With upward-slanting eyelids, a little nose in a round face, and
incompletely chiseled features, Down syn-drome patients look more like children
than the usual child does. Every child has short hands with short fin-gers, but
theirs are shorter. All their anatomy is rounded, with no harsh features or
stiffness. Their liga-ments and muscles have a suppleness producing a tender
languor in their posture. This general softness ex-tends even to their
character: cheerful and affectionate, they have a special charm easier to
cherish than to describe.
That is not to say that Down syndrome is a desirable condition. It is
an implacable disorder depriving the children of 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 attractive nature
reveals, in a glimpse, what med-icine is all about: to fight against disease
and to love the disabled.
While pondering over this evening's talk, I suddenly realized that
with all the progress accumulated during the last 30 years, the destiny of the
trisomy 21-affected persons has not yet been substantially ameliorated.
Remarkable achievements in cardiac surgery and in management of
infectious or malignant diseases have greatly extended their life expectancy.
But at the same time, early detection and selective abortion have dras-tically
reduced their rate of survival.
Looking at some statistics, it seems that for a few-month-old trisomic
21 baby in utero the rate of survival up to 10 years of age was possibly
greater 30 years ago than it is today. Such an estimate includes the postnatal
dangers: deliberate neglect, denial of life-saving inter-ventions or of simple
nutrition, and even direct infan-ticide; health by death is a desperate mockery
Let us look at another terrible and incurable ailment: Alzheimer
disease. An enormous effort, worldwide, is very aptly made in its study. The
lives of millions depend on the success of this effort.
But the gene of the familial form  is on chromo-some 21; the gene
of the precursor of the amyloid sub-stance [11,131] is also on 21 and trisomy
21-affected persons are especially prone to presenile dementia [59,36,52],
although there is no excess of Alzheimer disease in their families ,
Certainly a microscope must not be construed into a crystal ball, but I would
venture to say that a victory aver the neural disturbances resulting from the
genie overdose of trisomy 21 would very likely also lead to a cure or to a
prevention of Alzheimer dementia. The reciprocal prediction looks much less
Could it be that in the absence of a cure far the latter, it looks
futile to try to cope with the inborn form of mental deficiency? Is a genie
overdose never amenable to treatment? So grave a matter deserves careful
Tide symphony of intelligence
The message of life can be compared to a symphony: each musician (the
genes) reads a scare and follows the tempo of the conductor.
During a solo, a too-quick musician (in case of trisomy could
transform an "andante" into a "prestissimo" : the ears will be too small and
the fingers too short. Conversely, a slow musician (in the case of monosomy)
could change an "allegretto" into a "largo": the ear will be chiseled and the
fingers too slender. In both cases, because the musician played a solo, he
modified a trait but did not spoil the whole symphony. Hence the
type-countertype opposition between trisomy and monosomy .
On the contrary, when the full orchestra is playing, all the musicians
playing in a "tutu," it does not matter whether the faulty musician accelerates
or slaw down; the result will be cacophonic, even if he reads his music
correctly! Hence the mental deficiency in trisomy as well as in monosomic
states: human intelligence is the tap of our genetic endowment.
Detecting the discordant output musicians is not an easy task
especially when a whole chromosome is involved as in Down syndrome. Surely,
most of the genes do not produce harm when in triplicate, because trisomic
children would not survive at all. Few of the accelerated reactions are
dangerous; but how will we detect the culprits among so many innocents!
This detective story could be avoided if we knew how to silence a
specific chromosome without disturbing the eithers. Let us suppose that a
competent car-repair man has received from the factory a 4-cylinder engine
equipped by mistake with 5 sparkplugs. He would certainly notice that the
engine does not run smoothly. An ignorant man would discard this motor, but an
expert would cleverly disconnect the extra plug and thus bring the rhythm to
normal. Nature is that shrewd; she knows how to silence one of the X
chromosomes in female 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 are still
ignorant of how this turning-off is achieved.
