Reflexions in Human intelligence

Le Caire


Sommaire

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 way.

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 itself.

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 them !

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.

Haut

I - The sensibility of the iris of 21-trisomics children

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 (1969).

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. 1976).

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 frequent constipation.

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.

Haut

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 ß-hydroxylation).

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).

Haut

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 disparate findings.

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 creases.

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 diphospho-glyceromutase.

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.

Haut

Fig. 1

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.


Haut

Bibliographie

BERG, J. M., BRANDON, M. W. G, and KIRMAN, B. H. 1959. Atropine in mongolism. - Lancet (2): 441

BOURDAIS, M. 1973. Contribution à l'étude de la sensibilité pharmacologique de l'iris des enfants trisomiques 21. Thesis. Paris

CLOPATH, P., SMITH, V. C, and McCULLY, K. S.1976. Growth promotion by homocysteic acid. - Science 192: 372-374

COLEMAN, M., CAMPBELL, M., FREEDMAN, L. S., ROFFMAN, M., EBSTEIN, R. P. and GOLDSTEIN, M.1974. Serum dopamine ß hydroxylase levels in Down's syndrome. - Clin. Genet. 5: 312-315

HARRIS, W. S. and GOLDMAN, R. M. 1968. Hyperactivity to atropine in Down's syndrome. New Engl. J. Med, 279: 407-410.

Jérôme, H.1962. Anomalies du métabolisme du tryptophane daps la maladie mongolienne. Bull. Mem. Soc. Med. Hop. Paris 113:168-172

JÉRÔME, H. and KAMOUN, P.1969. Defaut do captation de la noradrenaline par les plaquettes sanguines de sujets triso-miques 21. Demonstration d'un mécanisme commun pour la noradrenaline et la serotonine. C. R. Acad. Sci. (Paris) 269: 516-519

JERVIS , G .A. 1970 Premature senility in Down's syndrome - Ann. New-York Acad. Sci 171, 559-561

KUCERA, J. 1969. Age at wolking, at eruption of deciduous teeth and response to ephedrine in children with Down's syndrome. - J. Mental Deficiency Res. 13:143-148

LEJEUNE, J. 1963. Autosomal disorders. Pediatrics 32: 326-337

LEJEUNE, J. 1975. Réflexions sur la débilité de l'intelligence des enfants trisomiques 21. Pont. Acad. Sci. Rome, Commentarii III (9): 1-12

LEJEUNE, J., BOURDAIS, M. and PRIEUR, M. 1976. Sensibilité pharmacologique de l'iris des enfants trisomiques 21. -Thérapie (in press)

MIR, G. H. and GUMMING, G.R. 1971. Response to atropine in Down's syndrome. Arch. Disease Childhood 46: 61-65

O'BRIEN, D., HAAKE, N. W. and BRAID, B. 1960. Atropine sensitivity and serotonin in mongolism. - J. Disease Childhood 100: 873

PRIEST, J.H. 1960. Atropine response of eyes in mongolism. - J. Disease Childhood 100: 869-872

PRISCU, R. and SICHITIU, S. 1975. Types of enzymatic overdosing in trisomy 21: Erythrocytic superoxide dismutase-AJ and phosphoglucomutase. Humangenetik 29: 79-83

RETHORÉ, M.O., KAPLAN, J.C., JUNIEN, C., CRUVEILLIER, J., DUTRILLAUX, B., AURIAS, A., CARPENTIER, S., LAFOURCADE, J. and LEJEUNE, J. 1975. Augmentation de l'activité de la LDH-B chez un garçon trisomique 12p par malségrégation d'une translocation maternelle t(12;14)(q12;p11). Ann. Génét, l8: 81-87

RETHORÉ, M.O., JUNIEN, C., MALPUECH. G., BACCICHETTI, C., TENCONI. R., KAPLAN, J.C., ROMEUF, J. DE and LEJEUNE, J. 1976. Localisation du gène de la glycéraldéhyde 3-phosphate déshydrogénase (G3PD) Sur le segment distal du bras court du chromosome 12. -Ann. Génét. 19 : 140-142

SCULLIN, D. C., SMITH, W. S. and HARRIS, W. S. 1969. Hyperreactivity to tropicamide in trisomy 21. Am. Sot. Clin. Pharmacol. Chem., Atlantic City, N. J.

SINET, P.-M. 1972. Contribution à l'analyse statistique des résultats de dosages d'acides amines sanguins. - Thesis, Paris

SINET, P.M., ALLARD, D., LEJEUNE, J. and JÉRÔME, H.1974. Augmentation d'activité de la superoxyde dismutase erythro-cytaire dans la trisomie pour le chromosome 21. C. R. Acad. Sci (Paris) 278: 3267-3270

SINET, P.M., LAVELLER, F., MICHELSON, A. M. and JÉRÔME, H. 1975. Superoxyde dismutase activities of blood platelets in trisomy 21. -Biochem. Biophys. Res. Commun. 67: 904-909

SINET, P.M., COUTURIER, J., DUTRILLAUX, B., POISSONNIER, N., RAOUL, O., RETHORÉ, M.O., ALLARD, D., LEJEUNE, J. and JÉRÔME, H. 1976a. Trisomie 21 et superoxyde dismutase-1 (IPO-A). Tentative de localisation sur la sous bande 21q22.1 . Exp. Cell Res. 97: 47-55

SINET, P.M., MICHELSON, A. M., BAZIN, A., LEJEUNE, J. and JÉRÔME, H. 1976b. Increase of glutathion peroxydase activity in erythrocytes from trisomy 21 subjects. Biochem. Biophys. Res. Commun, 67: 914-915

TAN, Y. H., SCHNEIDER, E. L., TIECHFIELD, J., EPSTEIN,, C. J. and RUDDLE, F. H. 1974. Human chromosome 21 dosage effect on the interferon induced antiviral state. Science 186: 61-63

TURNER, P. 1974. Etude du mode d'action des substances médicamenteuses à l'examen ophtalmologique. Triangle 10:13-19

WETTERBERG, L., GUSTAVSON, K.-H., BÄCKSTRÖM. M., Ross, S. B. and FRÖDEN, Ö. 1972. Low dopamine-ß-hydraxylase activity in Down's syndrome. Clin. Genet. 3:152-153