Down's Syndrome, the most frequent cause of mental retardation is also
the most studied. Nearly a quarter of a century after the discovery of the
chromosomal basis of the disease (1) the crop of scientific results is
impressive. To summarize this enormous bulk of knowledge is the very purpose of
this whole Congress. Various genes have been located on the 21 chromosome and
it is definitely established that the patients owe their disease to an excess
of genetic material, otherwise normal. Genic dosage effect, hypothesised long
ago (2) is now an experimental fact.
In contrast with this scientific exuberance the therapeutic side of the
research is still in infancy.
Alleged "cures" and so-called "treatments" are published nearly every
year, but no claim has yet withstood scientific scrutiny. This objective
judgement apply to the medication and not to the rehabilitation and training
techniques, which are still the best and only aid we can presently offer to the
In view of this terrible lag in therapeutic research, it seems worth
investigating how a heuristic program could be figured out.
In order to do so, three points must be discussed :
1) Does the actual knowledge point toward a particular biochemical
trouble : a general framework of research?
2) Is it possible to build a model of the spontaneous evolution of the
mental performance of trisomic 21 children so that an eventual therapeutic
effect could be tested?
3) How could clinical trials be divised according to 1 and 2?
I . A general framework for research.
As already proposed 4 years ago (3), a general discussion of the
metabolic blocks resulting from gene mutations and producing mental deficiency,
point to the metabolism of monocarbons as a very sensitive mechanism. Already
fragile-X syndrome, another chromosomal disease related to mental deficiency,
can be related to this monocarbon metabolism (4).
For trisomy 21, the relevance of this metabolism is much more
difficult to assess. Nevertheless, some of the available data seems compatible
with this general hypothesis.
A) Genes on the 21 and the phenotype of the trisomy 21
Five genes have been assigned to chromosome 21, namely : superoxyde
dismutase-1 (soluble), phosphoribosyl glycinamide synthetase, phosphoribosyl
aminoimidazole synthetase, antiviral protein (interferon receptor) and
a) Superoxyde dismutase 1
Superoxyde dismutase-1 was the first example in man of a gene
dosage effect resulting from a trisomy (5). This enzyme is 1"5 times more
active in trisomic 21 children than in normal ones. Various translocations have
shown that its locus is around the zone q22.1 of the long arm of 21 (6).
This excess of activity is expected in trisomics, because they
have three chromosomes 21 instead of the normal two. Hence if the quantity of
enzyme produced is proportional, to the number of genes, the activity ratio
must be 3 to 2. i.e a/1.5 fold ncrease.
The effect on the phenotype is difficult to predict. S.O.D.1.
transmutes the superoxyde ion O2- to H2O2 by a complex mechanism. The
superoxyde ion O2- is extremly reactive and is often considered as a toxic : it
can oxydize the fatty acids of the membranes and damage them gravely. Such a
mechanism has been postulated by some theories about ageing process. In the
organism the superoxyde ion is nevertheless used in some particularly important
reactions : indoleamine dioxygenase for example.
The hydrogen peroxyde, produced by superoxyde dismutase-1 must be
disposed of, for H2O2 is also a very active oxydant. The reaction H2O2 ? H2O
is controlled by glutathione peroxydase (GPX).
The GPX activity is augmented in trisomy 21 (7), although its gene
is located on chromosome 3. This excess of activity, obviously a regulation
effect, is particularly interesting for it shows a significant correlation with
the I.Q. of the patients : the greater, the I.Q. of a child the higher the GPX
activity of his red-cells. It could be hypothesised that the increase of GPX
activity protects the tissues against the excess of H2O2 produced by superoxyde
This enzyme of the glycolytic pathway is also 1,5 times more
active in trisomic 21 than in normals (8). This enzyme transforms the
fructose-6-phosphate into the fructose-1-6-diphosphate. This acceleration of
one of the first steps of glycolysis could be related to the well reported (9)
instability of the glycemia. Very often (10) (11) trisomics have been described
as "pre diabetics" although true diabetes does no seem more frequent than in
the general population.
A secondary effect of this accelerated transformation could be
related to the fact that fructose-1-6- diphosphate itself increases the
activity of another enzyme, the acetyl-CoA carboxylase biotine dependant ;
acetyl-CoA is carboxylated to produce malonyl-CoA which is the starting point
of the synthesis of fatty acids. It is an open possibility that stimulation of
this step could have some relation to the well known tendancy to obesity, so
frequent in Down's Syndrome.
c) Phosphoribosyl glycinamide synthetase and
phosphoribosyl aminoimidazole synthetase.
