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fragile-X syndrome

Martin Kennedy mkennedy at chmeds.ac.nz
Wed Nov 2 23:26:01 EST 1994

In article <3945tf$gs9 at ixnews1.ix.netcom.com>, SJB at ix.netcom.com (Stephen Barrett) writes:
> I am a teacher of mildly mentally retarded children & am in contact with
> a child whose behavior is quite bizzare.  Our psychologist thinks this child
> might be fragile-X.  Can anyone direct me to reliable literature, or relate personal
> experience on this disorder?  I am new on the net and not too familiar with how to find
> things, other newsgroups etc.
> Steve Barrett

This disorder is the most common of the X-linked mental retardation 
syndromes.  Since early 1992 there has been a DNA test available, which is 
straightforward, definitive and identifies carriers, affected individuals 
and can be applied prenatally.  Many centres are now doing the test, and
there should be one near you (any cytogenetics or human genetics department 
ought to know about it).

For references try:

Rousseau F, Heitz D, Biancalana V, Blumenfeld S, Kretz C, Boue J, Tommerup N, 
Van der Hagen C, DeLozier-Blanchet C, Croquette MF, et al. Direct diagnosis 
by DNA analysis of the fragile X syndrome of mental retardation. 
N Engl J Med 1991, 325: 1673-1681.

Yu S, Mulley J,  Loesch D, Turner G, Donnelly A, Gedeon A, Hillen D,  
Kremer E, Lynch M,  Pritchard M, Sutherland GR, Richards RI.  Fragile-X 
syndrome: unique genetics of the heritable unstable element.  Am J  Hum Genet 
1992,  50: 968-80.

These are rather oriented toward the molecular genetics, but there will be
many more general articles in the literature as it is a fairly hot research 

Here is a partial copy of the explanatory notes we send out with the 
test results:


Fragile-X syndrome (Fra-X) is the most common cause of inherited mental 
retardation,  with an incidence of about 1/1500 in males and 1/2500 in 
females.  The inheritance pattern of the disease is unlike other X-linked 
disorders, because it shows significant numbers of apparently unaffected 
male carriers and some clinically affected females.  The disease derives 
its name from the presence of a fragile site on the X chromosome of 
affected individuals.

Until 1991 chromosome analysis was the only available means for diagnosing 
Fra-X.  However, this test is ineffective at detecting carriers of the 
disease, not totally reliable in the detection of affected individuals, 
and time-consuming and costly to perform.  In contrast, the DNA test for 
Fra-X is virtually 100% effective in the detection of carriers and for 
diagnosis of affected individuals.  For this reason, the DNA test has 
superseded cytogenetic testing for Fra-X.

The DNA test is specific for Fra-X and cannot detect any other disorders.  
Therefore, if chromosomal abnormalities other than Fra-X are suspected 
then a separate cytogenetic analysis must be performed.  Requests for 
standard chromosome analysis in addition to the Fra-X DNA analysis 
should be clearly marked on the request  form.

Genetics of the disorder

The genetic lesion underlying Fra-X was recently identified.  Individuals 
suffering from the syndrome have a novel mutation in a gene known as FMR-1.  
The mutation is due to an expansion of DNA, in a region that normally 
consists of several repeats of the triplet nucleotide sequence CGG.  
Affected individuals have a very large repeat expansion (known as a 
full mutation).  This expanded CGG repeat tract interferes with expression 
of the gene, the function of which is unknown, and it seems that the 
consequent absence of the FMR-1 gene product results in the syndrome.  
Carriers of Fra-X have an intermediately sized repeat-expansion (known as 
a premutation) that does not appear to affect function or expression of 

Although the great majority of Fra-X patients exhibit the expanded DNA 
repeat,  a few families have been identified in which other mutations 
have inactivated the FMR-1 gene.  These families do not show the unusual 
inheritance pattern of Fra-X, and they will not be detected by this DNA test.

The DNA test

The expansion of DNA that causes the mutation is detected by Southern 
blotting.  This involves isolation of DNA from the blood sample, digestion 
of the DNA with enzymes that cut at specific sites, size-separation of 
these fragments by electrophoresis (sieving by electrically forcing the 
DNA fragments through a gel), and then transfer of the separated DNA 
fragments onto a nylon membrane.  The membrane is then probed with 
radioactively labelled DNA that specifically identifies the relevant 
part of the FMR-1 gene, and the size of the fragments is revealed by 
exposing to X-ray film.  Each of these steps takes at least 1-2 days.

When to test?

Rousseau et al (1991; NEJM 325, 1673-1681) proposed that the DNA test 
should be used "to test systematically for a fragile X mutation in boys 
or girls with unexplained mental retardation, late onset of speech, or 
autistic or hyperactive behaviour, even if there is no family history 
of mental retardation".  Large pedigrees of carriers can exist in the 
absence of a family history, and these can be identifed by screening 
relatives of apparently sporadic affected individuals.  Due to the complex 
inheritance pattern of the disorder, family studies should be carried out 
in consultation with a clinical geneticist or genetic counsellor.

Hope this is helpful,


NNNN   NN  Martin A Kennedy (E-mail = mkennedy at chmeds.ac.nz)  ZZZZZZZ  
NN NN  NN       Cytogenetic and Molecular Oncology Unit          ZZZ
NN  NN NN           Christchurch School of Medicine            ZZZ
NN   NNNN              Christchurch, New Zealand              ZZZZZZZ

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