The rapid growth of human cytogenetics imposes, as a corollary, the
progressive restriction of the scope of a talk on this subject. Two years ago,
a quarter of an hour was sufficient for a general survey; today, a whole hour
is filled with one topic only. without being a prophet, it can he seriously
foreseen that some day, a Blackfan Lecture restricted to "the genic content of
the short arm of chromosome 22" will be considered a very brief summary of the
current knowledge.
I would like to discuss the general implications of the available data
on autosomal disorders. Chromosomes are divided into sex chromosomes and
non-sex chromosomes, which are generally called autosomes. My subject can be
considered under three points of view : the recognition of autosomal disorders,
the mechanism of their production and, finally, the practical or heuristic use
of this knowledge, as it enables more to be learned.
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Syndromes determined by autosomal disordersHaut
The Numerical Abnormalities
The numerical abnormalities are no longer limited to classic
mongolism, with its 47 chromosomes and its trisomy for No. 21.(1, 3).
The trisomy for chromosome 17, in which there occurs a typical
deformity of the head, a small mandible, low set ears, other nonspecific
malformations of heart, hands and feet, and severe mental retardation,(4) is
also quite classic. Possibly more than 25 different patients suffering from
this disease are now known.
The 13-15 trisomy with eyeball defects, polydactyly, cardiopathy,
and mental defect, together with deformities of lips, palate, skin, and ears
(5) is also well established.
These three syndromes, each clinically distinct and rather easy to
diagnose, once the physician becomes aware of their existence, are determined
by an excess of genetic material. Hence we can keep in mind a preliminary
conclusion: excess of genetic material is harmful, and the effect of genic
dosage can be so marked as to prevent the development of the embryo.
Such an arrest of developrnent is possibly the reason trisomies for
big chromosomes such as a 1 or a 3, for example, have not been observed. This
hypothesis is confirmed by the lethal effect of total triploidy found in some
abortion products (6, 7) and the existence of a diploid-triploid mosaic in a
severely malformed infant, previously described (8).
Other possible instances of trisomies or, more precisely, of extra
small acrocentric chromosomes, have been recorded in relation to various
clinical syndromes, ranging from Sturge-Weber syndrome, (9) schizophrenia, (10)
congenital hypotonia, (11) and mental deficiency, (12) to malformations rather
close to mongolism (13) or to the 17 trisomy (14). In all these cases great
uncertainty remains concerning the identity of the extra chromosome or even its
etiologic significance (12, 15). Presumably, the apparently small acrocentric
element reported in these instances is a chromosome modified as the result of
translocation or deletion or of other rearrangements. This uncertainty
precludes determination of what part of the genome is involved in the extra
element.
This problem of chromosomal rearrangements is well exemplified only
in instances of translocations between acrocentric chromosomes, perhaps because
other translocations are selectively disadvantageous, or perhaps because some
observational bias (16) has as yet prevented their recognition.
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The Structural Abnormalities
Depending upon the size of the elements involved, the structural
abnormalities can be classified in three categories.
Translocations between big and small acrocentric chromosomes are
rearrangements between a member of the 13-15 group and one of the 21-22 group.
For simplicity, any member of the 13-15 group can be symbolized by the number
13 in brackets [13], the translocation itself being noted by the mark ~ (Fig.
1).
The first example known in our species was that of 22 ~ [13] type.
This was found in a retarded child with multiple lesions of the vertebrae
(Polydysspondyly) (17).
This type was also found in a family with speech and mental
retardation (18) and again in a father and his child (19) without phenotypic
effect linked to the translocation.
A word must be said about the criteria of recognition of the
chromosomes involved in these rearrangements, for the diagnosis of the anomaly
is not based merely on the abnormal chromosome but on the normal ones also. For
instance, if two chromosomes 21 and only one chromosome 22 are present, the
translocated one would be supposed to be a chromosome 22.
In view of the difficulty of distinguishing between 21 and 22, this
diagnosis remains rather uncertain. Nevertheless, the genetic analyses can in
some instances confirm the cytologic inference, as in the family (18) in which
a mother, carrying a 22 ~ [13] translocation, had a typical mongol child with a
free 21-trisomy with out the translocated chromosome. In such a case, if the
translocated acrocentric chromosome had been a 21, the mother would have had
only one 21 free, and nondisjunction of this would have been unlikely.
