Metabolism of monocarbons and deficiencies of intelligence (an heuristic hypothesis)

Professor Jérôme Lejeune


Mental deficiency is assuredly the most typically human disease for only man can suffer from it. But it is also the most inhuman for it deprives patients of the most precious quality of our genetic patrimony.

Strictly speaking mental deficiency must be regarded as a symptom because a formidable array of diseases can produce it; traumas, infections, toxic substances and genetic as well as chromosomal afflictions. But a very simple example can lead us to impose some order upon this accumulation of catastrophes.


The substratum of intelligence

When Pascal discovered that arithmetic calculus could be simulated by the working of gears and rods, he demonstrated at the same time that logic can be inserted into duly shaped matter.

Nowadays computers are much more sophisticated and make use of a great number of the properties of matter and energy (jet deflection, migration of magnetic bubbles, laser impulses or the semi-conductors of integrated circuits). But all these systems like the Pascalian ones, obey three fundamental constraints:

(1) A pre-established network, logical by construction;

(2) Transmission without diffusion;

(3) A clear-cut response by each component without inertia or imprecision.

To think that these mechanisms could be a model of the thought processes would re mechanical thinking; but to state that the machines satisfy the exigencies of reason can help us to grasp some important analogies.

All the diseases affecting intelligence are characterised by one or more breakdowns affecting one or other of these three constraints.


The thinking network

1. Our brain far outclasses the most imposing machines. Some eleven thousand million neurones, interconnected by some eleven million million synapses, are an astronomical number.But the length of wiring which unites this assemblage is also astronomical. If the smallest nerve fibres were disentagled and joined end to end, they would go from here to Tokyo. But if the bundle of neurotubules (which are considered by some as the elementary wiring were unravelled, they would go from here to the moon (and possibly back)

2. Notwithstanding the remarkable discoveries of neurology, the detailed, map is far from being elucidated. Nevertheless, exactly like the repairman who observes that a whole rack of informative hardware is burning, we can detect severe anatomical destruction ruining the brain.

3. If one part of the network is lacking, like in arrhinencephaly of trisomy 13, the whole machinery is severely damaged. In the same way, secondary destruction by haemorrhage or ischaemia or infection, or compression by a tumour, or even lamination of the brain by pressure of the fluid in hydrocephalus, can damage our precious network.

4. No repair seems possible at the present time, for neurons do not divide after birth and cannot replace the damaged parts, but prevention is sometimes possible, like diversion of the cerebrospinal fluid through a valve, as in the case of hydrocephalus. In some cases the disease itself can possibly be prevented.

5. In Anglo-Saxon populations, neural tube defects, ranging from spina bifida to anencephaly (including hydrocephalus) are the most prevalent types of cerebral deficiency.

Up to very recent times neural tube defects, as they are collectively called, were only known for their curious familial, sociological, and geographical distribution. Extremely rare in sun-favoured countries, their frequency rises when one travels northwards.

(1) The lower social class of the mother is an added danger, the children of upper-class parents being less often affected. In families the risk is increased if an affected child has previously been born. In the British Isles the general prevalence is 1 in 500 infants. But if a mother has an affected child already the risk rises to five per cent for the next child.

(2) To complicate the picture, RENWICK (i) discovered that the eating of blighted potatoes was much more frequent among the mothers of affected babies than among the mothers of healthy children. This remarkable correlation remained unexplained.

(3) This mixture of environmental effects (geographical, sociological and familial recurrence) was an inextricable puzzle.

(4) In the meantime it was discovered that open neural tube defects could lead to a leakage of alpha-feto-protein (AFP) in the amniotic fluid. The level of alpha-feto-protein can be raised even in the blood of the mother; hence a possibility of early detection, eventually confirmed by amniotic fluid analysis.(

(5) In Britain for the last four years an enormous and costly systematic screening programme has been promoted in order to destroy the affected children by abortion.

(6) A recent discovery of SMITHELLS (ii) and co-workers shows us again that the correct path of medicine is never to fight the patients but to fight the disease.

(7) In the light of the data quoted earlier and noting the observation by HIBBARD and HIBBARD (iii) that mothers of neural tube defect babies have low blood levels of folic acid, SMITHELLS decided to give a polyvitamin preparation to expectant mothers (who had previously delivered an affected child). Among 178 children only one was born affected instead of the eight or nine expected. In a control group of untreated mothers (having also previously delivered an affected baby) there were 13 neural tube defects amongst 260 infants, as predicted by the recurrence statistics (5%).

