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.
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
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 hypothesis.
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
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
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.
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
Fig. 1. Localisation of SOD-1 on chromosome 21
(after LEJEUNE 1975).
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
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
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
Fig. 3. - Localisation of G3PD (GAPD) and LDH-B on the short arm of
chromosome 12 (after RETHORÉ 1976).
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