With their upward slanting eyelids, their little nose in a round face,
their incompletly chiseled features, Down syndrome patients look more children
than usual. Every child 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 a suppleness producing a tender langor in
their posture. This general softness extend even to their character : cheerful
and affectionate, they have special charm, easier to cherish than to
That is not to say that Down syndrome is a desirable condition. It is an
implacable disorder 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 medecine is all about : to fight against the
disease and to love the disabled.
While pondering over this evening 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.
Indeed 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 drastically
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 post natal
dangers : deliberate neglect, denial of life-saving interventions or of simple
nutrition, and even direct infanticide ; 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. Life
of many millions depends of its success.
But the gene of the familial form (115) is on the chromosome 21, the
gene of the precursor of the amyloid substance (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
(9). Sure enough, a microscope must not be construed into a crystal ball, but I
would venture to sav that a victory over the neural disturbances resulting from
the genic overdose of trisomy 21 should 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 want of a cure for the late one, it looks futile
to try to cope with the inborn form of mental deficiency? Is a genic overdose
for ever unamenable to treatment? So grave a matter deserves careful
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 cases, because the musician played a solo, he modified a
trait but did not spoiled the whole symphony. Hence the type-countertype
opposition between trisomy and monosomy (69).
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! Hence the mental deficiency in trisomy as well as in
monosomic states : human intelligence is the top performance of all our genetic
Detecting the discording musicians is not an easy task especially when
a whole chromosome is involved like 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 that
peculiar chromosome without disturbing the others. Let us suppose (a competent
car repair-man has received from the factory a four-cylinder engine equipped by
mistake with five spark-plugs. He would certainly notice that the engine does
not run smoothly. An ignorant 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 still ignore how this turning off
Pending such a "tour de force" applied to chromosome 21 we have to
analyse its genic contents and consider how it could affect neural
A biochemical scheme
As already discussed (72) the functioning of the brain necessitates
- An enormous number of components : Some eleven thousand millions of
- A logical wiring of a considerable length : Some 5.000 kms if
counted in dendrites and axones and from here to the moon and hopefully back if
measured in the neurotubules network inside neurones.
- A specific response of the gating system, through chemical mediators
acting on appropriate post-synaptic membranes.
To meet these three 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 (72).
The painful task of unravelling one by one, the genes of chromosomes
21 is achieved by two methodes :
- The molecular biologists split the DNA and letter by letter decipher
the message encoded in each piece.
- The biochemists carefully analyse chemical reactions in order to
pick out these running too fast in trisomy 21.
The results of these two convergent approachs can be summarized in a
general chemical scheme (see fig. 1)
- The first columms deals with purine synthesis.
- The second deals with pyrimidine (top) and purine (below)
- The third deals with folate and monocarbons metabolism (top),
biopterin and hydroxylases (middle) and methylation (bottom).
At the far right end products appear, required for an informative
network (tubulin), a gating process (chemical mediators) and an insulating
These three categories are absolute prerequisites for the function of
the brain (see (72) for general discussion).
Genes on chromosome 21
Superoxide dismutase :
First enzyme assigned to a gene on chromosome 21, superoxyde
dismutase activity is increased by a 1,5 factor (120). Too much O2- is
transformed into hydrogene H2O2. Glutathion peroxydase, which disposes of H2O2
into H2O, is also increased (121), although its gene is in chromosome 3.
Remarkably a glutathion peroxydase like gene is located on chromosome 21
Superoxyde ion is required by indolamine oxydases ( tryptophane and
hydroxytryptophane) and biopterines are involved also in these reactions
Experimentally SODI protects the activity of the 5'deiodinase,
normally inactivated by superoxide ion (55). 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 (76).
In transgenic mice (5) excess of the Cu/Zn SOD gene produces
abnormal neuromuscular junctions reminiscent of these seen in trisomy 21.
It is also to be remarked that the production of superoxide ion by
human neutrophiles is inhibited by adenosine acting upon a membrane receptor
The excess activity of SODI could thus be related to :
- Diminished input of oxydized monocarbons (indoleamine oxydases)
and impaired biopterine metabolism
- Decrease of rT3 (5'deiodinase)
- Correlative change in neuro muscular junction
Cystathionine beta synthase :
Inactivity of the cystathionine beta synthase (CBS), leads to
accumulation of homocysteine not transformed in cystathionine - Homocystinuric
children are tall, slender with long tapering fingers with extra flexion
creases, contrasting to the small stature and short fingers lacking some
creases of trisomic 21 children. This type and counter type effect led to
prediction of an anomaly of CBS (70) confirmed ten years later by the
localisation of the gene on chromosome 21 (123) and the dosage effect
In homocystinuria, excess of S-adenosyl-homocysteine (SAH) compete
with S-adenosyl-methionine (SAM) and inhibits the transmethylases. In trisomy
21, insufficient level of homocysteine (20) could impair the remethylation
pathway via 5 methyl-THF and B12, and slow down the recovery of SAM. An
insufficient speed of methylation was demonstrated 30 years ago (45) for
Homocysteic acid promotes the growth of the rat (24), but it remains
an open question how homocysteine availability, which regulates the thymidine
synthetase, could also modify the thyroid regulation or the growth hormone
S100ß. Recently localized on chromosome 21 (2), the S100ß protein
subunit plays an important role in neural function. Appearing late in the
forebrain (23), (142), its level is high in hippocampal region, it increases
during the learning process (56) and resembles the neurite extension factor
(66). Modulated by calcium (95),it has also great affinity for phenothiazine
(83) and, remarkably,for zinc(7).
Zinc has neurotrophic properties (128), it modulates the thyrotropin
excretion (60) and modifies the sensitivity of the N-methyl-D-aspartate
receptor in the hippocampus (136). Zinc is reported to be beneficial in Down
syndrome : it enhances neutrophil chemotaxis and the immune function (10), it
reactivates the serum thymic factor (39) which is low in Down syndrome as well
as in hypothyroidism (37).The increase of (CuZn) 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 (30).
Phosphofructo kinase (PFK). Excess of activity of PFK could increase
the fructose-1, 6-diphosphate which is known to accelerate the biotin
acetyl-CoA carboxylase, first step of lipid synthesis. Whether this could be
related to adiposity is not known.
Curiously, S100ß has a special affinity for fructose-1,
6-diphosphate aldolase (141), the step following the PFK. Could this
peculiarity be another indication of a subjacent biochemical logic to gene
The same reflexion could apply to the enhancement of PFK activity by
NH4 produced by the AMP deaminase in the "purine cycle" (80) especially
important in the brain, and probably abnormal in trisomy 21.
