Fragile X syndrome is the second most common chromosomal cause of
mental retardation and the most common cause of familial mental retardation.
The mutation rate is high. The calculated incidence is 1/1,250 in males and
1/2,000 in females. Thus, accurate and early diagnosis is important for
specific pharmacological and cognitive treatment.
Table 1. Patient characteristics
treatment received mg/kg/day||Clinical response
0.9/INO 37/FOLIN 0.9||+/0/+
0.6/FOLIN 0.5/INO 32||+/0/0
0.6/FOLIN 0.9/INO 51||+/0/-
27||FOL 0.6/FOLIN 1/INO 27 + FOL||+/+/+
0.6/FOLIN 0.8/INO 15||0/0/0
|Psychotic = self-aggressive or disruptive
behaviour, stereotypes; FOL = folic acid; FOLIN = folinic acid; INO = inosine;
+ = beneficial, less agitated; o = no changes; - = regression, more
The syndrome is characterized by a marker X chromosome, identified by
the presence of a fragile site on the distal long arm at Xq27. Mental
retardation is transmitted in an X-linked dominant with incomplete penetrance
pattern. Approximately 30% of the heterozygous female carriers are mentally
retarded and about 20% of transmitting males show neither the fragile site nor
clinical symptoms. Genotype and phenotype are therefore not absolutely
Sutherland observed that the expression of this fragile site in vitro
depends on the composition of the culture medium and that deficiences of folic
acid and thymidine promote expression of the fragile site in lymphocytes as
does the addition of methotrexate . This led to the hypothesis that folic
acid may play a role in the pathogenesis of the mental retardation of this
syndrome. Clinical trials using conventional doses of folic acid or high doses
of folic or folinic acid do not seem to ameliorate the intellectual
performances of these patients, but may have a positive effect on the
behavioural manifestations [2-5]. A study of cells derived from fragile X
patients and carriers seem to indicate that a primary folate defect is unlikely
Glover  and Tommerup et al.  independently showed that
expression of the fragile site can be elicited by adding
5-fluoro-deoxy-uridine, an inhibitor of thymidylate synthetase, to culture
medium containing folic acid but not thymidine. These observations suggest that
perhaps some impairment in the de novo synthesis of thymidylate may play a role
in fragile X syndrome. However, cellular thymidylate metabolism has been shown
to be normal in cells with fragile X .
Much work has been done in vitro, modulating culture conditions needed
to demonstrate fragile X expression [1,11-13]. In spite of all this work, the
basic metabolic defect responsible for both fragile X expression and clinical
manifestations remains unknown.
Recent work has focused on molecular research trying to locate the
culpid genes found at the Xq27 locus. DNA research has been successful in
unraveling the genetics of fragile X syndrome, but all remains to be done in
understanding the pathophysiology of the disease. Both changes in methylation
patterns and DNA fragment sizes have been shown in patients expressing the
fragile X phenotype [14-19]. The condition is characterized by an inheritable
DNA sequence that consists of an abnormal number of CGG repeats which are
unstable during both meiosis and mitosis. Recently, a gene (FMR-1) has been
identified which contains the unstable DNA region and which is not expressed in
most fragile-X-affected males [20, 21].
Gene localization and sequencing does not necessarily mean
understanding of global cellular metabolic dysfunction and the
patho-physiological consequences thereof, thus leading to comprehension of how
the gene abnormality produces disease. One might therefore be peering down the
wrong end of a telescope.
We have, in recent years, been investigating the hypothesis that a
defect of purine metabolism, be it primary or secondary, may play a major role
in mental retardation syndromes [22-24].
Material and Methods
Twenty-eight peripheral blood samples from patients with documented
fragile X syndrome (24 males and 4 retarded females) were cultured for 72 h in
TC199 medium (Seromed) supplemented with 25% human AB serum, phytohaemagglutin
C (IBF France), penicillin and streptomycin. Culture technique, harvesting and
microscopic examination were carried out according to the previously described
method . Patient characteristics are shown in table 1.
The following products were added on initiation of culture (all
products were Sigma products unless otherwise specified); the entire panel
could not always be performed for each patient: (1) inosine 125 mg/l; (2)
alanosine 0.0625 mg/l, kindly provided for by the Laboratory of Biochemical
Pharmacology (National Institute of Health, Bethesda. MD, USA); (3) aza-serine
0.0156 mg/l; (4) adenosine 16 mg/1; (5) HAT medium, 62.5 µM
hypoxanthine, 0.25 µM aminopterin, 10 µM thymidine; (6) cytidine
6.25 mg/l; (7) guanosine 3.1 mg/l; (8) putrescine 6.25 mg/l.
