DOES
S-ADENOSIL-L-METHIONINE (SAMe) DECREASE
ARTICULAR LAXITY IN DOWN CHILDREN?
Preliminary report
Renato COCCHI MD, a neurologist
and a medical psychologist
Summary
Since 1986 Down subjects treated by drug
therapy were also given oral S-adenosyl-l-methionine (SAMe) because a decreased
new synthesis of this physiological compound by trisomy 21 carriers. One
observed effects has been the reduction of the articular laxity, when this
symptom is present. This preliminary report deals with the biochemical
feasibility of such a result.
Key words: Down's syndrome; S-adenosyl-l-methionine; articular
laxity; improvement; theoretical premises.
Down Syndrome
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Within a drug regimen prescribed to Down's
syndrome Ss since 1979, starting from 1986 I added S-adenosil-l-methionine
(SAMe)
Studies of Lejeune and al., 1986 justified
its prescription. These researchers noted the need for a larger supply of
tetrahydrofolates and SAMe because the excess activity of the
cystathionine-beta-synthetase. This one was found three times higher in those
persons (Skovby, Krassikoff and Francke, 1984; Chadefaux, 1985).
The whole result, as limited to this
biochemical pathway, beyond an anomalous homocysteine metabolism by an
increased turnover due to a larger demolition, is also a general methylation
deficit, already suggested in 1958 by Gershoff, Hegsted & Trulson.
SAMe metabolic activities.
According to the review of Stramentinoli
(1987a) where I found the following data, the synthesis of the SAMe comes out
from the methionine and the ATP; it is a physiological compound of paramount
importance and it is part of every living cell.
Supposedly the SAMe has the second place soon
after the ATP as for the various reactions it helps as cofactor. It is involved
in three leading biochemical mechanisms such as transmethylation,
transulfuration and aminopropylation.
As for the transmethylation itself, the SAMe
takes part in more than 40 biochemical processes. In them there is a transfer
of the methyl group to various substrates, among which nucleic acids, proteins,
lipids.
As for the osteo-articular system, antipain and
functional effects of the SAMe in osteoarthrites are out of any discussion
(Ceccato et al., 1979; Cucinotta, Mancini and Ceccato, 1980; Marcolongo et al.,
1985; Caruso and Pietrogrande, 1987; Berger and Novak, 1987; Koenig, 1987;
Maccagno et al., 1987).
During experiments on "in vitro"
cartilaginous cells cultures, Hermand et al., 1987 found a specific effect on
these cells metabolisms, with the stimulation of their proteins synthesis. In
the surgically induced rabbit knee osteoarthritis, the microscopy investigation
of the lesion, showed a protective effect of the SAMe on the cartilaginous
cells of the proband animals (Barcelo` et al., 1987).
The therapeutic effect clinically seen in
men in this way found confirmation both in animal experiments and in the treatment
of in vitro cell cultures. As for we are interested in, the SAMe induces a
proliferating stimulation of the cartilaginous cells.
Articular laxity in Down subjects
Among various motor impairments the Down
child could have hypotony and articular laxity too. Hypotony seems a symptom
that comes out from a cerebellar trouble, already noted by some researchers
(Lambert & Rondal, 1979, Cocchi, 1987). Till now articular laxity,
sometimes not present, did not find its reason. We can have at least two suggestions:
- First, for an unknown cause, tissues of
articular ligaments are more elastic then in normal people, so allowing a
greater excursion of that same articulation;
- Second, it could stand an impairment between
the possible normal growth of the articular tissue, and the possible inhibition
of the bones of that same articulation.
There is only one clinical report on the
positive effects of the SAMe on primitive muscular fibres' pain, as poor
support of the first suggestion. Its interpretation is quite doubtful since
these effects do not seem attributable to a local action but to the
antidepressant action of the SAMe (Tavoni et al. 1987).
As for the second hypothesis there are more
than one supportive element. First we need to remember that the bones' growth
depends on the activity of bones cartilages of growth, which is function of
available homocysteine.
Of there is homocysteine excess, as it happens in
homocystinuria - an illness where the enzyme cystathionine-beta-synthetase is
lacking -, people affected should be toll, thin, with many folds in flexing
surfaces (Groebe, 1980).
In Down Ss we can find nearly exact the
opposite. The 50% increasing of the same enzyme activity (the so-called
"dosage effect") more actively metabolizes homocysteine, so reducing
its availability. Then we have short, fat individuals with reduction of flexing
folds (Lejeune, 1979). On the other hand we know that cysteinic acid stimulates
body growing in rats (Clopath, Smith and McCully, 1976)
SAMe and possible lowering of articular laxity in Downs.
Since homocysteine comes out from the SAMe,
the prescription of SAMe could then drive, among other results, to a larger
availability of homocysteine. Consequently it could drive to an increased
activity of growing bones cartilages, in the years when the body grows.
By this way we could reach a reduced
imbalance between articular tissues and articular bones size, so decreasing the
articular laxity.
This one is a suggestion not too ease to
verify, even because many variables coexist.
First, there is the fact that I add the SAMe to
the previous regimen in a second time, having started the treatment with
antistress drugs (Lamma and Cocchi, 1988; Cocchi, 1990).
Second, the prescription of the SAMe as the
sole drug seems to have contradictory effects on psycho-endocrine responses to
stress (Stramentinoli, 1987b). So it could be difficult to use it as
monotherapy in Down persons.
Finally, I cannot affirm that improved
articular laxity has a necessary link with the SAMe. Nevertheless, I noted this
result on children with articular laxity only after I added the SAMe to the
regimen.
