Chromosomal abnormalities in human beings have the trist privilege of
pruducing not only somatic disturbancies, but also severe mental damage.
The accumulation of data on many different syndromes permits a general
discussion on the mechanisme by wich such effects do occur.
In classical, mendelian, human genetics, most of the disease were
thought of in term of gene mutation, very correctly indeed. This means that any
change in the chimical formula in the DNA, i.e. a genic mutation, is reflected
by a correlative change in the formula of the protein controlled by this gene.
Secondarily the missprint in the protein changes its behaviour, leading thus to
an enzymatic abnormality exprimed in the individuality a fonctional or a
morphological defect, that is a constitutionnal disease.
Aside this concept of qualitative change, chromosomal pathology is
introducing another concept, the notion of genic dosage effect. As far as we
know, chromosomal errors do not indice any mistake in the genetic message
itself, and quasi experimental data are know at hand to demonstrate it. When a
chromosomal segment is in excess (trisomy) or at fault (monosomy), it is only
the quantity of the genetic message wich is changed, not its quality of
instead of having normally two examplar of "rules of life" trisomic
cells possess three of them and monosomic noly one. The reason why a change in
the amount of an otherwise normal information can lead to a disease will be the
subject of our discussion.
Excess of autosomal material
It is unfortunately too easy to show that excess of genetic material
The earliest reckognised chromosomal error, trisomy for chromosome
21, is a well known example of this fact. The disease throw a dysmorphic mask
over the personnal features of the child so that they look like each other in
stricking manner. The flat bridge of the nose, the slanting eyes, the
epicanthus underlining the internal comissure of the eyelids, the broad face
and the short neck are vaquely reminiscent of some of the normal features of
the yellow race.
Hence, the old name given to the disease.
The fact that the disease has nothing to do with any racial
connotation is demonstrated by its occurence in every human population and by
the fact that with aging all ressemblances with mongolian traits vanishes and
only the difformity persists.
Along with the other difformities the trisomy 21 can produce, a
curious "signature" of the disease is found in the prints of the fingers, the
hands and the feet.
The dermatoglyphic patterns of the hand with its mediopalmar axial
triradius, ulnar loop or the hypothenar region and transversal crease of the
palm, is an important symptom of the disease.
Trisomy 18, a condition too severe that most of child died before
six month of age, produce a very different morphological aspect, but also
present a rather stereotyped picture. The head is small, laterally retracted,
the mandibule is hypoplastic and the ears malformed and low set. many other
difformities can complete the picture, like cleft palate, pterygium colli,
small pelvis, club foot and scon, but the most evident trait is the particular
configuration of the hands, hel in the position of surrender. The second and
the fifth digits are incurved so that they cover respectively the 3° and 4°
digits. This quite pathognosonic difformity include, as in trisomy 21, a
particular dermatoglyphic structure. The distal flexion crease of the digits 2
to 5 is generally absent, and on the finger prints, the ridges are piled simply
on top of each other; the singlest figure possible, called arches.
Trisomy 13 is still more deleterious and the children die very
early. Their dismorphy includes always ocular anomaly, ranging from
microphtalmia to complete anophtamia. Microcephal, hare lip, cleft palate,
congenital heart disease are the rule. Super-numerary digits are present in
hands and feet and here, also, dermatoglyphs are abnormal; the axial triradius
is extremely distal and patterns in the thenar region are very complex.
Quite always the children suffer from aplasy of the rhinencephale
without olfactif lobes, even with typical cyclocephaly.
Their survival is extremely reduced and most of them die in neonatal
period or early infancy.
These three examples show us that excess of chromosomal material is
deleterious and roughly speaking the greater is the fragment in excess, the
more sever is the condition.
Also, two general conclusions can be drawn :
1) The excess of a given segment of the genome produce a specific
change of some characters, presumably controlled more or less directly by the
genes carried on this chromosomes. This implication is unavoidable to exp^lain
why a typical clinical picture is always associated with a particular
2) Among all the functions of the organism intelligence is always
affected. From other data pertaining to excess of other chromosomes it can be
safely stated, as an extremely general rule, that excess of autosomes always
results in reduced mental ability.
It would be extremely naive to conclude straight forwardly that
every autosome contains "intelligence genes".
more accurately it means that in an extremely complex and
coordinated system, any change in the construction is bound to reduce its top
To suppose that human intelligence is the top performance of living
systems could possibly seems too anthropomorphic statement but it just happens
to seems to be the case, as far as cytogenetics is concerned.
Sex chromosom imbalance
In human being the sexual dismorphism is easily detectable at the
chromosomal level, also - women possess two X chromosome and men on X and a
tiny Y. It is thus obvious that man possess less genetic material than woman,
and it can be anticipated that nature must have devised some regulatory
mechanism to compensate this difference of chromosome contents for man is not
obviously in a disadvantageous position, biologically speaking.