Genes on purine synthesis :
Slight overproduction and overexcretion of uric acid in Down
syndrome patients has been recognized long ago (42),(93),(4). Among the various
steps of purine synthesis, three are known to be controlled by genes on
chromosome 21 : the third, leading to synthesis of 5-P-rybosylamine, the
fourth, formyl-transferase leading to N-formylglycineamidine riboside (FGAM)
and the sixth, amino-imidazole synthetase, leading to 5-aminoimidazole riboside
Overproduction of purine necessitates more phosphoribosyl
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 upon PRPP and monocarbon metabolisms remains
moderate, there are reasons to believe that purine methabolism unbalance is
worth further investigations.
In trisomic 21 erythocytes (111) and lymphocytes (110), there is an
excess of adenosine deaminase ( ADA) and of purine nucleoside phosphorylase
(PNP), in accordance with increased urate excretion. An excess of AMP (63) and
ADP (129), (81) exists in erythrocytes with however a normal level of ATP.
This would draw attention to adenosine metabolism, especially
because a block of adenylosuccinate lyase producing AMP from adenylosuccinate
as well as 5-amino-4-imidazole-carboxamide riboside (AICAR) from
4-N-succinocarboxamide-5-aminoimidazole riboside (SCAIR), which is located on
chromosome 22 (65), induces a very severe syndrome described by JAEKEN et al.
(57)(58). The psychotic behaviour is quite the countertype of the happy
character of "easy going" Down syndrome children.
But, in rare case, severely affected trisomic children exhibit
autoagressive behaviour, biting their fingers, banging their heads, quite
reminiscent of the Lesch-Nyhan syndrome. In this devastating disease the lack
of hypoxanthine guanine phosphoribosyl transferase (HPRT) prevents the salvage
of guanine, hypoxanthine and xanthine, and necessitates a excessive synthesis
of purine to cope with this permanent leakage. Some Lesch-Nyhan patients
excrete AICAR, possibly by insufficient availability of 10-formyl
tetra-hydrofolate, too severely sollicitafced by the purine production (107).
Remarkably AICAR is the step just following SCAIR, the product insufficiently
metabolized in adenylosuccinate lyase deficiency.
The block of adenylosuccinate synthase in mouse cells produces an
excess of GTP (133), demonstrating the intrication of these regulations.
Adenosine modulates the release of chemical mediator (106), (34) at
central and peripheric synapses. Its action essentially presynaptic, has
numerous pharmacological consequences (38), (41), (28), (82), (138). From the
experimental data one can forsee many effects which could result from excessive
adenosine formation and compare them to frequent trisomy 21 symptomes :
- A mild deficit of immune reaction, suggested by the dramatic
effect of ADA deficiency (68), vs. the classical sensitivity to various
- A deficiency of the neuromuscular transmission (118), (122), the
- A deficit of growth hormone secretion (31), vs. short stature with
normal sensitivity to growth hormone (3).
- Inhibition of lipolysis after adrenergic stimulation of the
adipocytes (117), (135) especially in hypothyroidism (92), vs. frequent obesity
and thyroid deficiency.
- Instability of glycemia (17), (78), (139), vs. the frequent
- Abnormal pupillar reaction (48), Vs. the hypersensitivity of the
iris to atropine (71).
- Relaxation of the vascular muscle (28), vs. the livedo
reticularis, observed also in homocytinuria, and relaxation of intestinal
muscle (28), vs. the frequent constipation.
- The hypersensitivity of fibroblastes to ß-adrenergic stimulation
(87) could possibly be related to adenosine effect.
The importance of adenosine modulation in the cerebellum, in the
hippocampus (33) and on the innervation of trigeminal mescencephalic primary
afferent neurons from hypothalamus (89) 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.
Similarly, adenosine deficiency could produce instability,
irritability, anxiety or even convulsions, as suggested by the effects of
adenosine antagonists like theophylline (106), (82), (112) and caffeine (32),
(29), (26), (67) or even psychotic behaviour as suggested by the antipsychotic
like properties of adenosine receptors agonists (51).
ß amyloid precursor protein (A4) :
Different from the locus of the familial predisposition to Alzheimer
disease (115), (15) the B amyploid precursor gene (46) is closer to the
centromere (21q21.1) than the "Down syndrome region" (21q22.1), (108), (130),
Accumulation of amyloid substance in the plaques is one of the
symptoms of Alzheimer disease (86). It occurs also In Down syndrome and other
diseases (16), (47), in angiopathy (25), in thyroxin transport defect
(transthyretine) (54), (84) or even in pugilistic dementia (53), (114).
The first 28 aminoacids of A4, as a free polypeptide, increase the
survival of pyramidal neurons of the hippocampus cultured in vitro (137).
Accumulation of A4, could result from an inappropiate utilisation and be a
symptom more than a cause of the cerebral impairment.
Thyroid dysfunction :
BOURNEVILLE was the first, in 1906, to treat by opotherapy,
hypothyroid in a trisomic patient (14). The two diseases have always been
closely linked and BENDA described "Thyroid exhaustion" after a series of
Since 1981 (116) an excess of thyreostimuline hormone (TSH) has been
widely observed (for a general review, see ret. (76)). 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'
-triiodothyronine (T3) remain within normal values. Moreover, a characteristic
deficit of 3, 3', 5' - triiodothyronine, or reverse T3 (rT3) is observed
The ratio rT3/TSH (an index of the yield of rT3 per unit of TSH) is
highly significantly diminished. This rT3/TSH ratio, highly correlated with T3
level normally, is not correlated in trisomy 21 (76).
These new facts demonstrate a thyroid dysfunction, especially for
rT3 which regulates T4 and T3 (22).
Low rT3, possibly related to superoxide dismutase excess (see above)
could impair growth hormone stimulation (94) possibly jeopardized also by an
adenosine effect (see below). Intrication of these regulations is illustrated
by the fact that the level of 5' nucleosidase, one of the producers of
adenosine, is controlled by thyroxine (124).
Remarkably, thyroid hormone induces gene expression through a
responsive element common to retinoic acid (134) ; disorder of carotene and
vit. A is frequent in Down syndrome (127).
Monocarbon metabolism, which could play a keyrole in mental
deficiency (72), is strongly connected to thyroid function. Thyroxin increases
the input of oxydized monocarbons (-CHO) by activating the 10-formyl-synthase
and the output of reduced monocarbons (-CH3) by activating the 5-10-methylene
-THF-reductase (119). Simultaneously thyroxine preserves the monocarbon pool by
inhibiting the 10-formyl -THE- dehydrogenase (which eliminates -CHO into CO2)
(62), and by inhibiting the cystathionase (21) (which disposes of homocysteine
into cysteine and homoserine).
This interference with the methyl carrier is so much more
interesting, since methionine has antinomic properties (119). It increases
activity of 10-formyl-THF-dehydrogenase (deplenishing the monocarbon 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 upon the monocarbon metabolism, abnormal
also in this disease (see purine metabolism).
