Is the fragile X syndrome amenable to treatment?

Jérôme Lejeune

The Lancet, January 30,1982.


Sir, - Interest in the in utero detection of the fragile X chromosome for the purpose of aborting affected fetuses (10-13) seems to have blurred the real prospect open to research.

The fragility of the X chromosome can be rectified in vitro by thymine, folic acid, 5-formyltetrahydrofolate (14), or even aminoacids, precursors of " monocarbons " (15). Monocarbons are moieties of molecules containing only one carbon atom, such as -CH3, - CH2-, -CH=, -CHO2 and -CH=NH, and are carried by the reduced form of folic acid (tetrahydrofolate). These monocarbons are used for the synthesis of the purine bases adenine and guanine and the pyrimidine base thymine and are thus indispensable to DNA and RNA production. The reduced monocarbons are also supplied to the transmethylase systems through the methylation of homocysteine to methionine, leading to S-adenosylmethionine, the common donor of methyl groups. The transmethylases control the building and the functioning of the nervous system, through the synthesis of myelin (methylation of phospholipids) and through the production and secondary inactivation of chemical mediators (methylases and catechol-O-methyltransferases).

These facts and data on genetic diseases producing mental retardation led to the hypothesis that monocarbon troubles could be a major cause of meptal deficiencies (16). Althrough some confirmation of this hypothesis is afforded by the fra(X) syndrome, this mechanism has not yet been sufficiently investigated.

In vivo, folic acid, 5-formyltetrahydrofolate, and donors of monocarbons such as dimethylaminoethanol (all non-toxic substances of everyday use in medicine) dramatically reduce the fragility of the X chromosome when given to patients (17). The clinical effects of this medication are even more important : the psychosislike symptoms, if present, are greatly reduced after a few weeks. Of our sixteen patients eight had severe behavioural trouble, ranging from " psychotic complication of mental retardation " to " autistic status noted from infancy ". The letter by Dr Brown and colleagues (Jan. 9, p. 100) on autism and fra(X) is confirmation of this association of psychosis-like trouble with fra(X) syndrome. Of our eight psychotic-like, fra(X) patients, seven have been much improved by folic acid, and especially by 5-formyltetrahydrofolate at intramuscular doses around 0.5 mg/kg body weight daily. Three are close to a total recovery from their psychosis-like symptoms (18).

Assessment of improvement in mental retardation requires a longer study to interpret correctly any psychometric changes. Perhaps a European cooperative study should be set up to assess the long-term benefits of chemical management.

As far as early diagnosis is concerned, an interesting possibility could be the treatment of pregnant fra(X) women. Re-equilibration of the monocarbon metabolism could protect affected fetuses. One reason for this hope is our experience with a 1½ year od child with fra(X) who was profoundly hypotonic and totally uninterested in his surroundings. After 2 months of oral treatment with folic acid 1 mg/kg body weight daily he was able to sit and crawl on all fours and became aware and responsive.

Research on the treatment of fra(X) patients has only just begun but this could be the first example in the history of cytogenetics where a chromosome associated disease related to a partly understood chemical abnormality has proved amenable to treatment. Preliminary findings give rise to the hope that cytogenetics will some day become another chapter of true medicine-that is, curative medicine.



10. Jenkins EC, Brown WT, Duncan CJ, Brooks J, Ben-Yishai M, Giordano FM, Nitowaky HN. Fessibility of fragile X chromosome prenatal diagnosis demonstrated. Lancet 1981 ; ii: 1292.

11. Shapiro LR, Wilmot PL, Breholl P, Leff A, Martino M, Harris G, Mahoney M, Hobbins J. Prenatal diagnosis of fragile X chromosome. Lancet 1982; i: 99.

12. Mattei MG, Mattei JF, Vidali, Giraud F. Expression in lymphocite and fibroblast culture of the fragile X chromosome : a new technical approch. Hum Genet 1981; 59: 166-69.

13. Sutherland GR, Jacky P. Prenatal diagnosis of fragile X syndrome. Lancet 1982; i: 100.

14. Sutherland GT. Heritable fragile sites on human chromosomes. I: Factors affecting expression in lymphocyte culture. Am I Hum Genet 1979; 31: 125-35.

15. Lejeune J. Site fragile Xq27 et métabolisme des monocarbones. CR Acad. Sci Paris 1980; 200: (ser D) : 1075-77.

16. Lejeune J. Investigations biochimiques et trisomie 21. Ana Génét Paris 1979; 22: 67-75.

17. Lejeune J. Maunoury C, Rethore MO; Prieur M, Raoul O. Site fragile Xq27 et métabolisme des monocarbones : Diminution significative de la fréquence de la lacune chromosomique par traitement in vitro et in vivo. CR Acad Sci Paris 1981; 292 (ser III): 491-93.

18. Lejeune J. Le métabolisme des monocarbones et le syndrome de l'X fragile. Bull Acad natl Méd 1981; 163 (session of Dec. 1, 1981).