Pending such a "tour de force" applied to chromosome 21 we have to
analyze its genie contents and consider haw it could affect neural
A biochemical scheme
As already discussed  the functioning of the brain
- An enormous number of components: Some 11 billion neurons.
- A logical wiring of a considerable length: Some 5,000 km if counted
in dendrites and axons and from here to the moon and hopefully back if
measuring the neurotubule network inside the neurons.
- A specific response of the gating system, through chemical mediators
acting on appropriate post-synaptic membranes.
To meet these 3 requirements, the brain has to synthesize a
considerable amount of:
- Monocarbons for synthesis of chemical mediators and for their
subsequent inactivation, and all the methylation pathways.
- Purine and pyrimidine for RNA and DNA maintenance.
- Tubuline for the wiring and biopterine for the aromatic
hydroxylations of the mediators.
It has already been remarked that a block of one step of any of these
pathways does produce mental retardation .
The painful task of unraveling one by one the genes of chromosomes 21
is achieved by 2 methods:
- The molecular biologist split the DNA and letter by letter deciphers
the message encoded in each piece.
- The biochemists carefully analyze chemical reactions in order to
pick out those running too fast in trisomy 21.
The results of these 2 convergent approaches can be summarized in a
general chemical scheme (Fig. 1)
The first column deals with purine synthesis.
The second deals with pyrimidine (top) and purine (below)
The third deals with folate and monocarbon metabolism (top), biopterin
and hydroxylases (middle), and methylation (bottom).
At the far right end products appear, required for an informative
network (tubilin), a gating process (chemical mediators) and an insulating
These 3 categories are absolute prerequisites for the function of the
brain (see  for general discussion).
Fig. 1 - Biochemical
aspects of metabolic basis of intelligence ; see text.
Genes on chromosome 21
The first enzyme assigned to a gene on chromosome 21, superoxide
dismutase activity is increased by a factor of 1.5 . Too much O2- is
transformed into hydrogen peroxide H2O2. Glutathione peroxidase, which turns
H2O2 into H2O, is also increased , although its gene is on chromosome 3.
Remarkably a glutathione peroxidase gene is located on chromosome 21 .
The superoxide ion is required by indolamine axidases (tryptophane
and hydroxytryptophane); biopterines are also involved in these reactions
Experimentally, SODI protects the activity of the 5' deiodinase,
normally inactivated by the superoxide ion . Thus, excess of SODI could
increase the transformation rate of rT3 into inactive T2, thus, contributing to
the low rT3 level found in trisomy 21 .
In transgenic mice  excess of the Cu/Zn SOD gene produces
abnormal neuromuscular junctions reminiscent of those seen in trisomy 21.
Note that the production of the superoxide ion by human neutrophils
is inhibited by adenosine acting upon a membrane receptor .
Thus, excess activity of SODI could be related to:
- Diminished input of oxydized monocarbons (indole-aminase oxydases)
and impaired biopterine metabolism.
- Decrease of rT3 (5'deiodinase).
- Correlative change in neuromuscular junction.
Cystathionine Beta Synthase
Inactivity of the cystathionine beta synthase (CBS) leads to
accumulation of homocysteine not transformed in cystathionine. Homacystinuric
children are tall and slender with fang, tapering fingers with extra flexion
creases, contrasting to the small stature and short fingers lacking same
creases of trisomic 21 children. This type and counter-type effect led to
prediction of an anomaly of CBS  confirmed 10 years later by the
localization of the gene on chromosome 21  and the dosage effect
In homocystinuria, excess S-adenasyl-homocysteine (SAH) competes
with S-adenosyl-methioni.ne (SAM) and inhibits the transmethylases. In trisomy
21, insufficient homocysteine  could impair the remethylation pathway via 5
methyl-THF and B12 and slow down the recovery of SAM. A reduced rate of
methylation of nicotinamide was demonstrated 30 years ago .
