Jerome Lejeune is a physician and geneticist who discovered the cause of Mongolism. From 1965 onward, he held the chair of genetics at the Faculty of Medicine in Paris. He has authored numerous studies in human genetics. In 1959, working with N. Turpin, he discovered that Mongolism results from the presence of an extra chromosome in the twenty-first pair—trisomy 21. This finding sparked a series of important investigations, still ongoing in laboratories worldwide, into chromosomal distribution anomalies in humans and the resulting genetic diseases. Professor Lejeune offers here a synthesis of current knowledge (as of 1983, Editor's note) about this condition.
The Child with Trisomy 21
Among all conditions that impede the development of intelligence, trisomy 21 is both the most common and the most visibly apparent. It can occur in any family; it is known in every country.
Far from being a recurrence of ancestral traits from invaders who came from the steppes of Central Asia (hence the once-proposed term "Mongolism"), this alteration of body structure results from an incomplete realization of certain stages of embryonic development. The inner corner of the eye is bounded by a fold of skin—an epicanthal fold—which becomes less pronounced with age; the outer corner of the eyelids is drawn slightly upward and outward; the bridge of the nose is underdeveloped; the face is very round; the nape is thick and the back of the skull flat. The overall appearance gives the impression of being imperfectly, or rather incompletely, finished. The fingers are short, with flexion creases very close together, especially on the fifth finger and sometimes on the index finger.
Children with trisomy 21 have all the normal chromosome pairs but receive an extra third chromosome 21 (which is why it is called trisomy 21), giving them 47 chromosomes instead of 46.
Children with trisomy 21 have all the normal chromosome pairs but receive an extra third chromosome 21 (which is why it is called trisomy 21), giving them 47 chromosomes instead of 46.There are other, less visible but diagnostically important anomalies in fingerprint patterns and palm prints. All these signs can be found in normal individuals, but separately; only in children with trisomy 21 are they present simultaneously, though some may occasionally be absent.
The constellation of these signs—not any single one in isolation—permits recognition of the condition.
These morphological disturbances are sometimes accompanied by internal malformations. The most frequent are congenital heart anomalies, most of which are fully correctable by surgery. Among these, the milder cases may resolve on their own or require only minimal precautions without need for surgical intervention.
A rare but dangerous malformation is duodenal atresia—an almost complete narrowing of the digestive tract in that region. In such cases the passage of food stops beyond the stomach, and surgery is essential from the first day of life; otherwise the child cannot be fed.
Without listing all other possible complications, the general picture can be summarized this way: most infants, toddlers, and children are free from severe malformations, and their early years proceed without incident apart from the characteristic appearance (which varies considerably from child to child) and above all hypotonia—insufficient muscle tone. All children with trisomy 21 are too calm, too flexible, too limp.
Most children are free from serious malformations. Their early years proceed normally, apart from the characteristic appearance and muscle tone deficiency. The most serious symptom is the disturbance in intellectual development, which occurs roughly at half the normal rate.
If we try to fit together all the symptoms of this condition, we notice that none is specific—each anomaly can be found in isolation in other children with normal chromosomes. Yet their simultaneous presence suggests that a common "cause" exists: a disturbance, a difficulty in the execution and completion of certain embryonic structures. It is as if some product essential to the organism were subjected to a constant limitation, forcing the child to leave unfinished buildings here and there—hence the cardiac malformations, for instance, or the underdevelopment of the face, the nasal bones, the ear cartilage, or the hands and feet.
None of the symptoms is specific. Each anomaly can appear in isolation in other children with normal chromosomes, but their simultaneous presence suggests that the cause is common.
None of the symptoms is specific. Each anomaly can appear in isolation in other children with normal chromosomes, but their simultaneous presence suggests that the cause is common.The most serious symptom, one that is never absent, is the disturbance in intellectual development. Here too, as we shall see, it appears that the organism is constrained by a limitation—that the supply of certain molecules essential to nerve cell function is deficient. By all known criteria, the brain itself appears well-constructed, but it fails to achieve either complete maturity or maximum functional efficiency.
