On the mechanism of mental deficiency in chromosomal diseases

Jérome LEJEUNE

LEJEUNE, J.1977. On the mechanism of mental deficiency in chromosomal diseases. - Hereditas 86: 9-14. Lund, Sweden. ISSN 0018-0661. Received February 10, 1977

Résumé :

• 1. Pharmacological approach


• 2. Systematic biochemical investigations


• 3. Gene mapping


• 4. Heuristic approach


• Annexes

Mental retardation is the main symptom of chromosomal diseases, and the most elusive one.

The fact that autosomal trisomies and monosomies always induce intellectual deficiency does not imply that "intelligence genes" are randomly scattered over the whole karyotype. More likely it means that nothing like "intelligence genes" does exist but that human intelligence, being the top performance of our genetic make-up, needs the concourse of an enormous array of morphological and chemical functions highly integrated.

In the case of gene mutation the situation is relatively simple: the malfunction results from the blockade of one enzymatic step (see BRADY 1976; and for review, ROSENBERG 1976). But even here, the precise knowledge of the chemical trouble, as in phenylketonuria (PKU), does not give a clear-cut explanation of the mechanism of the mental impairment.

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-B (LDH-B) in trisomy 12p (RETHORÉ et al.1975).

But this change in the dynamics of chemical reaction is likely to affect a great number of steps, because the segments involved in cytogenetically recognizable diseases contain some 100 or 1000 genes. Hence we need to devise a heuristic approach in order to decide what to look for. Three ways are open - one is clinical investigation of the affected persons, a second is systematic biochemical investigations, and a third is gene mapping.

The most fruitful approach would be to link together, if at all possible, these apparently disparate facts. In trying to do so we will limit ourselves to very few examples, mainly trisomy 21.

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1. Pharmacological approach

Besides careful description of morphological symptoms, detection of pharmacological trouble could give some useful clues.

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 GUMMING 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 (dilatator 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 hypothesis.

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2. Systematic biochemical investigations

So much has been published on general investigations of the biochemistry in trisomy 21 that a full report is beyond the scope of this brief survey (for review, see BENDA 1960; PENROSE and SMITH 1966). As a very general summary the following points may be mentioned (see LEJEUNE 1975, for discussion).

Many steps related to the glycolytic process seem to be slightly accelerated (phosphoglucomutase, glucose-6-phosphate 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 NH, 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 (JÉRÔME 1962, 1969).

These disparate findings hardly fit together but, as we shall see, some of there play be related to each other.

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3. Gene mapping

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). As summarized in Fig. 1, 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. 19766). 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 those that are very severely handicapped mentally.

Fig. 1. Localisation of SOD-1 on chromosome 21 (after LEJEUNE 1975).

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4. Heuristic approach

At this stage it may be of interest to return to a general view of the biochemical make-up of the energy system used in the neurons. Fig. 2 is an artist's view (so to speak) of the dynamics of the machinery.

The manufacture (at top left) of both adrenergic and cholinergic mediators is tightly correlated with methylation mechanisms (at the top, the S-adenosyl/homocysteine/methionine cycle) which must be fed by the hydroxy-methyl transferase system (plane below, centered on serin). On the plane underneath, the Krebs cycle, pyruvate and acetyl CoA systems are linked, more or less directly to the sulphate cycle by the cystathionine reaction, which disposes of the homocysteine resulting from transmethylation (top plane). Finally, on the bottom plane, the energy producing glycolysis from fructose 1-6-diphosphate to pyruvate is shown.

The main interest of this dynamic oversimplification is to show how intricate the equilibrium must be, to make the machine run smoothly and respond immediately to any demand.

Many known disturbances of the neural system can be localised in this scheme, but we shall focus only on very few of them. 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 RETHORÉ 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, RETHORÉ et al. (1976) were able to locate the gene 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 also located the gene for triosephosphate isomerase (TPI) in the sane terminal segment. The actual order of the GAPD and TPI loci is not yet ascertained (Fig. 3). 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

enzymatic changes so close to each other. Many more investigations are needed, before any model can be proposed to give a reason for these convergences. It seems that only when clinical symptoms, gene mapping and biochemical disturbances are correlated, the first possibility of understanding the mechanism of mental deficiency will really be open. From this stage, when reached, the next one will be to try to palliate the ill effects of genic overdosage, either by turning off the extra chromosome by some kind of induced inactivation (like the lyonisation of supernumerary X chromosomes) or by substitution therapy capable of shifting the important metabolites back into normal level. Both eventualities may sound quite futurist to us today, but if the children are to be helped, the task has to be undertaken.

Fig. 2. - A simplified scheme of the chemical machinery for adrenergic and cholinergic mediators.

Fig. 3. - Localisation of G3PD (GAPD) and LDH-B on the short arm of chromosome 12 (after RETHORÉ 1976).

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