Homocysteic acid promotes growth of rats , but it remains an
open question how homocysteine availability, which affects thymidine
synthetase, could also modify thyroid regulation or growth hormone
Recently localized an chromosome: 21 , the S100ß protein subunit
plays an important role in neural function. Appearing late in the forebrain
[23, 142], its level is high in the hippocampal region; it increases during the
learning process  and resembles the neur-extension factor . Modulated
by calcium , it has also great affinity far phenothiazine  and,
remarkably, far zinc .
Zinc has neurotrophic properties . It modulates thyrotropin
excretion  and modifies the sensitivity of the N-methyl-D-aspartate
receptor in the hippocampus . Zinc is reported to be beneficial in Down
syndrome; it enhances neutrophil chemotaxis and immune function ; it
reactivates the serum thymic factor  which is low in Down syndrome as well
as in hypothyroidism . The increase of Cu Zn SOD and of S100ß could very
well increase the requirements of Zn+ +. In addition 5' nucleotidase, the main
producer of adenosine, is also a Zn+ +-requiring enzyme.
Beside these interactions, an excess of S100ß could be deleterious
because of its ability to disassemble brain microtubules .
Excess activity of PFK could increase fructose- l,6-diphosphate,
which is known to accelerate biotin acetyl-CoA carboxylase, the first step of
lipid synthesis. Whether this could be related to obesity is not known.
Curiously, S100ß has a special affinity far
fructose-1,6-diphosphate aldolase , the step following PFK. Could this
peculiarity be another indication of a subjacent biochemical logic to gene
The same notion could apply to the enhancement of PFK activity by
NH4 produced by AMP deaminase in the "purine cycle" , which is especially
important in the brain and probably abnormal in trisomy 21.
Genes Pertaining to Purine Synthesis
Slight overproduction and overexcretion of uric acid in Down
syndrome patients were recognized long ago [42,93,4].Among the various steps of
purine synthesis, 3 are known to be controlled by genes an chromosome 21; the
third, leading to synthesis of 5-P-rybosylamine; the fourth,
formyl-transferase, leading to N-formyl-glycineamidine riboside (FGAM); and the
sixth, aminoimidazole synthetase, leading to 5-aminaimidazole riboside
Overproduction of purine necessitates more phospho-ribosyl
pyrophosphate (PRPP) and the first step in the production of its precursor
ribulose-5-P, by the hexose monophosphate shunt, is accelerated
Although the demand on PRPP and monacarbon metabolism remains
moderate, there are reasons to believe that purine metabolism imbalance is
worth further investigation.
In trisomy 21 erythocytes  and lymphocytes , there is an
excess of adenosine deaminase (ADA) and of purine nucleoside phosphorylase
(PNP), in accordance with increased urate excretion. An excess of AMP  and
ADP [129,81] exists in erythrocytes, however, with a normal level of ATP.
This draws attention to adenosine metabolism, especially because a
block of adenylosuccinate lyase producing AMP from adenylosuccinate as well as
5-amino-4-imidazole-carboxamide-5-aminoimadazole riboside (AICAR) from
4-N-succinocarboxamide-5-aminoimidazole riboside (SCAIR), which is located on
chromosome 22 , induces a very severe syndrome [57,58]. The psychotic
behavior is quite the counter-type of the happy character of "easy-going" Down
But, in rare cases, severely affected trisomic children exhibit
autoagressive behaviour, biting their fingers, banging their heads, quite
reminiscent of children with the Lesch-Nyhan syndrome. In this devastating
disease lack of hypoxanthine guanine phosphoribosyl transferase -(HPRT)
prevents the salvage of guanine, hypoxanthine and xanthine and necessitates an
excessive synthesis of purine to cope with this permanent leakage. Some
Lesch-Nyhan patients excrete AICAR, possibly because of insufficient
availability of 10-formyl tetra-hydrofolate, too severely required by purine
production . Remarkably, AICAR is the step just following SCAIR, the
product insufficiently metabolized in adenylosuccinate lyase deficiency.
The block of adenylasuccinate synthase in mouse cells produces an
excess of ATP , demonstrating the intricacy of these regulations.