The following products were added 12-16 hours prior to termination of
the culture: (9) mycophenolic acid 0.6 x 10-6 M; (10) theophylline
The lymphocyte cultures were harvested with the standard techniques
used for chromosomal analysis. Slides were stained with Giemsa and coded. A
minimum of 3,000 cells were read by two different observers to calculate the
mitotic index, expressed as the ratio of mitosis over the total number of
Table 2. Percentage increment or decrease of mitotic index in
patients with fragile X syndrome, controls and patients with mental retardation
of other etiologies
|Results were analyzed by comparing the values
observed in fragile X patients with those obtained in dif-ferent patient
populations. N = number of patients; M = mean mitotic index (increase or
decrease); SD = standard deviation; t = Student's t test.
Twenty-six patients were on no medication at the time of the
Controls used for the analysis were as follows: 135 normal adults, 79
patients with trisomy 21,10 patients with cri-du-chat syndrome and 68 patients
with mental retardation (with or without a chromosomal anomaly other than the
ones mentioned above).
Results were analyzed by comparing the mitotic index of each
experiment to the patient's own control culture and were expressed as the
percentage increment or decrease in mitotic index. Statistical comparisons
between groups were based on Student's t test (two-tailed test).
As is shown in tables 2-4 (only data relevant to the present study are
shown), there were three products which, when added to the lymphocyte culture,
altered the mitotic index in a significant and specific manner.
Table 3. Percentage increment or decrease of mitotic index in
males with fragile X syndrome, male controls and patients with mental
retardation of other etiologies
|P||0.005 <p< 0.001||0.025||-
|P||0.025||0.05 <p< 0.025||0.05
|P||0.005 <p< 0.001||-||-
|Results were analyzed by comparing the values
observed in fragile X male patients with those obtained in different male
patient populations. Symbols are as in table 2.
The addition of guanosine increased the mitotic index significantly
in patients with fragile X syndrome. When compared to the total patient sample,
patients with mental retardation of various etiologies and patients with Down's
syndrome, the difference was highly significant (0.01 < p < 0.005); when
compared to the total control sample the difference was not as marked but
remained significant (0.05 < p < 0.025). On analysis, this seemed to be
due to differences between male and female response to guanosine (female
controls increasing their mitotic index significantly more than male control
patients: p = 0.025). We therefore broke down the analysis to examine response
only in male patients. As is shown in table 3, there was a highly significant
difference in the response to guanosine when fragile X males were compared to
the total male sample (p = 0.001), normal male controls (0.005 < p <
0.001) or retarded males of other etiologies (0.005 < p < 0.001). The
difference between fragile X males and males with Down's syndrome was
significant (p = 0.025).
Table 4. Percentage increment or decrease of mitotic index
in patients with fragile X syndrome and in patients with Down's
|Trisomy 21, non
|Trisomy 21, psychot,
|Trisomy 21, non compl,
|Results are analyzed by comparing the values of
the mitotic index in fragile X patients and those obtained in Down's syndrome
patients. Symbols are as in table 2. Psychot = psychotic complications; no
compl = uncomplicated Down's syndrome.
We observed a significant decrease in the mitotic index in patients
with fragile X syndrome when compared to the response observed in the total
control sample (p < 0.001) and in the trisomy 21 sample (p = 0.005).
However, there was no difference between the response observed in
fragile X syndrome patients and patients with mental retardation. When the
response in the male population was analyzed, a difference was observed between
normal male controls and fragile X males (p = 0.025); none of the other
categories studied showed a difference in response. Moreover, the sex
difference which had been noted between normal males and females in their
response to guanosine was not observed with theophylline.
Azaserine is a glutamine antagonist inhibiting numerous steps of
nucleic acid synthesis, the most sensitive reaction being the inhibition of
phosphoribosylformylglycineamidine synthetase. A slight increase in the mitotic
index was observed in male patients with Down's syndrome, the difference in
response was significant when compared with that observed in fragile X males
(0.05 < p < 0.025). Further analysis was difficult given the small sample
size. This difference was observed only with Down's syndrome patients, not with
Changes in Mitotic Index
To test whether the changes observed were specific for fragile X
syndrome, we looked for patients manifesting an increment in mitotic index of
more than 10% (over their baseline) in the presence of guanosine: (1) 13/19
patients with fragile X showed an increment of over 10% in the presence of
guanosine (all fragile X patients increased their mitotic index); (2) 29/80
normal controls (?2 = 6.5; 0.02 < p < 0.01); (3) 7/29
normal male controls (?2 = 9.3; 0.01 < p < 0.001); (4)
12/34 patients with trisomy 21 (?2 = 5.4; p = 0.02), 7
females and 5 males (all 5 males had psychotic complications); (5) 17/58
patients with mental retardation (?2 = 9.2; 0.01 < p <
0.001), 7 females and 10 males. It is of note that 9 of the 10 male patients
had associated psychiatric complications. Seven males showing an increase in
mitotic index in the presence of guanosine had originally been referred for
Xqfra investigation but had been found to be Xqfra negative on cytogenetic
In our whole sample, 72 persons were tested for both theophylline
and guanosine reactions. Of these 72, 18 showed the association: increment of
over 10% in the presence of guanosine, decrease of greater than - 15% in the
presence of theophylline, 7 were fragile X patients, 2 were parents of fragile
X patients, 2 were patients with X-linked mental retardation syndrome (at least
2 affected male sibs). Therefore, 11/18 (73%) of the positive sample were
related to fragile X syndrome. The remaining 7 patients (9%) were: 4 normal
female controls, 2 patients with mental retardation and 1 patient with Down's
Attempts to explain our findings and to correlate them with the
mechanisms responsible for the various neurologic manifestations are hampered
by the inexistence of data on the neurochemical and purinergic derangements in
fragile X syndrome. We will therefore review what is known about the biological
effects of both guanosine and theophylline and advance hypotheses as to how our
observations could tie in with both known effects and clinical findings in
fragile X. We will then review drug trials which have been tried in fragile X
syndrome and how the results correlate with our observations.
