Mental handicap is cured mechanics

General Practitioner, May 15


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Fifteen years ago Professor Jérôme Lejeune identified a fragile X chromosome in three mentally retardated children - two boys and a girl.

It wasn't the first time the Professor had discovered a chromosomal abnormality since it was he who identified the extra chromosome of Down's syndrome in 1958.

But it was not until three years ago that the 'fragile' chromosome was confirmed as a misty area at the end of the long arm of the X chromosome.

More than this, it seemed that if cells containing the faulty chromosome were deprived of folic acid - an important reservoir for the basic chemical monocarbons used to build membranes - a gap would appear at the fragile zone.

No one knows exactly what this region of the chromosome codes for but there is no doubt that boys with the aberration are mentally retarded and, to a lesser extent, so are girls. This difference between the sexes is logical since, while the girls can make up for the disorder with their second, normal X chromosome the boys remain at a disadvantage.

Increase the folate supply to the cells and the gaps in the chromosomes disappear.

Monocarbons are exactly what they sound : Small mole-cules with a single carbon atom surrounded by hydrogen, hydroxyl or almost any other che-mical group. Those which Professor Lejeune has become most interested in, at his Paris laboratory in the school of medicine, are the methyl - CH3 -groups.

In fact. he has based a whole theory around their central metabolic role. Methylation is one of the commonest metabolic reactions. It accounts for the production of neurotransmitters such as acetylcholine and for the deactivation of adrenergic transmitters. It occurs when methyl groups are added to phospholipids in the production of myelin essential to nerve function.

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Mental retardation is consequence

If the availability of monocarbons for all these vital nerve functions is low - as seems to be the case - then it follows that mental retardation could well be a consequence.

The theory is neat but what of the reality ? To test his hypothesis Professor Lejeune and his colleagues used blood lymphocyte cells to examine the chromosomes from 13 people carrying the fragile chromo-some in their genetic material. They looked at no fewer than 44 629 mitoses in these cells.

The lymphocytes were sub-jected to a variety of chemicals - same which were known to - and donate methyl groups such as - and others which were known to take up methyl groups and prevent them from working.

Normally, patients have 10 to 30 per cent of their X chromosomes afected. Professor Lejeune found that the number of cells with the chromosomal gap was significantly less when they were subjected to methyl donors but remained much the same when chemicals which did not donate methyl groups were used.

Most striking was the effect ot THF. In control cultures not exposed to any chemical 1,109 chromosomes of 3,006 dividing cells has the gap at the fragile zone. But when THF was given only 14 of 3,500 chromosomes showed the same deformity.

In other words the propor-tion of affected chromosomes was reduced from 22 per cent to a fraction of its former value - 0.4 percent.

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Spectacular results

These impressive results were published in February (C. R. Acad. Sc. Paris 1981, 292, 491) together with the only clinical application of the theory yet attempted. This refers to a 10-year-old boy with the fragile chromosome syn-drome whose mental disturb-ance was so se\ere that he was in danger of doing himself permanent physical damage. He was given a daily injection intra-muscularly of 50 mg of 5-formyl-THF for eight days.

The results, explains Professor Lejeune, were spectacular. The boy was calmer and less disturbed and there was an immediate improvement in his general psychiatric condition. His lymphocytes were tested during the whole period and it emerged that while 45 out of 283 X chromosomes showed a gap in the fragile region before treatment only three of 528 chromosomes were found to be abnormal after eight days' treatment.

After the eight days the folate injections were stopped and the boy relapsed both psychologically and in his cellu-lar profile almost immediately. So treatment was restarted with the same remarkable effect.

' At one time everyone said you just cannot help patients with genetic diseases.' says Professor Lejeune. ' What they should have said is that we cannot treat them now '. But there are things that can be done as we are now showing for fragile chromosome and I be-lieve for many other types of mental disturbance including Down's syndrome and spina bifida. '

Professor Lejeune does not believe that the fragile chromo-some disorder is due to a folate deficiency itself but to some disturbance of monocarbons - transfer to other metabolic pathways.

Professor Richard Smithells provided evidence last year to suggest that multivitamin treat-ment in women who have had spina bifida baby might prevent further affected children. And folate deficiency has been im-plicated in spina bifida since the late 1960s.

So it all lies in well with Professor Lejeune's theory of monocarbons. Fragile X chromosome is not a rare disease - it may be as common as Down's syndrome, and prob-ably one in 1,000 children are born with it each year.

Professor Lejeune believes that much more menial illness may be treatable than first thought. Having discovered the genetic deformity of Downs syndrome his big hope is to discover a cure for the mental aspects of the disease.

He is adamant that there will be no miracle cures and he is worried about prematurely arousing the hopes of parents of Down's children.