Vitamin depletion could thus explain the neural tube defect and completely solve the aetiological puzzle. Certainly the vitamin content in the diet is pretty low during the winter in northern countries; probably poor women buy less expensive food than wealthy ones; they also consume less fruit or fresh vegetables (the disease is more prevalent in towns than rural areas); also some deplorable cooking habits can be deleterious, since bailing destroys folic acid.

All these fact are in accordance with the atrocious statistics of THIERSCH (iv, v) which curious enough went unnoticed. His experiments tried to produce artificial abortion in women 3-8 weeks pregnant, by administering aminopterin, which is a powerful antifolate drug (normally used against cancer cells).

A few of the surviving babies were aborted surgically and malformations were noticed: Meniningoencephalocoele, hydrocephalus, cleft palate and hare lip.One child "escaped" and was born but cleft palate and hare lip. One child "escaped" and was born but died twelve days later from anecephaly.

It is too early to proclaim that SMITHELL discoveries have definitely solved the question but for the first time a serious hope of true prevention has emerged. If these early successes are confirmed in succeeding years, it will be a classic example of good medicine: i.e., eliminating the disease and saving the children!


Transmission and insulating substances

1. The second constraint is: efficient transmission must occur without dispersion or diffusion in any part of the network because it would blur the signal and destroy the information. Such diffusion as everybody knows can cause the most refined circuit to be ruined by short-circuiting. "Spattering solders or wandering streams are mortal enemies of electronics."

2. Genetic pathology offers a vast array of examples of "diseases of the insulating substances". Direct short-circuits between bared fibres are rare but the influence of myelinization on the efficiency of transmission has been overwhelmingly demonstrated. We know with certainty that the successive steps of myelinization of the infant's brain correspond exactly in time with the appearance of motor and mental functions governed by each part of the brain. The order in which the brain regions acquire their myelin insulating sheet is the same as the order of neurological progress.

3. Conversely, many afflictions are known in which the assembly and, more frequently, the breaking down of the molecular components of insulating substances are impaired. The intermediate products accumulate and finally kill the neurons. From memory one can cite but a few of the diseases Nieman-Pick (Spyngomyeline), Gaucher (Glucoslyceramide), Krabbs (Galactosyl-ceramide), metachromatic leucodystrophy (Sulfetide) and Tay-Sachs and Sandhoff (Ganglioside).

4. Of course these "diseases of the insulators" cannot explain the large array of delays in myelinization nor the global deficiencies of cerebral growth (microcephaly) and some other mechanism has to be looked for.


The answer of the components

The binary system used by the machine is in fact a summary-of what logic is, i.e. the formal necessity of being one thing or not that thing. Each logical step must be spelled out: yes or no. Everything uncertain must be eliminated, a fact easy to understand if one remembers that reason is only a means of excluding the fortuitous and retaining the deductible.

I. The electronic gates utilise to simulate logical catenations look very much like the doors of Alfred de Musset : "Il faut qu'une porte soit ouverte ou fermée" (A door must be either open or closed). If a door is half open or a gear slipping the argument vanishes.

II. The gates of our neurons are infinitely more sophisticated than those of electronics. At each synapse, the initiating cell discharges into the synaptic cleft a specific molecule, the chemical mediator (Acetylcholine, noradrenaline, sertonin etc.). Then the chemical mediator activates the membrane of the next cell and forces it to open its ionic channels, which will immediately engulf the appropriate ions. A model of the ionic channel is hard to construct at present. (vi).

III. Exactly as a security key is exclusively accepted by the appropriate lock, each chemical mediator is "recognised" by the membrane and only the correct one works efficiently.

IV. This specific adaptation makes possible the detection of functional systems which, inside this intricate network, use a common molecular language, specific to each of them (motor system, pain transmission, regulation of the mood etc...). it is this specificity which allows the precise pharmacological effect of some drugs which excite (or paralyse) one particular system and not the others.

V. Without going into detail too far removed from our purpose, one can conceive that many disturbances of the mind could be and indeed are related to some breakdown or overrunning of some of these systems.

VI. But one thing is certain; this molecular machinery must be of extreme precision in order to manufacture at the right time, at the exact place, and in the appropriate amount, this or that molecule of the mediator. Also it must ensure its "disposal" or its "re-absorption", as soon as the desired effect has been obtained.

VII. It could well be that a large proportion of mental deficiencies are related to difficulties in this constant supply or disposal of the necessary building blocks.