The 21 ~ [13] type seems to be the most frequent translocation, and
it was the first one recognized as a cause of heritable mongolism (85, 86, 87).
In fact, a 21 ~ [13] translocation carrier can produce diplo-21 gametes if the
free 21 migrates to the same pole as the translocated chromosome. Hence, after
fertiIization, a hidden trisomy will be produced, two chromosomes 21 being
free, the third one being involved in the translocation (Fig. 2).
Regular segregation can allow the transmission of the balanced
translocation, so that the anomaly can be transmitted through generations in
the same way as a dominant mendelian character.
A translocation between two small acrocentric chromosomes produces a
new element. Because the long arms of the small acrocentrics are of roughly the
same size as the arms of a 19-20 chromosome, the new element may be mistaken
for such a chromosome. Translocations between small acrocentric chromosomes are
of particular importance if the fused elements are both chromosome 21. A
carrier of a 21 ~ 21 translocation can be phenotypically normal, although
having 45 chromosomes only. But after meiosis, the gametes that are produced
either contain the translocated chromosome (that is two 21) or have no 21
chromosome at all (Fig. 3). After fertilization, two types of zygotes will
result, one-half carrying three chromosomes 21. (21-trisomic), the other half
carrying only one (haplo-21). This last combination is probably lethal. The
pregnancy involving haplo-21 eggs will end in a miscarriage, and all the
surviving children will be mongols. In the literature, a total of 16 children
born from a 21 ~ 21 carrier parent are known and all of them are mongols (20,
22, 23). In one family, (24) the sibship consisted of one mongol and four
normal children, but the carrier father was in fact a mosaic, (25) or
individual in whom more than one chromosome component could be found.
Translocations between two big acrocentric chromosomes, in most of
the reported instances, have had no phenotypical consequences. The first case
observed was associated with Klinefelter's syndrome (26); a second was a
mosaic, with half of the cells normal, and half having the translocation (27).
The genetic transmission of this type of translocation is exemplified in a
remarkable family (28) in which there are nine carriers and eight normal
individuals in the progeny of a carrier ancestor. In this instance the
chromosome cannot be an isochromosome 13 ~ 13 or 14 ~ 14 or 15 ~ 15, but must
be a hybrid 13 ~ 14 or, 13 ~ 15, or 14 ~ 15, because no case of trisomy [13]
syndrome occurred in this extensive pedigree.
Trisomy [13] syndrome by nondisjunc-tion has been observed in
another family. A boy with 46 chromosomes was born to a father carrying a [13]
~ [13] translocation (29). In the other families is no record of a subsequent
abnormal segregation.
Other types of translocations involve an acrocentric chromosome and
another type of chromosome. A small extra fragment on a big acrocentric,
producing a probable partial trisomy, was observed in a child suffering f rom
Sturge-Weber's syndrome (34). We recently observed a child with an extra piece
on a chromosome [13]; with a clinical picture resembling that of the 17
trisomy, particularly in the abnormal frequency of arches in the digital
prints, reported as typical of the trisomy 17 (35). A translocation between
chromosomes 22 and 2, giving rise to a very big acrocentric chromosome, has
been observed in a phenotypically normal mother; her daughter with a typical
haplo-X Turner's syndrome, and two of her normal XY sons (36). Other
translocations between nonacrocentric chromosomes have been reported in the
oral-facial-digital syndrome (insertion on the 1) (37) and in an apparently
normal girl (2 ~ 10 possible) (38).
 Fig. 1 . Translocation 21
~ [13]. During the time a 21 and a [13] lie close together, a break may occur
near the centromere of each chromosome. The fragments can then recombine,
either as in the original chromosomes (no detectable effect) or in a rearranged
pattern producing a new hybrid chromosome: 21 ~ [13] and a centric fragment
bearing the satellites. Varying amounts of chromosome material can be attached
to the centric fragment, which is secondarily lost. The quantity of genes
involved in this loss determines the eventual phenotypic effect of the
translocation. This general process of rearrangement between acrocentrics is
commonly referred to by the term "centric fusion," which is a little
misleading.
 Fig. 2.
Progeny of a carrier of a 21 ~ [13] translocation. In this simplified diagram,
each chromosome is represented by one chromatin strand only, for sake of
simplicity, although two chromatin strands are actually present at meiosis. The
progeny shows the four types of possible children, of which only the three
first are effectively observed, the type Haplo-21 being not known (probably
lethal).