Tubulin organisation, using GTP (140) is largely controled by
thyroid function (91). As already discussed (74), 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 mifcotic machinery or to mount tubuline into an inner informative
circuitry. And this ordinated network is disrupted by neurofibril tangles in
three diseases : Down syndrome, Alzheimer and hypothyroidism.
Biopterin metabolism :
Controlling the production of adrenergic and serotoninergic
mediators via hydroxylases, biopterin seems imperfectly regulated in trisomy 21
(49) ; low level of BH. in the brain suggest a deficit of dihydrobiopterin
A recent investigation (18) showed an elevated urinary ratio of
neopterin/biopterin , a shift already observed in Alzheimer disease (49). A
slight overproduction of GTP, together with a lower
quinonoid-dihydropterine-reductase (QDPR) efficiency could be present.
Enzymes controlling folate (a vitamin ) and biopterin (a home made
cofactor) can partially replace each other, suggesting a kind of failfree
system (74). Both can be eliminated by oxydation into isoxanthopterin.
A trisomic 21 child, overeliminating isoxanthopterin (18) was
secondarily found by anamnesis to have been at that time suffering of a typical
regression diagnosed two months later as a 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 dosage of methotrexate if they were also affected by Down
syndrome. Toxicity of this inhibitor of dehydrofolate reductase appeared at
half the normal dose (99). This phenomenon has since be amply confirmed. (40),
In 1986, we demonstrated (73) that trisomic 21 lymphocytes are twice
as sensitive than normal ones. Sensitivity to chromosome breaks is also
increased (15), (104). These facts are in accordance with the symptomes of
folate deficiency in the leucocytes (44).
Generally speaking, it must be remembered that methotrexate is
dangerous for the human brain as observed after treatment for leukemias, with
or without cranial irradiation (61), (109), (35), (1).
Although time consuming, the mitotic index method allows a first
approach of the specific sensitivity of trisomy 21 lymphocyte as exemplified by
the results of PEETERS (101). Methotrexate hypersensitivity is fully confirmed
(103), (99) and systematic investigation showed that thymidylate synthase and
thymidine kinase pathways are normal (103).
Contrasting to this methotrexate toxicity, 6-mercaptopurine (inhibitor
of IMP dehydrogenase and also of adenylosuccinate synthase) has at low doses a
beneficial effect upon the mitotic index (102). Aracytine has also a beneficial
effect (101). All these facts points toward a disregulation of the folate
metabolism with a desequilibrium between adenosine and guanosine derivatives as
well as between purine and pyrimidine pathways.
IMP dehydrogenase can also be modified by a specific inhibitor :
mycophenolic acid (MPA) (79),a natural modulator of 2-3 diphosphoglycerate (2-3
DPG) (77) and reverse triiodotyrosine (rT3). In trisomy 21 erythrocytes, 2-3
DPG is low (63), (64), (81), its synthesis is under thyroxin command (123),
(126) and rT3 is also low in trisomy 21 (76). Preliminary data show a very
tight correlation between the effects of these three 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 in the same time diminish the IMP
deaminase, thus more AMP would be available. In the same time disposal of
homo-cysteine by C B S would liberate S-adenosyl-homocysteine hydrolase. These
two effects could increase the adenosine production (see purine synthesis).
Theoretical considerations and clinical
From these considerations an heuristic investigation could be directed
- Controlling the dysthyroidism.
- Compensating the abnormal purine derivatives.
- Equilibrating the homocysteine/methionine pathway.
- Increasing folate or biopterin availability.
Clinical data :
No systematic attempt has been made because each child has been
treated with the medication considered the best for his personal state.
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. Rethore and
Doctors M.C de Blois, C. Panqalos, M. Peeters, M. Prieur, P.M. Sinet and O.
Raoul at the Hospital 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 six months, a patient is submitted to a psychometric test. His
personal progression is compared step by step to the general chart established
long ago on hundred Down syndrome children, (see fig. 2)
After each period of six months under a given medication, an
eventual "inflexion" of the personal curve is calculated according to the
expected evolution (see legend of fig. 2). This parameter express 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 developpment which would have
probably taken place if no "treatment" had been given.
a) Thyroxin therapy. (see table 1)
Thyroxin (T4) was prescribed only if TSH was elevated with low T3
or T4. Varying from 3 mcg./kg/d. at 6 months to 1 mcg./kg/d. after 12 years of
age, the dose was adjusted according the ensuing shift in TSH, T3, T4
For children less than 5 years of age, 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" not receiving T4 nor
The highly significant difference between "gifted" doing poorly
with thyroxine and "less gifted" getting a great benefice of it (t = 4.3;
P<<0,001) is remarkable.
b) Methionine medication : (see table 2)
For children less than five years of age 275 "inflexions" are
available for patients receiving methionine(61,7 mg/k/j. ± 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 favourable for the "less gifted" (0,05> P>
0,025) and being nonsignificantly unfavourable for the "gifted" ones.
For children more than 5 years of age, the same tendency is
observed, although not significant ; 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.
c) Folic acid medication : (see table 3)
143 inflexions are available for less than 5 years old children
who received neither methionine nor T4.
69 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 + 0,1514 ±
0,828 for the folate group against - 0,037 ± 0,649 for the non folate, the
difference being not significant.
For children more than 5 years of age, the same tendancy is
observed and all the data could be pooled (children from 1 year to 12 years of
age).The 109 folate receivers showed a mean inflexion of + 0.129 ± 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 benefical effect of moderate
doses of folic acid and to investigate an eventual dose/effect relation.
d) Folinic acid medication : (see ref.
A trial of medication with folinic acid
(5-formyl-fcetrahydrofolate) was performed on 39 severely affected trisomic 21
patients (75). Thirty of them had an infantile psychosis and the other 9
suffered from Alzheimer-type regression.
the 69 assays, 57 were favourable and 52 were not, with no
untoward effects. Considering the quasi-inexorable course of these two
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 mg per kilo
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 metaphore of a "concerting" orchestra
was not purely rethoric. 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 very regressive infantile psychosis sometimes observed, were
sequelae from an hypothyroidism that went unnoticed and reequilibrated itself
The same may be true for purine, pyrimidine, folic acid, biopterine or
methionine metabolisms. Surely we are not yet able of restoring 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 was sound, it would remain
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 is really begun.
Sure enough nobody knows the length of the road to be covered before
reaching the achievement we are all longing for, dedicated parents, skillfull
teachers and research workers. But one thing is certain, thanks to cooperation
from all fields of Science, we will indefatigably try to render to the children
injured in their intelligence, this marvelous glaring which is the mark of the
In trisomy 21, pathogenesis of mental retardation is still poorly
understood although the knowledge of the genic content of chromosome 21 is
steadily increasing. Short of discovering how to silence selectively one of the
three exemplars of chromosome 21, no rational medication can be envisaged
before pathogenis has been unraveled, at least partially.
