Pathogenesis of Mental Deficiency in Trisomy 21

Jérôme Lejeune

Received for publication August 8,1989; revision received March 5,1990. Address reprint requests to Professeur Jérôme Lejeune, Institut de Progenese 45 rue des Saints Peres, 75270 Paris cedex 06, France.

Résumé :

In trisomy 21, pathogenesis of mental retarda-tion is still poorly understood although the knowledge of the genie content of chromo-some 21 is steadily increasing. Short of discov-ering how to silence selectively one of the 3 chromosomes 21, no rational medication can be envisaged before pathogenesis 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 100ß protein, phosphofructokinase, purine synthesis and adenosine pharmacology, thyroid distur-bance, and elevated TSH with low rT3 as well as biopterine metabolism interferences are reviewed. It is observed that the metabolic paths con-trolled 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 mutu-ally controlled regulation. Experiments in vitro have demonstrated a peculiar sensitivity of trisomic 21 lymphocytes to methotrexate. From this starting point, systematic research of special sensi-tivities has begun. Clinical observations and relevant statisti-cal methods allow study of the speed of mental development under various medications. The interest of regulating thyroid metabolism, when needed, is exemplified. Reequilibration of monocarbon metabolism is discussed and the seemingly favourable effect of folinic acid medication in pseudo-Alzheimer complica-tion is presented.




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 of medi-cine.

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 [115] 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 [9], 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 likely.

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 discussion.


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 [69].

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 efficiency.


A biochemical scheme

As already discussed [72] the functioning of the brain necessitates:

- 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 [72].

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) interconversions.

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 system (myelin).

These 3 categories are absolute prerequisites for the function of the brain (see [72] for general discussion).

Fig. 1 - Biochemical aspects of metabolic basis of intelligence ; see text.


Genes on chromosome 21


Superoxide Dismutase

The first enzyme assigned to a gene on chromosome 21, superoxide dismutase activity is increased by a factor of 1.5 [120]. Too much O2- is transformed into hydrogen peroxide H2O2. Glutathione peroxidase, which turns H2O2 into H2O, is also increased [121], although its gene is on chromosome 3. Remarkably a glutathione peroxidase gene is located on chromosome 21 [85].

The superoxide ion is required by indolamine axidases (tryptophane and hydroxytryptophane); biopterines are also involved in these reactions [90].

Experimentally, SODI protects the activity of the 5' deiodinase, normally inactivated by the 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 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 [27].

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 [70] confirmed 10 years later by the localization of the gene on chromosome 21 [123] and the dosage effect demonstration [19]

In homocystinuria, excess S-adenasyl-homocysteine (SAH) competes with (SAM) and inhibits the transmethylases. In trisomy 21, insufficient homocysteine [20] 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 [45].

Homocysteic acid promotes growth of rats [24], but it remains an open question how homocysteine availability, which affects thymidine synthetase, could also modify thyroid regulation or growth hormone production.



Recently localized an 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 the hippocampal region; it increases during the learning process [56] and resembles the neur-extension factor [66]. Modulated by calcium [95], it has also great affinity far phenothiazine [83] and, remarkably, far zinc [7].

Zinc has neurotrophic properties [128]. It modulates 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 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 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 [30].


Phosphofrucotokinase (PFK).

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 [141], the step following PFK. Could this peculiarity be another indication of a subjacent biochemical logic to gene localization?

The same notion could apply to the enhancement of PFK activity by NH4 produced by AMP deaminase in the "purine cycle" [80], 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 (AIR).

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 [11,88,105].

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 [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, 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 [65], induces a very severe syndrome [57,58]. The psychotic behavior is quite the counter-type of the happy character of "easy-going" Down syndrome children.

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 [107]. 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 [133], 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 [68] vs. the classical sensitivity to various infections.

- A deficiency of the neuromuscular transmission [118,122] vs. severe hypatonia.

- 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 blood sugar levels [17,78,139] vs. the frequent prediabetic state.

- Abnormal papillary 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. frequent constipation.