We found only one study examining the effect of guanosine on the
expression of the folate-sensitive fragile site . Although inhibition of
fragile site expression was noted, the culture medium (thymidine deficient), as
well as the guanosine dose used (30 times greater) were different from ours,
rendering any useful comparison impossible.
Guanosine and Thyroid Studies
Thyroid function tests in fragile X syndrome males and in X-linked
mental retardation males have shown normal basal serum levels of thyroid
hormones and thyroid-stimulating hormones (TSH) but a blunted TSH response to
thyrotropin-releasing hormone (TRH) [25, 26]. Since TRH receptor binding may be
allosterically regulated by guanine nucleotides , one might hypothesize
that, if fragile X males have some defect along the guanine nucleotide pathway,
this could alter TRH receptor binding and thus TSH response. These observations
are in keeping with the beneficial effect of guanosine reported here.
We recently published our observation suggesting a relationship
between TSH and reverse T3 in Down's syndrome . Although the metabolic
action of reverse T3 is not known, we have suggested that reverse T3 may be a
modulator of inosine monophosphate dehydrogenase , the precursor of
guanosine monophosphate (GMP). Reverse T3 levels have never been studied in
fragile X syndrome, but given our observations, it would be well worth an
Theophylline, Purine Metabolism and Autism
There are numerous studies suggesting that fragile X is related to
autism (an association which could be as high as 43%), but this is not
universally admitted [see 30 for review]. Although the biochemical defect
responsible for autistic behaviour is not known, it is worth remembering that
two interesting biochemical abnormalities have been reported in relation to
autism [31, 32]. Inborn deficiency of adenylosuccinate lyase gives rise to a
clinical picture rather similar to autism . Furthermore, autistic children
have been found to have elevated serum cyclic adenosine monophosphate (cAMP)
levels [see 32 for review]. These findings point to some defect or impairment
along the adenosine metabolic pathway.
Theophylline and other methylxanthines can produce clinical changes
which are not unlike those observed in patients with fragile X syndrome:
anxiety, restlessness, hyperactivity and behaviour abnormalities .
Theophylline is a non-selective antagonist of adenosine receptors
(both Al and A2). It is also a known phosphodiesterase inhibitor (which
increases cAMP intracellular levels). The decrease in mitotic index observed in
fragile X males, which is significantly different from the response observed in
normal controls could therefore indicate some degree of impairment in DNA
synthesis which could be due either to adenosine deficiency or imbalance in
adenosine-guanosine nucleotide (and/or cAMP/cGMP) ratio.
It has been shown that substances which elevate cAMP levels (as does
theophylline by virtue of inhibition of phosphodiesterase) can simultaneously
cause a decrease in cGMP levels . If fragile X patients already have some
impairment along the guanine nucleotide metabolic pathway, any further
impediment would be extremely detrimental and could explain the significant
decrease in mitotic index which we observed in these patients, when
theophylline was added to their lymphocyte cultures.
The possible association between autism and fragile X syndrome, the
observation that autistic patients have increased cAMP levels, the fact that
theophylline increases cAMP levels and our observation that theophylline
decreases the mitotic index in fragile X constitute an interesting and coherent
If one tries to tie together both the apparently beneficial effect
of low-dose guanosine with the theophylline toxicity, one might hypothesize
that the metabolic defect in fragile X patients lies somewhere in the complex
interaction between guanosine and adenosine, either by virtue of nucleotide
pool imbalances or at the receptor level. It is of great interest that
theophylline treatment has been found to have little action on the A1 receptor
number but may alter the coupling between Al receptors and regulatory
guanosine-5'-triphosphate (GTP)-binding proteins . In rat brain there are
regional differences in the effects of GTP on adenosine A1 receptor binding
. Both these observations have implications for future research.