One Chromosome Too Many
For a long time, the nature of this condition remained obscure after the initial clinical descriptions by Seguin in 1846 and Langton Down in 1866 (from whom the name often used by English speakers derives). Its true nature could only be understood after the discovery of the extra chromosome in 1959.
The normal number of chromosomes in all cells of the human body is 23 pairs (46 total), except in germ cells at the moment of fertilization, where the number is 23. Each of us receives 23 chromosomes from the paternal sperm and another 23 from the maternal egg. At fertilization, the chromosome number characteristic of our species is restored: 23 + 23 = 46. For each pair of chromosomes numbered 1 to 22, we have one element from the father and one from the mother.
Children with trisomy 21 have all the normal chromosome pairs but receive an extra third chromosome 21 (which is why it is called trisomy 21), giving them 47 chromosomes instead of 46.
Why this extra chromosome?
Most likely the error occurs during the maturation of reproductive cells, which must receive only one copy of each pair to reduce the chromosome number from 46 to 23. For reasons still unknown, one of the chromosome 21 copies sometimes goes astray, and the reproductive cell receives two instead of one, for a total of 24 chromosomes. This leads to trisomy after fertilization, when the other reproductive cell contributes its 23 chromosomes.
In some cases the error occurs during the very first divisions of the fertilized egg. The child then carries both normal cells with 46 chromosomes and a variable percentage of trisomy 21 cells (with 47 chromosomes). These "mosaic" cases are rare but important to recognize, because the child appears less affected the more normal cells are present. (It is also possible—though still poorly understood—that certain cells lose the extra chromosomes and somehow heal themselves.)
In general terms, we can say that 95 percent of children with trisomy 21 have homogeneous trisomy with 47 chromosomes, without our being able to identify the direct cause of the accident.
However, one factor significantly influences the risk: maternal age. For example, among children born to young mothers—ages 20 to 35—the disease occurs in roughly 1 to 2 cases per thousand births. After age 35, the frequency rises sharply, reaching 20 cases per thousand births after age 40.
Risk is also higher in very young mothers (under 18): it appears that the chromosomal mechanism undergoes more accidents during the "break-in" years of youth or during the "wear" years approaching the end of the reproductive period. Ovarian physiology seems to play an important role in the precision of this mechanism.
Confirmation of this appears to come from reports that prolonged use of oral contraceptives, which as is known disrupts ovarian function, seems to increase the risk of trisomy.
Evidence is accumulating that the disturbance responsible for intellectual disability is probably not so complicated to understand and certainly not impossible to repair.
All this applies, we have said, to 95 percent of cases. In the remaining 5 percent, chromosome 21, instead of being free, is stuck to another chromosome (often chromosome 14 or 22). In about half of these cases the translocation appears accidentally in the child or in the cells that produced him. In the other half, one of the parents carries this translocation and appears to have only 45 chromosomes.
This very rare peculiarity is important to know because if the mother is a carrier, the risk of trisomy 21 in her children is very high—almost 1 in 5. If the father carries the translocation, the risk is lower, about 1 in 50.
It is therefore absolutely essential to examine the chromosomes of every affected child and of both parents.
This is done by taking a few drops of blood from a fingertip and culturing it for three days in a special culture medium. Microscopic examination then allows identification of each chromosome. In 95 percent of cases, the parents' chromosomes are normal and the child carries free trisomy; we can then conclude that the risk for another child is not increased and depends only on the mother's age. In the rare cases where a translocation is observed, the parents can make an informed decision about whether to have more children.
Sometimes chromosome 21 is not transferred in its entirety to another chromosome but is in some way divided in two: one piece sticks to another chromosome and the other remains free. In the offspring of such structurally normal individuals, children can appear who are trisomic only for a small segment of chromosome 21. By analyzing these extremely rare cases, we can identify the effects of a given segment and confirm that a particular gene controlling a particular chemical function is located in a particular region of the chromosome.