- The hypersensitivity of fibroblasts to ß-adrenergic stimulation [87] may also be related to adenosine effect.

The importance of adenosine modulation in the cerebellum, in the hippocampus [33], and in 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 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 [51].


ß Amyloid Precursor Protein (A4)

Different from the locus of the familial predisposition to Alzheimer disease [115,15], the ß amyloid precursor gene [46] is closer to the centromere (21q21.1) than the "Down syndrome region" (21q23.1), [108,130,131].

Accumulation of amyloid substance in senile plaques is one of the signs of Alzheimer disease [85]. It occurs also in Down syndrome and other diseases [16,47], in angiopathy [25], 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 [137]. Accumulation of A4 could result from an inappropriate utilisation and be a symptom. more than a cause of the cerebral impairment


Thyroid Dysfunction

In 1906 de Bourneville was the first to treat hypo-thyroidism in a trisomic patient by opotherapy [14]. The two diseases have always been closely linked and Bend adescribed "thyroid exhaustion" after a series of autopsies [8].

Since 1981 [116] an excess of thyroid stimulating hormone (TSH) has been widely observed for a general review, see [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'-triiodothyranine (T3) remain within normal values. Moreover, a characteristic deficit of 3, 3', 5'-triiadothyronine, or reverse T3 (rT3) is observed [76].

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 [76].

These new facts demonstrate 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). 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 [124].

Remarkably, thyroid hormone induces gene expression through a responsive element common to retinoic acid [134]; disorder of carotene and vitamin A is frequent in Down syndrome [127].

Monocarbon metabolism, which could play a key role in mental deficiency [72], 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 [119]. Simultaneously, thyroxine preserves the monocarbon pool by inhibiting the 10-formyl-THF-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 much more interesting, since methionine has antinomic properties [119]. 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 [140] is largely controlled 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 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.


Biopterin Metabolism

Controlling the production of adrenergic and serotoninergic mediators via hydraxylases, biopterin seems imperfectly regulated in trisomy 21 [49]; a low level of BH4 in the brain suggests a deficit of dihydrobiopterin reductase (QDPR).

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 (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 [18], 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 [99]. This phenomenon has since been amply confirmed [40,98,43].

In 1986, we demonstrated [73] 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 [44].

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. [101]. Methotrexate hypersensitivity is fully confirmed [103,99] and systematic investigation showed that thymidylate synthase and thymidine kinase pathways are normal [103].

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 [102]; aracytine has also a beneficial effect [101]. 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) [79], a natural modulator: 2-3 diphosphaglycerate (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 [125,126], and rT3 is also low in trisomy 21 [76]. 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 observations

From these considerations an heuristic investigation could be directed toward:

- Controlling the dysthyroidism.

- Compensating 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 or her 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. 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.

Thyroxin therapy.

(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 T4 values.

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 methionine.

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.

Methionine medication.

(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 [75]. 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 mg/kilo/day.

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 worsening.

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 the spirit.

