Renato Cocchi M.D., Ph.D. (Sociology)
Italian Journal of Intellective Impairment 3 (2): 179-183 (1990 Nov)
  Reprinted with the permission of Renato Cocchi
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Summary

In the biological history of a Down subject, apart from the critical moment of conception as the starting point for an organism affected by an extra chromosome 21, birth may be an event that can heavily influence many negative biological developments.
An excess of compensatory glutathione peroxidase, alveolar pulmonary degeneration, myelination reduction, the greater risk of being affected by cerebral palsy, and accelerated reduction in visual cortex cells, all find their beginnings following birth. Four out of five of these events were certainly not present in the foetal stage.
The most probable hypothesis is that the maternal organism, in various ways, protects the Down foetus from the excess stress and can maintain compensated, at least in part, the homeostasis disturbed by 50% acceleration of all the metabolisms whose enzymes have control genes in chromosome 21.
If this were indeed the case, it would be therefore necessary to carry out compensatory therapy from the very first days of life.

Key words: Down's syndrome; birth; homeostasis; negative outcomes.

Obviously a Down subject becomes such a person because during conception either a maternal or paternal gamete (in the pure trisomy 21 and translocation forms) has introduced an extra chromosome 21, due to an error during the meiotic division; or is such because during the first mitotic divisions of the fertilized egg, for some reason one cell has retained an extra chromosome 21 (in the mosaic forms).

Right from the moment of conception therefore, the embryo — and successively the Down foetus — is subjected to an endogenous biological stress due to the 50% acceleration of all the enzymatic metabolisms who have their control genes (no longer two, but three) allocated to chromosome 21 (Cocchi 1984).

This fact needs full consideration, given the somatic modifications present in nearly all Downs subjects at birth, and the malformations that frequently accompany them (e.g. in 20-25% of cases, cardiac defects requiring surgical intervention).

From research into Down's syndrome to which I am personally contributing, five data referring to different structures have come out and four of these show large differences between before and after birth.

Each of these by itself may just seem odd but when put together the common denominator evidently points towards birth as a break point in an already precarious balance.

Pre- and post-natal differences in Downs

As well as 50% increase of the enzyme Superoxide-dismutase 1 (SOD-1), due to the presence of a third control gene allocated to chromosome 21 (Sinet et al., 1974; Sinet et al., 1976; Crosti et al., 1976; Feaster, Kwok & Epstein, 1977; Jezorowska et al., 1982; Neve et al., 1983; Brooksbank & Balasz, 1984), there has also been found, following birth, a roughly 30% compensatory increase in the enzyme Glutathione peroxidase (Sinet, 1975: Sinet, Lejeune & Jerome, 1979; Agar & Hingstoen, 1980; Neve et al., 1983).

Both these enzymes are scavengers of oxygen's free radicals, very toxic for the brain cells. Brooksbank & Balasz (1984) in comparing the foetal brain of Down persons with that of normal subjects of a similar gestation period, found the expected increase of SOD-1, but not the increased Glutathione-peroxidase.

The compensatory increase in this enzyme is therefore seen to be something that manifests itself only after the birth.

The development of the alveolar pulmonary acini has been investigated using a radiological count in Down patients (Cooney, Wentworth & Thurlebeck, 1988). While the lungs when fully formed in the foetus were found to be sound and the complexity of the alveolar acini was normal, already at four months following birth there was a reduction in the complexity of the acini, visible both to the naked eye and through the microscope.

Using the microscope, it was possible to see a numerical decrease in acini, their dilation with, often, a double capillary system that makes up a very singular phenomenon never previously described. Here too, the alterations discovered show them to be ONLY post-natal. A deficit in cerebral myelination has been found in Down subjects deceased between the beginning of the post-natal period until the age of six years.

The number of subjects affected increases with age and is much higher than that of the control subjects for which similar retardation is found only up to the age of four months. There is no retardation in myelination, compared to the control subjects, in Down subjects deceases at foetal or neo-natal age (Wisniewski & Schmidt-Sidor, 1989). Also here the deficit found is only post-natal.

In a consecutive non select series of 470 Down subjects no evidence of infantile cerebral palsy (CP) of pre-natal or peri-natal origin has been found. Following the risk percentages calculated by Susser et al., 1985, only for the presence of prematurity or low birthweight or both, we should have expected at least three cases of CP, a number that should have been higher bearing in mind the strong presence of series of other non-optimality and risk factors (Cocchi & Branchesi, 1988).

