Amongst the deleterious phenotypic effects resulting from genetic
disasters, from point mutation to chromosomal mistakes, one is the most
dramatic, the debility of intelligence. This is the most typically human
disease because only humans can suffer of it and also the most inhumane, for it
prevents the patients of sharing their full part of mankind's patrimony, the
blossoming of the thought.
To try to understand what is hampering the intelligence of genetically
affected people, we can possibly first ask ourselves wether the intellect is
really imprinted in this accretion of matter, we call the human body.
A very typical example of the power of the intellect is the field of
geometry, the purest or at least the most abstract of all sciences.
It is generally believed that geometry was invented by old Egyptians
and such a statement seems very plausible.
In years long past, before the Asswan reservoir was built, there was
every year a great flood of the Nile. After the Withdrowal of the waters the
land was very leveled off indeed. Hence what more natural than to sow few
pyramids on that flat plane !
Although I do not object to the ingeniosity of ancien Egyptians as a
geneticist, I do not guess that geometric knowledge really started that
Let me propose you another origin, which is perfectly undemonstrable,
buts as remarked a french philosopher : "the most true stories are not always
those which have happened".
As every-body knows lovers spend long hours (too short nevertheless)
looking at each other eyes. This is so true that quite all human languages have
the same definition of the circular opening of the iris, this dark little
window though which we observe the world. In french as in english they call it
"la pupille" "the pupilla", which means in Latin the little girl. Spanish would
say "la nine del ojo". Greeks would call it "chorea" ; Iranians : "Mardomak" ;
Arabians: "Insan el Ein" ; Vietnamese : "Ngu oï" and Japanese "Hito me".
The reason of this universality is obvious, when you look very close
to the eye of your beloved you see your own image reflected by the convex
mirror of her cornea and this tiny puppet is the most luminous against the dark
back-ground of the iris opening.
I would be inclined to suppose that women discovered first this
interesting optical property ; hence most of languages using the term of
"little girl". (and not "little boy").
The postulate we have to make now is that one day a would-be geometer
fall in love (such things can happen, even to mathematically minded people) and
he discovered geometry.
The cornea is a segment of sphere, intersecting another sphere of
greater radius, the ocular globe.
Such intersection is thus a circle. On this circle is anchored the
radial muscle of the iris (the dilator pupillae) and its fibers are stretched
by the constriction of the orbicular muscle which delineate the pupilla
Hence, under the sun of Egypt, the cholinergic orbicular muscle was
quite closing the pupilla so that the inventor of geometry, observed
experimentally the only perfect plane existing in this world, a surface
anchored on a circle and defining the shortest possible distance between any
two points of its fibers.
Euclide in a glimpse of love, how it would be comforting for school
boys to learn that ! (A friend of mine recently told me that modern geometers
do define the plane from the tensorial calculus !).
We can go deeper, but it took few millenaries before DESCARTES
achieved it. If you gently press your closed lids in a rather dark room, you
will suddenly see a kind of chessboard made of tiny cells alternatingly dark
purple and shiny golded, defining exactly the so-called cartesian coordinates,
imprinted in the network of the retina long before any man was there to notice
DESCARTES discovered it because he was doubting and doubt prompt you
to rub your lids to see if you have well seen. Hence the analytical geometry
that everybody uses intuitively and only algebrists are talking about.
We know still more nowadays Neurology has lead us farther on the
visual pathways. From the little window through which light is entering, to the
obscure center which sees (in the calcarine region of the posterior part of the
brain), we can follow all the development of modern mathematics.
Projections, bijections, rings and ideals, fibrous spaces, matrices
and lattices, all the progeny of the ensemble theories were genetically there
only awaiting topologists took notice of them.
And this mirror of the soul, as the eye is generally called, reveals
immediatly to a human geneticist if the child he examines is intellectually
unfitted or mentally gifted.
The look of a child affected by trisomy 21, is typically atonic and
does not have this sparkling light that a normal child would show.
Here we can take advantage of the fact that the radial muscle of the
iris is adrenergic and the orbicular muscle, cholinergic. By installing in the
eye various drugs which can either stimulate or paralyse the adrenergic or the
cholinergic mechanism, the answer of the muscles can be observed by the opening
or the closing of the papilla.
I - The sensibility of the iris of 21-trisomics
The hypersensitivity of trisomic 21 to atropin has been noted
repeatedly (BERG et al, 1959; O'BRIEN et al. 1960 ; PRIEST 1960 ; HARRIS and
GOODMAN 1968 ; SCULLIN et al. 1969 ; MIR and CUMMING 1971 ; BOURDAIS 1973).