Adenosine modulates the release of chemical mediator [100,34] at
central and peripheral synapses. Its action (essentially presynaptic) has
numerous pharmacological consequences [88,41,26,82,138]. From the experimental
data one can foresee many effects which could result from excessive adenosine
formation and compare them to frequent trisomy 21 symptoms:
- A mild deficit of immune reaction, suggested by the dramatic
effect of ADA deficiency  vs. the classical sensitivity to various
- A deficiency of the neuromuscular transmission [118,122] vs.
- A deficit of growth hormone secretion  vs. short stature with
normal sensitivity to growth hormone ,
- Inhibition of lipolysis after adrenergic stimulation of the
adipocytes [117,135] especially in hypothyroidism , vs. frequent obesity
and thyroid deficiency.
- Instability of blood sugar levels [17,78,139] vs. the frequent
- Abnormal papillary reaction  vs. the hypersensitivity of the
iris to atropine .
- Relaxation of the vascular muscle  vs. the livedo reticularis,
observed also in homocytinuria, and relaxation of intestinal muscle  vs.
- The hypersensitivity of fibroblasts to ß-adrenergic stimulation
 may also be related to adenosine effect.
The importance of adenosine modulation in the cerebellum, in the
hippocampus , and in the innervation of trigeminal mescencephalic primary
afferent neurons from hypothalamus  could be compared to the waddling gait,
the frequent grinding of teeth, the nystagmus, and, possibly, the slight
instability of the thermoregulation in the newborn infant.
Similarly, adenosine deficiency could produce instability,
irritability, anxiety, or even convulsions, as suggested by the effects of
adenosine antagonists like theophylline [105,82,112] and caffeine [32,29,26,67]
or even psychotic behaviour as suggested by the antipsychotic properties of
adenosine receptor agonists .
ß Amyloid Precursor Protein (A4)
Different from the locus of the familial predisposition to Alzheimer
disease [115,15], the ß amyloid precursor gene  is closer to the
centromere (21q21.1) than the "Down syndrome region" (21q23.1),
Accumulation of amyloid substance in senile plaques is one of the
signs of Alzheimer disease . It occurs also in Down syndrome and other
diseases [16,47], in angiopathy , in thyroxin transport defect
(transthyretine) [54,84] and in pugilistic dementia [53,114].
The first 28 amino acids of A4, as a free polypeptide, increase the
survival of pyramidal neurons of the hippocampus cultured in vitro .
Accumulation of A4 could result from an inappropriate utilisation and be a
symptom. more than a cause of the cerebral impairment
In 1906 de Bourneville was the first to treat hypo-thyroidism in a
trisomic patient by opotherapy . The two diseases have always been closely
linked and Bend adescribed "thyroid exhaustion" after a series of autopsies
Since 1981  an excess of thyroid stimulating hormone (TSH) has
been widely observed for a general review, see ). Aside from the increased
frequency of true hypothyroidism, a moderate excess of TSH is found in nearly
half of apparently euthyroid patients. Tetraiodothyronine (T4) and 3, 5,
3'-triiodothyranine (T3) remain within normal values. Moreover, a
characteristic deficit of 3, 3', 5'-triiadothyronine, or reverse T3 (rT3) is
The ratio rT3/TSH (an index of the yield of rT3 per unit of TSH) is
highly significantly diminished. This rT3/TRH ratio, highly correlated with T3
level normally, is not correlated in trisomy 21 .
These new facts demonstrate thyroid dysfunction especially for rT3,
which regulates T4 and T3 .
Low rT3, possibly related to superoxide dismutase excess (see
above), could impair growth hormone stimulation  possibly jeopardized also
by an adenosine effect (see below). The intricacy of these regulations is
illustrated by the fact that the level of 5'nucleosidase, one of the producers
of adenosine, is controlled by thyroxin .
Remarkably, thyroid hormone induces gene expression through a
responsive element common to retinoic acid ; disorder of carotene and
vitamin A is frequent in Down syndrome .