 Fig. 3. Progeny
of a 21 ~ 21 translocation carrier. At meiosis the new chromosome 21 ~ 21 has
no homologue and must go directly to one pole, the other cell being entirely
deprived of a 21 chromosome. As seen, the progeny can only include mongols or
miscarriages. Note: In case of a 21 ~ 22 translocation, the transmission would
be analogous to the case of a 21 ~ [13] translocation (Fig. 2).
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The mechanism of production of chromosomal
aberrations
Although the mechanisms are poorly known, we have at least some
indications concerning predisposing factors and the time of occurrence of the
aberration can be determined precisely in some particular instances.
Table I : Progeny of 21 ~ [13] translocation
carriers.
Children |
Translocation Carrier | Normal; 46 ckr. | Normal;
45 chr. ; Translocation Carrier | Mongols; 46 chr.; Triso. 21 by
Translocation | Normals; Unspecified Karyotype | Total
Children |
Mothers
(26) | 21 | 22 | 30 | 14 | 87 |
Fathers
(12) | 14 | 20 | 1 | 10 | 45 |
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Predisposing Factors
Maternal Age:
The first predisposing factor to be recognized is the
well-documented effect of maternal age on the frequency of trisomy 21 (39).
This effect, observed long before the chromosomal anomaly was detected, is also
found in other trisomies. In 25 cases of trisomy 17, the mean age of the mother
at birth of the child was 35.2 ± 3.8 years, and in 13 instances of trisomy
[13], the mean was 33.4 ± 1.7 years; these two means are statistically
different from the general mean maternal age at time of delivery in western
populations, which is between 26 and 27. This predisposition to abnormal
segregation in relation to the aging of the mother can be compared to analogous
data known in drosophila. In that insect, the older the mother, the greater is
the risk of mitotic errors of segregation of an X chromosome, generating mosaic
gynandromorphs by the loss of a ring X chromosome (40, 41).
Structural rearrangements:
The evidence that structural changes favor the abnormal
segregation of the chromosomes involved in the change is obvious from data now
at hand on the progeny of 21 ~ [13] translocation carriers. Briefly, the
available literature includes 26 mothers carrying such a translocation, who had
a total of 87 children. Three categories of children are expected : entirely
normal ones, normals carrying the translocation, and mongols with the
translocation. Table I sumiarizes the facts.
There is no statistical difference between the two groups of
normal children and the group of mongols. If we assume that the haplo-21
combination is produced as frequently as the trisomy-21 condition, but is not
viable, we can thus consider that one in every two divisions at meiosis gives
rise to abnormal segregation of the free chromosome 21.
The very different figures in the progeny of fathers with
translocation indicate that its risk of abnormal segregation could be such
lower in the male, but the alternative hypothesis that unbalanced spermatozoa
are less efficient than normal ones cannot be definitely rejected.
Besides this direct effect on the segregation of the chromosomes
actually involved in the translocation and their nor-mal homologues, the
likelihood of other chromosomes segregating abnormally might be affected. It is
difficult to believe that the association between sex chromosome abnormalities
and autosomal rearrangements cited above (XXY plus 14 ~ 15 transl) (26), (XXY
plus 22 ~ [13] transl) (19), and (XO plus 2 ~ 22 transl) (36) can be purely
fortuitous. Individually these changes are very rare, and their concurrence in
these individuals leads to the tentative conclusion that autosomal
rearrangements can increase the probability abnormal segregation for the sex
chromosomes, which are not themselves inolved in the structural change.
This hypothesis can be related to the observation made in
drosophila, that structural changes in autosomes do increase the frequency of
abnormal segregation of the X, (42) especially if the X chromosomes themselves
show structural changes (43). Also non random segregation of the Y chromosome
can be produced by autosomal rearrangements (44).
It is not impossible that such structural changes could be more
general than is now suspected, and that familial accumulation of various
chromosomal disorders (45, 47) could be related to some undetected structural
rearrangements in these families. Also, the hypothesis that one chromosomal
imbalance increases the risk of another occurring in the same cell line could
account for such complex conditions as XXX (48), XXXY (49) or XXXX (50) or
XXXXY (51), or XXYY (52), or for the associations of two different disorders:
21 trisomy + XXY (53, 54), 17 trisomy + XXX (55), or 21 trisomy + 17 trisomy
(56).