Also a somewhat paradoxical response to ephedrin was noted. by KUCERA
With Dr. Bourdais and Dr. Prieur we have systematically investigated
the pharmacological sensitivity of the autonomic system of trisomic 21
children. With its radial muscle (dilator pupillae) sensitive to noradrenalin,
and its orbicular muscle (constrictor pupillae) sensitive to acetyl choline,
the iris is best suited to studies of the adrenergic and the cholinergic
systems (TURNER 1970). Introduction into one eye of a drop of an agonist or an
antagonist drug allows the measurement by pupillometry of the intensity of the
reaction, the other eye of the subject serving as a control. All the
precautions and modalities are described in another paper (LEJEUNE et al.
Adrenergic sensitivity - Use of ephedrin, neosynephrin and adrenalin
showed no differences between trisomic 21 patients and their healthy sibs. All
adrenergic responses seemed to be normal.
Cholinergic sensitivity - As observed previously, hypersensitivity to
atropin was clearly demonstrated, but this hypersensitivity is found also with
eserine, which blocks acetylcholine esterase, and with pilocarpine, which is a
direct and indirect cholinomimetic.
Altogether these data indicate a constitutional deficiency of the
cholinergic activity in trisomic 21 children. An eventual excess of choline
esterase is not likely because it would probably lead to resistance to eserine
instead of hypersensitivity. Hence we are left with the alternative that either
trisomics 21 release acetylcholine less rapidly than normals or they have some
impairment in the manufacture of this chemical mediator.
A generalized hypocholinergy would fit in with many well-known
clinical features, such as imperfect accommodation, general hypotonia and
The lack of overtake by the adrenergic system may be due to regulation
mechanisms, The relatively low level of dopamine hydroxylase, found by
WETTERBERG et al. (1972) and by COLEMAN et al. (1974), could be in agreement,
with this hypothesise As discussed late the relative deficiency of Dopamine -
ß-hydroxylase could also be related to the oxygen troubles.
II - THE GENE DOSAGE EFFECT
With the gene dosage effect of autosomal imbalance (monosomy or
trisomy) no abnormality of enzymes is expected, for the genetic message is
normal, but excess or diminution of their turnover is expected. At the most
simple an enzymatic activity of 0.5 in monosomy and 1.5 in trisomy is expected
compared to normal level (LEJEUNE 1963) and has been discovered for superoxide
dismutase-1 (SOD-1) in trisomy 21 (SINET et al. 1974) and for lactate
dehydrogenase-ß (LDH-B) in trisomy 12p (RÉTHORÉ et al. 1975).
It is rather surprising that the enzymatic activity determined by gene
dose should follow such a simple arithmetics, but the experiments seems to
warrant this elementary calculation.
After TAN et al (1973) had published the localisation of the gene for
superoxide dismutase (called at that time indophenol oxidase) on chromosome 21,
SINET et al. (1974, 1975) and PRISCU and SICHITIU (1975) demonstrated that the
activity of superoxide dismutase-1 (SOD-1) was 1.5 in trisomics 21, as compared
to 1.0 in normals. Later on, this has been widely confirmed.
A careful analysis of different familial translocations involving
chromosome 21 allowed us to compare children monosomic or trisomic for various
segments of the 21 (SINET et al. 1976a).
The typical phenotype of trisomy 21 is found only when band q22.1 is
in triplicate. Excess of SOD-1 activity is also found when this band is in
excess. In one case of trisomy for the q21 segment alone, that is the half of
the long arm close to the centromere, no morphological syndrome and no SOD-1
excess was found. Thus, the localisation in the q22,1 zone of SOD-1 and of the
genes responsible for the typical phenotype can be accepted rather firmly.
Investigations of glutathion peroxidase, which disposes of the H2O2
produced by SOD-1, showed also an excess of this substance in trisomics 21
(SINET et al, 1976b). The localisation of the gene is still to be investigated,
since a regulation mechanism could possibly have blurred the conclusions.
For the moment there is no direct information on the eventual effect
of the SOD-1 excess on the mental retardation. There is an impression that
SOD-1 and glutathion peroxidase levels are better correlated in trisomics 21
that are rather well developed than in the severly handicapped children.
A double possibility must be envisaged here. On the one hand the
excess of SOD-1 could deplete the cytoplasm in O2 and thus diminish many
oxydation process like hydroxylations (including, dopamine
On the other hand, the excess of H2O2 produced by SOD-1, could be
deleterious and produce oxydation of the fatty acids in membranes. An ageing
process could follow, and could be related eventually to the very frequent
Alzheimer like disease observed in trisomic 21 (JERVIS 1970).
