Among all the diseases affecting human intelligence, trisomy 21 is the
most frequent one and, also, the most obvious. Over the personnel
characteristics of the child, the disease super imposes a kind of mask
producing an unmistakable "air de famille". This clinical evidence allowed
LANGDON-DOWN, after SEGUIN, to isolate the condition : hence the current name
of Down's Syndrome.
With their upward slanding eyelids, their little nose in a round face,
their incompletly chiselled features, Downs' patients look more children than
usual. Every baby has short hands with short fingers; but theirs are shorter.
All their anatomy is rounded of with no asperity nor stiffness. Their ligaments
and their muscles have also a suppleness producing a tender langor in them
This general softness extend even to their character : cheerfull and
affectionate they have special charm, easier to cherish than to describe.
That is not to say that Down's Syndrome is a desirable condition. It
is an implacable disease depriving the children from the most precious quality
afforded by our genetic patrimony, the full power of rational thinking.
This combination of a tragic chromosomal error with a really
attracting nature reveals in a glimpse what all medicine is about : to fight
against the disease and to love the disabled.
Sure enough it is now well establised that an extra chromosome 21 is
the cause of Down's Syndrome. But how this super-numerary piece of genetic
information produces its deleterious effect:
- how the intellectual damage is resulting from it,
- how it could possibly be compensated or repaired,
All this remains to be discovered.
Hence, instead of an historical review, I'll take the liberty of
presenting you briefly the state of affairs, and discussing the various ways
open to research.
I - Types and counter-types
Normally, at the moment of conception, every child recieves two
exemplars of each chromosomes : one from father, one from mother. If by
misfortune one of the reproductive cells carries two elements, the child
becomes trisomic ; that is he has three exemplars of chromosome 21.
Sometimes the contrary occurs, a piece of chromosome is lacking and
the child is monosomic, having received only one exemplar of this segment.
If we compare the two conditions, a stricking opposition appears: the
excess modify the morphology in one way and the deficit on the contrary
For example, trisomy 21 produces small ears with a small nose and
partial monosomy 21 induces large ears with a protruding nose.
This opposition in "Type and Counter-type" is observed for all the
chromosomal aberrations for which these reciprocal syndromes are known.(1). But
not matter the chromosome involved, be it the 21, the 18, the 13 or the 5 or
any other, when it comes to intelligence both the excess or the deficit of
genetic material invariably produce the same deleterious effet: mental
In order of resolving this paradoxe, we must remember that the genes,
carried by the chromosomes, dictate the production of enzymes. Enzymes are the
machine - tools of the cell, manufacturing all the biochemical products. Hence
the more genes there are, the more enzymes are produced and the fastest the
chemical stuff is produced or destroyed.
The symphony of intelligence
The message of life can be compared to a symphony : each musician (the
genes) reads its score and follows the tempo of the conductor.
During a solo, a too-quick musician (in case of trisomy) could
transform an "andante" in a "prestissimo" : the ears will be too small and the
fingers too short. conversly, a slow musician (in case of monosomy) could
change an "allegretto" in a "largo" : the ear will be chiseled and the fingers
too slender. In both ease, because the musician played a solo, he modified a
trait but did not spoiled the whole symphony.
On the contrary, when the full orchestra is concerting, all the
musician playing in a "tutti", it does not matter wether the faulty musician
accelerates or slows down; the result will be cacophonic, even if he reads
correctly his music!
Detecting the discarding musician is not an easy task especially when
a whole chromosome is involved like in Down's syndrome. In simple genic
diseases like in phenylketonuria for example, only one biochemical reaction is
blocked and the failure is obvious... once discovered. But there may be some
thousand genes in chromosome 21.
Surely, most of them do not produce arm when in triplicate, because if
each of them was discarding, the trisomic children would not survive at all.
Thus only few of the accelerated reactions are dangerous. But how will we
discover the culprits among so many innocents!
This detective story could be avoided if we knew how to silence a
peculiar chromosome without disturbing the others. If the extra musician was
turned off, the symphony would be restored.
Let us suppose a competent repair-man has recieved from the factory a
four cylinder engine equipped by mistake with flue spark-plugs. He would
certainly notice that the engine does not run smoothly. An expert would not
discard this motor. He would cleverly disconnect the extra plug and thus bring
the rythm to normal.
Alas, we are not yet as skilled than this car repair man! But nature
is that shrewed. She knows how to silence one of the X chromosomes in feminine
cells, so that the woman with her two X chromosomes is not so much superior to
the man who has only one X and a tiny Y!