A biochemical scheme of impairment of mental efficiency is presented.
Secondarily, the possible deleterious effects of a given gene overdose, are
discussed. Cu / Zn SOD, cystathionine beta synthase, S 100B protein,
phosphofructokinase, purine synthesis and adenosine pharmacology, thyroid
disturbance and elevated TSH with low rT3, as well as biopterine metabolism
interferences are reviewed.
It is observed that the metabolisms controlled by these genes,
although unrelated at first glance, are in fact tightly related by their
effects. Just as if synteny was in some way related to biochemical cooperation
or mutually controlled regulation.
Experiments in vitro, have demonstrated a peculiar sensitivity of
trisomic 21 lymphocytes to methotrexate. From this starting point, systematic
research of special sensitivities is underway.
Clinical observations and relevant statistical methods allow the study
of the speed of mental developpment under various medications. The interest of
regulating thyroid metabolism, when needed, is exemplified. Reequilibration of
monocarbon's metabolism is discussed and the seemingly favourable effect of
folinic acid medication in pseudo-Alzheimer complication is presented.
2. (cf annexe)
Table 1 - Mean "inflexion" ± s.d. for non treated and
thyroxine treated trisomic 21 children (six months period)
|Trisomic 21||number of six
months periods||"inflexion" mean ± s.d.||significance
gifted"||untreated||82||+ 0.140 ±
0.754||N.S.||age< 5 years
|thyroxine||36||+ 0.454 ± 0.709||P<
"gifted"||untreated||61||- 0.062 ±
|thyroxine||59||- 0.201 ± 0.724||P =
gifted"||untreated||62||+ 0.005 ±
0.307||N.S.||age> 5 years
|thyroxine||54||- 0.001 ±
"gifted"||untreated||36||- 0.189 ±
|thyroxine||12||- 0.061 ±
Table 2 - Mean "inflexion" ± s.d. for non treated and
methionine treated (60 mg.k.j.) trisomic 21 children (six months
|Trisomic 21 ||number of six months
periods||"inflexion" mean ± s.d.||significance||age< 5 years
|I.Q. = "less
gifted"||untreated||82||+ 0.140 ± 0.754||N.S.
|methionine||155||+ 0.381 ± 0.777||P<
"gifted"||untreated||61||- 0.062 ±
|methionine||142||- 0.183 ±
|I.Q. =54 "less
gifted"||untreated||62||+ 0.005 ±
0.307||N.S.||age> 5 years
|methionine||136||+ 0.062 ±
"gifted"||untreated||56||- 0.189 ±
|methionine||150||- 0.038 ±
Table 3 - Mean "inflexion" ± s.d. for non treated and folic
acid treated trisomic 21 children (six months period)
|Trisomic 21||number of six months
periods||"inflexion" mean ± s.d.||significance
|I.Q. =69 "less
gifted"||untreated||40||+ 0.093 ± 0.577||N.S.||age< 5 years
|folic acid||42||+ 0.185 ± 0.896||N.S.
"gifted"||untreated||34||- 0.190 ± 0.702||N.S.
|folic acid||27||+ 0.099 ± 0.722||N.S.
0.037 ± 0.649||N.S.
|folic acid||69||+ 0.151 ± 0.828||N.S. ||P = 0.15||age< 5
|I.Q. =54 "less
gifted"||untreated||62||+ 0.005 ± 0.307||N.S.
|folic acid||16||+ 0.094 ± 0.408||N.S||age> 5 years
"gifted"||untreated||56||- 0.189 ± 0.442||N.S.
|folic acid||24||+ 0.088 ± 0.308||N.S.
0.066 ± 0.372||N.S.||P = 0.025||age> 5 years
|folic acid||40||+ 0.090± 0.346||N.S.
total||untreated||172||- 0.054 ± 0.508||N.S.||P = 0.01||
|folic acid||109||+ 0.129 ± 0.689||N.S.
Legend of fig. 2.
A cohort of hundred Down's syndrome affected children was followed from
one year up to 14 years of age. A psychometric test was administered twice a
year (Brunet-Lezine first, Borel Maisonny later and finally Binet-Simon). Mean
mental age was reported in ordinates with chronological age in abscisses. The
local value of standard deviation (S.D.) is given in months.
Analysis of more than 700 successives tests (independant of those
reported here)"demonstrated that each child follows his "personnal trajectory",
roughly parallele to the curve of the general mean. For each child fluctuations
around his own trajectory happened to be contained inside a corridor having a
width sensibly equal to one S.D. of the general population (data not
On the fig. 2 for example the child had a mental age of 3y. at 4y. of
age. His next performance six months later, Xe, was thus expected to lie on a
line coparallele to the curves of the mean and of the S.D. ; Xe = 3y.3m. at
4y.6m. of chronological age.
The observed performance, Xo, 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" Xo - Xe / 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 5-12 years of age to 0.7 for
children less than 5 years old.
For a cohort of children submitted to a given treatment, the "mean
inflexion" ± s.d, can be calculated (see tables 1, 2 and 3). 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.
1- Allen JC, Mehta B, Rosen G, Horten B (1979) : Leukoencephalopathy
following high-dose intravenous methotrexate chemotherapy with citrovorum
factor rescue.Ann Neurol 6:173
2- Allore R, O'Hanlon D, Price R, Neilson K, Willard HF, Cox DR, Marks
A, Dunn RJ (1988) Gene encoding the beta submit of S 100 protein is on
chromosome 21:implications for Down'syndrome. Science 239:1311-1313
3- Anneren B, Sara VR, Hall K, Tuvemo T (1986) : Growth and
somatomedin responses to growth hormone in Down'syndrome. Arch Dis Childhood
4- Appelton MD, Haab W, Burti U, Orsulak PJ (1970 ): Plasma
urate-levels in mongolism. Am J Ment Def 74:196-199
5- Avraham KB, Schickler M, Sapoznikov D, Yarom R, Groner Y (1988):
Down's syndrome : Abnormal neuromuscular junction in tongue of transgenic mice
with elevated levels of human Cu/Zn-superoxide dismutase. Cell 54:823-829
6- Barthey JA, Epstein CJ (1980) : Gene dosage effect for Glycinamide
ribonucleotide synthetase in human fibroblasts trisomic for chromosome 21.