These two enzymes belong to successive steps producing the purine
bases in vivo.
The increase of their activity (12) (13) could lead to an
excessive production of these nucleotides, indispensable for the building of
nucleic acids molecules (DNA and RNA) .
If it was so, such an over production should be accompanied by two
biochemical symptoms : 1° the turnover of phosphoribosyl pyrophosphate should
be increased. 2° the excess of bases should be disposed of via uric acid. And
both phenomenous are observed in trisomic 21.
The production of phosphoribosyl pyrophosphate is achieved via the
shunt of the hexose monophosphates and this particular pathway is faster in
trisomics (14), although the amount of the respective enzymes is not increased
The elimination of uric acid is augmented in Down's Syndrome as it
was observed long ago. Even in the plasma, there is a significant excess (15)
not only of uric acid but also of xanthine and hypoxanthine bases.
All together these various data point toward an over production of
the purine bases fitting with the gene dosage effect.
d) Interferon reactive protein
It is now established that trisomic 21 lymphocytes have more sites
responsive to interferon than normal (16) (17). It could be surmised that this
could affect the immunologic reactions and induce a compensatory rise in gamma
These relationships between the five genes known to be on the 21
chromosome and the phenotype of the patients are plausible. However it remains
to be seen if these troubles could play some role in the monocarbons
B) A possible deficit in the monocarbons
Keeping in mind the long synthetic pathway of purines one can see
(fig. 8) that monocarbons are required at two different steps (one carried by
the 10-formyl tetrahydrofolate and the other by the 5-10 methenyl
tetrahydrofolate). Precisely two monocarbon moieties are lost for each excreted
molecule of uric acid. It follows that ah. unnecessary synthesis of purine,
secondarily excreted as uric acid, would require an extra amount of monocarbons
which would be at the end, spilled over.
Monocarbons are probably in limited supply (18); thus this overuse
could constitute a severe depletion in the organism.
Apparently, superoxyde dismutase hyperactivity has nothing to do
with monocarbons. Curiously a series of experiments (19) carried out on the
fragile-X Syndrome, have demonstrated an interesting correlation. If the
purified enzyme is added to the culture medium for a sufficiently long time
(72h or 48h before harvesting) it diminishes remarkably the frequency of the
gap seen at the end of the long arm of the X chromosome (site Xq28). From this
experiment it can be inferred that the level of superoxyde ions has some effect
upon the monocarbon metabolism which is definitely very sensitive in this
Before accepting the hypothesis that a trouble of monocarbon
metalolis could result from the gene dosage effects already qu ted, other
symptoms of trisomy 21 must be analysed.
a) Hypocholinergy in trisomy 21
As demonstrated long ago, trisomic 21 children are hypersen-sitive
to atropine (20). A systematic study of the pharmacologic reactivity of their
iris showed hypersensitivity to cholinomimetic and adrenolytic compounds ; a
low production of cholinergic mediators seems the simplest explanation (21). In
this respect, it must be remembered that the production of each molecule of
acetylcholine, requires three monocarbons in order to trimethylate the
b) Pseudo Alzheimer complication
Trisomic 21 adults are very prone to precocious senility. More
dramatically, the frequency of Alzheimer-like syndrome is greatly increased
(22). In both diseases the ultra structural anomaly of the entangled
neuro-filaments is typical. Cholinergic troubles are well know in Alzheimer
disease : deficiency of acetylcholine esterase and of choline
acetyltransferase, with disorder of cortical cholinergic innervation (23).
c) Pseudo Lesch-Nyhan complication
In rare case of severly retarded trisomic 21 children, an
agressive and even auto-agressive behaviour is sometimes observed. This
behaviour is reminiscent of the Lesch-Nyhan disease, a hyper-uricemic condition
due to a deficiency of the hypoxanthine-guanine-phosphoribosyl-transferase.
These patients cannot recuperate free guanine (for recycling it in the
ribonucleotide pathway) and thus suffer of a very severe loss of purines,
excreted as uric acid. This imply a very severe demand upon the monocarbon
It remains to investigate on a large number of pseudo Lesch-Nyhan
trisomic 21 children, whether they have especially high blood levels of uric
acid and especially high excretion.
d) A possible deficit of methylation
These three clinical findings, hypocholinergy, tendancy to
Alzheimer disease and pseudo Lesh-Nyhan behaviour do not demonstrate a
monocarbon trouble but are not in desagreement with the hypothesis.