We still ignore how this turning off is achieved. Il we could master
that trick, and if we could apply it to the extra chromosome 21, we could
redress the destiny of Down's Syndrome affected children, even without knowing
what kind of biochemical reaction was modified by the discording musician!
Pending such a tour de force, (and nobody knows wether it could at all
be feasible some day) we can try to decipher the genie content of chromosome
Genes of the 21
The painfull task of unravelling one by one the genes of chromosome 21
is less brilliant indeed, but it has the great advantage of being already on
the way. Two methods are available:
- the molecular biologists split the long ribbon of the DNA contained
in chromosome 21 and, letter by letter, decipher the message encoded in each
- on the other hand the biochemists carefully analyses all the
chemical reactions they can, in order to see if some of them are running faster
in trisomic 21 cells.
We can localize the genes by analysis of the effect of small
duplications or deletions, and any improvement an microscopic techniques is
very much worth of ours efforts.
These approachs complement each other and engender a healtly
scientific competition between the research teams.
For the moment six genes are known I and I apologize for being too
technical about it: chemical language is very simple indeed, with the slight
difficulty that it cannot be translated in every days words!
One, the superoxyde dismutase (S.O.D.I), plays a special role in the
metabolism of oxygen (2). So to speak, it regulates the carburation. Its over
activity possibly deteriorates some cell constituants, inducing the too rapid
ageing of Down's Syndrome patients. They also become more frequently deficients
and some of them are affected by a redoutable complication looking very much
like the ALZHEIMER disease.
- Another, the phosphofructokinase (3) controles the sugar met part of
the fatty acids production. Trisomics 21 are prone to diabetes and are ften
- Two twin-genes, the glicineamide phosphoribosyl synthase (4) and the
ammoimidazole phosphoribosyl synthase deal (5) with the production of purines,
the building blocks of DNA. Trisomics spill over these purines as demonstrated
by an increased excretion of uric acid.
- The gene responsible of the protein reactive to interferon (6) works
also too fast. The trisomics are prone to various infections.
- The last one, discovered last year, is the
cystathionine-ß-synthase (7) which transform homocysteine into cystathionine,
a very important compound. A rabbit has less cystathionine in its brain than a
dog; a chimpanzee has more than a dog, and a man more than a chimpanzee...
The monocarbon hypothesis
To suggest some strategy for efficiently continuing the attack, we
need a theoretical framework to put in order these miscellaneous informations
and to conduct the next assaults.
Could it be that a peculiar chemical mechanism would be the most
frequently affected in mental retardation? Few years ago I proposed that the
metabolism of monocarbons could be this sensitive target (8).
In order to build the eleven thousand millions of neurons in our
brain, to insulate its enormous wiring (as long as from Paris to Tokyo ) and to
chisel the security keys who open and close the eleven millions of millions of
connections between our neurons the brain makes an enormous consumption of
monocarbons. These bits of molecules, containing only one atom of carbon (hence
their name) are the smallest building stone of our nervous system, but the most
Thus if the supply of monocarbons was insufficient, if its
transportation by folic acid and B12 vitamine was not efficient, if its
utilisation by transmethylases was not appropriate, a severe disturbance of the
functionning of the brain would ensue. All that we know about the mentally
deleterious effect of these impairements is in accordance with this
If some very precious stuff was burned too fast by trisomic 21
children, this wastage could possibly deplete their organism of a very
When over-producing purines, as previously mentioned, trisomic 21
cells waste quite a lot of those precious monocarbons.
In this respect the newly discovered acceleration of the
cysthionine-ß-synthase could even be of a greater interest.
In a different type of mental retardation, the homocystinuria, this
very reaction is totally blacked ; exactly the contrary of the acceleration in
trisomy 21. Curiously homocystinuric children are tall, slender, with long
tappered fingers, just the opposite of the short stature and the short fingers
of trisomics 21. Even the homocystinurics have extra creases on their fingers
in contrast to the lack of some flexion creases in trisomy 21.
The type and counter-type we started with in our discussion is very
obvious here (9).
And this comparison is also in accordance with the monocarbon's
hypothesis. Homocysteïne, if not transformed into cystathionine, recieves a
monocarbon carried by folic acid and B12 and becomes later S-adenosyl
methionine ;this is the transport form of monocarbons. The next step is the
construction of neurons, of insulating substances and of security keys of the
nervous connections! Taken together the wastage of purine and the excessive
destruction of homocysteine could produce a borderline but chronic shortage of
monocarbons in trisomy 21.