TABLE I. Mean "Inflexion" ± S.D. for Untreated and Thyroxine-Treated Trisomy 21 Children (6-Month Period)
AgeTrisomy 21 No. of 6-month periods "Inflexion" mean ± S.DSignificance
Less than 5 yearsI.Q. = 69 "less gifted"untreated 82, thyroxine 36+ 0.140 ± 0.754, + 0.454 ± 0.709N.S., P<0.001
I.Q. = 70 "gifted"untreated 61, thyroxine 59-0.062 ± 0.720, -0.201 ± 0.724N.S., P=0.05
Over 5 yearsI.Q. = 54 "less gifted"untreated 62, thyroxine 54+0.005 ± 0.307, -0.001 ± 0.481N.S., N.S.
I.Q. = 55 "gifted"untreated 36, thyroxine 12-0.189 ± 0.442, -0.061 ± 0.389N.S., N.S.
TABLE II. Mean "Inflexion" ± S.D. of Untreated and Methionine-Treated (60 mg/kilo/day) Trisomy 21 Children (6-Month Period)
AgeTrisomy 21 No. of 6-month periods "Inflexion" mean ± S.DSignificance
Less than 5 yearsI.Q. = 69 "less gifted"untreated 82, thyroxine 36+0.140 ± 0.754, +0.381 ± 0.777N.S., P<0.05
I.Q.= 70 "gifted"untreated 61, thyroxine 59-0.062 ± 0.720, -0.183 ± 0.655N.S., N.S.
Over 5 yearsI.Q.= 54 "less gifted"untreated 62, thyroxine 54+0.005 ± 0.307, +0.062 ± 0.509N.S., N.S.
I.Q.= 55 "gifted"untreated 36, thyroxine 12-0.189 ± 0.442, -0.038 ± 0.471N.S., N.S.
TABLE III Mean "Inflexion" ± S.D. for Untreated and Folic-Acid-Treated Trisomy 21 Children (6 -Month Period)
AgeTrisomy 21No. of 6-month periods"Inflexion" mean ± s.d.Significance
Less than 5 yearsI.Q.= 69 "less gifted"untreated 40, folic acid 42+0.093 ± 0.577, +0.185 ± 0.896N.S., N.S.
I.Q.= 70 "gifted"untreated 34, folic acid 27-0.190 ± 0.702, +0.099 ± 0.722N.S., N.S. .
Totaluntreated 74, folic acid 69-0.037 ± 0.649, +0.151 ± 0.828N.S., p=0.15, N.S., p=0.15
Over 5 yearsI.Q.= 54 "less gifted"untreated 62, folic acid 16+0.005 ± 0.307, +0.094 ± 0.408N.S., N.S.
I.Q.= 55 "gifted"untreated 36, folic acid 24-0.189 ± 0.442, +0.088 ± 0.308N.S. N.S.
Totaluntreated 98, folic acid 40-0.066 ± 0.372, +0.090 ± 0.346N.S. p=0.025, N.S. p=0-025
General totaluntreated 172, folic acid 109-0.054 ± 0.508, +0.129 ± 0.689N.S. p=0.01, N.S. p=0.01



1. Allen JC, Mehta B, Rosen G, Horten B (1979): Leukoencephalopa- 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 subunit of S 100 protein is on chromosome 21: implications for Down syndrome. Science 239:1311-1313:

3. Annerén B, Sara VR, Hall K, Tuvemo T (1986): Growth and somatomedin responses to growth hormone in Down syndrome. Arch Dis Child 81:48-52.

4. Appleton MD, Haab W, Burti U, Orsulak PJ (1970): Plasma urate-levels in mongolism. Am J Ment Defic 74:196-199.

5. Avraham KB, Schickler M, Sapaznikov D, Yarom R, Groner Y (1988): Down's syndrome: Abnormal neuromuscular junction in tongue of transgenic mice with elevated levels of human Cu/Zn- 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 Commun 93.1286-1289.

7. BaudierJ, Haglid K, Haiech J, Gerard D (1983): Zinc ion binding to human brain calcium binding proteins, calmodulin, and S100ß protein. Biochem Biophys Res Commun 114:1138-1148.

8. Benda CE (1969): "Down's: Syndrome: Mongolism and its Management." New York: Grune and Stratton.

9. Beer C, Borghi E, Rethoré M0, 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, Hillmans G, Hägglof B, Tärnik A (1980): Zinc and immune function in Down's syndrome. Acts Paediatr Scand 69:183-187.

11. Blanquet V, Goldgaber D, Turleau C, Créau-Goldberg N, Delabar J, Sinet PM, Rowdier 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 Génét (Paris) 30:68--69.

12. Blatt J, Aldo V, Prin W, Orlando , Wallman M (1986): Excessive chemotherapy related myelotoxicity in children with Dawn syndrome and acute lymphablastic leukaemia. Lancet 2:914.

13. Borghi E, Recan D, Rethoré MO, de Blois MC, Peeters M, Lejeune J (1987): Chromosomal breaks in trisomy 21: Increased sensitivity to methotrexate. (personal communication).