Remarkably, in 1958 GERSHOFF and Al., (24) came to the same
conclusion. Studying the urinary excretion of trisomic 21 children challenged
with high doses of niacin, they discovered that the patients excreted less
creatinine and less N-methyl-nicotinamide than controls (nicotinamide is
excreted after methylation) . GERSHOFF concluded then that, possibly, trisomic
21 children had a diminished methylation power. A potentially very important
conclusion which, curiously, remained quite unnoticed for a quarter of a
To sum up this rapid review we can simply state that the general
hypothesis of monocarbon disturbancies in mental retarda-tion, already strongly
suspected in the fragile-X syndrome, could be applied as an heuristic model to
Down's syndrome investigations.
Let us now turn to the second question : how could we devise a
test in order of demonstrating a possible relationship between monocarbon
metabolism and mental deficiency in Down's Syndrome? Obviously the first step
would be to quantify the mental evolution of the children in order to see
secondarily if any correction of the monocarbon metabolism could ameliorate
II. A quantitative approach of the mental deficiency in
A) A follow up during fourteen years
In order to follow the mental evolution of Down's syndrome children,
we have selected the case history of 183 children (94 boys and 89 girls)
followed at the Institut de Progenèse at the specialised consultation in the
Hopital des Enfants Malades à Paris. Most of them have been examined and tested
every year or twice a year and followed from one year to 14 years of age ; the
chosen cohorte, was only selected on the basis of the date of birth, between
January 1968 and January 1973.
B) Psychometric examinations
No one psychometric test is available for the entire follow-up from
one year to 14 years of age. Hence three different tests have been used
according to the actual performances of the patients. From 10 months of age up
to three years, all the patients are subjected to the "test de developpement de
la premiere enfance de Brunet-Lezine". - 143 children have been tested at least
once with this test.
After 3 years, the best developed patients satisfy all the items of
the Brunet-Lezine test and are then subjected to the "test sans parole de
Borel-Maisonny" ; the less rapid children continue with the Brunet-Lezine.
At around 4-5 years of age, practically all the children are tested
with the Borel Maisonny non-verbal test.
Later, the development of the language is so important that
non-verbal tests become irrelevant. Then the classical Binet-Simon tests is
relied upon. At 8 years, 75 % of the patients are tested with the Binet-Simon
and 90 % at 11 years.
C) Difficulty of this follow-up
The choice of these three tests is open to criticism. Other more
refined protocols could have been used as well. This battery has the advantage
of simplicity and our team of dedicated psychologists are well accustomed to
Another imperfection, (and no training of the psychologist can
overcome it) stems from the fact that the estimation of the performances (the
"mental age") is not exactly identical with two tests at the zone overlapping.
As it can be seen in the figures 1 to 7, this unescapable difficulty do not
blurr too much the general picture.
The main interest of this compound statistics is that every child
can be followed individually and that groups of children of comparable
performances at a given age can be followed in their or future (or previous)
More generally one can also calculate at each chronological age, the
mean mental age and estimate the standard deviation. If this process is
completed by a "smoothing of the curves" one can establish the figure 1 in
which the mean mental age is represented, with the curves corresponding to one
and two standard deviations.
It must be emphasized that the distribution of these mental age, for
each chronological age is not perfectly qaussian, 93 % of the children are
within the limits (m + 2s) and (m - 2s), But if the extrems are considered, 2
% are better than (m + 2s) and 5 % are below (m - 2s). The distribution is
slightly asymetrical. This is due mainly to cohort of children who make very
slow progress, instead of following the general trend.
A manner of visualizing the individual evolution is to choose the
age class 11 to 12 years. For this class the population can be seperated
according to quantiles.
The figures 2, 3, 4, 5, 6, 7 exemplify very clearly the homogeneity
of the pathway if it is reconstructed for all the children achieving a given
mental efficiency at 11-12 years period.
It follows that for each child the predictive value of his actual
achievment is quite good. The cohort reaching the upper level, cross the
barrier of 5 years of mental age much earlier than the cohort achieving just 5
years at the same age. The width of the path for a cohort is generally smaller
than 2 of the general population. It must be stressed at this point of the
analysis that all the data have been split according to sexe ; there is no
difference between boys and girls for all the trends analysed.
3) The "relative progress"
As shown by the general distribution the standard deviation is not
constant with ageing : the s much greater at 12 years of age than at 1 year
To normalize the estimation of the "progress" during a given period
(six months in most of the experiments described later) a new parameter can be
chosen : the "relative progress".
