Download Kenneson, A and Warren, ST: The female and the fragile X reviewed. In: Adashi, E. (Ed.) Seminars in Reproductive Medicine 19:159-165 (2001).

The Female and the Fragile X Reviewed
Aileen Kenneson, Ph.D.1 and Stephen T. Warren, Ph.D.1
ABSTRACT
Nearly 15 years ago, female carriers of the fragile X mental retardation syndrome
were noted to have an increased incidence of twin pregnancies. Since then, much evidence has accumulated supporting the notion of ovarian dysfunction in fragile X carriers,
in the forms of increased dizygotic twinning and premature ovarian failure. However, despite a decade and a half of research regarding this association, the underlying mechanism
remains a mystery. This article reviews the population-based studies that have examined
this association and discusses possible reasons for the variations in results. In addition, results from more recent studies on endocrine function in fragile X carriers are discussed.
These data, when considered in conjunction with our emerging understanding of the
molecular biology of the fragile X gene (FMR1) and its protein product (FMRP), are beginning to elucidate possible mechanisms for the association between fragile X syndrome
and ovarian dysfunction.
KEYWORDS: Fragile X syndrome, FMR1, FMRP, premature ovarian failure,
trinucleotide repeat
T
he surplus of males among patients with mental retardation was noted over a century ago, so it was not
surprising when an X-linked gene for mental retardation
was identified.1,2 However, research on this gene, FMR1
(fragile X mental retardation1), has yielded several surprises since then. The first was a novel mutational mechanism associated with human disease: trinucleotiderepeat instability and expansion.3 In the case of FMR1, a
CGG repeat tract exists in the 5 untranslated region. In
the general population, the number of repeats ranges
from about 5 to 50 and does not change when transmitted through the generations. Repeat tracts with 50 to
200 repeats are unstable during transmission and are referred to as premutation alleles in reference to their general lack of associated phenotype and their propensity to
expand to disease-causing lengths in offspring. Alleles
with greater than 200 CGG repeats, full mutations,4 are
associated with hypermethylation of the CGG tract and
surrounding CpG island,5 resulting in transcriptional silencing6; the consequent lack of the protein product,
FMRP, causes mental retardation and macroorchidism,7–12 the hallmarks of fragile X syndrome.
The mental retardation associated with fragile X
syndrome ranges from mild to severe. In addition to
macroorchidism after puberty, patients present with subtle but characteristic somatic signs, such as prominent
ears.13 Many patients display autistic-like features such as
repetitive motor mannerisms, impaired verbal communication, and gaze aversion14–17; however, they do not typically meet the full diagnostic criteria for autism.16,18 Social anxiety and shyness are also common.19,20
Upon the cloning of the FMR1 gene, two key
observations were made: that premutation alleles appeared to express the same amount of FMRP protein
as did normal alleles and that premutation carriers
were unaffected.4,21–25 However, a decade of data has
indicated that premutation carriers have increased
incidences of several fragile X–like phenotypes, including social anxiety,24,26 affective disorder,27 obsessivecompulsive disorder,28 and prominent ears.27,29–31 In
Seminars in Reproductive Medicine, Volume 19, Number 2, 2001. Reprint requests: Dr. Warren, Departments of Biochemistry, Genetics, and
Pediatrics, Emory University School of Medicine, 1510 Clifton Road NE, Atlanta, GA 30322. 1Howard Hughes Medical Institute and
Departments of Biochemistry, Genetics, and Pediatrics, Emory University School of Medicine, Atlanta, Georgia. Copyright © 2001 by Thieme
Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662. 1526-8004,p;2001,19,02,159,166,
ftx,en;sre00117x.
159
160
SEMINARS IN REPRODUCTIVE MEDICINE/VOLUME 19, NUMBER 2 2001
addition, premutation carrier females have an increased
incidence of ovarian dysfunction. This feature is unique,
however, as it is not apparent in females with full mutations. More recently, two molecular phenotypes of premutation cells have been identified, which may account
for these phenotypes: increased FMR1 transcription
and decreased FMRP protein levels.
OVARIAN DYSFUNCTION
The first observed sign of ovarian dysfunction related to
fragile X syndrome appeared in Fryns’ characterization
of obligate carrier females in Belgium in 1986. Of the
642 offspring of 134 carriers, there were 18 pairs of
twins: 12 dizygotic and 6 of unknown zygosity.32 This
twinning rate (1 in 35 births) is higher than the twinning rate reported for the general population (1 in 40 to
1 in 110 births).33–36 The following year, in a fragile X
conference in Denver, it was anecdotally noted that several of the attending female carriers of fragile X mutations had experienced premature ovarian failure
(POF).37 As a consequence of these two observations,
and given FMR1’s cytological location at Xq27.3, a region implicated in ovarian function,38–42 many researchers undertook to examine the possible relationship
between fragile X mutations and ovarian dysfunction.