Guanosine: The Brain and Mental
In recent years, the association between purine metabolic disorders
and neurological dysfunction has been reported in a variety of genetic
disorders [24, 37], opening new and exciting research perspectives.
The effect of guanine nucleotides on central nervous system
neurotransmitters is exceedingly important. It is not known whether guanosine
is a neurotransmitter, as is adenosine, but guanine nucleotides are known to
negatively modulate agonist binding to adrenergic, dopamine, muscarinic
cholinergic and opiate receptors [38, 39]. Phencyclidine receptors are also
regulated by guanine nucleotides . Furthermore, guanine nucleotides play a
major role in pterin metabolism (GTP is the precursor of tetrahydrobiopterin),
as well as in microtubule dynamics .
Both cAMP and cGMP play a unique role in neurotransmitter
regulation, and their ratio seems to be of clinical importance. Indeed, it has
been suggested by Goldberg et al.  that these two cyclic nucleotides
function together via dual opposing effects regulating the
cholinergic-adrenergic balance (the Yin-Yang hypothesis). An imbalance between
cAMP and cGMP has been reported, for example, in Lesch-Nyhan syndrome .
After birth, purine metabolism in the central nervous system is
characterized by reduced de novo purine synthesis, increased
hypoxanthine-phosphoribosyltransferase activity and absent xanthine oxidase
activity . Therefore, the brain is largely dependent on salvage pathways to
sustain GTP levels. The switch in purine metabolism from essentially de novo
during brain development to via the salvage pathway after the main burst of
neuroblast and neuroglial proliferation might explain why patients with fragile
X have essentially normal cerebral morphology, the main neuro-anatomical change
documented in these patients (as well as in patients with autism) being
hypoplasia of the posterior cerebellar vermis [44, 45]. This situation is
therefore quite different from cri-du-chat syndrome, in which we suggested a
defect in de novo purine synthesis and which is associated with significant
morphological changes of the brain [24, 46].
Any metabolic defect along the purine salvage pathway would have
neurological and behavioural consequences manifest after this period of
neuroblast and neuroglial proliferation. The perinatal period during which gene
switching and receptor imprinting occurs is sensitive to late 'metabolic
teratogenesis' . A genetic, metabolic defect involving a gene or group of
genes normally activated during this period will have important repercussions
on membrane receptor imprinting and postnatal brain development. It is of
interest that the analysis of the neocortex in fragile X adults showed abnormal
dendritic spine morphology suggesting an anomaly of postnatal dendritic
maturation [48, 49].
Our findings suggest that fragile X patients have some metabolic
anomaly along the guanine pathway, an observation which has important
implications. Given the complexity of guanosine metabolism, of the interactions
between the different nucleotide pools as well as ofpurinergic neuromodulation,
further research is required for comprehension of the pathophysiology of
fragile X syndrome.
Medication Used in Fragile X Syndrome and Possible
Folate has been found to inhibit GTPase activity and stimulate the
release of guanosine-5'-diphosphate from brain membranes (greatest in
cerebellar and hippocampal membranes) . These findings are interesting,
since folate therapy has been found, in a few studies, to be beneficial in
fragile X patients. The fact that cerebellar and hippocampal anatomical
anomalies have been reported in patients with autism and that cerebellar
anomalies are known in fragile X patients is also noteworthy [44, 45, 51]. The
link between guanine nucleotide metabolism, cerebellar function, fragile X and
autism seems worth to be further investigated.
Stimulant medication (methylphenidate and dextroamphetamine) which
inhibit the synaptic re-uptake of dopamine and noradrenaline has been reported
to be beneficial for some patients with fragile X syndrome . Imbalance
between the cholinergic and dopaminergic systems has been implicated in the
etiology of several neurological and psychiatric disorders, and both these
systems are modulated by cGMP .
Several drugs have been found to modulate cGMP levels and/or alter
cAMP/cGMP interaction: haloperidol, lithium and carbamazepine [53 - 56]. It is
of note that these drugs have been reported anecdotally to be beneficial in
some cases of fragile X syndrome .
Given our findings, which suggest that fragile X patients have a
metabolic defect along the guanine nucleotide pathway, further studies on the
biochemical defects in these patients seem promising. Since this pathway plays
a major role in both neurological and psychiatric disorders, studies allowing
the pinpointing of the exact metabolic defect as well as investigations on
membrane receptors, cyclic nucleotides, possible neurotransmitter deficiencies
or imbalances should be performed not only in patients with fragile X syndrome
but also in patients with X-linked mental retardation. Better understanding of
the biochemical defects is mandatory for comprehension of the pathogenesis and
is a prerequisite for designing possible therapies for these patients.
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