Somatic chromosomes in mongolism


Mental Retardation Vol. XXXIX, 1962, Chapter IV, 67-77


In 1866, when Langdon-Down (1) published his historic description of a group of mental defectives whose physiognomy resembled features normally exhibited by the Mongolian race, he thereby introduced to the scientific world one of its most irritating and elusive etiological puzzles. Over the past century, mongolism has been the most meticulously studied and differently interpreted syndrome of mental deficiency. The voluminous literature on this medical enigma includes the observations and experimentations of not only pediatricians, neurologists, psychologists, and psychiatrists, but also many other scientific specialists.

In this communication, we are concerned primarily with reporting our demonstration of the chromosomal basis of mongolism. We believe, however, that it is essential to acknowledge and remark upon the many revealing clinical studies which were influential in the development of our hypothesis. A review of the literature describing the clinical research on mongolism indicated four general features of the disease.

Mongolism is a constitutional disease. Mongolian children are mongols from their heads to their feet. The possible deductions from the concordance of the condition in monozygous twins and the habitual discordance in dizygous twins strongly suggest genetic determinants. The extremely rare cases of mongolien women giving birth either to normal (2) or to mongolien children (3) also support the existence of an inherited mechanism. Although a hypothesis of a dominant mutation could be drawn from the foregoing data, it would imply a mutation rate more than a thousand times greater than any other rate known in our species.

Mongolism presents certain traits of a familial disease. Two facts suggest an hypothesis of polygenic inheritance. First, although the recurrence of the disease among siblings is extremely low, it appears to be higher than chance alone would explain. Secondly, a slight but still significant excess of minor mongolian stigmas has been noted among the near relatives of mongolian imbeciles (4).

Mongolism is influenced by nongenic factors. The principal factor affecting the incidence of mongolism is the age of the mother. Discovered and directly incriminated by Shuttelworth in 1906 (5), this fact has since been confirmed by every work on the subject and is actually the only point of agreement in the whole literature on mongolism. All of the invoked influences of heredosyphilis and fetal injuries have been unsubstantiated.

Mongolism displays features of a regressive entity. Occurring with the same features in every human race, the disease seems to be characterized by a regressive evolution of the human type. The dermatoglyphic traits which allow the diagnosis of mongolism by the inspection of palm prints are taxonomically specific of low monkeys and markedly different from those of anthropoids (6).

These clinical facts have provided a basis for describing and classifying mongolism. In our opinion, the disease may be defined as a constitutional change that is influenced by genetic factors and the biological state of the mother and that always produces a variant of the human type. Consideration of this definition led us to the conviction that the discovery of a chromosomal abnormality would be the only means of fitting together the diverse existing data. Conceiving of a single dominant event acting on polygenic deterrninants, we began our study of the chromosomes of mongols. The definition we had adopted stimulated our thinking along the lines of the well known research on Drosophila melanogaster. We were impressed with the very satisfying model that the haplo (or triplo) IV Drosophila presented. Compared to a normal fly, the triplo IV has as rough and as badly delineated chape as a mongolian child when he is compared to a normal child. Of course, we recognized the weak point of such a parallel, that "feeblemindedness" is not easily detected in a fly!



The study of the chromosomes of the three mongols who were our first patients was delayed until our technique of tissus culture was judged reliable. For the details of the technique and an expanded discussion of the results of the study, we refer the reader to another paper (7). The first step was the aseptic removal of a fragment of connective tissus. The tissus was then grown in a test tube for a week. The outgrowth of cells on a coverslip allowed, without the addition of mitosis-blocking drugs, the observation of normal mitotic figures. An hypotonic treatment was used to disperse the chromosomes, and the preparation was flattened by air dryine. Microscopic observations which revealed the chromosomes and their arrangement were then photographed. To individualize and classify the chromosomes, a photo enlargement was made, which was then carefully cut so that each pair could be reconstructed by matching the two homologues. (See fig. IV.1 showing the microscopic view of the 46 normal human chromosomes, in this case of a girl. Figure IV.2, the karyotype, shows the reconstruction of the chromosome pairs from the photo enlargernent.)



Examination of the chromosome arrangement of a normal female cell (fig. IV.2) will show a total of seven groups, including the X. The bottom row has four telocentric elements, with the centromere located at the end of the chromosome; the Y is absent. The first pair, Vh, has two small heterochromatic arms just beyond the centromere. The second pair, Vs, does not have these characteristic appendices. The full 46 chromosomes are present due to the existence of XX.

In contrast to the 46 chromosomes of the normal cell, our work has demonstrated that the mongolian cell has a total of 47 chromosomes (fig. IV.3), in particular, three instead of two Vh chromosomes. The karyotype for a mongolian boy (fig. IV.4) shows that the supernumerary on the bottom row is of the Vh type and that the Y is normal. For the mongolian girl, there are also 47 chromosomes and one extra Vh. The Y is absent, and the XX chromosomes are normal.

We presented the first descriptions of our findings on three mongols in January 1959 (8) and again on March 9, 1959 (9). Soon afterwards Ford and his colleagues (10) at Harwell confirmed our work in the one case that they studied. Jacobs and colleagues (11) at Glasgow followed shortly with similar observations on six cases. In May, Book and Fraccaro (12) at Uppsala reported similar observations on three cases and also confirmed the presence of three chromosomes of the Vh type.

At this writing, .our own group of mongols numbers 15, all of whom exhibit a characteristic extra Vh chromosome. Added together, data now exist based on the study of 25 mongols (3 Swedish, 7 English and 15 French). Each of the studies has confirmed the presence of the extra chromosome, even though the results were obtained on different tissues by different workers using different methods. In our opinion, the question of whether a normal variation of the basic chromosome number occurs in a fresh tissue culture is net relevant to the work. If only indisputable figures are recorded, there is no variation, at least in the 300 mitoses in mongolism thus far observed.