VIII. An outrageously over-simplified model of these chemical gears can help to grasp these dynamic facts (vii).

IX. On such a pseudo-Pascalian machine, we can plot the enzyme blockage corresponding to various genetic diseases which produce mental deficiency. It appears that they do cluster in two regions: those of insulating sustances (as already noted) and those relating to mucopolysaccharides (components of the membranes)

X. The remaining points seem at first glance to be scattered at random over the whole system. For example, what can be common to both P.K.U., the lack of hydroxylation of phenylalamine and homocystinuria? A detailed analysis (viii) of the gearing system shows that all these breakdowns have at least one common-consequence they diminish the supply of monocarbon residues entering or leaving the folate cycle.

XI. Here we again find this vitamin which has already been mentioned in the context of neural tube defects. And it is not by chance. It could well be that the metabolism of monocarbons is of crucial. importance for the functioning as well as for the building of the whole cerebral network.


The monocarbon hypothesis

First of all, the production of the components of myelin requires a methylation of the phospholipise. Hence an intense activity of the monocarbon's cycle (the vector of which is the folate) takes place during the building of the nervous system. Moreover the production of the chemical mediators (acetylcholine in the first place) also requires this methylation activity. Even the inactivation of mediators (adrenergics for example) necessitate the appropriate methylations.

Indeed the monocarbons are not only the smallest building stones of the cerebral construction, but they are also the most frequently used in the most varying sites. Hence a general hypothesis (viii), actually purely a heuristic one, is that deficiencies in the supply of raw materials (precursors of monocarbons) or of the transport of monocarbon particles (folate cycle) or of their proper utilisation (methyltransferase) could be of the utmost importance. Many arguments reinforce this point of view. First of all, the brain possesses a folate pump, such that the cerebral concentration is always very much higher than in the remaining organs of the body (four times higher). Even in cases of folate deprivation the store in the bone marrow or in the liver is depleted long before the cerebral reserve is affected. Moreover, all the diseases blocking the transformation inside the folate cycle (xxix) or the transport of monocarbons to the transmethylases (acute depletion in B12 vitamin) cause very severe neurological and mental syndromes (ix).

Diseases related to chromosomal aberrations do not fit so easily into this general framework. Effectively, excess or lack of segments of chromosomes cause a particular syndrome, clinically recognised and specific to the segment involved. Even the syndromes resulting from an extra piece (trisomy) and those resulting from the lack of the same piece (monosomy) are mirror images like type and counter-type (x). The excess of genetic material modifies a given morphological character in a given way, and the lack of this material changes it in the contrary way.

But when considering intelligence, this does not occur. If a chromosome 21 is in excess (trisomy 21) or if it is partially lacking (monosomy 21 in mosaic) the result is always the same - a severe impairment of intelligence.

Moreover, any sizeable segment of autosome, either in trisomy or monosomy, has the same dramatic effect on intellectual capability. We do not know enough about the effects of genetic dosage to discuss here the whole of chromosomal pathology, and we will focus deliberately on the most frequent syndrome: trisomy 21 or Down's Syndrome.


The effect of genetic dosage in trisomy 21

A careful cytological and biochemical analysis remonstrates that some enzymes are under the command of genes carried by chromosome 21.

The first example was the superoxide dismutase (SOD I) which is 1.5 times more active in trisomic 21 children (xi) and which is located around zone G221 of the long arm of chromosome 21 (xii).

This excess in trisomic 21 children is expected because they have three chromosomes 21 instead of two, and they produce three times the quantity of enzyme (instead of two). Hence the ratio 1 : 1.5.

The same analysis has demonstrated that the gene of glycinamide ribonucleotide synthetase is also located on chromosome 21 (xii, xiii and xiv). A third gene, the one controlling the synthesis of protein reactive to interferon, is also on this same chromosome (xvi).

It would be premature to try to explain all that we know about Down's syndrome by the acceleration of these four reactions, although it seems very probable that their role is quite important. For example excess of glycinamide ribonucleotide synthetase could include an acceleration of purine synthesis and indeed trisomic 21 children do excrete more uric acid than normal children (xvii and xviii).If this acceleration of purine synthesis occurs it could have two probable effects : an acceleration of the synthesis of ribose (an acceleration of the hexose monophosphate shunt has been detected (xii)) and a greater utilisation of monocarbons (two of them are required for the synthesis of each molecule of purine).