This compensation mechanisme can be briefly summarised as follow. Of
the two X's of a woman, one is tightly coiled to form a little do in the
nesting nuclei, the Barr body. This coiling is supposed to interest mainly the
long arm of X chromosome and to make him genetically inefficient ; thus the two
sexes come back to equality, not for the total content of genetic material, but
for the amount of active genetic information.
The very existence of this compensatory mechanism explains why
imbalance of sex chromosomes is better supported by the organism than changes
in autosomes quantity. Nevertheless, the sexual chromosomes cannot be added or
substracted without of arm, as it is exemplified in the many instances now
If one X is lacking, that is if the subject possess only one X and no
other sex chromosome, their phenotype is still feminine, but the height is
reduced, the ovary do not developp and many other difformities complete the
picture of the Turner syndrome. It was generally considered that these
incomplete women were of normal intelligence, but it has been shwon beyond any
doublt that low borderline I.Q. are much more frequent among than in normal
population. Also a typical difficulty in handling aritmethic abstractions in
counting is welle established.
Women possessing one extra X chromosome (i.e; three X in all) do not
exhibit obvious phenotypic trouble, but this constitution is much more
frequently found among mentally retarded persons than in general population.
Another extra X, (i.e. four Xs) lead always to feeble mindness.
In males one extra X Chromosome (i.e. XXY formula) produce the so
called Kliefleter syndrome in wich testicules do not mature properly,
determining sterility. Altough some XXY persons are normally intelligent and
even really gifted, the frequence of the XXY condition is much great among
retarded than in general population.
Another extra X (i.e. the XXXY formula) always produce retardation
among other disorders, and the XXXXY individuals have an I.Q. still lower than
od trisomic 21.
A particular effect has been found to be related to excess of Y
chromosome. Alhough XXYY subject ressembles quite closely XXY Klinefleter, the
XYY constitution seems to produce specific mental changes.
These patients having one extra male chromosome are not at all
"supermales". on the contrary they seems to be sexually under developped, but
two male characteristics are increased : the agressive behaviour, and the
In an institution for retarded agressive people, JACOBS and all. found
that XYY were uncommonly frequent, and that the affected were exceptionnaly
They estimated that in this particular population of agressive
delinquants people taller than 1,80 meter had something like one chance in two
of being XYY.
Before trying to discuss the mechanism by wich these chromosomal
imbalances affect human mind, it is necessary to review briefly what we know
about deficiencies of autosomes.
Faults of autosomal material
until three years ago it was generally believed that chromosomal loss
were unviable for autosomes in wich no compensatory mechanism exists.
In fact, the lack of chromosomal segment is obviously much more
deleterious that the excess of the same fragment, but syndrome related to
autosomal deletions are definitely observed in our species.
The Cri du chat syndrome
Loss of a part of the short arm of chromosome 5 produced a very
typical condition and very severe feeble mindness. The affected children are
microcephalic, have wide spaced eyes (hypertelorism), epicanthic fold an a
small chin, laryngeal immaturation produce a very remarkable abnoramlity of the
voice. the cry of the newborn and young babies is polonged, high pitched and
its plaintive tonality is strongly similar to the cry of distress of a
suffering cat. Hence the name of the disease.
As in other autosomal conditions, palmprints exhibits the signature
of the disease with a straight distal creases, stopped at the aplomb of the
thirs digit and a t' axial triradius.
An exceptionnal familie carying a translocation gave a quite
experimental demonstration of the fact that the disease is determined by the
loss of part of chromosome 5. It must be emphasised that other similar instance
now known confirmed entirely this fact.
In this family an apparently healthy mother had an abnormal
caryotype. one of her chromosome 5 was lacking part of the short arm (as in
typical cri du chat syndrome) but this fragment was transolcated to a
chromosome 13 so that in fact the whole genetic material was present, although
In this family one case of cri du chat syndrome was observed
(possibly another one occured but could not be examined), and the child had
received from her mother the deleted 5 and the normal 13.
Persons having received the deleted 5 and the big 13 were normals,
but carriers of the translocation, and, indeed children receiving the normal 5
and the normal 13 were entirely normal.
Two children received the normal 5, and the long 13. Tey are
trisomics for a part of the short arm of chromosome 5.
This constitution is exactly the contrary of the Cri du chat
syndrome. That is trisomy instead of monosomy for the same chromosomal
the two children are feeble minded ant the young one had a
particularly raucous cry. But it is difficult to forsee what should have been
the contrary of the Cri du chat voice.
Those two reciprocal conditions, monosomy of Cri du chat disease and
trisomy for the same fragment gave us the first example of type and countertype
for a given part of genetic material.
It can be forseen that countertype should exhibit anomalies which
are the contraries of the stigmata of the type, a fact experimentally
established by Bridges studying drosrphilae haplo IV and triplo IV.
Countertype of trisomy 21
No observation or subject possessing only one chromosome 21 (pure
haplo 21) has been yet reported, although such a condition was expected among
the some hundred children known to be born from a mother carrying a
translocation involving chromosome 21.