On the contrary, the accumulation of homocysteine (in the blockade
disease) produce S-adenosyl-homocysteine which entirely blocks the
transmethylase system ; thus the blockade is just as deleterious as the
Research on monocarbon's metabolism in trisomy
This hypothesis of a disturbance of monocarbon's metabolism in trisomy
21 was put forward some years ago (LEJEUNE, 1979) but no experimental protocol
was avaible at that time.
A - Oxydized monocarbons and the synthesis of purines
a) State of the art in 1984
It is known that 21 trisomic persons produce and excrete more uric
acid 10 than normally (10). This excess of purine synthesis could be due to the
excess of activity of phosphoribosyl-glycinamide-synthetase and of
phosphoribosyl-aminoimidazole-synthetase. Both these enzymes are on chromosome
This oversynthesis of purine would demand excess production of
phosphoribosyl, which is produced by the shunt of hexose monophosphate ; this
pathway is accelerated in trisomic 21 children.
At the end of the process, for each molecule of uric acid spilled
over, two monocarbons would be lost, for the synthesis of a purine requires one
formyl carried by 10-formyl-tetrahydrofolate and another one carried by
Hence a chronic depletion of monocarbons could ensue.
This patways seemed so much the more important that PEETERS et
al.1985 (11) found that trisomic 21 children when affected by leukaemia had an
over sensitivity to methotrexate ; this substance was twice as much toxic for
them than for normal children affected by the same type of leukaemia.
b) Demonstration of sensitivity in vitro of trisomic 21
lymphocytes to methotrexate 1986. LEJEUNE et coll. (1986)(12)
Effects of methotrexate.
In dividing cells the synthesis of thymidine is very important.
It requires the transfer of a monocarbone carried by 5-10 methylene
tetrahydrofolate to deoxy-uracile-monophosphate in order to produce thymidine
monaphosphate. During this reaction the tetrahydrofolate is oxydized into
dihydrotetrahydrofolate. This inactive compound must be reduced again to
tetrahydrofolate by dihydrofolate reductase. This last enzyme is specificelly
blocked by methotrexate. This methotrexate blocks the transfer of oxydized
monocarbons and blocks also the cellular division.
Hundred fifty cultures of lymphocytes were made from six
trisomic 21 children and from six normal persons. The effect of four different
dosage of methotrexate was studied by mesurement of the mitotic index of the
cultures (i.e. the member of dividing cells aver the total number of
The doses studied were 0,6 x 10-8M 1,2, 2.4, 4.8 x
a) The mitotic index is diminished proportionnally
to the square of the dose of methotrexate.b) The sensitivity of trisomic 21 lymphocytes is
twice that of normal lymphocytes:
We could thus demonstrate:
a given dose produced twice as much damage in trisomic 21
cells than in normal ones.
These two effects highly significant, are the first
experimental proof that a disturbance of monocarbon's metabolism really exist
in trisomy 21.
B - Reduced monocarbons and the
Reduced monocarbons (methyl radicals) are used in the building of
the nervous system, in the production and secondary inactivation of the
chemical mediators and in all the process of methylation (production of the
insulating substances like myelin and regulation of specific sites of the DNA
or of the RNA).
1) State of the art in 1985
An anomaly of the homocystein's metabolisms was suspected ten
years ago (9). In homocystinuria, a mental deficiency due to a block of the
enzyme cystathionine-ß-synthase, the patients exhibit the countertype of
trisomy 21 (they are tall, slender, with extra creases on the fingers). In 1984
SKOVBY,(7), a former student of the Institut de Progenese, demonstrated in
U.S.A. that the gene of cystathionine-ß-synthase is indeed on the chromosome
21. Recently CHADEFAUX et al. 1985 (13) and JEROME et al. 1985 (14).
demonstrated that the enzyme is 1.5 time more active in trisomic
21 cells than in normal cells. They demonstrated also that the amount of newly
formed methionine (from the 5-methyl-tetrahydrofolate) is less in trisomic 21
cells than in normal cells. This can be explained if, due to the acceleration
of cystathionine-ß-synthase, less homocysteine is available for
It thus seems likely that beside the trouble of oxydized
monocarbones (demonstrated by the methotrexate effect), there could exist also
a deficit of reduced monocarbons in trisomy 21. This hypothesis would fit with
the relative cholinergic deficiency observed in trisomy 21 and with the
relative deficiency of methylation of nicotinamide observed long ago by
GERSHOFF, 1958 (15).
2) Work in progress
In order to investigate this open possibility, a protocol similar
to the one utilized for testing methotrexate is now developped. Some new
culture medium will be especially produced for this experiment. From the very
preliminary data available to days it is obvious that the level of methionine
in the medium affects the mitotic index ; the investigation is in progress.
II - Clinical investigation
From the available experimental data, two ways of palliative
medication can be already envisaged.