Conclusions
The anecdotal observations of articular
laxity decreasing, when present, after adding the SAMe to the drug regimen in
Down Ss, led me to discuss if and how such a result was feasible, in order to
avoid the logical fallacy of the post hoc ergo propter hoc.
From a biochemical point of view a similar result
could justify the clinical observations, but an exact verification shell need a
difficult investigation because of many variables involved.
References
Barcelo` H.A., Wiemeyer J.C.M., Sagasta
C.L., Macias M., Barreira J.C.: Effect of S-adenosylmethionine on experimental
osteoarthritis in rabbits. Am. J. Med. 1987. 83 (suppl. 5A): 55-59.
Berger R., Novak H.: A new medical approach
to the treatment of osteoarthritis: Report of an open phase IV study with
ademetionine (Gumbaral). Am. J. Med. 1987. 83 (suppl. 5A): 84-88.
Caruso I., Pietrogrande V.: Italian double
blind multicenter study comparing S-adenosylmethionine, naproxen and placebo in
the treatment of degenerative joint disease. Am. J. Med. 1987. 83 (suppl. 5A):
66-71.
Ceccato S., Cucinotta D., Carapezza C.,
Passeri M.: Indagine clinica aperta e comparativa sull'impiego della SAMe e del
ketoprofen nell'osteoartrosi. Prog. Med. 1979, 35: 177-191.
Cucinotta D., Mancini M., Ceccato S.: Studio
clinico controllato sull'attivita` della SAMe somministrata per via parenterale
nella patologia osteo-articolare. Clin. Med. 1980, 61: 553-556.
Chadefaux B., Rethore` M.O., Raoul O.,
Ceballos I., Poissonnier M., Gilgenkranz S., Allard D.: Cystathionine beta
synthetase: Gene dosage effect in trisomy 21. Bioch. Biophys. Res. Comm. 1985,
1: 128:132-144.
Clopath P., Smith V.C., McCully K.S.: Growth
promotion by homocysteic acid. Science 1976, 192: 372-374.
Cocchi R.: Presenza di scavengers e
incidenza di paralisi cerebrali infantili da prematurita` e basso peso alla
nascita in 381 soggetti Down allevati in famiglia. Giorn. Neuropsich. Eta`
Evol. 1987, 7: 317-323
Cocchi R.: The use of drugs to modulate
stress responses reduces the time of intensive care needed bù Down children to
ricover after open-heart surgery. Ital. J. Intellect. Impair. 1990, 3: 11-16.
Gershoff S.N., Hegsted D.M., Trulson M.F.:
Metabolic studies of mongoloids. Am. J. Clin. Nutr. 1958, 6: 526-530.
Groebe H.: Homocystinuria (cystathionine
synthetase deficiency). Results of treatment in late-diagnosed patients. Eur.
J. Pediatr. 1980, 135: 199-203.
Harmand M.-F., Vilamitjana J., Maloche E.,
Duphil R., Ducassou D.: Effects of s-adenosylmethionine on human articular
chondrocyte differentiation: An in vitro study. Am. J. Med. 1987. 83 (suppl.
5A): 48-54.
Koenig B.: A long term (two years) trial with S-Adenosylmethionine for the treatment of osteoarthritis. Am. J. Med. 1987. 83 (suppl. 5A): 89-94.
Lambert J.L., Rondal J.A.: Le mongolisme. Mardaga, Bruxelles 1979..
Lamma A., Cocchi R.: Drug therapies of
bruxism in Down children: Preliminary report. Ital. J. Intellect. Impair. 1988,
1: 19-24.
Lejeune J.: Investigations biochimiques et
trisomie 21. Ann. Genet. (Paris) 1979, 22: 67-75 .
Lejeune J., Rethore` M.O. et al.:
Metabolisme de monocarbones et trisomie 21: sensibilite` au
methotrexate.(Dattiloscritto) Universite` Rene` Descartes, Paris 1986..
Marcolongo N., Giordano N., Colombï B. et
al.: Double-blind multicentre study of the activity of S-adenosyl-L-methionine
in hip and knee osteoarthritis. Curr. Ther. Res. 1985, 37: 82-94.
Maccagno A., Di Giorgio E.E., Caston O.L.,
Sagasta C.L.: Double-blind controlled trial of oral S-adenosylmethionine versus
piroxicam in knee osteoarthritis. Am. J. Med. 1987. 83 (suppl. 5A): 72-77.
Skovby F., Krassikoff N., Francke V.: Assignment
of the gene for cystathionine beta synthetase to _human chromosome 21 in
somatic cell hybrids. Hum. Genet. 1984, 39: 291-294..
Stramentinoli G.: Pharmacologic aspects of
S-Adenosylmethionine - Pharmacokinetics and pharmacodynamics. Am. J. Med. 1987a,
83 (suppl. 5A): 35-42.
Stramentinoli G.: Neuroendocrine effects of
S-adenosylmethionine (SAMe) (dattiliscritto). BioResearch, Milano 1987b.
Tavoni A., Vitali C., Bombardiere S., Pasero
G.: Evaluation of S-adenosylmethionine in primary fibromyalgia: A double-blind
crossover study. Am. J. Med. 1987. 83 (suppl. 5A): 107-110.
First published in Italian on Riv. It. Disturbo Intellet. 1990, 3: 141-143.
Translated for Internet on August 2001.
Author's address: dr. Renato COCCHI, via
Rabbeno, 3
42100 Reggio Emilia (Italy)
renatococchi@libero.it
Down Syndrome
Mental Retardation
Drugs
Symptoms
Italian translation
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