III - A GENERAL BIOCHEMICAL VIEW
The oxygen trouble is not the only one detected in trisomy 21 (see
LEJEUNE 1975, for discussion). For example, many steps related to the
Glycolytic pathway seem to be slightly accelerated (phosphoglucomutase,
glucose-6phosphate dehydrogenase, hexokinase, gluconate dehydrogenase,
phosphofructokinase, enolase), and a partial instability of the glycemia with
abnormal response to insulin and adrenalin has been quoted.
An excessive use of some amino acids to feed the bicarboxylic cycle
seems possible, and is compatible with the slight excess of urea, of NH4 and of
glutamic acid in the blood of 21 trisomic children.
The amino acid level in the serum shows an excess of ethanolamine and
a diminution of serine (SINET 1972) ; trouble with the tryptophan metabolites
has been found repeatedly (JEROME 1962, 1969).
A first sight it seems very difficult to fit together so many
A possible way out would be to build a semi-pascalian machine in wich
axes and gears could represent the complex interaction of the chemical pathways
wich are at work in nervous cells. (Fig. 1)
In this "artistic view", if I can say so, are figured a few of the
enzymatic reactions described in text books.
Can the top of the machine are the chemical mediators released at
nerve endings. At left are the various components of insulating sheets of the
nerve fibers and at right the mucopetides used in the membranes.
In the middle the energy producing Krebs cycle and all the feeding and
regulating systems around it.
The dots represent the genetic blocks already known to produce
diseases affecting the nervous system. Two clusters are obvious, one around the
insulating substances, the other around the components of the membranes. This
is not a surprise because correct insulating of the circuitry and efficient
membranes components are obvious perequisites of the brain fonctions.
The other dots seems to be much more scattered in the machine, but
most of them can be shown to have an effect on the regulating system, mainly
the Tetrahydrofolate metabolism and its chemical connexions.
For example, if we compare clinically homocystinuria and trisomy 21,
we find these conditions to be quite antithetical. Homocystinurics (lacking
cystathionine synthetase) are slim and have long fingers with extra flexion
Trisomics 21, with their low serine level and excess of ethanolanine
and hypocholinergy, are small, have short fingers and lack some of the flexion
creases. The nose of homocystinurics is well developed that of trisomic 21 is
hypoplastic. If we consider the role of homocysteine on the growth of the bone
cartilage (CLOPATH et al. 1976), this could be an example of countertype,
chemically and clinically (LEJEUNE 1975).
If we now focus on the bottom plane, we will find two other mental
deficiences with flat nose, apparently totally unrelated, one is thyroid
deficiency, the other being trisomy for the short arm of chromosome 12. As
described by RÉTHORÉ et al. (1975), these children are short, hypotonic, with
flat nose and short neck and often with only one palmar crease. The
differential diagnosis is essentially with trisomy 21. By comparison of cases
involving trisomy and monosomy of various segments of the short arm of
chromosome 12, RÉTHORÉ et al. (1976) were able to locate the one for lactate
dehydrogenase-B (LDH-B) in the segment between zones 12.2 and 12.1, the gene
for glyceraldehyde-3-phosphate dehydrogenase (GAPD) being located in the end
segment beyond the band 12.2. Recent studies have else located the gene for
triosephosphate isomerase (TPI) in the same terminal segment. The actual order
of the GAPD. and TPI loci is not yet ascertained. Curiously, the two main
biochemical effects of thyroxine on the glycolysis process are very close.
Thyroxine increases the conversion of dihydroxi acetone to
glyceraldehyde-3-phosphate (GAPD) and diminishes the
It seems difficult to consider as purely, fortuitous the fact that
three mental deficiences, correlated with short nose, short stature and
adiposity, and clinically sometimes very similar are related to chemical change
relatively so close to each othe on the machine.
It is much to early to propose a general heuristic scheme from. these
general considerations, but the feeling emerge that mental deficiency in isomy
21 could be related to biochemical imbalances, comparable to those already
known in point mutation diseases.
Following this comparison between chemical troubles and phenotypic
stigmata it can be hoped that some pathways will be discovered, the
acceleration of whose could produce the clinical picture.
If thus detected by the logic of the chemical machinery, the
metabolic shifts could be tested one by ones the insuperable difficulty
actually encountered being not the technicalties of the research, but the very
lack of indication of where we should look for.
Such a prospect is still very uncertain but a start has to be made if
we want to be able some day to help these children who having recieved a super
fluous chromosome are, paradoxically, among the most desinherited of the
children of men.
A pseudo pascalian machine representing the chemical pathways and
some of their interconnexions.
The stars are located at enzymatic blocks already recorded in
genetic diseases affecting the intellectual fonction.
The arrows point to some enzymatic reactions quoted in the text.
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