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
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
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
JAMA 271: 536-542.
Return Case Studies in Virtual Genetics