1) Increase the production of oxydized monocarbons by folic acid
medication or by addition of specific precursors to the regimen.
2) Increase the production of reduced monocarbons by administration
of B12 and B6 vitamines, as well as methionine or homocysteine or other
derivative of this particular pathway.
All these assay will utilise, at physiological doses, substances
normally present in the food and in the healtly organism.
Possible changes in the speed of mental acquisitions (IQ) will be
controlled by psychometric tests. The service in the Hopital des Enfants
Malades, is fully equipped and staffed for this research.
Although some of these investigations are already on the way with
some, preliminary results not too discouraging, the matter is so important and
touchy that no comment can be included in the present report.
It must be very precisely stressed that this general model is for
the moment strictly speculative. Even if the reasoning was sound, it would
remain to be seen wether the correction of such a trouble, if at all possible,
could alleviate the mental deficiency. A specific treatment is yet to be
No specialist can for-see the length of the road to be covered,
until reaching such an achievement, but the future of research sounds very much
like a wellknown song : "we shall overcome some day".
(1) LEJEUNE J. - Types et contre typres. Journées parisiennes de
Pédiatrie. 75-83. Ed. Med. Flammarion 1966.
(2) SICHITIV S., SINET M.M., LEJEUNE J., FREZAL J. - Surdosage de la
forme dimérique de l'indophénoloxydase dans la trisomie 21, secondaire au
surdosage génique. Humagenetik. 1974, 23, 65.
(3) VORA S., FRANCKE V. - Assignment of the human gene for liver-type
6-phosphofructo-isozyme (PFKL) to chromosome 21 by using somatic cell hybrids
and monoclonal anti-L antibody. Proc. Natl. Acad. USA. 1981, 78, 3738-3742.
(4) MOORE E.E., JONES C., KAO F.T., OATES D.C. - Synteny between
glycinamide ribonucleotide synthetase and superoxyde dismutase (soluble). Am.
J. Hum. Genet. 1977, 29, 389-396.
(5) PATTERSON D., GRAW S., JONES C. - Demonstration, by somatic cell
genetics, of coordination of genes for two enzymes of purine synthesis assigned
to human chromosome 21. Proc. Natl. Acad. Sci. USA. 1981, 78, 405-409.
(6) TAN Y.H., TISCHFIELD J., RUDDLE F.M. - The linkage of genes for the
human interferon induced antiviral protein and indophenol oxidase B traits to
chromosome G 21. J. Exp. Med. 1973, 137, 317-330.
(7) SKOVBY R., KRASSIKOFF N., FRANCKE V. - Assignment of the gene for
cystathionine-ß-synthase to human chromosome 21 in somatic cell hybrids. Hum.
Genet. 1984, 65, 291-294.
(8) LEJEUNE J. - Le metabolisme des monocarbones et la débilité de
l'intelligence. in : La débilité mentale p. 3-18. Masson Editeur 1983.
(9) LEJEUNE J. - Réflexions sur la débilité de l'intelligence des
enfants trisomiques 21. Pont. Acad. Sc. Rome, 1975, 9, 1-12, commentarr
(10) APPELTON M.D., HAAB W., BURTI U., ORSULAK P.J. - Plasma urate
levels in mongolism. Am. J. Ment. Def. 1970, 74, 196-199.
(11) PESTERS M., POON A.L., ZIPURSKY A., OLIVE D. - Mongolisme et
leucémie : toxicité accrue au méthotrexate. Compte rendu du Congrès
National d'Hématologie et de Transfusion Sanguine. Bordeaux, 1985, p. 71.
(12) LEJEUNE J., RETHORÉ M.O., BLOIS M.C. de, MAUNOURY-BUROLLA C. MIR
M., NICOLLE L. BOROWY F., BORGHI E., RECAN D. - Metabolisms des monocarbones et
trisomie 21 sensibilité au méthotrexate. Ann. Genet. 1986, 29, n° 1,
(13) CHADEFAUX B., RETHORÉ M.O., CEBALLOS I., ALLARD D. - Effet de
dosage génique et consequences métaboliques de la trisomie 21. Académie
Nationale de Médecine, seance du 3 décembre 1985.
(14) JEROME H., CHADEFAUX B., CEBALLOS I., ALLARD D. - Effet de dosage
génique et consequences métaboliques de la trisomie 21. Académie Nationale
de Médecine, seance du 3 décembre 1985.
(15) GERSHOFF S.N., HEGSTED D.M., TRULSON M.F. - Metabolic studies of
mongoloids. Am. J. Clin. Nutr, 1958, 6, 526-530.