The most obvious therapy of a trisomic condition would be to silence
the extra chromosome  so that only a diploid amount of genetic information
would remain active. Indeed nature is that shrewd and inactivation of
supernumerary X chromosomes is a very efficient trick. Unfortunately the basic
mechanism is still unknown, although the recent use of anti-sense RNA gives
already the possibility of silencing some specific sequences .
Pending the "tour de force" of inhibiting in every cell one chromosome
21 among the three present in Down's Syndrome affected children, this elegant
way of getting rid of an undesirable genie overdose is, for the moment, out of
reach. Hence the tedious and laborious comparison of the clinical data and of
the DNA deciphering is, currently, the starting point of any pathogenic
The molecular biology approach
By digesting, transferring, cloning, hybridizing and blotting various
stretches of DNA (or RNA) sequences, the contents of chromosome 21 can be
progressively analyzed. Optimists consider that the total sequence of the 21
could possibly be unraveled in some 5 to 10 years. With the increasing
automation of all the steps involved, this optimistic view could very well turn
out to be a quite realistic one. But spelling out every base of the DNA
sequences of chromosome 21 is not the final answer. Remains to understand the
properties of the proteins coded, the functions of the enzymes and the complex
activity of other stretches: activators, repressers, enhancers etc... etc. Time
prophecies are quite dangerous in front of such an enormous task.
Clinical chemistry and mental retardation
Awaiting the expected results of DNA exploration, another way of
investigation can be opened by the apparently very naive question: "Why are
trisomic 21 children mentally retarded?" Or, in more operational terms, "How
could a genie overdose hamper the functionning of their brain?".
We know for sure that the genie information carried by the extra
chromosome is normal (as demonstrated by the trans-location cases). Then we are
forced to look for some metabolisms in which a shift of the equilibrium between
the specific speeds of biochemical reactions could be, per se, deleterious.
In 1979, a trouble of monocarbon's metabolism was presented as the
possible sensitive target in mental retardation .
This proposal  did not raise discussions after it was applied to
21 trisomy in the Down's.
The monocarbon's hypothesis
A schematic drawing (fig. 1) reveals the complexity of the
Fig. 1. Genetic diseases and specific
biochemical abnormalities related to severe neurological and/or mental
deficiencies. Legends of fig. 1: see annexe.
From the raw material like FIGLU, DOVA, etc, (see 1 to 7 columns of
precursors) monocarbons are transferred to tetra-hydrofolate (8 to 11 column at
left) and part of them, the oxidized forms, are directly injected in the purine
synthesis (third column, 14 to 19).
At both ends, the monocarbons, at the reduced levels, are used to
synthesize thymidine (12) or to remethylate homo-cysteine into methionine via
5-methyl THF and B12 (23, 24, 25).
In the middle of the scheme, the enzymatic machinery handling the
tetrahydrofolate derivatives, in close connexion with the one related to
biopterin metabolism looks like a maze or the blueprint of a quite intricate
For example 5-10 methylene THF reductase (20), normally reducing the
5-10 methylene THF to 5 methyl THF, can also reduce biopterine Bq2 to B4 (29),
. Dihydrofolate reductase (21), besides reducing DHF to THF, can also reduce
B2 into B4 [5, 6]. Folic acid is a vitamin which must be found in the diet.
Biopterin (14, 28), on the contrary, is synthesised in our cells from GTP.
Chemically the pteridine moiety is identical and those two molecules differ
only by their lateral chain. In vitro, "THF" can replace B4 as cofactor of
The cooperation  between the enzymes specific of each system
cannot be taken as a mere coincidence. If such a built in salvage system
exists, it shows how absolutely vital are the processes involved. Exactly as in
rocket technology engineers double some very important parts, so that one could
take over if the other fails, here nature seems to have realized the most
fool-proof system possible.
All these safety measures explain maybe why mental retardation exists
at all. If no supplementation existed, every break-down would produce complete
neurological disaster, hence prevent any survival at all. On the contrary,
thanks to the emergency measures, if one entry is blocked, some deleterious
effect will result but sufficiently compensated so that only a diminution of
the performances (and not a complete breakdown) would ensue.
Although the diseases enumerated in the legend of the figure 1 affect
very different chapters of biochemistry their common effect is a severe trouble
of monocarbon metabolism:
- By a diminished input of raw material, left column 1 to 7,
- or an imperfect transformation, 8 to 12,
- or an excessive consummation, 15 to 19,
- or a trouble in the complex pteridine regulating system, 14, 22, 28,
- and its consequences even very remote, 37 to 42,
- or a shortage of reduced monocarbons, 23 to 27, and finally a lack
of definite products 30 to 36.
