Fragile X Syndrome
by S Kashif Haque

Mental retardation is a very common clinical problem with a prevalence in the human population of about 1-2%. Genetic forms of mental retardation account for about half of the severely retarded patients. The most frequent of all genetic forms of mental retardation is fragile X (FRAXA) or Martin-Bell syndrome. This particular form of mental retardation has been estimated to affect approximately 1 in 1250 males and 1 in 2000 females.

Fragile X can be detected at three levels: whole body symptoms, abnormal chromosomes, and DNA level mutation. Body symptoms have a diverse range of expression and can include: mental impairment ranging from learning disabilities to mental retardation, attention deficit and hyperactivity, anxiety and unstable mood, autistic-like behaviors, long faces with coarse features, large lopsided ears, flat feet, large testicles, hyperextensible joints, and sometimes even mild heart abnormalities. Since the gene that causes fragile X is on the X chromosome, and females carry two X chromosomes while males carry only one, fragile X is therefore expressed more frequently and with more severity in males. Fragile X can be detected at the abnormal chromosomal level by the fact that,when fragile X chromosomes are cultured in a medium lacking the vitamin folic acid, a characteristic constriction can be seen near the end of chromosome Xq27.3 (Eichler et al. 1993).

At the DNA level, fragile X can be detected due to excess methylation (addition of CH 3 groups) to a CpG island, which is a stretch of sequence preceding the structural gene called FMR-1 (See Fig. 1-2 below). This excess methylation was found to occur due to a large increase in the number of CGG repeats just upstream from the FMR-1 coding region (Fig. 1-2). In the normal population the number of CGG repeats varies between 6-50. CGG repeat numbers between 50 and 200 (premutations) have been observed in unaffected carrier males and females. In persons diagnosed with severe fragile X, such as Barry and Joseph, in the pedigree in Fig. 1-1, this sequence has been found to repeat between 200 to 1,000 times. Due to this large number of repeats, transcription suppression of the promoter region of FMRP occurs, which results in the absence of the encoded protein FMRP. This lack of FMRP protein is believed to be responsible for the fragile X symptoms (or phenotype) that are manifested.

Carrier men (transmitting males) have been found to pass the premutation to all of their daughters but none of their sons. Each child of a carrier woman has a 50% chance of inheriting the gene. The fragile X premutation can be passed silently down through generations in a family before a child is affected with the syndrome. In addition, fragile X has been found to display "anticipation" or a worsening of symptoms with each generation. Often a severely affected boy would have been found to have had a mildly retarded grandfather. Anticipation has been found to have a physical basis in the increasing number of CGG repeats. The fragile X phenotype has also been found to be incompletely penetrant, that is, 20% of the males who have the same microscopic symptoms as carrier females (intermediate increase in CGG number and normal methylation of the CpG island) have no symptoms. In some cases, even with the lack of the fragile site on the X chromosome, the manifestation of the fragile X mutation has been found to occur.

Current medical research in terms of treatment for fragile X has been focusing in on: (1) gene therapy, studying the gene that causes fragile X in order to determine whether a healthy gene may be inserted into the DNA of affected individuals, thereby replacing the mutated ineffective gene, (2) protein replacement therapy, studying the protein product that is found lacking due to the mutation, in hopes that the protein may be supplemented from an external source, and (3) psychopharmacology, treating symptoms of the disorder with medications. Based on this current work, experts believe that the missing FMR protein has a regulatory function in the brain, rather than a structural one, and that this protein is needed throughout a person's life. Also, current research (Vaisanen et. al 1996) has also found reductions in paternal transmissions of premutations. These reductions have suggested an intergenerational reduction in the CGG repeat from premutation size to the normal size range and stable transmission of the contracted repeat to the next generation.

Work on this particular disease has paralleled that of other inherited diseases in which an expansion of unstable trinucleotide repeats has been shown to be the causative mutation, such as myotonic dystrophy and several neurodegenerative diseases, such as Huntington's disease, spinal and bulbar muscular atrophy, spinocerebellar ataxia type 1, dentatorubral-pallidoluysian atrophy, and Machado-Joseph disease. It is hoped that this research as well as that of others in this rapidly expanding field, will lead to more effective ways of coping with this terrible disease and possibly even a cure in the near future.


Brown WT, Nolin S., Houck GE Jr., Zhong N., Glicksman A., Ye L, Ding X, et al (1994) Reverse mutations in Fragile X syndrome. Am. J Hum Genet Suppl 55: 1246.
Eichler E., Richards S., Gibbs R., Nelson D. (1993) Fine Structure of the Human FMR1 gene. Hum Mol Genet 2: 1147-1153.
Hagerman RJ, Silverman AC (1991): Fragile X syndrome: Diagnosis, Treatment, and Research. John Hopkins University Press.
Vaisanen M-L, Haataja R., Leisti, J. (1996) Decrease in CGG Trinucleotide Repeat Mutation of the Fragile X Syndrome to Normal Size Range During Paternal Transmission. Am J Hum Genet 59: 540-546.
Warren ST, Nelson DL, (1994): Advances in molecular analysis of Fragile X Syndrome.
JAMA 271: 536-542.

Return Case Studies in Virtual Genetics 1996-1997