14. Bourneville, DM, Royer M (1908): imbécilité prononcée congénitale (type mongolien) : Traitement thyroidien Arch 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'deoxyadenosine and N6 phenylisopropyl adenosine on rat islet cell function and metabolism, Biochem J 204:689,

18. Cattell RJ, Hamon CGB, Corbett JA, Lejeune J, Blair JA (1989): Neapterin: biopterin ratios in Down's syndrome. J Neural Psychiatry 52:1015-1016.

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. Biochem Biophys Res Commun 128:1-10.

20. Chadefaux B, Ceballos I, Harriet M, Coude M, Poissonnier M, Kamoun P, Allard D (1988): Is absence of atheroma in Dawn syndrome due to decreased homocysteine levels? Lancet 2:741.

21. Chatagner F, Durieu-Trautmann 0, Rain MC (1967): Effects of puromycin and actinomycin D on the increase of cystathionase and cysteine sulphinic acid decarboxylase activities in the liver of thyroidectamized rats. Nature 214:88-90.

22. Chomard P, Loireau A, Dumas P, Autissier N (1987): Effet de la 3, 3', 5' triodo-L-thyronine (rT3) sue la concentration sérique des hormones thyroidiennes chez le rat. CR Soc Biol (Paris) 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 Neurochem 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, Buts GT, Luyendijk W, Shelanski ML, Frangiowe B (1988): ß protein deposition: A pathogenetic link between Alzheimer's disease and cerebral amyloid angiopathies. Brain Res 463:187-191.

26. Corradetti R, Pelota F, Pepeu G, Vannucchi MG (1983); Chronic caffeine treatment reduces caffeine but not adenosine; effects on cortical acetylcholine release. Br J Pharmacol 88:671-678.

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 118:359-362.

30. Donato 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 117:2330-2337.

32. Dragunow M, Goddard GV, Laverty R (1985): is adenosine an endogenous anticonvulsant? Epilepsia 26:480-487.

33. Dunwiddie, TV, Proctor WR (1986): Mechanisms underlying responses to adenosine in the central nervous system Europ J Physiol Suppl 1407:541.

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 childhood leukemia as a function of C N S irradiation. Arch Dis Child 53:391-395.

38. Ellis WG, McCulloch JR, Corley CL (1974): Presenile dementia in Down's: syndrome: Ultrastructural identity with Alzheimer's disease. Neurology 24:101-108.

37. Fabris N, Mocchegiany E, Mariotti S, Pacini F, Pinchera A (1986): Thyroid function modulates thymic endocrine activity. J Clin Endocrinol Metab 62:474.

38. Fox IH, Kelley WN (1978): The rule of adenosine and 2'deoxyadenosine in mammalian cells. Anna Rev Biochern 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 Defic Res 32.

40. Frankel LS, Pullen J, Boyett J, Eastment C, Ragab A, H vizdala E, Berry D, Sexauer C, Crist W, Vietti T (198G): Excessive drug toxicity in children with Down's syndrome (DS) treated for acute lymphatic leukemia (ALL) despite similarity of clinical and 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 mongol ism. Science 137:868.

43. Garre ML, Relling MV, Kalwinsky D, Dodge R, Crom WR, Abromowitch M, Pus CH, Evans WE (1987): Pharmacokinetics and toxicity of methotrexate in children with Down syndrome and acute lymphocytic leukemia. J Pediatr 111:606-612.

44. Gericke GS, Hesseling PD, Brink S, Tiedt FC (1977): Leucocyte ultrastructure and folate metabolism in Down's syndrome. S Afr Med J 51:369-374.

45. Gershon Hegsted DM, Trulson MF (1958): Metabolic studies of mongoloids. Am J Clin Nutr 8:526-530.

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. Curling H (1986): Candidate genes and favored loci: strategies for molecular genetic research into 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-chalinergic neuro-transmission in the rabbit iris sphincter. Br J Pharmacol 88;197-204.