The excess of SOD I could produce various ill-effects. This dismutase disposes of the superoxide radical OT2 and produces ide H2O2. This toxic hydrogen peroxide is secondarily disposed of by glutathione peroxidase which transforms it into ordinary water, H2O. Curiously, although the gene of glutathione peroxidase is not located on chromosome 21, its enzymatic activity is raised in trisomic 21 children and this elevation is correlated to their I.Q. (xii); the better they are the higher the activity. This could well be related to a detoxification effect. Generally speaking the excess of superoxide dismutase could produce two disturbances; on the one hand, the availability of the superoxide radical could be diminished (and this form of OT2 is necessary for some oxidations like indoleamine 2-3 dioxygenase) and on the other hand, toxic radicals like H2O2 (and others) could have a deleterious effect, especially in the peroxidations of the lipids (xii).

5-aminolevulinate metabolism is also of potential interest. it has been mentioned (xix) that urinary excretion of coproporphyrin was in excess only in very severely retarded trisomic 21 children. Such a wastaga of the 5-amino-levulinate could diminish the yield of 4 ceto-glutarate semialdehyde. This other product of the metabolism of 5-amino-levulinate is a very important precursor of monocarbons (xx).

The excess of interferon reactive protein could impair defence against ordinary infections and also induce a compensatory rise in gamma globulins (a fact already noted in Down's Syndrome (xviii)).

At least we can predict that trisomic 21 children might waste some monocarbons in the purine synthesis and have some shortage of supply via the 4 ceto-glutarate semialdehyde pathway.

Although these remarks remain very speculative it should be stressed that general biochemistry already gives some hints about the convergent effects we have just discussed.

Glutathione peroxidase for example needs selenium ions to perform its function. Protections against peroxidation can be achieved, on the other hand by alpha-tocoPherol (Vit. E) and the deficiency of this vitamin can be helped by selenium. But vitamin E also has a remarkable regulatory effect on the synthesis of 5-amino-levulinate dehydratase (xxi).

Hence prevention of peroxidation and 5-amino-levulinate metabolism are influenced by the same vitamin (Vit. E). It is possibly not by pure chance that enzymes of basic importance in these processes are found to cluster around the trisomy 21 syndrome. Eventually there could be some logic in the localisation of the gene on certain parts of the genome, and if it was a biochemicallyminded logic, one would not be too surprised.


Special pathology and trisomy 21

Another way of looking at the situation is to compare the major symptoms of trisomy 21 with those of other genetic diseases and to try to find some biochemical relationship between, the diseases in which are a priori very dissimilar (for discussion see (viii)).

Some examples are quite straightforward. HYPOTHYROIDISM is noted for shortness of stature and "stubbiness" of the feet and hands, very similar to those of trisomy 21. Also the flat nose and protruding tongue are features of the two syndromes. Mental deficiency is also present in both diseases. Indeed oxygen metabolism is also abnormal in hypothyroidism, but as well as this fact, an abnormality of collagen is present. Its synthesis and its metabolism are reduced and the output of 4-hydroxyproline is abnormally low.

In our organism 4-hydroxyproline is a precursor of glyoxylate, a very versatile substance which, among other facts, can be transformed into monocarbons either via the 10 formyl-THF or via the glycine to 5-10 methylene-THF. If glyoxylate is in excess, it is excreted as oxalate in the urine.

An-abnormality of this metabolism is to be suspected in trisomy 21 according to the curious findings of McCOY (xxii). Trisomic 21 children when deprived of pyridoxine (by the anti-metabolite deoxypyridoxine) excrete more oxalate than normal children. This over excretion is even increased when they also receive tryptophan. Because tryptophan is also a precursor of monocarbons via 10 formyl-THF, this curious effect could be explained if trisomic 21 child( children were using 4-hydroxyproline as a precursor of monocarbons (via the glyoxylate and the glycine) to a greater extent than normal; with deoxypyridoxine blocking the transformation, of glyoxal to glycine, the extra glyoxylate would accumulate and be disposed of as oxalate.

Here we may notice a convergence between a deficiency in monocarbons and a disorder in the collagen metabolism leading to the same morphological conditions.

IMINODIPEPTIDURIA, an extremely rare condition, reinforces this impression for the patients have features very similar to trisomic 21 children. They even show webbing of the toes, a unique palmar crease and a waddling gait, just as trisomic 21's have. The unique trouble here is the impossibility of cleaving the iminopeptide bond. Iminodipeptiduric patients lose up to 10 mg/kg. of body weight of 4-hydroxyproline daily. As a result they possibly also suffer from a shortage of monocarbons supply. They are also mentally deficient.