If a child has attained a given mental age at a given chronological
age,(dark circle)at the left of the figure 1, it is expected that, six months
later, his performance (open circle) would lie on an imaginary line, pseudo
parallele to the lines of the standard deviation of the general population. If
the observed point (second dark circle) is higher than this predicted
trajectory the difference, the observed gain (a), is measured. In order to
standardize this value (expressed in months of mental age), it is divided by
the expected standard deviation (b).
Thus, the "progress" or the "regression" are expressed as a
percentage of the standard deviation : the "relative progress".
It follows from this procedure that the mathematical expectation of
the "relative progress" is zero, (if the tables are representative for all the
children). Moreover, if this procedure is repeated all along the evolution of a
child it allows to control the regularity of its trajectory.
For prediction purpose it must be checked, wether the observed
"relative progress" is nil (as the mathematic expectation would predict) or
whether it is significantly lower or higher.
This has been checked systematically on 529 six months changes and
the observed "relative progress" was as a mean + 2,10 ± 46,14. That is two
percent of the standard deviation, with a sof half a standard deviation. Hence
the observed value is as close to zero as it could be expected. Each child
follows its own personal paths, with ups and downs y but his whole trajectory
is inscribed in 95 % of the cases within borders of +1 sand -1 sof the
This predictive value of the "relative progress" is of extreme
importance, because it indicates that if a sample of say 20 to 25 children
submitted to a given treatment, were experiencing as a mean an increase or a
decrease of greater than 1 sof the general population, this would be highly
Without going into too much statistical details, it can be stressed
that if the "relative progress" is tested against its own standard error, "t"
Student statistics will detect the eventual significance of the change.
Having thus at hand the clinical instrument, it was possible to
settle a heuristic investigation.
Ill. A heuristic analysis of mental development. According
to attempts of modification of the monocarbon metabolism in trisomic 21
A) heuristic clinical trials
Coming back to the central hypothesis of a deficit of monocarbon's
metabolism, it becomes clear that correction could possibly be achieved by
three different interventions.
1) A supply of precursors of monocarbons could increase their
availability. This could be achieved by administration of any of the precursors
listed in figure 8 (column of precursors).
2) Amelioration of the transportation system could also increase the
amount of monocarbons available to the organism. This could be achieved by
administration of the vitamines folic acid and cobalamin (and their
derivatives) figure 8 (column of monocarbons).
3) An alleviation of the demand of monocarbons could be obtained if
final products were supplied. This could be achieved by administration of extra
amounts of purines or of carnitine figure 8 (column of synthesis).
A systematic check of these possibilities is underway and the
present stage can be summarized as follow.
B) Administration of precursors
Among the products listed in the first column, tryptophan and
5-hydroxytryptophan were excluded. They have already been tested by other
workers using a very different rationale. Tryptophan did not gave appreciable
results (25) and 5-hydroxytryptophan gave either inconclusive results at low
doses (26)(27) or dangerous effect in high doses (28), a number of West
Syndrom's (hypsarythmia) was provoked by this treatment. It must be stres-sed
that the choice of 5-hydroxytryptophan was a seemingly favourable bet, for it
has long been known (29) that trisomic 21 children have a trouble of the
tryptophan metabolism : an accelaration of the kynurenin pathway. They have
also a low level of serotonin, due to a defective pumping mechanism in their
platelets (30) (31) (32).
Histidine has not yet been checked, nor 5-aminolevulinate because of
their possible toxicity as experienced in histidinemia or in porphyrias. This
caution does not preclude at all their possible interest.
Serine seemed a better choice especially because trisomic 21
children have a slight deficiency of serine in their plasma together with an
excess of ethanolamine (33). Also 4-hydroxyproline was tested, considering the
phenotypic similarities between trisomy 21 and iminodipeptiduria (34) (35) a
rare disease in which, due to the lack of an enzyme, patients loose each day
some 10 to 20 mg of hydroxyproline.
Awaiting the availability of N.N.dimethylglycine (now under
experimental trial) a very much used derivative, but non natural, was tested :
The results are summarized in table 1.
In a preliminary trial at dose of 25 mg/kg/d serine appeared
promising with a "relative progress" of + 26,82 ; s= 81,95. A second test
using 50 mg/kg/d looked also beneficial with a "relative progress" of 24,93 ;
s= 33,79 (table II).
This prompted us to start a full double blind test in which serine
at 100 mg/kg/d, was tested, together with proline 100 mg/kg/d and
hydroxyproline 50 mg/kg/d, carefully randomized with placebo on 93 children.