Peculiarities of Chromosomes Themselves:
The overwhelming majority of translocations involving acrocentric
chromosomes show that, even though an observational bias is likely (16), this
type of chromosome does have a special risk of undergoing rearrangements. Also,
the relative harmlessness of loss of satellites shows their low content (if
any) of genetic material.
The increased risk of acrocentric chro-mosomes undergoing a
rearrangement is probably related to the presence of satellites. Because these
bodies are joined in the resting nucleoli, the acrocentric chromosomes lie very
close together during the entire interphase (57) and thus are more exposed to
exchanges than other types of chromosomes.
Finally, the relative rates of DNA synthesis seem to show that
chromosomes 21 and 14 have the same thymidine uptake rhythm, a functional
peculiarity enhancing the possibility of fusion during the synthetic period
(58).
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The Time of Occurrence
With the general acceptance that non-disjunction was the basic
mechanism for production of chromosomally unbalanced zygotes, the time of the
accident was believed to be during the meiotic process, either at the first
(reductional) division or at the second (equational) one. The meiotic accident
is surely at work in case of trisomies appearing in the progeny of mothers (59)
affected by trisomy 21 or in the progeny of translocation-carriers.
Nevertheless, it may be dangerous to consider that all autosomal or
sex aneuploidies result from fertilization of an unbalanced gamete by a normal
one or by fusion of two unbalanced gametes. One evident exception is the
existence of mosaic individuals bearing two different cell lines, one normal,
the other unbalanced. A few instances of diplo 21/triplo 21 mosaic individuals
are now reported (60, 61); in sexual disorders, the mosaicism is much more
frequent. In an exceptional observation, a chromosomal mosaicism for the sex
chromosome was related to a mosaicism of the erythrocytes, for two different
autosomal blood groups. This raises the possibility of fusion of two different
zygotes in the formation of one individual (62).
More generally, the mosaics are genetically homogeneous, except for
the chromosome concerned. The most likely explanation is that the abnormal
segregation of the chromosome occurred after the zygote was constituted, during
the early cleavage in the blastomere stage. The discovery of monozigotic
heterokaryotic twins shows that this process can be as early as at the two
blastomere stage. One observation concerned a couple of monozygous twin boys,
one a typical trisomic 21 mongol, the other a perfectly normal individuals
(63).
This type of twinning, previously observed in monozygotic twins, one
XY, the other X0 (64, 65) shows that a mitotic error, just after karyogamy, can
result in twins who differ by only one chromosome. These heterokaryotic
monozygous twins are entirely comparable to mosaic individuals, the difference
being that the two cell lines separated, each to form an individual, instead of
remaining mixed in only one embryo.
Another reason to suspect that mitotic errors, after fertilization,
can occur as early as karyogamy itself is that both sets of chromosomes, having
lived for years in two entirely different individuals, are suddenly put
together in an entirely new environment at least for the set coming from the
father. That the beginning of the life together could be difficult, even at the
cellular level, does not seem too surprising.
In this respect, it is to be remembered that the maximal loss of X
chromosomes induced by x-rays in mice is observed (66) at the moment of the
fecundation of the egg. Moreover, the chromosome must frequently lost is net
the maternal X but the paternel one (67).
Another consideration about the time of occurrence of aberrations is
related to their clinical manifestation. Late changes, producing an aneuploid
cell line in an embryo may well remain entirely unnoticed if the proportion of
aneuploid tells is too small to provoke detectable morphological or biochemical
anomalies in the individual. Another phenomenon could also be at work: a
selective advantage would favor the euploid line, if the aneuploid one were not
represented from the first by a sufficiently large number of cells.
The postulate of a selective barrier against chromosomally
unbalanced cells newly produced in the organism is a particular aspect of the
general law of homeostasis. Some exceptions to this law are, however, already
known, such as the appearance, late in life, of mutant clones having a
particular chromosomal aberration. This is observed in granulocytic leukemia
(68-71) or in Waldenstrom macroglobulinemia (72, 73). That the mutant line
possesses a selective advantage, is apparent from the malignancy of these
conditions. The chromosome imbalance of most invasive cancers is possibly
related to a similar mechanism, but this is too broad a question to be
discussed here (88).