Biochem Biophys Res Comm 93:1286-1289
7- Baudier J, Haglid K, Haiech J, Gerard D (1983) : Zinc ion binding
to human brain calcium binding proteins, calmodulin, and S100ß protein. Bioch
Biophys Res 114: 1138-1146
8- Benda CE (1969) : Down's syndrome:mongolism and its management. New
York Grune et Stratton Edit
9- Berr C, Borghi E, Rethoré MO, Lejeune J, Alperovitch A (1989):
Absence of familial association between dementia of Alzheimer type and Down
syndrome. Am J Med Genet 33: 545-555
10- Björksten B, Back O, Gustavson KH, Hallmans G, Hagglof B, Tarnik
A (1980) : Zinc and immune fonction in Down's syndrome. Acta Paediatr Scand
11- Blanquet V, Goldgaber D, Turleau C, Créau-Goldberg N, Delabar J,
Sinet PM, Roudier M, Grouchy J. de (1987) : The beta amyloid protein (AD-AP)
C-DNA, hybridizes in normal and Alzheimer individuals near the interface of
21q21 and 21q22.1. Ann Genet 30: 68-69
12- Blatt J, Aldo V, Prin W, Orlando S, Wollman M (1986) : Excessive
chemotherapy related myelotoxicity in children with Down syndrome and acute
lymphoblastic leukaemia. Lancet II: 914
13- Borghi E, Recan D, Rethoré MO, de Blois MC, Peeters M, Lejeune J
(1987) : Chromosomal breaks in trisomy 21: Increased sensitivity to
methotrexate. (personnal communication)
14- Bourneville DM, Royer M (1906): Imbecilite prononcee congenitale
(type mongolien) : Traitement thyroidien. Archives de Neurol 22: 425-456
15- van Broeckhoven C... Hardy JA (1987) : Failure of familial
Alzheimer's disease to segregate with the A4 amyloid gene in several european
families. Nature 329:153-157
16- Buhl L, Bojsen-Moller M (1988) : Frequency of Alzheimer's disease
in post mortem study of psychiatric patients. Dan Med Bull 35:288-290
17- Campbell IL, Taylor KW (1982): Effects of adenosine,
2'deosyadenosine and N6 phenyl-isopropyl adenosine on rat islet cell
function and metabolism. Biochem J 204: 689
18- Cattell RJ.Hamon CGB, Corbett JA, Lejeune J, Blair JA (1989) :
Neopterin : biopterin ratios in Down's syndrome. J Neurol Neurosurg Psych (sous
19- Chadefaux B, Rethoré MO, Raoul O, Ceballos I, Poissonnier M,
Gilgenkrantz S, Allard D (1985) : Cystathionine beta synthase : Gene dosage
effect in trisomy 21. Bioch Biophys Res Comm 128:1-10
20- Chadefaux B, Ceballos I, Hamet M, Coude M, Poissonnier M, Kamoun
P, Allard D (1988) : Is absence of atheroma in Down syndrome due to decreased
homocysteine levels? Lancet 2:741
21- Chatagner F, Durieu-Trautmann O, Rain MC (1967) : Effects of
puromycin and actinomycin D on the increase of cystathionase and cysteine
sulphinic acid decarboxylase activities in the liver of thyroidectomized rats.
22- Chomard P, Loireau A, Dumas P, Autissier N (1987) : Effet de la
3,3',5' triodo-L-thyronine (rT3) sur la concentration s6rique des hormones
thyroidiennes chez Ie rat. CR Soc Biol 181:395-400
23- Cicero TJ, Ferrendelli JA, Suntzeff V, Moore BW (1972) : Regional
changes in CNS levels of the S-100 and 14-3-2 proteins during development and
aging of the mouse. J Neurochemistry 19:2119-2125
24- Clopath P, Smith VC, McCully KS (1976) : Growth promotion by
homocysteic acid. Science 192:372-374
25- Coria F, Prelli F, Castano EM, Larrondo-Lillo M,
Fernandez-Gonzales J, Van Duinen SG, Bots GT, Luyendijk W, Shelanski ML,
Frangiowe B (1988): ß protein deposition : a pathogenetic link between
Alzheimer's disease and cerebral amyloid angiopathies. Brain Research 463:
26- Corradetti R, Pedata F, Pepeu G, Vannucchi MG (1986) : Chronic
caffeine treatment reduces caffeine but not adenosine effects on cortical
acetylcholine release. Br J Pharmac 88: 671-676
27- Cronstein BN, Kramer SB, Rosensteine D, Weissmann G, Hirschhorn R
(1985) : Adenosine modulates the generation of superoxide anion by stimulated
human neutrophils via interaction with a specific cell surface receptor. Ann
Acad Sci New York 451:291-301
28- Daly JW (1982) : Adenosine receptors :target sites for drugs. J
Med Chem 25:197-207
29- Delong RE, Phillis JW, Barraco RA (1985) : A possible role of
endogenous adenosine in the sedative action of meprobamate. Eur J Pharmacol
30- Donate R (1985) : Calcium-sensitivity of brain microtubule
proteins in the presence of S-100 proteins. Cell Calcium 6:343-361
31- Dorflinger LT, Schonbrunn A (1985) : Adenosine inhibits prolaction
and growth hormone secretion in a clonal pituitary cell line. Endocrinology
32- Dragunow M, Goddard GV, Laverty R (1985) : Is adenosine an
endogenous anticonvulsant. Epilepsia 26:480-487 (5)
33- Dunwiddie TV, Proctor WR (1986): Mechanisms underlying responses
to adenosine in the central nervous system. Europ J Physiol sppl 1 407:541
34- Dunwiddie TV (1985) : The physiological roles of adenosine in the
central nervous system. Int Rev Neurobiol 27:63-139
35- Eiser C (1978) : Intellectual abilities among survivors of
chilhood leukemia as a function of C N S irradiation. Arch Dis Child
36- Ellis WG, McCulloch JR, Corley CL (1974): Presenile dementia in
Down's syndrome : Ultrastuctural identity with Alzheimer's disease. Neurology
37- Fabris N, Mocchegiany E, Mariotti S, Pacini F, Pinchera A (1986) :
Thyroid function modulate thymic endocrine activity. J Clin Endocrinol
38- Fox IH, Kelley WN (1978): The role of adenosine and
2'deoxyadenosine in mammalian cells. Ann Rev Biochem 47; 655-686
39- Franceschi C, Chiricolo M, Licastro J, Zannotti M, Masi M,
Mocchegiani E, Fabris N (1988) : Oral zinc supplementation in Down's syndrome :
restoration of thymic endocrine activity and of some immune defects. J Ment Def
40- Frankel LS, Pullen J, Boyett J, Eastment C, Ragab A, Hvizdala E,
Berry D, Sexauer C, Crist W, Vietti T (1986) : Excessive drug toxicity in
children with Down's syndrome (DS) treated for acute lymphatic leukemia (ALL)
despite similarity of clinical an biological features of other patients. Proc
ASCO 5:161 (631)
41- Fredholm BB, Hedqvist P (1980): Modulation of neurotransmission by
purine nucleotides and nucleosides. Biochem Pharmacol 29:1635-1643
42- Fuller RW, Luce M, Mertz ET (1962): Serum uric acid in mongolism.