Other diseases such as Lesh Nyhan disease or homocystinuria, although very different clinically and bio-chemically also converge in this particular field of monocarbons shortage (See (viii) for discussion).

Even the rare Alzheimer disease, the frequency of which seems to be greatly increase in trisomic 21 adults, corresponds also to a related disturbance. As a first conclusion it can be estimated that tie monocarbon deficiency hypothesis does not contradict the general phenomenon observed in trisomy 21. Curiously a possible deficit of the methylisation process has been noted (xxiii). Beside its heuristic interest this hypothesis has the interesting consequence that a prudent use of precursors of monocarbons, and of the vitamins regulating their use, could help to answer the fundamental question: Can a rational approach to treatment of trisomy 21 be envisaged?

For example a double blind trial has been carried out, by administering serine (precursor of monocarbons via 5-10 methylene THF) as a dose of 50 mg/kg. of body weight, for six months. The children are checked every six months for I.Q. determination, and a chart has been constructed (xxiv) so that the prospective development of a child can be predicted, a priori and expressed as a fraction of the standard deviation at this age and level.

For instance the net gain (that is the observed gains minus the expected ones) can be studied before treatment, after six months' trial, and during the next six months, after cessation of the trial. On 21 children, between 5 and 8 years old, the net gain, expressed in per cent of standard deviation was -10.19 ± 46.45 before, + 26.91 ± 37.18 at the end of the trial period and - 2.23 ± 39.46 during the following period. In other words, the children did slightly better during the following period, with a probability level of 1%. No significant change was observed among the 22 children receiving the placebo.

This type of clinical research can be extended and is in progress in order to investigate whether increasing the input of monocarbon precursor could modify the expected outcome of the mental development.


An experimental approach, the xqfra syndrome

A very different approach on the possible role of monocarbons metabolism in mental deficiency is offered by a very different chromosomal anomaly, the so-called Xqfra 27 or 28 Syndrome.

Among sore mentally deficient children, more frequently of the male sex, a fragile zone is observed near to the end of the long arm of the X chromosome at the level of bands 2.7 and 2.8. Hence the name Xqfra 27 or 28. If the culture medium is deprived of folate, a gap appears at this zone, in a great number of the cultured lymphocytes (xxv). On the other hand if the folate level of the medium, is raised or if it is enriched with 5-formyltetrahydrofolate, the fragile site remains unaffected (xvi). Recently we have confirmed these findings (xxvii) arid even demonstrated clearly that the addition of precursors of monocarbons (like serine, 4-hydroxyproline or 5-amino-levulinate) could also protect the fragile site, even in a rather low folate medium.

It is much trio early to conclude that these in vitro experiments will lead to a direct application in vivo. Already we have obtained some interesting indications that 5-formyltetrahydrofolate can cure the fragility in vivo and at the same time greatly ameliorate the clinical condition. But the crucial question cannot yet be fully answered: is a bio-chemical cure of the condition possible? And if achieved would it modify the mental development of the affected children? At least it seems plausible that this particular disease willfurnish a remarkable experimental model. When a few drops of blood are put into a culture with monocarbon precursors added, the entire metabolic process can be gone thro without any danger or discomfort to the patient. For the first time a chemical and chromosomal disease related to mental deficiency is amenable to true experimental procedures in vitro.



At the end of this too brief though too broad review, it appears that new avenues of research for the prevention and cure of diseases affecting the intelligence have now been opened up. Until recent years the role of monocarbon metabolism has been related only to the synthesis of nucleic acids, hence the importance of the folate (and the anti-folate) drugs, in the whole field of malignant and haematological disorders. But it now appears that the real role of monocarbons greatly exceeds this restricted point of view and already neuropsychological correlations have been demonstrated between the utilisation of folate derivatives and the functioning of the brain (xxviii). These independent studies are clearly pointing in the same direction as the general hypothesis we have just discussed.

It would be unreasonable to state that all mental deficiency states are the result of a disorder of monocarbon metabolism, but it must seriously be considered that this perspective is worthy of careful examination.

The patient analysis of gene dosage effects, together with the clinical evaluation of symptoms common to very different conditions are probably the best way to mount a convergent assault against mental deficiency and its causes.

The difficulties of such an endeavour are numerous, the length of the road is unpredictable and in facing the vastness of the task and the tremendous necessity of achieving it, the motto of research is self dictating: we will never give up.



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