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
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
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
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.
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
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
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.
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
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.