Science 137: 868
43- Garre ML, Rolling MV, Kalwinsky D, Dodge R, Crom WR, Abromowitch
M, Put CH, Evans WE (1987): Pharmacokinetics and toxicity of methotrexate in
children with Down syndrome and acute lymphocytic leukemia. J Pediatr
44- Gericke GS, Hesseling PD, Brink S, Tiedt FC (1977) : Leucocyte
ultrastructure and folate metabolism in Down's syndrome. S Afr Med J
45- Gershoff SN, Hegsted DM, Trulson MF (1958) : Metabolic studies of
mongoloids. Am J Clinic Nutr 6:526-530
46- Goldgaber D, Lerman MI, McBride OW, Saffiotti U, Gajdusek DC
(1987) : Characterization and chromosomal localization of a cDNA encoding brain
amyloid of Alzheimer's disease. Science 235:877-880
47- Gurling H (1986) : Candidate genes and favoured loci: strategies
for molecular genetic research in to schizophrenia, manic depression, autism,
alcoholism and Alzheimer disease. Psychiatric developments 4: 289-309
48- Gustafsson LE, Wiklund NP (1986) Adenosine-modulation of
cholinergic and non-adrenergic non-cholinergic neuro-transmission in the rabbit
iris sphincter. Br J Pharmac 88:197-204
49- Hamon CGB, Blair JA (1987): Tetrahydrobiopterin metabolism in
disease, in. Unconjugated pterins in neurobiology. Taylor et Francis ed. London
50- Hards RG, Benkovic SJ, Van Keuren ML, Graw SL, Drabkin HA,
Patterson D (1986): Assignment of a third purine biosynthetic gene (glycinamide
ribonucleotide transformylase) to human chromosome 21. Am J Hum Genet
51- Heffner TG, Downs DA, Bristol JA, Bruns RF et al (1985) :
Antipsychoticlike effects of adenosine receptor agonists. Pharmacologist
52- Heston LL (1979) : Alzheimer's disease and senile dementia.
Genetic relationship to Down's syndrome and hematologic cancer, in : Congenital
and acquired disorders. Ed R Katzman Raven Press New York: 167-176
53- Heyman A, Wilkinson WE, Hurwitz BJ et al (1983) : Alzheimer's
disease; genetic aspects and associated clinical disorders. Ann Neurol
54- Holmgren G, Haettner E, Nordenson I,Sadgren O, Steen L, Lundgren E
(1988): Homozygosity for the transthyretin met - 30 gene in two Swedish sibs
with familial amyloidotic polyneuropathy. Clinical Genetics 34:333-338
55- Huang FS, Boado RJ, Chopra IJ, Solomon DH, Teco GNC (1987) : The
effect of free radicals on hepatic 5'monodeiodination of thyroxine and 3,3',5'
triiodothyronine. Endocrinolog 121: 498-503
56- Hyden H, Lange PW (1970): S-100 brain protein :correlation with
behaviour. Proc Ntl Acad Sci (US) 67:1959-1966
57- Jaeken J, Wadman SK, Duran M, van Sprang FJ, Beemer FA, Holl RA,
Theusissen PM, de Cock P, van den Bergh F, Vincent MF, van den Berghe G (1988)
: Adenylosuccinase deficiency : an inborn error of purine nucleotide synthesis.
Eur J Pediatr 148:126-131
58- Jaeken J, van den Berghe G (1989) : Screening for inborn errors of
purine synthesis. Lancet 1:500
59- Jervis GA (1970) : Premature senility in Down's syndrome. Ann New
York Acad Sci 171: 559-561
60- Jordan D, Suck C, Veisseire M, Chazot G (1986) : Zinc may play a
role in the regulation of thyrotropin function. Hormone Res 24:263-268
61- Kay HEM, Knapton PJ, O'Sullivan JP (1972) : Encephalopathy in
acute leukemia associated with methotrexate therapy. Arch Dis Child
62- Keating JM, Choe H, Stokstad ELR (1986) : The effect of thyroxine
status on hepatic levels of 10-formyl tetrahydrofolic acid:NADP oxydoreductase.
Chemistry and Biology of Pteridines. Cooper and Whiteheas editors Walter de
Gruyter et Co Berlin : 905-908
63- Kedziora J, Rodriguez-Paris J, Bartosz G, Lukaszewicz R, Leyko W
(1982) : Glycolytic defect in Down's syndrome erythrocytes : may concern
aldolase but not glyceral-dehyde -3-phosphate dehydrogenase. IRCS Med Sci
64- Kedziora J, Hübner H, Kanski M, Jeske J, Leyko W (1972):
Efficient of the glycolytic pathway in erythrocytes of children with Down's
syndrome. Pediatr Res 6:10-17
65- van Keuren Ml, Hart IM, Kao FT, Neve Rl, Bruns GAP, Kurnit DN,
Patterson D (1987) : A somatic cell hybrid with a single human chromosome 22
corrects the defect of CHO mutant (A de -1) lacking adenylosuccinate activity.
Cytogenet Cell Genet 44:142-147
66- Klingman D, Marshak DR (1985) : Purification and characterization
of a neurite extension factor from bovine brain. Proc Natl Acad Sci (USA)
67- Kostopoulos G, Veronikis DK, Efthimiou I (1987): Caffeine blocks
absence seizures in the tottering mutant mouse. Epilepsia 28 (4):415-420
68- Kredich NM, Hershfiels MS (1983) : Immunodeficiency diseases
caused by adenosine deaminase deficiency and purine nucleoside phosphorylase
deficiency, in : the metabolic basis of in herited disease. Stanbury Ed
69- Lejeune J (1966) : Types et contretypes. Journées parisiennes de
pediatrie :75-83 Flammarion Edit Paris
70- Lejeune J (1975) : Réflexions sur la débilité de l'intelligence
des enfants trisomiques 21. Pont Acad Sc Rome Commentarii III 9:1-12
71- Lejeune J, Bourdais M, Prieur M (1976) : Sensibilité
pharmacologique de l'iris des enfants trisomiques 21. Thérapie 31:447-454
72- Lejeune J (1983) : Le métabolisme des monocarbones et la
débilité de l'intelligence. in Débilité mentale:4-18 J. Lejeune Edit Masson
73- Lejeune J, Rethore MO, de Blois MC, Maunoury-Burolla C, Mir M,
Nicolle L, Borowy F, Borghi E, Recan D (1986): Métabolisme des monocarbones et
trisomie 21:sensibilité au methotrexate. Ann Génét 29:16-19
74- Lejeune J (1987) : Research on pathogeny of mental retardation in
trisomy 21. in: Aspect of the uses of Genetic Engineering oct 12-13 Pont Acad
Sci Rome Commentarii III 31:1-18
75- Lejeune J, Rethore MO, de blois MC, Peeters M (1989) : Psychose
infantile, syndrome pseudo Alzheimer et trisomie 21. Essai de médication par
1lacide folinique : rapport préliminaire. Thérapie 44:115-121
76- Lejeune J, Peeters M, de Blois MC, Bergere M, Grillot A, Rethoré
MO, Vallée G, Izembart M, Devaux JP (1988) : Fonction thyroidienne et trisomie
21. excès de TSH et deficit en rT3. Ann Génét 31:137-143
77- Lommen EJP, de Abreu RA, Trijbels JMF, Schretlew EDAM (1974) : The
IMP dehydrogenase catalalysed reaction in erythrocytes of normal individuals
and patients with hypoxanthine quanine phosphoribosyl transferase deficiency.