Monocarbon metabolism, which could play a key role in mental
deficiency , is strongly connected to thyroid function. Thyroxine increases
the input of oxidized monocarbons (-CHO) by activating the 10-formyl-synthase
and the output of reduced monocarbons (-CH3) by activating
5-10-methylene-THF-reductase . Simultaneously, thyroxine preserves the
monocarbon pool by inhibiting the 10-formyl-THF-dehydrogenase (which eliminates
-CHO into CO2  and by inhibiting the cystathionase  (which disposes of
homocysteine into cysteine and homoserine).
This interference with the methyl carrier is much more interesting,
since methionine has antinomic properties . It increases activity of
10-formyl-THF-dehydrogenase (depleting the monacarbon pool) and blocks the
10-formyl-THF-synthase and the 5-10-methylene-THF-reductase (diminishing the
input and the output).
Hence, thyroxine and methionine metabolisms, both abnormal in
trisomy 21, play antagonistic roles in the monocarbon metabolism, and are
abnormal also in this disease (see purine metabolism).
Tubulin organisation, using GTP  is largely controlled by
thyroid function . As already discussed , the spindle of the mitotic
apparatus and the neurotubules are made of the same building blocks: tubuline.
Hence, a cell has to choose either to keep assembling and disassembling
tubuline for mitotic machinery or to mount tubuline into an inner informative
circuitry. And this ordinated network is disrupted by neurofibrillary tangles
in 3 diseases: Down syndrome, Alzheimer, and hypothyroidism.
Controlling the production of adrenergic and serotoninergic
mediators via hydraxylases, biopterin seems imperfectly regulated in trisomy 21
; a low level of BH4 in the brain suggests a deficit of dihydrobiopterin
A recent investigation  showed an elevated urinary ratio of
neopterin/biopterin, a shift already observed in Alzheimer disease . A
slight overproduction of GTP together with a lower quinonoid (QDPR) efficiency
could be present.
Enzymes controlling folate (a vitamin) arid biopterin (a "home-made"
cofactor) can partially replace each other, suggesting a kind of fail-free
system [?4]. Both can be eliminated by oxidation into isoxanthopterin.
A trisomy 21 child, overeliminating isoxanthapterin , was
secondarily found by anamnesis to have been at that time suffering a typical
regression diagnosed 2 months later as severe hypothyroidism.
Whether thyroid hormones could prevent folate and biopterin
elimination via isoxanthopterine is an open question.
Experiments in vitro
In 1985, clinical serendipity paved the way to experimental
investigation. PEETERS et al. [96, 97] discovered that leukemic children could
not tolerate normal doses of methotrexate if they also had Down syndrome.
Toxicity of this inhibitor of dehydrafolate reductase appeared at half the
normal dose . This phenomenon has since been amply confirmed
In 1986, we demonstrated  that trisomy 21 lymphocytes are twice as
sensitive as normal ones to methotrexate. Sensitivity to chromosome break is
also increased [13,104]. These facts are in accordance with the symptoms of
folate deficiency in the leucocytes .
Generally speaking, it must be remembered that methotrexate is
dangerous for the human brain as observed after treatment for leukemia, with or
without cranial irradiation [61,109,35,1].
Although time consuming, the mitotic index method allows a first
approach to the specific sensitivity of trisomy 21 lymphocytes as exemplified
by the results of PEETERS et al. . Methotrexate hypersensitivity is fully
confirmed [103,99] and systematic investigation showed that thymidylate
synthase and thymidine kinase pathways are normal .
Contrasting with this methotrexate toxicity, 6-mercaptopurine
inhibitor of IMP dehydrogenase and also of adenylosuccinate synthase) has, at
law doses, a beneficial effect on the mitotic index ; aracytine has also a
beneficial effect . All these facts paint toward a dysregulation of Palate
metabolism with a dysequ-ilibrium between adenosine and guanosine derivatives
as well as between purine and pyrimidine pathways.
