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