Nevertheless the situation to haploidy 21 was observed two years
The child at 7 months had the size and the weight of a normal
newborn and died at 7 and a half month.
One of his 21 chromosome was ring shaped and although this ring was
present in two third of the cells of the body, it had been lost in the oder
third. then he was pure haplo 21 in one third of his cells. Moreover, in the
blood end the bone marrow the loss of the ring had been so frequent that 95 %
of the cells were haplo 21.
The anomalies of the child were each the contrary of the symptoms of
trisomy 21. for example hypertony v. hypotony, saillant nose v. flat nose
bridge, hypocanthus v. epicanthus, narrow pelvis angles v. Broad angles,
Hypogammaglobulinemia v. Hypergammaglobulinaemia, hypereosinophilia v.
Hypoeosinophilia. Also, metabolic troubles were minor image. The ratio of 5
hydroxy indol acetic and acid to kynurenin was increased (it is diminished in
trisomy 21) and alcaline phospatase of granulocytes was diminished (it is
increased in trisomy 21). In the hands, ridges are known to be immature in the
young baby affected by trisomy 21. They sere abnormally mature in the
A second observation confirmed this year the same particular picture
and even both children were operated hypertrophic pyloric stenosis.
A third case has been mentionned, giving a definite support to the
notion that the countertype of trisomy 21 can exist at least partially.
Deletion of the long arm of chromosome 18
This condition individualised this year is another example of
The pathognosomic features are opposed to that of trisomy 18. The
medium satge of the face is retracted v. the nose finely developped in trisomy
18, saillant chin v. microretrognathie, saliant helix and anthelix v. aplsy
hyperabduction of tigh v. narrow pelvis, long fuseled digits v. short, and high
frequency of whorls in the finger prints v. arches.
Other symptoms like acromial dimple and jugal nodes have no known
counterpart in trisomy 18.
The children are extremely retarded. it must be noted that deletion
of short arm of chromosome 18 is also known and the general picture has been
discribed. the variance of the symptome seems rather great, and although the
most typical of them are in minor image with trisomy 18 symptoms, it is too
early to try to oppose them one by one.
Also cases of ring chromosome 18, involving some loss of chromosomal
part, exhibit partial countertype features.
Actually one typical example of pure loss of chromosome 13 have been
described, but cases of ring 13 chromosome, with loss of the ring are now
The genic dosage effect
This very brief resume of the present data show us how future research
could be designed.
With the opposition of type and countertype a new tool is available to
precise the impact point of a given chromosomal change.
Much more than a semeilogical refinement, this investigation could
possibly lead to demonstration of basic phenomenon.
A very single hypothesis could be put forward.
Genes are controlling the fabrication of enzymes and it is plausible
that there is a correlation between the number of genes at work and the
quantity of enzymes produced. If this general statement was not true, trisomics
should be normal, and obviously they are not.
The quantitative relationship could be thus :
monosomy = one gene : 1 unit of enzymatic activity
normal = two gene : 2 units -.
trisomy = three genes : 3 units -.
then comparing trisomics to normal, enzymatic reaction controlled by
genes involved in the chromosomal changes, would be accelerated, and the
enzymatic activity would be 3 in trisomics compared to 2 in normal, that is a
ration of 1,5 if the enzymatic activity of normal is taken as the unit of
In comparing trisomics to monosomics, the resolving power of the
system is much better. In monosomic, we expect a value of 1 and in trisomics 3,
so that we get a factor of 3 in the comparison.
It is perfectly obvious that such elementary arithmetic is an over
simplification of a very complex reality, but it seems quite possible that the
carefull examination of very rare countertype could tell us more about types,
than the direct study of these.
this way of reasoning about enzymatic activity is very different from
the classical notion of lockage like in P.K.V. for example. Here mental
deficiency is the end result of a biochemical stop, the necessary enzyme being
In chromosomal imbalance, the biochemical pathway would be entirely
normal, but some reaction will go too fast or too slow, thus destroying the
dynamic equilibrium requested for normality.
To replace a lacking enzyme seems to be e very difficult task, but to
accelerate or decelerate an existing reaction is currently realised by using
appropriate metabolites or antimetabolites.
Then the detection of biochemical changes in affected children could
lead to palliative measures.
It may be said that this is pure speculation and that those
significant biochemical traits have get to be identified. This is quite true.
But before trying to find something we have to know what we are searching for.
I do not think it is wrong to try to build a logical model before going to
clinical observation. Only in this way can we reckognise if the observed facts
If you remember that at birth one in every hundred child is affected
by some chromosomal error, you understand that this is not a thoretical problem
but an immediate challenge.
As difficult and hasardous as such a research may be, it must be
undertaken. it represents the only hope for those children, who having not
received an equitable patrimony are, in the true sense of the term, the most
desinherited of the children of men.