IMP dehydrogenase can also be modified by a specific inhibitor:
mycaphenolic acid (MPA) , a natural modulator: 2-3 diphosphaglycerate (2-3
DPG)  and reverse triiodotyrosine (rT3). In trisomy 21 erythrocytes, 2-3
DPG is low [63,64,81], its synthesis is under thyroxin command [125,126], and
rT3 is also low in trisomy 21 . Preliminary data show a very tight
correlation between the effects of these 3 products when tested on the
lymphocytes of the same patient.
A possible explanation of the disequilibrium observed in purine
metabolism could be that a small excess of GTP (see biopterin) would accelerate
adenylosuccinate synthase and at the same time diminish the IMP deaminase
making more AMP available. At the same time, disposal of homocysteine by CBS
would liberate S-adenosyl-homocysteine hydrolase. These 2 effects could
increase adenosine production (see purine synthesis).
Theoretical considerations and clinical
From these considerations an heuristic investigation could be directed
- Controlling the dysthyroidism.
- Compensating abnormal purine derivatives.
- Equilibrating the homocysteine/methionine pathway.
- Increasing folate or biopterin availability.
No systematic attempt has been made because each child has been
treated with the medication considered the best for his or her personal
Nevertheless, some data on thyroxine, methionine, and folic acid,
however scanty or possibly biased, can be extracted from the observations
accumulated with the collaboration of associate Professor M.O. Rethoré and
Doctors M.C de Blois, C. Pangalos, M. Peeters, M. Prieur, P.M. Sinet, and O.
Raoul at the Hôpital des Enfants Malades.
Thanks to the extraordinary cooperation of the patients and of their
sibs, and with the fully informed consent of their dedicated parents,
laboratory and/or clinical examinations are gathered at a rate of some 2,000
per year, with a total of some 5,000 recorded files.
Every 6 months, a patient is submitted to a psychometric test. His
or her personal progress is compared step by step to the general chart
established long ago on 100 Down syndrome children (Fig. 2)
After each period of 6 months on a given medication, an eventual
"inflexion" of the personal curve is calculated according to the expected
evolution (see legend of Fig. 2). This parameter expresses the eventual
betterment or deterioration of the personal curve of a given child. "Inflexion"
has by definition a mathematical expectation of zero and an experimental
standard deviation of about 0.5.
All the assays have been followed in this manner. If the mean
"inflexion" is statistically different from zero, this is taken as an
indication that the "treatment" has modified the development which would have
probably taken place if no "treatment" had been given.
(Table I) Thyroxin (T4) was prescribed only if TSH was elevated
with low T3, or T4. Varying from 3 µg/kg/day at 6 months to 1 µg/kg/day after
age 12 years, the dose was adjusted according the ensuing shift in TSH, T3, and
For children less than age 5 years 95 "inflexions" could be
calculated. The mean I.Q. of this sample being 74.3 ± 15.9 the patients could
be classified as "gifted" above 70 and "less gifted" below 70, The 36 "less
gifted" had a mean inflexion of + 0.454 ± 0.709, this value being
significantly higher than the + 0.140 ± 0.754 observed in 82 equally "less
gifted" of the same age receiving no T4 (and no methionine). The 59 "gifted"
ones had a mean inflexion of - 0.201 ± 0.724 which did not differ from the -
0.062 ± 0.720 observed in equally "gifted" children not receiving T4 nor
The highly significant difference between "gifted" doing poorly
with thyroxine and "less gifted" getting a great benefit of it (t = 4.3; P
<< 0.001) is remarkable.
(Table II) For children less than age 5 years 275 "inflexions" are
available for patients receiving methionine (61.7 mg/kilo/day ± 21.6) with no
association to T4 or folinate.
Splitting the sample at the mean I.Q. (69.7 ± 12.7) we observed
for the 133 "less gifted" a mean inflexion of -0.381 ± 0.777 and for 142
"gifted", a mean of - 0.183 ± 0.655.