Act Paediat Scand 63:140-142
78- Lönnroth P, Davies JI, Lönnroth I, Smith V (1987) : The
interaction between the adenylate cyclase system and insulin stimulated glucose
transport. Bioch J 234 :789-795
79- Lowe JK, Brox L, Henderson JF (1977) : Consequences of inhibition
of guanine nucleotide synthesis by mycophenolic acid and virazole. Cancer
80- Lowenstein JM (1972) : Ammonia production in muscle and other
tissues; the purine nucleotide cycle. Physiological Rev 52:382-414
81- Magnani M, Stocchi V, Novelli G, Dacha N, Fornaini G (1987) : Red
blood cell glucose metabolism in Down's syndrome. Clin Physiol Bioch 5:9-14
82- Marangos PJ, Boulenger JP (1985) : Basic and clinical aspect of
adenosinergic neuro-modulation. Neurosc Biobehav Rev 9:421-430
83- Marshak DR, lAlatterson DM, van Eldik LJ (1981) : Calcium
dependent interacion of S l00b, troponin C, and calmodulin with an immobilized
phenothiazine. Proc Natl Acad Sci (USA) 78:6793-6797
84- Mascarenhas Saraiva MJ, Costa PP, Groodman Dewitt S (1986):
Genetic expression of a transthyretin mutation in typical and late-onset
protuguese families with familial amyloidotic polyneuropathy. Neurology
85- McBride OW, Lee BJ, Hatfield DL, Mullenbach G (1988) : Glutathione
peroxidase gene maps on human chromosomes 3, 21 and X. Faseb J 2A:1001
86- McGeer (1984) : Aging, Alzheimer's disease and the cholinergic
system. Can J Physiol Pharmacol 62:741-754
87- McSwigan JD, Hanson DR, Lubineicky A, Heston LL, Sheppard JR
(1981) : Down syndrome fibroblasts are hyperresponsive to ß-adrenergic
stimulation. Proc Natl Acad Sci (USA) 78:7670-7673
88- Nadler HL, Monteleone P, Hsia D (1967) : Enzyme studies during
lymphocyte stimulation with phyto-hemagglutinin in Down's syndrome. Life
89- Nagy JI, Buss M, Daddona PE (1986): On the innervation of
trigeminal mesencephalic primary afferent neurons by adenosine deaminase
containing projections from the hypothalamus in the rat. Neuroscience
90- Nishikimi M (1975): A function of tetrahydropteridines as
cofactors for indoleamine -2-3 dioxygenase. Biochem Biophys Res Com
91- Nunez J (1985) : Microtubules and brain development : the effects
of thyroid hormones. Neurochem Int 7:959-968
92- Ohisalo JJ, Stouffer JE (1979) : Adenosine, thyroid status and
regulation of lipolysis. Biochem J 178:249-251
93- Pant SS, Moser HW, Krane SM (1968) : Hyperuricemia in Down's
syndrome. J Clin Endocrinol 28:472-478
94- Papavasilious SS, Martial JA, Latham KR et al (1977): Thyroid
hormone like actions of 3,3',5' L-triiodothyronine and 3,3' diiodothyronine. J
Clin Invest 60:1230-1239
95- Patel J, Marangos PJ (1982) : Modulation of brain protein
phosphorylation by the S-100 protein. Biochem Bioph Res Corn 109:1089-1093
96- Peeters M, Poon A, Zipursky A, Olive D (1985): Mongolisme et
leucemie : toxicité accrue au métlhotrexate. Congrès national d'hématologie
et de transfusion sanguine. Bordeaux p.17
97- Peeters M, Poon A, Zipursky A, Olive D (1985): Down's syndrome and
leukemia :unusual clinical presentation;unexpected methotrexate sensitivity.
Eur J Pediat 144:115
98- Peeters M, Poon A, Zipursky A, Lejeune J (1986) : Toxicity of
leukemia therapy in children with Down syndrome. Lancet 2 :1279
99- Peeters M, Poon A (1987) : Down syndrome and leukemia unusual
clinical aspects and unexpected methotrexate sensitivity. Eur J Pediatr
100- Peeters M, Lejeune J (1989) : Correlation of the effects of
mycophenolic acid, 2-3 DPG and rT3 in trisomy 21 lymphocytes. (submitted for
101- Peeters M, Rethoré MO, Lejeune J (1989) : In vitro sensitivity
of trisomy 21 lymphocytes to chemotherapy : implications for future research.
Abst Intern Symp Trisomy 21 Rome 21-24 mai
102- Peeters M, Lejeune J (1989) : Beneficial effect of 6
mercaptopurine on the mitotic index of trisomy 21 lymphocytes:implication for
future research. Ann Génét Paris 32:21-25
103- Peeters M, Lejeune J (1989) : Methotrexate toxicity in Down
syndrome : investigation of thymidylate synthetase and thymidine kinase
pathways. Abst IV Int Down Syndrome Conv :57 Jerusalem 19-24 mars
104- Pelz L, Götz J, Kruger G, hlitt G (1988) : Increased
methotrexate-induced chromosome breakage in patients with free trisomy 21 and
their parents. Hum Genet 81:38-40
105- Philips J, Herring RM, Goodman HO, King jr JS (1974) : Leucocyte
alkaline phosphatase and erythrocyte glucose-6-phosphate dehydrogenase in
Down's syndrome. J Med Genet 4:268-273
106- Phillis JW, Wu PH (1981) : The role of adenosine and its
nucleotides in central synaptic transmission. Prog Neurobiol 16:187-239
107- Pignero A, Giliberti P, Tancredi F (1978) : Effect of the
treatment with folic acid on urinary excretion pattern of
aminoimidazole-carboxamide in the Lesch-Nyhan syndrome, in Perspectives in
inherited metabolic Diseases: volume 1
108- Podlinsky MB, Lee G, Selkoe DJ (1987) : gene dosage of the
amyloid ß precursor protein in Alzheimer disease. Science 238:669-677
109- Price RA, Janieson PA (1975) : The central nervous system in
childhood leukemia. II subacute leukoencephalopathy. Cancer 35:306-318
110- Puukka R, Puukka M, Perkkila L, Kouvalainen K (1986) : Levels of
some purine metabolizing enzymes in lymphocytes from patients with Down's
syndrome. Biochem Med Metabol Biol 36:45-50
111- Puukka R, Puukka M, Leppilampi M, Linna Cl, Kouvalainen K (1982)
: Erythrocyte adenosine deaminase, purine nucleoside phosphorylase and
phosphoribosyi transferase activity in patients with Down's syndrome. Clinica
Chimica Acta 126:275-281
112- Rachelefsky GS, Wo J, Adelson J, Mickey R, Spectors L, Katz RM,
Siegel SC, Rohr AS (1986) : Behaviour abnormalities and poor school performance
due to theophylline use. Pediatrics 78:1133-1138
113- Robakis NK, Wisniewski HN, Jenkis EC (1987) : Chromosome 21q21
sublocalisation of gene encoding beta amyloid peptide in cerebral vessels and
neuritic (senile) plaques of people with Alzheimer disease and Down syndrome.