All these trials were made on children more than 4 years old and
less than 9 years of age. This interval is possibly not the most sensitive one,
but it was selected in view of two facts : first the curves of mental
development are quite linear in this interval. Second the parents could easily
detect any unforeseen deleterious effect. This would not be the case in newborn
(28). Indeed if the medication is really good, the children would react better,
the younger they are. But "primum non nocere" is an absolute prerequisite.
All the trials are performed with the fully informed consent of the
parents. They understand that these assays are no definite treatment but
systematic research of an eventual sensitivity of trisomic 21 children.
The fully randomized trial gave perfectly null results as seen in
the table II. This is a warning, if at all necessary, against premature
conclusion of uncompletly controled trials.
To sum up the available results, we have now indication that neither
serine nor dimethyl amino ethanol can be taken as efficient , although a
possible dose/effect could still be discussed. All the same, administration of
final products, purines or methionine or relevant vitamines, folic acid (*) and
B 12 (see table I) cannot be detected as beneficial with this procedure.
C) Toward the next step
Before rejecting the general hypothesis we started with, numerous
investigations are still to be conducted. As already said, 5-amino levulinate,
histidine and N.N.dimethylglycine are still to be investigated.
On the other hand, end products could be tested, and among them
carnitine which is a very important metabolite. This trimethylated molecule is
the carrier of fatty acid residues inside the mitochondria. It is thus
indispensable for muscular foncfion and its synthesis from hydroxylysine is
very demanding upon the monocarbon's metabolism. Carnitine given orally, can
alleviate the neurological troubles of children affected by carnitine
synthetase deficiency (36). This shows that it can be directly used from the
Its possible effect could be twofold : alleviate the demand upon the
monocarbon metabolism and increase the turn-over of fatty acids.
Another intervention is still open : a direct modification of the
methionine/homocysteine equilibrium. Homocysteine has not yet been administered
in View of its potential toxicity in homocystinuria (37) and of its convulsing
properties in animals (38).
But the interest of such an investigation is not to be over-looked.
As already noted (3), homocystinuria produces quite the countertype of the
phenotype of trisomy 21. Homocystinurics are tall, slim, with extra creases on
fingers, in contrast with the trisomic 21 who are short, bulky and lack some
In this context it can be noted that homocysteic acid stimulates the
growth in rats (39).
Moreover, the two diseases have in common, beside the mental
retardation a peripheral vascular trouble : frequent livedo reticularis and
Another reason for checking the homocysteine pathway is the deficit
in urinary taurine (by-product of cystathionine metabolism, see (fig. 8)
observed in trisomy 21 (40)(41).
Although methionine and homocysteine have a very intricate
regulating action on the whole monocarbon's metabolism, a cautious clinical
assay does not seems out of reach.
This review of the present stage of research on a medical treatment of
trisomy 21 is possibly not as negative as the few results obtained so far.
Sure enough, no proven therapy has yet been found, but a heuristic
model can be presented and tested. The hypothesis of a trouble of the
monocarbon pathway is far from demonstrated but up to now, there is no
experimental fact to contradict it formally. Moreover the model is susceptible
of systematic investigation for eventual disproval.
But the time factor must no be disregarded : the few inconclusive data
discussed here represent six years of efforts. In this context it is a duty and
a pleasure to pay homage to the marvellous dedication of the parents and to the
willingness of the children in complying to very precis schedules.
Fig. 1- Mean and standard deviation of the mental age of trisomic
21 children, according to their chronological age. The example given explains
the calculation of "the relative progress". See text for explanation.
Fig. 2- Path of children
reaching a mental age below 3 years at 11 years of chronological age.
Fig. 3- Path of children
reaching a mental age between 3 and 4 years, at 11 years of chronologic al
Fig. 4- Path of
children reaching a mental age between 4 and 5 years, at 11 years of
Path of children reaching a mental age between 5 and 6 years, at 11 years of
Path of children reaching a mental age between 6 and 7 years, at 11 years of
Path of children reaching a mental age above 7 years, at 11 years of
Table I : Open trials of products interfering with monocarbon
metabolism. Trisomic 21 children from 4 to 9 years old.
|Tested product||Mean dose||Number of
children||"Relative progress"||Standard deviation
Table II : Double-blind trial on 93 children, trisomics 21,
treated during 6 months. Age range : 5 to 8 years.
|Tested product||Mean dose||Mumber of
children||"Relative progress"||Standard deviation
(*) Preliminary assays of folinic acid (5-formyl-tetrahydrofolate) in
severly retarded trisomic 21 children, exhibiting psychotic symptoms or
Alzheimer-like complication have given us some favourable results.
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