The difference is highly significant (t = 6.53; P << 0.001),
the effect being significantly favorable for the "less gifted" (0.05 > P
> 0.025) and being insignificantly unfavorable far the "gifted" ones.
For children over age 5 years, the same tendency is observed,
although not significantly; for 136 "less gifted" (below the mean I,Q. of 55)
inflexion = + 0.062 ± 0.509 and for the 150 "gifted" (I.Q. above 55) infl = -
0.038 ± 0.471.
Folic acid medication.
(Table III) One hundred forty-three "inflexions" are available for
less than 5-year-old children who received neither methionine nor T4.
Sixty-nine received moderate folic acid doses ranging from 5 mg to
35 mg per week and 74 received no folate at all. The mean "inflexion" was +
0.1.514 ± 0.828 for the folate group against - 0.037 ± 0.649 for the
non-folate, the difference being not significant.
For children over age 5 years, the same tendency is observed and
all the data could be pooled (children from 1 year to age 12 years). The 109
folate receivers showed a mean inflexion of + 0.1.29 ± 0.689 and the 172
non-folate a mean of - 0.054 ± 0,508. The difference is significant (t=2.56;
0.05 > p > 0.01).
A multivariate analysis on a greater sample (now in progress) will
be required in order to confirm this seemingly beneficial effect of moderate
doses of folic acid and to investigate an eventual dose/effect relation.
Folinic acid medication.
[see ref. 75] A trial of medication with folinic acid
(5-fortnyl-tetrahydrofolate) was performed on 39 severely affected trisomic 21
patients . Thirty of them had an infantile psychosis and the other 9
suffered from Alzheimer-type regression.
Of the 69 assay , 37 were favorable and 32 were not, with no
untoward effects. Considering the quasi-inexorable course of these 2
complications, this modest result is nevertheless very suggestive of a really
beneficial effect. Unexpectedly, a dose/effect relationship was noted,
suggesting the efficient dose being rather high at some 0.8 to 1
Fig. 2. - A cohort of 100 Down syndrome children
was followed from one year up to age 14 years. A psychometric test was
administered twice a year (Brunet-Lezine first, Borel Maisonny later, and
finally Binet-Simon). Mean mental age is reported on the ordinate with
chronological age on the abscissa. The local value of standard deviation (S.D.)
is given in months. Analysis of more than 700 successives tests (independent of
those reported here) demonstrated that each child (allows his "personal
trajectory," roughly parallel to the curve of the general mean. For each child
fluctuations around his own trajectory are contained inside a corridor with
width equal to 1 S.D. of the general population (data not shown). For example
at chronological age 4 the child had a mental age of 3y. His performance 6
months later, Ye, was thus expected to lie on a line parallel to the curves of
the mean and of the S.D.; thus, Ye = 3y 3m at ronological age 4y.6m. The
observed performance, Yo, being 3y 10m, the "inflexion" of his curve can be
expressed as (3y 10m - 3y 3m)/(6.5m) = +7/6.5 = 1.08. This "inflexion" (Yo -
Ye)/(local S.D.) has a mathematical expectation equal to zero. The standard
deviation of this parameter was found to be of the order of 0.5, ranging from
0.4 for children between 5 and 12 years of age to 0.7 for children less than 5
years old. For a cohort of children receiving a given treatment, the "mean
inflexion" ± S.D. can be calculated (see Tables II-III). If this "mean
inflexion" is more than twice its S.D., this is taken as an indication that the
medication has modified the speed of development of the mental age.
No simple management, short of chromosome turning-off, can be
predicted for trisomy 21.
The chemical basis of the mental deficiency must be a disruption of a
fantastically co-ordinated system. The metaphor of an orchestra in "concert"
was not purely rhetoric. Trisomy 21 is dis-concerting. For each chemically
defined disease known to produce mental retardation, one finds a more or less
evident anomaly of the sensitive step in Down syndrome.