114- Roberts GW (1988) : Immunochemistry of neurofibrillary tangles in
dementia pugilistica and Alzheimer disease : evidence for common genesis.
Lancet 2 :1456-1457
115- St George -Hyslop PH, Tanzi R, Gusella JE (1987) : The genetic
defect causing familial Alzheimer's disease maps on chromosome 21. Science
116- Samuel AM, Krishna Murphy DS, Kadival GV et al (1981) : Thyroid
function studies in young Down syndrome. Indian J Med Res 73: 223-227
117- Schimmel RJ, Elliott ME, McCarthy L (1986): Adenosine and
thermogenesis in brown adipose tissue : interaction with beta and alpha
adrenergic responses.. Europ J Physiol Suppl 1 407:S14
118- Sebastiao AM, Riberio JA (1986) : Enhancement of transmission at
the frog neuromuscular junction by adenosine deaminase : evidence for an
inhibitory role of endogenous adenosine on neuromuscular transmission. Neurosci
119- Shane B, Stokstad EL (1985): Vit. B12-folate interrelationships.
Ann Rev Nutr 5:115-141
120- Sinet PM, Allard D, Lejeune J, Jerome J (1974) : Augmentation
d'activité de la super oxyde dismutase erythrocytaire dans la trisomie pour Ie
chromosome 21. CR Acad Sci (Paris) 278 D:3267-3270
121- Sinet PM, Lejeune J, Jerome H (1979) : Trisomy 21 (Down's
syndrome) glufcathione peroxydase, hexose monophosphate shunt and IQ. Life
122- Singh YN, Dryden WF, Chen H (1986) : The inhibitory effects of
some adenosine analogues on transmitter release at the mammalian neuro-muscular
junction. Can J Physiol Pharmacol 64:1446-1450
123- Skoby F (1985) : Homocystinuria. Act Paed Scand Suppl 321
124- Smith RM, Patel AJ, Kingsbury AE et al (1980) : Effect of thyroid
state on brain development : ß adrenergic receptors and 5'nucleotidase
activity. Brain Res 198:375-387
125- Snyder LM, Reddy WJ (1970) : The effect of 3,5,3'
-triiodothyronine on red cell 2,3-diphosphoglyceric acid. Clin Res 18:416
126- Snyder LM, Reddy WJ (1970) : Mechanism of action of thyroid
hormone -on erythrocyte 2,3-diphosphoglyceric acid synthesis. J Clin Invest
127- Sobel AE, Strazzulla N, Sherman BS, Elkan B, Morgenstern SW,
Marius N, Meisel A (1958) : Vit A absorption and other blood composition
studies in mongolism. Amer J Ment Defic 62:642
128- Stewart GR, Frederickson CJ, Howell GA, Gage FH (1984) :
Cholingeric denervation-induced increase of chelatable zinc in mossy-fiber
region of the hippocampal formation. Brain Res 290:43-51
129- Stocchi V, Magnani M, Cucchiarini L, Novelli G, Dallapiccola B
(1985) : Red blood cell adenine nucleotides abnormalities in Down syndrome. Am
J Med Genet 20:131-135
130- Tanzi RE, St George -Hyslop PH, Gusella JF (1987) : The genetic
defect in familial Alzheimer's disease is not tightly linked to the amyloid ß
protein gene. Nature 329:156-157
131- Tanzi RE, Gussela JF, Watkin S, Bruns GAP, St George-Hyslop PC,
van Keuren ML, Patterson D, Pagan S, Kurnit DM, Neve RL (1987) : Amyloid ß
protein gene : cDNA, in RNA distribution, and genetic linkage near the
Alzheimer locus. Science 235:880-884
132- Tikuma K, Yoshihara S, Aoki T, Miyagawa F (1989) : Abnormal
glycolysis in adolescents and adults with Down syndrome. Abst IV Int Down
Syndrome Conv Jerusalem 19-24 mars p.34
133- Ullman B, Clift SM, Cohen A, Gudas LJ, Levinson BB, Wormsted MA,
Martin DW (1979) : Abnormal regulation of de novo purine synthesis and purine
salvage in a cultured mouse T-cell lymphoma mutant partially deficient in
adenylosuccinate synthetase. J Cell Physiol 99:139-152
154- Umesono K, Giguere V, Glass DK, Rosenfeld MG, Evans RM (1988) :
Retinoic acid and thyroid hormone induce gene expression through a common
responsive element. Nature 336:261-265
135- Vernon RG, Finley E, Taylor E (1985) : Adenosine and the control
of lipolysis in rat adipocytes during pregnancy and lactation, Biochem J
136- Weiss JH, Koh JY, Christine CH, Choi DM (1989): Zinc and LTP.
137- Whitson JS, Selkoe DJ, Cotman CW (1989) : Amyloid ß protein
enhances the survival of hippocampal neurons in vitro. Science
138- Williams M (1987) : Purine receptors in mammalian
tissues-.pharmacology and functional significance. Ann Rev Pharmacol Toxicol
139- Wong EHA, Ooi SO, Loten EG, Sneyd JGT (1985) : The action of
adenosine in insulin on the low-km cyclic AMP phosphodiesterase of rat
adipocytes. Biochem J 227:815-821
140- Zabrecky JR, Cole RD (1982): Binding of ATP to tubulin. Nature
141- Zimmer DB, van Eldik LJ (1986) : Identification of a molecular
target for the calcium modulated protein S 100. Fructose-1.6-biphosphate
aldolase. J Biol Chem 261:11424-11428
142- Zuckerman JE, Herschman HR, Levine L (1970) : Appearance of a
brain specific antigen (the S-100 protein) during human foetal development. J