The neurological approach
Indeed the fact that the vast majority of diseases producing mental
retardation could be located on this diagram can hardly be accounted for by
mere chance. But neuro anatomy tells us that the very structure of the brain
explains this accumulation of catastrophes.
In order to build the eleven thousand millions of neurons of our
brain, and to insulate with myeline the enormous wiring of the axones and
dendrites (the length of which could extend from Paris to Mexico), an enormous
production of monocarbons is necessary for the coded molecules (nucleic acids)
as well as for various methylations. Moreover the production at the right
place, right moment, and right amount of the security keys which open or shut
the connexions, the synapses between neurons, necessitates also a full
efficiency of the folic-biopterin systems.
If an experimental proof of these considerations is needed, it
suffices to remember that antifolic drugs can produce incomplete closure of the
nervous system  and folic acid during pregnancy can very effectively
protect the children against these terrible diseases, spina bifida,
anencephalia etc... [7, 8, 9]. The same is true with atresias of the digestive
Remains a last term, not figured out in this scheme. Any
logic-mimicking device invented by us requires the components (neurones), the
insulation (the myeline), the efficiency of the gates (the yes or no of the
synapses) but also an extremely refined wiring.
Inside the axones and the dendrites there exists a fantastically
orderly network of very fine tubes, the neurotubules. They are considered by
many authors as the real wiring of our brain. A network of a tremendous length.
If put end to end all these neurotubules would go from here to the moon (and
hopefully, back). Whether the constitution of the neurotubule network is
directly affected by monocarbon metabolism is, for the moment, unknown. At
least it is well established that this network is typically disturbed in
Alzheimer  dementia and in a regressive Alzheimer-like syndrome so frequent
in trisomic 21 patients. Also, the maturation of the neurotubule network is
under control of thyroid metabolism , and deficiency of neurotubule network
seems to be the cause of the mental retardation of untreated cretins 
(athyreose or severe iodin deficiency). This role of neurotubules could
possibly explain why neurones do not regenerate. The spindles of the mitotic
apparatus and the neurotubules are made of the same building stones: the
tubuline. Hence a cell has to choose definitely, either to keep assembling and
disassembling tubuline for the mitotic machinery or to mount tubuline
conservatively into an inner informative circuitry.
Clinical chemistry of trisomy 21
Uric Acid Excess and Purine Synthesis 17, 18,
The oldest known chemical trouble in trisomy 21 is possibly their
slight excess of production and of excretion of uric acid [13, 14, 15].
This increased production of purine necessitates an over consumption
of phospho-ribosyl and the first steps of its synthesis (shunt of hexose
monophosphate) is accelerated in Down's syndrome .
The genes controlling the third (PRGS) the fourth (PRGFT) and the
sixth (PRAIS) steps of the purine synthesis are on chromosome 21 [17,18] and
explain this over-production of purines, finally excreted as urate.
The Lesch Nyhan Complication 15
Rarely very retarded trisomic 21 children, exhibit an irritable
behaviour with autoaggressivity (beating their fingers, hurting their head)
reminiscent of the automutilations in Lesch Nyhan syndrome .
In this terrible sex-linked disease, purines are spilling over
because the salvage pathway (HGPRT) is deficient. The resulting
over-consumption of monocarbons is probably the cause of the neurological
The Homocystinuria Contertype 26, 27
If the enzyme cystathionine beta synthase does not function,
homocysteine accumulates and is excreted as homocystine. The children affected
by this disease are mentally retarded, have livedo reticularis (like trisomic
21) but are tall, slender, with long tapered fingers with some extra flexion
creases. On the contrary trisomic 21 are of short stature have short fingers
and frequently lack some flexion creases.
On this type-countertype effect, the hypothesis of a trouble of this
reaction was put forward in 1975  and demonstrated in 1984 . In
homocystinuria, excess of homocysteine blocks by competition the S-adenosyl
methionine-methyltransferase. On the contrary in trisomy 21 the overburning of
homocysteine impairs its remethylation in methionine, hence diminishing also
the efficiency of the S-adenosylmethionine methyl transferases. Hence in both
cases a deficiency of the various products of methylation.
It must be remarked that in trisomy 21 the furniture of
5-methyltetrahydrofolate is also impaired by the spilling over of monocarbons
in the purine overproduction. Hence the deficit in cholinergic efficiency 
and methylation of nicoti-namide , also noted in depressive illness
Super oxide Dismutase Excess 3, 4
The metabolism of oxygen is impaired in trisomy 21. The enzyme
superoxyde dismutase  is too active, so that too much of the 0-2 superoxide
ion is destroyed and too much hydrogen peroxide H2O2 is produced. This toxic
H2O2 is eliminated by glutathion peroxydase, the activity of which is increased
in trisomy 21 .