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The use of cytogenetic knowledge
One of the basic questions in any discipline is the value of the
knowledge already gathered. What are its possible uses?
Human cytogeneticists are not collecting rare syndromes in order to
realize a kind of chromosomal taxonomy of congenital deformities. The real
goals of this type of research are two: One is its immediate application for
practical medicine, the other is its use in raising questions and suggesting
their solutions. This second, heuristic, use may be the more important
goal.
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Practical Use
The first evident application is in the refinement of diagnosis and
the establishment of the chromosomal basis of constitutional disease. If one
considers that more than 1% of live births are affected by a detectable
chromosomal abnormality, the task of cytogeneticists in helping the clinician
is enormous. Although sexuel disorders are excluded from this brief review,
their early recognition and the decision concerning their therapeutical
correction is so important that it can be safely stated that, in a few years,
karyological diagnosis of sexually ambiguous cases will be considered as a
routine step.
Also, genetic counselling can be directly based upon cytogenetical
investigation, especially in cases of translocation. The fact, previously
quoted, that nearly one third of the progeny of a mother carrying a 21 ~ [13]
translocation is composed of mongols, indicates that every family in which one
mongol child is born should be examined, especially if the mother is young. In
this case, detection of translocation carrier parents could help to prevent the
recurrence of the disease. Also the catastrophic progeny of the 21 ~ 21
translocation carriers could be prevented.
More broadly, the discovery of a translocation, even perfectly
balanced, could be considered as a real eugenic danger; possibly routine
examination of the chromosomal set will be considered some day as a useful
complement of the actual prenuptial medical examination.
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The Heuristic Use of Chromosomal
Aberrations
This use can be envisaged for theoretical research as well as for
medical application. Determining the location of the individual genes on the
human chromosomes, the "mapping" of the chromosomes, is the most obvious
theoretical task. The use of small deletions occurring in some translocations
(16) as well as the interpretation of eventual partial trisomies (34) have been
proposed as tools for such research. In these cases, a search was made for
evidence of a deficiency or excess of functioning genes that could be
correlated directly with the cytologic evidence of an abnormal amount of given
chromosome.
The main difficulty lies in the quality of the characters chosen as
"markers." For example, the dermatoglyphic anomalies observed in mongolism
(specifically the Simian crease) were tentatively related to hypothetical genes
located on the chromosome 21 after the discovery of the trisomy (59). However,
their existence in other different constitutional anomalies, the trisomy [13]
for example, or in pseudohypoparathyroidism, investigated in Boston, seems to
show that even such a precise and localized morphological feature can be
controlled by complex genotypic interaction.
Heterokaryotic monozygous twin studies could possibly be used for
genic localization; for instance, besides the symptoms of mongolism the only
difference found in the two twins previously mentioned was that the mongol had
straight hair while the normal had curly hair. This discrepancy could be taken
as a presumption that the gene governing curly hair is sensitive to genic
dosage of chromosome 21, but is not a proof that the "curl gene" is on the 21
chromosome.
Notwithstanding these difficulties there is no doubt that the
accumulation of data on partial trisomies or partial deletions will become a
useful tool in investigating the alleles which are sensitive to genic
dosage.
Biochemical disorders are much easier to deal with, once they have
been recognized. The best example now available is possibly that of alkaline
phosphatase. In order to understand the data, we must consider the Philadelphia
chromosome observed in granulocytic leukemias. In this disease, it is known
that there is a decrease of the activity of alkaline phosphatase in the
granulocytes and also that leukemic cells carry a deletion of the long arm of
one of the chromosomes 21 (68). The hematologic evolution of the affection
shows a strong correlation with the relative number of cells carrying the Ph1
chromosome in the peripheral blood (69).
It was thus interesting to know if mongols who carry the trisomy 21
(that is, present in triplicate the segment which is lost in the Ph1
chromosome), have a higher enzymatic activity than normal people. This is
indeed the case (74). The alkaline phosphatase activity of granulocytes of
mongols is approximately 1.5 times greater than the control value. Thus the 3
to 2 ratio, found for chromosome 21, applies also to the enzyme activity.
Further publications on this comparison of mongols and normal children have
substantiated this observation (75, 76), and even demonstrated that this excess
of enzyme is not due to the appearance of younger polymorphonuclear cells (77),
another hematologic trait typical of trisomy 21 (82). These relationships are
summarized in Table II.