49. Hamon CGB, Blair JA (19$7): Tetrahydrobiopterin metabolism in disease. In Taylor et Francis (eds): "Unconjugated Pterins in Neurobiology." London: pp 201-213.

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 39:179-185.

51. Heffner TG, Dawns DA, Bristol JA, Bruns RF et al (1986): Anti-psychoticlike effects of adenosine receptor agonists. Pharmacologist 27:293.

52. Heston LL (1979): Alzheimer's disease and senile dementia. Genetic relationship to Down's syndrome and hematologic cancer. In Katzman R (ed): "Congenital and Acquired Disorders." New York: Raven Press pp 167-176.

53. Heyman A, Wilkinson WE, Hurwitz BJ et al. (19$3): Alzheimer's disease: Genetic aspects and associated clinical disorders. Ann Neural 14:507-516.

54. Holmgren G, Haettner E, Nordenson I, Sadgren O, Steep L, Lundgren E (1988): Homozygosity for the transthyretin met 30-gene in two Swedish sibs with familial amyloidatic polyneuropathy. Clip Genet 34:333-338.

55. Huang FS, Boado RJ, Chopra IJ, Solomon DH, Teco GNC (1987): The effect of free radicals an hepatic 5'monodeiodination of thyroxine and 3, 3', 5'triiodothyronine. Endocrinology 121:498-503.

56. Hyden H, Lange PW (1970): 5-100 brain protein: correlation with behavior. Proc Natl Acad Sci (USA) 67:1959-1966.

57. Jaeken J, Wadman SK, Duran M, van Sprang FJ, Beemer FA, Hall 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 NY Acad Sci 171:559-561.

60. Jordan D, Suck C, Veisseire M, Chazot G (1988): zinc may play a role ire the regulation of thyrotropin function. Horm Res 24:263-268.

61. Kay HEM, Knapton PJ, O'Sullivan JP (192): Encephalopathy in acute leukemia associated with methotrexate therapy. Arch Dis Child 47:344-354.

62. Keating JM, Choe H, Stokstad ELR (1986): The effect of thyroxine status on hepatic levels of 10-farmyl tetrahydrofolic acid: NADP oxydoreductase. In Cooper and Whiteheas (eds): "Chemistry and Biology of Pteridines." Berlin: Walter de Gruyter et Co. pp 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 glyceraldehyde-3-phosphate dehydrogenase. IRCS Med Sci 10:391.

64. Kedziora J, Hübner H, Kanski M, Jeske J, Leyko W (I972): Efficiency of the glycolytic pathway in erythrocytes of children with Down's syndrome. Pediatr Res 6:10-17.

65. van Keuren MI, Hart IM, Kao FT, Neve RI, Bruns GAF, Kurnit DN, Patterson D (1987): A somatic cell hybrid with a single human chromosome 22 corrects the defect of CHO mutant (Ade -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. Prat Natl Acad Sci (USA) 82:7136-7139.

67. Kostopoulos G, Veranikis DK, Efthimiou I (1987): Caffeine blocks absence seizures in the tottering mutant mouse. Epilepsia 28 (4):415-420.

68. Kredich NM, Hershfiels MS (19$3): Immunodeficiency diseases caused by adenosine deaminase deficiency and purine nucleoside phosphorylase deficiency. In Stanbury (ed): "The Metabolic Basis of Inherited Disease." McGraw-Hill.

69. Lejeune J (1966): Types et contretypes. Journées Parisiennes de Pédiatrie Paris: Flammarion Edit, pp 75-83.

70. Lejeune J (1975): Reflexions sur la débilité de l'intelligence des enfants trisomiques 21. Pont Acad Sc Rome Commentarii II119:1-12.

71. Lejeune J, Bourdais M, Prieur M (1976): Sensibility 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 Lejeune J (ed): "Débilité Mentale." Paris: Masson, pp 4-18.