Whether the diminution of the superoxide ion concentration could
affect the tryptophane and 5 OH tryptophane indolamine oxydase or the synthesis
of serotonine and 5HIAA via the biopterine system, or the synthesis of
thyronine from tyrosine is presently unknown but may be worthy of
Hypothyroidy and Down's Syndrome 10, 20,
The association between the two diseases has been discussed for a
long time and Bourneville was the first in 1904 to treat a recognized
hypothyroidy in a trisomic 21 patient .
Since that time the discussion went over and Benda concluded from a
series of autopsies that there was "exhaustion" of the thyroid among these
Unfortunetly the recognition of the chromosomal basis of the disease
slowed down the impetus of research in this field. Many reports quoted that
hypothyroidy and to a less degree hyperthyroidy were too frequent in the
disease [26, 27, 28] but Samuels et al. were the first to demonstrate in 1971
an excess of thyreostimuline hormone (TSH), soon confirmed by various authors
The excellent work of Pueschel and Pezzullo 1985  and the
experimental data of Ozand et al. (1987)  confirmed formally the frequency
of an elevated TSH and, seemingly a relative inefficiency ot T4 in Down's
syndrome cells. Ozand even postulated some deficit of deiodination
Independently we have systematically investigated thyroid function
of our patients in Paris and found a highly significant elevation of TSH. On 52
patients the mean value is 4,59 ± 2,28, compared to 1,80 ± 0,87 in 51
controls (t = 8 for 101 d.f.).
Experimental work has shown an important effect of thyroxin upon the
level of some enzyme activities. Thyroxine increases the 10-formyl THF synthase
(9) and the 5-10 methylene THF reductase (20) thus increasing the input of
oxydized monocarbons and the availability of reduced ones, 5-methyl THF, [32,
33, 34]. It also reduces the activity of 10-formyl dehydrogenase and diminishes
the overflow (10), of CHO in CO2  and diminishes the destruction of
cystathionine and cysteine by cystathlonase (soluble cysteine desulphydrase)
All these effects favour the de novo synthesis of methionine hence
favouring the methylation process. On the contrary, high doses of methionine
diminish the 10 formyl THF synthase and directly excite the enzymatic
efficiency of 10 formyi dehydrogenase . These two regulations diminish the
input of oxydized monocarbons.
Whether a fine tuning of TSH secretion and of T4 production by
methionine and homocysteine levels exists is not known. But if it did, then the
excess of cystathionine beta synthase should produce the elevated TSH and
subnormal T4 of trisomic 21 patients. Also a possible regulatory role of
reverse Ts, interfering with some enzymes of the folate pathway seems worthy of
Sensitivity to Methotrexate 22
As discovered by Peeters et col. in 1985, trisomic 21 children, when
affected by leukemia, cannot suffer normal doses of methotrexate. This
inhibition of dihydrofolate reductase causes toxicity at half of the dose
tolerated by nontrisomic leukemic children . We confirmed (Lejeune et al.,
1986) on lymphocyte cultures that trisomic 21 are twice as sensitive as their
normal sibs to mitotic index inhibition by methotrexate .
This sensitivity, now amply confirmed , must be compared to the
production of encephalopathies in non-Down's Syndrome leukemics treated by
Using it as a tool it becomes feasible to test various additives to
see if some substances can bring trisomic 21 cells back to a normal
sensitivity. With Marie Peeters we are presently exploring the possible effects
of various effectors and inhibitors. We already know  that methionine and
homocysteine do not prevent the methotrexate toxicity.
The Heuristic Prospect
The present model of the pathogenesis of mental retardation in
Down's syndrome is rather simple but encompasses most of what is known today.
To summarize it briefly: There is a leakage of oxydized monocarbons due to the
excess of purine production. Another leakage of reduced monocarbons corresponds
to the increased turnover of cystathionine beta synthase  and is possibly
related to difficulties of thyroid regulation. A slight deficit could also be
related to the effect of superoxyde dismutase upon dioxygenases or various
hydroxylases and reductases.
This would be in accordance with the serum level of
dihydrobiopterin, higher in Down's syndrome  and lower in non-specific
mental retardation in males .
Remains the association of Down's Syndrome and Alzheimer. The gene
of familial Alzheimer's disease is possibly linked to chromosome 21  and
the gene controlling the precursor of amyloid substance is also in the 21 [42,
43). These facts could explain the relation between Alzheimer's disease and
Down's Syndrome. Just as well the abnormal development of the neurotubules in
the three related diseases: D.S., A.D. and hypothyroidy could point toward a
common mechanism of these diseases; a propos, comparable lesions can be
observed after head injuries [71, 72].
Medication trials with non toxic natural products interfering with
monocarbon's metabolism can be conducted. Some are in progress and few
In case of severe regression pointing toward an Alzheimer-like
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