The Growth of the Child with Trisomy 21
From birth, which often occurs one or two weeks early, the child with trisomy 21 is notable, as we have said, for hypotonia and slight growth delay.
Over the years this delay becomes more evident. If we observe the growth curve of normal children, we see that height and weight values cluster around an average bounded by two extreme curves.
This representation of the normal growth zone appears in all pediatric textbooks. When the same analysis is applied to children with trisomy 21, we find that their average corresponds to the lower curve delimiting the normal lower limits. The same phenomenon appears in the development of intelligence as measured by IQ. Here too the curve for children with trisomy 21 is shifted relative to normal values, even more so than height and weight.
Given that psychometric tests are imperfect, each result imprecise, and that great differences exist from child to child, we can say roughly that intellectual development proceeds at an average rate of about half the normal speed. Again there is the impression of a brake that somehow prevents the intellectual machinery from running at full capacity.
Abstract faculties—important in calculation, for example—are most affected, while moral and artistic faculties remain intact. This is why children with trisomy 21 are often said to love music very much, which is quite true. It is not that they are more gifted than others; since this faculty is normal in them while others are reduced, it appears more remarkable. As a result, a person with trisomy 21 has the same slim chances as anyone else of becoming a musician.
We can say that the child with trisomy 21 is serene, enjoys living, sometimes a bit restless, and that all his difficulties amount to delayed maturation.
We can say that the child with trisomy 21 is serene, enjoys living, sometimes a bit restless, and that all his difficulties amount to delayed maturation.The difficulty with abstraction seems linked to a certain sluggishness, a "stickiness" in ideation.
It is as if—since the machinery does not run fast enough—thought fails to formulate itself and is somehow jammed. The child responds to this "clogging" as a normal traffic officer responds to a flow of vehicles moving too slowly: he closes some freeway entrances and blocks certain circuits. So the child with trisomy 21, unable to monitor everything at once, neglects postural control, keeps his mouth open, lets his tongue protrude. We do the same sometimes: the artist sticks his tongue out while drawing the most difficult line, or the man stands slack-jawed admiring a painting.
The same phenomenon appears in the eyes—gentle and affectionate but always somewhat vague. This is explained by the fact that the muscle tone of the iris is more sensitive than normal to certain drugs.
Before reaching the age of reason, the immune system too is imperfect; respiratory infection sensitivity is notable. The running nose is customary. It is an exaggeration of the fragility common to all young children. We normally say—without much respect—that children are "runny-nosed" until they reach the age of reason. Similarly, the child with trisomy 21 typically overcomes these difficulties around the same age, often with some delay.
Finally, we can say that the child with trisomy 21 is serene, enjoys living, sometimes a bit restless, and that all his difficulties amount to delayed maturation. This is very clear with balance: for example, it is very difficult for a child with trisomy 21 under ten to stand on one foot.
Often interpreted as laziness or fear, the reluctance of children with trisomy 21 to perform certain exercises (such as going up or down stairs) simply reflects the fact that their neurological mechanisms develop more slowly than in normal children.
Medically, we are still far behind in addressing all these challenges. Certainly the proper use of certain vitamins (vitamin B6) and certain natural products has real but modest benefit. What remains is that patient and continuous education, combined with unstinting affection from parents and others, are the best means to help the child achieve his fullest development. Reaching adulthood, most of them become likeable people. Often they find it easier to live than so-called normal people. They do require a sheltered environment, work suited to their abilities, and always unlimited affection. This is true for everyone. Moreover, we know well that some of them are subject—with troubling frequency—to depressive episodes, periods of regression and loss of interest that closely resemble a disease linked to the effects of aging: Alzheimer's disease. It appears that the deficiency of certain products essential to nervous system function is the cause. If this hypothesis could be confirmed (Editor's note: see developments in 2014) it would represent a true revolution in the medicine of intelligence, as we shall see below.