73. Lejeune J, Réthoré MO, de Blois MC, Maunoury-Burolla C, Mir M, Nicolle L, Borowy F, Borghi E, Recap D (1986): Métabolisme des monocarbones et trisomie 21: sensibilité au methotrexate. Ann Genet (Paris) 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 I2-13." Pont Acad Sci Rome Commentarii III.31 :1-18.

75. Lejeune J, Retort MO, de Blois MC, Peeters M (1989): Psychose infantile, syndrome pseudo Alzheimer et trisomie 21. Essai de Médication par l'acide folinique: rapport préliminaire. Thérapie 44:115-121.

76. Lejeune J, Peelers 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 (Paris) 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 guanine phosphoribosyl transferase deficiency. Acta Paediatr 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. Biochem J 234:789-795.

79. Lows JK, Brox L, Henderson JF (1977): Consequences of inhibition of guanine nucleotide synthesis by mycophenolic acid and virazole. Cancer Res 37:736-743.

80. Lowenstein JM (1972): Ammonia production in muscle and other tissues: the purine nucleotide cycle. Physiol 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. Clip Physiol Bioch 5:9-14.

82. Marangos PJ, Boulenger JP f 1985): Basic and clinical aspect of adenosinergic neuromodulation. Neurasci Biabehav Rev 9:421-430.

83. Marshak DR, Watterson DM, van Eldik LJ (1981): Calcium dependent interaction of S 100b, 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 Portugese families with familial amyloidotic polyneuropathy. Neurology 36:1413-1417.

85. McBride OW, Lee BJ, Hatfield DL, Mullenbach G (1988): Glutathionine 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. Prat Natl Acad Sci (USA) 78:7670-7673.

88. Nadler HL, Monteleone P, Hsia D (1967): Enzyme studies during lymphocyte stimulation with phyto-hematgglutinin in Down's syndrome. Life Sci 6:2003-2008.

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 17:141-156.

90. Nishikimi M (1975): A function of tetrahydropteridines as cofactors for indoleamine-2-3 dioxygenase. Biochem Biophys Res Commun 63:92-98.

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, Maser HW, Krane SM (1968): Hyperuricemia in Down's syndrome. J Clin Endocrinol 28:472-478.

94. Papavasilious SS, Martial JA, Latham KR et al (197'l): Thyroid hormone like actions of 3, 3', 5' L-triiodothyranine and 8, 3' diiadothyranine. J Clin Invest 60:1230-1239.

95. Patel J, Marangos PJ (1982): Modulation of brain protein phosphorylation by the S-100 protein. Biochem Biophys Res Common 109:1089-1093.

96. Pesters M, Poon A, Zipursky A, Olive D (1985): Mongolisme et leucémie: toxicité accrue au methotrexate. Congrès national d'hé-matologie 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 Pediatr 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. Feelers M, Poon A (198?): Down syndrome and leukemia: unusual clinical aspects and unexpected methatrexate sensitivity. Eur J Pediatr 146:416-422.

100. Peeters M, Rethoré MO, de Kermadec 5, Lejeune J (1989); Correlation between the effects of rT3 and IMP dehydrogenase inhibitors on normal and trisomy 21 lymphocyte sutures. Ann Genet (Paris) 32:211-213.

101. Peelers M, Rethoré MO, Lejeune (1989): In vitro sensitivity of trisomy 21 lymphocytes to chemotherapy: implications for future research. Abst Intern Symp Trisomy 21 Rome 21-24 mai.

102. Peelers M, Lejeune J (1989): Beneficial effect of 6 mercaptopurine on the mitotic index of trisomy 21 lymphocytes: implication for future research. Ann Gent (Paris) 32:21-25.

103. Peelers M, Lejeune (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, Krüger G, Witt 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 H0, King Jr Js (19?4): 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 18:187-239.

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; "Perspective in Inherited Metabolic Diseases: volume 1."

108. Podlinsky MB, Lee G, Selkoe DJ (198?): 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 CI, Kouvalainen K (1982): Erythrocyte adenosine deaminase, purine nucleoside phosphorylase and phosphoribosyl transferase activity in patients with Down's syndrome. Clin Chim Acta 126:275-281.