On the other hand however, from the whole series, there are 3 Down children affected by CP of an exclusively post-natal origin (Cocchi, 1990).

Even in Downs, we cannot rule out the possibility that the CP may be the effect of pathological events having taken place in the pre-, peri-, and neo-natal periods, the onset periods for CP in the most part of normal subjects.

Such an obvious discrepancy between what happens with normal infants compared to this series of Down children has led, and leads, to the hypothesis that up to birth, in some way there is a protection against the damages of hypoxia-anoxia, but this diminishes at birth and lessen with age. The fact that the compensatory increase in glutathione peroxidase only appears after birth supports the theory that it plays a precise role in allowing the organism to defend itself against the toxic action of oxygen free radicals. The problem of such a toxic action in Down subjects, of particular interest from a speculative point of view, as a possible causal explanation for Alzheimer's dementia, had already its discussion in this journal (Cocchi, Somenzini & Zerbi, 1988).

Finally, by comparing the brain of a six-year-old Down child to that of a same age normal subject, there was net reduction in aspinous stellate cells particularly evident in area 17 (primary visual area) and, somewhat less, in area four (primary auditory cortex). These are cells that use GABA as their main neurotransmitter (Ross, Galaburda & Kemper, 1984).

Further studies have been carried out on the dendritic development of the visual cortex in 8 Down children, ages ranging from 4 months to 7 years, deceased due to non neurological causes. Compared to 10 non-Down control subjects of the same age, it was found that only in the first group there is evidence, between six months and two years, of a progressive mental atrophy, while the dendritic development is superior to that of the normal group in the brains of Downs of less than six months old (Becker, Armstrong & Chang, 1987).

Here too, the degenerative process has no foetal origin as it is not present until six months of age. The process begins only after birth. It is however known that the corticosteroids, among which we find cortisol — physiologically excreted in stress conditions of any nature (physical, chemical, biological and metabolic, psychological), — reduce the dendritic development of the nerve cells (De Kosky, Sheff & Cotman, 1984).

Discussion

Four pathological effects; The compensatory increase of glutathione peroxidase, the numerical reduction and structural transformation of the alveolar pulmonary acini, the reduction of myelination, and the dendritic reduction of the visual cortex can be said to start only following the birth of the Down subject.

Sensitivity to anoxia and to relative cerebral damage from the production of oxygen free radicals, is a process that grows after birth, as confirmed by the discrepancy between CP of pre-, peri-, neo-, and post-natal origin in Downs, and the compensatory increase of Glutathione-peroxidase, a scavenger of oxygen free radicals.

The dendritic reduction already present at six months, particularly evident in the visual cortex, is a phenomenon that is surely connected to stress, to that condition of permanent biological stress caused by the acceleration of all the metabolism due to the presence of a third control gene over the relative enzymes, increased by the stress of the actual childbirth.

Drawing on research carried out on deceased subjects, even though the causes were not neurological, it was seen that the illness led to death also due to inadequate non specific individual resistance, a phenomenon in which stress plays a prominent role.

In general however, birth seems to be a time of sudden acceleration of a pathological process already in course, characterised by a sharp change in its linearity (catastrophe), and so certain apparatuses become attacked "ex-novo." Having summarised these facts, certain hypotheses may be put forward which are not mutually exclusive:

  1. The stress undergone by the Down foetal organism during birth surpasses its tolerance limit, setting off new pathological processes;
  2. The change over to a low sensitivity threshold along the sensorial channels, the entrance to which are no longer filtered by amniotic liquid and by maternal teguments, leads to an excess of glutamergic stimulation. It is known that glutamate is the main neurotransmitter for all the afferent pathways (Fagg, 1985) and that in moments of stress it becomes more neurotoxic (Sapolsky, 1986).
  3. The antistress substances that the mother could pass through the placenta (precursors of GABA like glucose and glutamine, and pyrodoxine) are missing, and their substitution may prove lacking.

This all implies that, right from birth, a Down subject requires substituting intervention able to act on these processes, or at least slow them down. Such intervention, despite the advice of many ill-informed medical specialists, can only be pharmacological, using as far as possible physiological substances.

These are however ideas that, for the moment, at least in Italy, are not widely accepted, for ideological refusal as well as the more practical lack of knowledge about information that strangely enough is actually available.

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