This evidence is, in a sense, encouraging. For example, it could very
well be that the regressive infantile psychosis sometimes observed is caused by
hypothyroidism that went unnoticed and reequilibrated itself later.
The same may be true for purine, pyrimidine, folic acid, biopterine,
or methionine metabolism. Surely, we are not yet able to restore the destiny,
but we are possibly just in the situation of being able to prevent its
It must be very precisely stressed that this general model is for the
moment strictly speculative. Even if the reasoning is sound, it remains to be
seen whether the correction of such troubles will, in the long run, alleviate
the mental deficiency.
Mr. President and dear friends, please forgive me for this too
technical discussion. Its only purpose was to show that research on the
pathogenesis of inborn mental deficiency has really begun.
Nobody knows the length of the road to be covered before reaching the
achievement we are all longing for, dedicated parents, skillful teachers and
research workers. But one think is certain, thanks to cooperation from all
fields of science, we will indefatigably try to return to the children injured
in their intelligence the spark and sparkle in their eyes which are the mark of
TABLE I. Mean "Inflexion" ± S.D. for Untreated and
Thyroxine-Treated Trisomy 21 Children (6-Month Period)
|Age||Trisomy 21 ||No. of 6-month periods
||"Inflexion" mean ± S.D||Significance
|Less than 5 years||I.Q.
= 69 "less gifted"||untreated 82,
thyroxine 36||+ 0.140 ± 0.754, + 0.454 ± 0.709||N.S.,
|I.Q. = 70
"gifted"||untreated 61, thyroxine 59||-0.062 ± 0.720, -0.201 ±
|Over 5 years||I.Q.
= 54 "less gifted"||untreated 62,
thyroxine 54||+0.005 ± 0.307, -0.001 ± 0.481||N.S., N.S.
|I.Q. = 55
"gifted"||untreated 36, thyroxine 12||-0.189 ± 0.442, -0.061 ±
TABLE II. Mean "Inflexion" ± S.D. of Untreated and
Methionine-Treated (60 mg/kilo/day) Trisomy 21 Children (6-Month
|Age||Trisomy 21 ||No. of 6-month periods
||"Inflexion" mean ± S.D||Significance
|Less than 5 years||I.Q. = 69 "less gifted"||untreated 82, thyroxine
36||+0.140 ± 0.754, +0.381 ± 0.777||N.S., P<0.05
"gifted"||untreated 61, thyroxine 59||-0.062 ± 0.720, -0.183 ±
|Over 5 years||I.Q.= 54
"less gifted"||untreated 62, thyroxine 54||+0.005 ± 0.307,
+0.062 ± 0.509||N.S., N.S.
"gifted"||untreated 36, thyroxine 12||-0.189 ± 0.442, -0.038 ±
TABLE III Mean "Inflexion" ± S.D. for Untreated and
Folic-Acid-Treated Trisomy 21 Children (6 -Month Period)
|Age||Trisomy 21||No. of 6-month
periods||"Inflexion" mean ± s.d.||Significance
|Less than 5 years||I.Q.=
69 "less gifted"||untreated 40, folic acid 42||+0.093 ± 0.577,
+0.185 ± 0.896||N.S., N.S.
"gifted"||untreated 34, folic acid 27||-0.190 ± 0.702, +0.099 ±
0.722||N.S., N.S. .
|Total||untreated 74, folic acid
69||-0.037 ± 0.649, +0.151 ± 0.828||N.S., p=0.15, N.S.,
|Over 5 years||I.Q.= 54
"less gifted"||untreated 62, folic acid 16||+0.005 ± 0.307,
+0.094 ± 0.408||N.S., N.S.
"gifted"||untreated 36, folic acid 24||-0.189 ± 0.442, +0.088 ±
|Total||untreated 98, folic acid
40||-0.066 ± 0.372, +0.090 ± 0.346||N.S. p=0.025, N.S.
|General total||untreated 172, folic acid
109||-0.054 ± 0.508, +0.129 ± 0.689||N.S. p=0.01, N.S.
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