The Future of Research
The impression of incomplete finishing, of insufficient regulation and control—already mentioned repeatedly—must be subjected to experimental research.
Thus we have been able to show that certain enzymes (the tools of cells' biochemical equipment) are more active in individuals with trisomy 21. This is easily understood: the genes that direct production of these tools—which normal individuals have two copies of on each chromosome pair—produce two quantities of enzymes. Those with trisomy 21, having three copies of chromosome 21, produce three times the quantity of enzymes directed by that chromosome.
Three genes thus controlling precise chemical reactions are located on chromosome 21. These findings are too recent for us now to connect these phenomena to the clinical observations already discussed. However, this field of research offers important prospects.
Another way of viewing the matter is to note that numerous other diseases, quite different from trisomy 21, also lead to intellectual disability. Enumerating and analyzing these conditions in detail would exceed the scope of this article, but it is possible to sketch out the conclusions, provisional and hypothetical as they may be. It appears that one of the most important biochemical mechanisms for proper nerve cell function is the steady supply—in appropriate quantities and at the right moment—of certain molecules carrying "monocarbon radicals." These radicals, containing a single carbon atom, are in some sense the building blocks that nerve cells use to construct their membranes and the insulating sheaths that protect nerves against short circuits.
Moreover, these same monocarbon radicals serve to make very particular molecules which, resembling security keys, enable the locks of nerve cells to function, opening one circuit or closing another.
Now, it is known that practically all diseases resulting from a known and localized chemical disturbance capable of disrupting intellectual development also have the consequence of reducing the supply of these indispensable monocarbon components.
This general hypothesis is far from proven, and it is conceivable that other mechanisms are also impaired in trisomy 21 (difficulties with oxygen metabolism, for example). But the greatest value of the hypothesis is not to predict with certainty how nature is made. Much more modestly, scientific hypotheses point us in the direction and show us the place where nature must be questioned to give us the answer.
Redirecting Destiny
Faced with these research prospects, one might think the entire scientific community is actively engaged in this work.
Sadly, the truth is quite otherwise. Unable yet to cure their patients, some physicians propose to eliminate them instead. This is precisely what prenatal diagnosis of trisomy 21 accomplishes.
By drawing a small amount of amniotic fluid around the fourth month—the fluid in which the baby floats—we can culture his cells and detect the presence of an extra chromosome 21 (or any other chromosomal or biochemical anomaly).
If we had an effective remedy that could cure the child with trisomy 21 in utero, this amniocentesis would be of great value. This is the case, for example, with Rh incompatibility, where amniocentesis allows us to assess the baby's condition so we can perform, if necessary, an in utero transfusion and achieve a cure.
In the case of biochemical diseases or chromosomal diseases like trisomy 21, no fetal treatment is available. Some propose to eliminate the disease through abortion. In some recent medical texts this decision is even described as "treatment"! As if the elimination of a sick person ever meant victory over disease!
All of medical history teaches us that those who smothered rabies patients between mattresses, or those who burned plague victims in their homes, did not liberate humanity from plague or rabies. We must conquer disease, not hunt down the sick.
Of course, it would be dishonest to claim that research stands on the brink of a final breakthrough. We do not yet have a true curative treatment for trisomy 21. Yet evidence accumulates that the fundamental disturbance—the chief cause of intellectual disability—is probably not so complicated to understand and certainly not impossible to repair.
Without falling into science fiction, it seems reasonable to think that if civilized nations decided to assault diseases of the mind with the same vigor devoted to space exploration, success would be assured. It might prove less difficult and less costly to nurture the intellectual development of a small human on earth than to send a cosmonaut to the moon.
Without claiming prophecy, I believe the next generation will judge ours very severely for having despaired when the signs of possible success were accumulating in our laboratories.
In any case, medicine's proper use dictates our conduct. Faced with this enormous task and the pressing necessity to succeed, our duty can be summed in one word: we will never abandon.
(Article from Ombres et Lumière n. 50)