Fig. IV.1. - Microscopic view of the 46 chromosomes of a normal girl

Fig.IV.2. - Karyotype of Fig. IV.1; 22 autosomic pairs of chromosomes + 2 X chromosomes.

Fig. IV.3. - Characteristics of chromosomes in a boy with mongolism; 47 chromosomes

Fig. IV.4. - Karyotype of Fig. IV.3; 22 normal autosomic pairs + 1 X chromosome and 1 Y chromosome. Note the extra chromosome (arrow) of the Vh type.




The Origin and Influence of the Vh Chromosomes

Our cytological findings strongly suggest a trisomy, that is, the presence of three "normal" Vh chromosomes. One possible and plausible explanation for this anomaly is the occurrence of a non-disjunction process during the meiosis. Conceivably, the two homologous chromosomes, instead of each separating and migrating to its own pole, clamp together and migrate to the same pole. Observations on the fourth chromosome of D. melanogaster strongly support this explanation. Earlier work has shown that non-disjunction processes are increased by the aged female flies, a finding that corresponds well with our human data.

The presence of a trisomy serves to explain the reproductive characteristics of mongolien mothers. In as much as chromatic reduction occurs unequally in a trisomy, some eggs will receive two Vh chromosomes, and others only one; mongolien eggs will result in the first circumstance and normal eggs in the second. The unequal reduction theory also provides a means for explaining the production of either normal or mongolian children.

The trisomic theory can elucidate the resurgence of simian stigmata on the mongols palm prints. Modificator genes, accumulated through evolution, have rendered the gene determinants of these stigmata recessive. The presence of triplicate genes in the Vh chromosome could make them dominant by a gene dosage affect. The minor mongolien stigmata that may be displayed by relatives of mongols could be accounted for by the statistical bias in the diagnosis of mongolism and by the fact that the disease is individualized merely by the accumulation of certain small signs in an imbecile child. The possibility should not be overlooked that even when two parents do not carry the gene determinants of mongolien physical stigmata, they may still produce a Vh trisomic imbecile. Because the child did not display the typical features of the disease, he might be diagnostically excluded as a mongol. The authors have already encountered this bias, which can be demonstrated easily with mathematical models, in one of their "borderline" cases.



The discovery of the Vh trisomy provides a new basis for the etiology of mongolism. From our research as well as that of several other investigators, it now appears that this mysterious disease not only follows the general laws of genetics but also is the first exemple of an autosomal aberration in our species. We note, in this connection, our recent description of a second such aberration (1).

With the finding of the key to the etiology of mongolism, the next goal of research is the elucidation of its pathogenesis. Despite the congeries of different studies and approaches, the mechanisms and systems underlying the pathogenesis still defy our best efforts and understanding. The challenge in conquering this last problem before the development of therapeutic applications now passes to the biochemists.



1. LANGDON-DOWN, J.: Ethnic classification of idiots, 1866.

2. SAWYER, G. M.: Case report: Reproduction in a mongoloid. Am. J. Ment. Deficiency, 54: 204-206, 1949.

3. LELONG, M., BORNICHE, P., KREISLER AND BANDY: Mongolien issu de mère mongolienne. Arch. franc. pédiat., 6: 231-238, 1949.

4. TURPIN, P., CARATZALI, A, AND ROGIER, A.: Étude etiologique de 104 cas de Mongolisme et considérations sur la pathologenie de cette affection. Premier Congrès de la Federation internationale latine des Stés d'Eugénique, p. 154-164. Masson Edit., Paris, 1937.

5. SHUTTLEWORTH, G. E.: Mongolien imbecility. Brit. M, J., 2: 661-665, 1909,

6. TURPIN R. AND LEJEUNE, J.: I. Analogies entre le type dermatoglyphique palmaire des singes inférieurs et celui des enfants atteints de mongolisme. C. R, Acad. Sciences (Paris, 238: 395-397, 1954; II. Étude comparé des dermatoglyphes de la partie distale de la paume de la main, chez l'homme normal, les enfants mongoliens et les simiens inférieurs. C. R. Acad. Sciences (Paris), 238, 1449-1450, 1954.

7. LEJEUNE, J., TURPIN, R. AND GAUTIER, M.: Le Mongolisme, premier exemple d'aberration autosomique humaine. Ann. de Génét., 2: 41-49, 1959.

8. LEJEUNE, J., GAUTIER, M. AND TURPIN, R. - Les chromosomes humains en culture de tissus. C. R. Acad. Sciences (Paris), 248: 602-603, 1959.

9. LEJEUNE, J., GAUTIER , M. AND TURPIN, R.: Etude des chromosomes somatiques de neuf enfants mongoliens. G. R. Acad. Sciences (Paris), 248: 1721-1722, 1959.

10. FORD, C. E., JONES, K. W., MILLER, O. J., MITTWOCH, U., PENROSE, L. S., RIDLER, M. AND SHAPIRO, A,: The chromosomes in a patient showing both mongolism and Klinefelter syndrome. Lancet, l: 709-710, 1959.

11. JACOBS, P., BAIKIE, A. G., COURT BROWN, W. M. AND STRONG, J. A.: The somatic chromosomes in mongolism. Lancet, 1: 710, 1959.

12. BÖÖK, J. A., FRACCARO, M, AND LINDSTEN, J.: Cyto-genitical observations in mongolism. Acta paediat., 48: 453-468, 1959.

13. TURPIN, R., LEJEUNE, J., LAFOURCADE, J. AND GAUTIER, M.: Aberrations chromosomiques et maladies humaines. La polydysspondylie à 45 chromosomes. C. R. Acad. Sciences (Paris) 248: 3636-3638, 1959.