BIRTH - THE SECOND
BREAKPOINT IN THE DOWN SUBJECT'S
BIOLOGICAL BALANCE:
CONFIRMATION AND IMPLICATIONS
Renato COCCHI, a
neurologist and a medical psychologist
Summary.
In the biological history of a Down
subject, apart from the critical moment of conception as the startingç point
for an organism affected by an extrachromosome 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.
Down Syndrome
Mental Retardation
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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 (eg 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
previosulsy 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 lessenó 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 oć 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 fourą (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
neurotransmiter 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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First printed on It. J. Intellect. Impair. 1990, 3:179-183.
Author's address dr.
Renato COCCHI, via Rabbeno, 3
42100 Reggio Emilia (Italy)
renatococchi@libero.it
Down Syndrome
Mental Retardation
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