Table II : anomalies of the 21 chromosome
| Polymorpho-nuclear Cells | Général
Phenotype |
Normal (diplo 21) | Normal | Normal |
Constitutional Triplo 21 | low segmentation of nuclei
(82) | Mongolism twenty-fold increase of acute leukemia frequency
(84) |
Clonal Deletion of part of long arm (Ph1)
(68) | Diminution of aïkaline phosphatase (83) | Chronic myeloid
leukemia |
Loss of a 21 (70) | (?) | Acute myeloid
leukemia |
Two preliminary conclusions are suggested by the data in the Table.
First, there is probably on chromosome 21 a segment containing genes Which
normally control leukopoiesis. Excess of them raises the risk of acute
leukemia, a partial loss of them is linked with chronic granulocytic leukemia.
The existence of Haplo 21 clones in some cases of myeloblastic leukemia could
mean that the degree of the loss can influence the evolutive type of the
disease. Secondly, the correlation between alkaline phosphatase activity and
the chromosomal dosage of chromosome 21 raises the problem of the localization
of an "alkaline phosphatase gene" an the distal part of chromosome 21. It has
to be stressed that file present data do not prove that the structural gene is
on this locution, but they do demonstrate that "same gene (or genes) doing
something" to the alkaline phosphatase is (or are) there.
Such inferences from somatic aberrations will probably extend
rapidly to other forms of clonal mutations. There are reasons to believe that
many changes can be observed in tissue culture which would not be compatible
with embryonic development. This research would give a double reward, one the
study of chromosomal changes of the type occurring in cancerous tissue, the
other a contribution toward the mapping of genes. Even in established cell
strains, sudden modification of alkaline phosphatase activity in clones has
been reported (79). This could furnish another source of information to relate
this enzymatic fonction to chromosomal changes, if modification of enzyme
activity could be correlated with chromosomal changes.
Another way of mapping, closer to the conventional manner of linkage
study, is to follow a translocated chromosome through generations in large
families to see if it does carry a genetic marker, in particular a blood group
factor. As yet no definite statement can be made about results obtained with
this method which some day will undoubtedly allow the autosomal localization of
marker genes; for example, the ABO locus may possibly be located on a [13] or
21 chromosome (78).
From these data, chromosome 21 would seem a very important
chromosome, in fact, the autosome about which we know the most. Yet, in a
paradoxical way, this state of affairs probably means also that the 21 is one
of the less genetically important chromosomes, precisely for the reason that it
can suffer so many changes and still permit the development of the embryo or
the survival of a clone. Indeed, if gross changes involved really basic genes,
such changes would not be compatible with life.
Research into Pathogenesis: research an the pathogenesis of
syndromes is so far in the future that it may be considered utopian to mention
it in this context. Briefly, the main goal of such research, besides that of
eventually localizing a few genes on some chromosomes is the understanding of
the biochemical mechanism by which an excess of genetic material, otherwise
perfectly normal, can produce a very severe abnormality.
As a tentative hypothesis, the law "one gene-one enzyme," could be
extended to a quantitative assessment: "two genes-two enzymes in diploids,
three genes-three enzymes in trisomics." The deleterious effect of this excess
of enzyme in trisomics might be an unfavorable increase in same metabolites
and/or a relative deprivation of others (by accelerated turnover of the
metabolite by a side reaction).
No metabolic abnormalities have yet been found in trisomy 13 and
trisomy 17 and systematic, studies have yielded few significant results in
mongolism. Nevertheless, in this disease there are indications that a disorder
of the intermediary metabolism of tryptophane may be of importance (80, 81).
While the hypothesis of an accelerated turnover has yet to be solidly based on
observational data, the gene/enzyme dose relationship found for alkaline
phosphatase is at least in agreement with such a scheme.
It is much easier to block a specific enzyme than to replace a
missing one. Thus, a trisomic condition might be more favorable for future
therapy than is now sup posed. It is for the moment purely theoretical to
speculate on this prospect. Nevertheless, a relation bas to be established
between chromosomal accidents and their metabolic consequences before any
palliative therapy can be thought of.
Then and only then will cytogenetics be able to alleviate these
errors of partition of the human patrimony and to help those disabled patients
who are, in true sense of the word, the most disinherited of the children of
men.
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