acting on the autonomic system. A clinical example is that every case of deletion of long arm of 18, 18q-syndrome, has to be controlled psychogenically when they are rather old, let us say after 5 or 10 years. They are often referred to us with the diagnosis of psychotic child. I am not sure they have to be controlled, but at least it seems that they have a special marked biochemical trouble also related to chemical mediators in the brain.

Let us try to put together what we do with this mirror of the brain, which is the eye, and what we do with the chromosome map. A lot of accelerations of reactions have been described in trisomy 21, but in general these have not been thought to be of great interest to understand the disease, being explained as compensatory, due to the aging of the cells, immaturity of the cells, and so on. It is very likely that we should not discard any piece of information when we want to understand why these people do not walk as they should, as they could. As one considers the extremely complex interactions involved in the various conversions of serine and homocysteine, one thing that is very important in man is that cystathionine is extremely highly concentrated in the brain. It is very low in lower mammals, it rises a little in the apes, especially chimpanzees and gorillas, but it is around 10 times higher in man.

This gives us a first comparison between trisomy 21 and a well-known disease related to only one blockage of biochemistry such as homocystinuria. In homocystinuria, patients cannot make cystathionine as they should and so they produce homocystine, which is released into the urine. If we compare the two diseases, one with one specific metabolic block which is homocystinuria, and the other due to an extra chromosome, trisomy 21, we see that those two diseases are more-or-less mirror-images of each other. If you look at a homocystinuric child, he is rather tall, he has an arachnodactylia, and sometimes he is mistaken for a Marfan's disease, and he may have extra creases on the fingers. If you look at a child with trisomy 21, he is small, he has small fingers, and there is only one crease on the fifth finger. They are more-or-less type and counter-type diseases, but for all these differences they are much alike. They have mental retardation which is so important in trisomy 21, less in homocystinuria. They have red cheeks, which is very typical in both diseases, and they have some dry desquamation of the skin in both diseases. That cannot be all chance. We can relate what we know about the metabolism of serine and what we see in acetylcholine in trisomy 21, and that the picture has some kinship, in same cases the contrary and in some cases the same, with typical blockage as in homocystinuria.

The tentative conclusion I would propose for the moment is that if we take from a very general body of information, we can guess at a whole machinery. If we start from sugar, we got to Krebs cycle, from here we go to the coenzyme cycle, and let us say from there we get to serine, which can be produced by sugar, and from serine, we go somewhere with methionine - all the systems we have already seen -and then it goes back, slowly back to the Krebs cycle. Obviously, this system must be enormously controlled in order to produce at the right moment the right amount of transmitter which is needed, and any block somewhere in one of those steps will produce mental deficiency, no matter which is the chemical step that is wrong. It could very well be, since we know from analysis of the blood that trisomy 21s are quite low in serine, that eventually they have something wrong in the pathway of sugar metabolism that would explain why all the enzymes are slightly increased. For the moment, this cannot lead to a direct proposal to then do a specific therapy and these children will become intelligent. It is too early. But it seems that the old idea that because they had an extra chromosome everything is lost, is definitely wrong. Nothing is lost if we keep hope.



[1] - This is an edited transcript of a tape recording of a spoken paper.