112. Rachelefsky G5, Wo J, Adelson J, Lickey R, Specters 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 (198?): Chromosome 21q21 sublocalisation of gene encoding beta amyloid peptide in cerebral vessels and neuritis (senile) plaques of people with Alzheimer disease and Down syndrome. Lancet 1:384-385.

114. Roberts GW (1988): Immunochemistry of neurafibrillary 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 an chromosome 21. Science 235:885-890.

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 Lett 62:267-270.

119. Shane B, Stokstad EL (1985); Vit. B 12-folate interrelationships, Annu Rev Nutr 5:115-141.

120. Sinet PM, Allard D, Lejeune J, Jerome H (1974): Augmentation d'activité de la superoxyde dismutase erythrocytaire dans la trisomie pour le chromosome 21. CR Acad Sci (Paris) 278 D:3267-3270.

121. Sinet PM, Lejeune J, Jerome H (19?9); Trisomy 21 (Down's syndrome) glutathione peroxydase, hexose monophosphate shunt and IQ. Life Sci 24:29-34.

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): Hamocystinuria. Acta Paediatr Scand [Suppl] 321.

124. Smith RM, Patel AJ, Kingsbury AE (1980): Effect ox thyroid state an brain development: ß adrenergic receptors and 5'nucleotidase activity. Brain Res 198:375-387.

125. Synder LM, Reddy WJ (1970): The effect of 3, 5, 3'-tri- on red cell 2,3-diphosphoglyceric acid. Clin Res 18:416.

126. Snyder LM, Reddy WJ (1970): Mechanism of action of thyroid hormone an erythrocyte 2.3-diphosphoglyceric acid synthesis. J Clin Invest 49:1993-1998.

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. Am J Ment Deric 62:642.

128. Stewart GR, Frederickson CJ, Howell GA, Gage FH (1984): Cholinergic denervation-induced increase of chelatable zinc in mossy-fiber region of the hppocampal formation. Brain Res 290:43-51.

129. Stocchi V, Magnani M, Cucchiarini L, Novelli G, Dallapiccola B (1985): Red blood cell adenine nucleotide abnormalities in Down syndrome. Am J Med Genet 20:131-135.

130. Tanzi RE, 5t George-Hyslop PH, Gusella JF (198?): 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, Gusella JF, Watkin S, Bruns GAP, St George-Hyslop PC, van Keuren ML, Patterson D, Pagan S, Kurnit DM, Neve RL (1987): Amyloid P 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 glycalysis 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 nova purine synthesis and purine salvage in a cultured mouse T-cell lymphoma mutant partially deficient in adenylosuccinate synthetase J Cell Physiol 99:139-152.

134. Umesono K, Giguere V, Glass DK, Rosenfeld MG, Evens RM (19881: Retinoic acid and thyroid hormone induce gene expression through a common responsive element. Nature 336:261-265.

135. Vernon RG, Finley E, Taylor E (1983): Adenosine and the control of lipolysis in rat adipocytes during pregnancy and lactation, Biochem J 216:121-128.

136. Weirs JH, Koh JY, Christine CH, Choi DW (1989): Zinc and LTP. Nature 338:212.

137. Whitson JS, Selkoe DJ, Cotman CW (1989). Amyloid ß protein enhances the survival of hippocampal neurons in vitro. Science 243:1488-1490.

138. Williams M (198?): Purina receptors in mammalian tissues: pharmacology and functional significance. Annu Rev Pharmacol Toxicol 27:315-345.

139. Wong EHA, Ooi S0, Loten EG, Sneyd JGT (19$5): The action of adenosine in insulin on the low-km cyclic AMP phasphadiesterase of rat adipocytes. Biochem J 227:815-821.

140. Zabrecky JR, Cole RD (1982): Binding of ATP to tubulin. Nature 296:775-776.

141. Zimmer DB, van Eldik LJ (1986): Identification of a molecular target far 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 5-100 protein) during human foetal development. J Neurochem 17:247-251.