The early studies did not distinguish between premutation and full mutation carriers, as our understanding of
the molecular nature of the gene did not come until its
cloning. These studies found that 13–28% of obligate
fragile X carriers experienced POF, significantly higher
than in the control group, with the entire distribution of
age at menopause shifted toward a younger age in fragile
X carrier women.37,43 Likewise, one study confirmed
Fryns’ observation of increased twinning by reporting an
increased rate of twin births from obligate fragile X carrier mothers (1 in 18 births).44 However, other studies
were unable to detect a difference in twinning rate
among women with fragile X mutations compared with
controls.45,46
Later studies, using molecular techniques to distinguish premutation carriers from full mutation carriers, indicated that the increased risks of POF and twinning are limited to premutation carriers, providing one
possible explanation for differing results if the study
groups varied in makeup of premutation and full mutation carriers. POF was experienced by 14 to 24% of
premutation-allele carriers,47–49 whereas only 3 of 75 full
mutation carriers experienced POF in the three studies
combined. Likewise, the frequency of premutation carriers among women with idiopathic familial POF (6 to
13%)50–54 is higher than that for the general population
(1 in 250).55,56 As expected, the two aspects of ovarian
dysfunction (twinning and POF) are sometimes found
in the same individual.52 Also, the premutation allele
cosegregates with POF in families.49,50,52,53,57–59 Tables 1
and 2 summarize the reports of twin birth rates and
POF prevalence, respectively, among fragile X carriers
and controls. Table 3 summarizes reports of the frequency of premutation carriers among women with
POF and controls.
Although these data provide convincing evidence
of an association between ovarian dysfunction and premutation alleles, the association is far from complete.
Many fragile X families do not have members with POF
or twinning, and some population-based studies have
failed to detect the association.60–62 Likewise, increased
twinning was not observed in two studies of premutation
carriers.46,63 Various mechanisms have been invoked to
explain the discrepancy in results, including linkage disequilibrium,60 population differences, and imprinting
mechanisms. Evidence has been presented that premutations inherited from paternal sources are associated
with POF, whereas maternally inherited premutations
are not.64 Although this study group was large, other
groups failed to find similar phenomena,65,66 and the implied imprinting mechanism is at odds with many of the
published pedigrees of fragile X families with POF.
Again, population differences and ascertainment issues
are likely to be key in resolving this issue.65–67
Table 1 Prevalence of Twin Births Among Pregnancies Ending in Livebirths in Fragile X Carrier and
Noncarrier Females
Population
Carriers*
Australia
Australia
Belgium
Brazil
Italy
Netherlands
United Kingdom
United States
17/735
Premutations
Full Mutations
Noncarriers
1/34
1/139
1/140
7/220
0/40
24/148
3/116
3/231
3/31
2/101
Controls
Ref.
8/589
45
102
32
103
49
64
46
63
18/624
1/176
12/201
*Molecular status undetermined.
14/205
THE FEMALE AND THE FRAGILE X REVIEWED/KENNESON, WARREN
Table 2 Prevalence of POF Among Fragile X Carrier and Noncarrier Females over the Age of 40
Population
Italy
North America
United Kingdom
United Kingdom
United States
Worldwide
Carriers
Premutations
Full Mutations
Noncarriers
6/42
10/47
0/25
3/8
0/44
10/66
2/11
2/92
43/182
0/42
0/109
Controls
1/33
30/106
8/61
2/41
Despite two case reports of precocious puberty in
fragile X females,68,69 larger studies indicate that the age
of menarche is normal in both premutation and full mutation carrier females.48,70
ENDOCRINOLOGY
Data on endocrinology function in premutation carriers is limited. In vitro fertilization clinics report that
premutation carrier clients have increased folliclestimulating hormone (FSH) levels despite their young
age and have a subnormal response to exogenous ovarian stimulation.71 Successful pregnancies have nonetheless been achieved, although donor eggs are sometimes required.72
To date, only three other studies have examined
the endocrinology of premutation carriers. In the first,
endocrine serum concentrations were analyzed in nine
randomly chosen premutation carriers from 31 to
40 years of age. Only one had normal menstrual cycles
and a normal hormone profile. Two women had elevated FSH levels on day 1 of their cycle. Two had elevated progesterone levels at this time but had a surge of
luteinizing hormone (LH) at day 14, consistent with a
shortened cycle. Two other women also showed a shortened follicular phase of the cycle, as their hormone levels were postovulatory at day 14. And finally, one
woman had no LH surge, suggesting that the cycle was
anovulatory.73
In the second endocrine study of fragile X carriers, FSH and estradiol serum levels were measured in
19 premutation carriers, 9 full mutation carriers, and
Ref.
49
48
43
46
37
47
23 noncarriers. Participants ranged from age 16 to
53 years, although only three premutation carriers were
under the age of 30. No differences were detected between full mutation carriers and noncarriers. However,
FSH levels were elevated in premutation carriers compared with the levels in the other two groups.74 The
FSH levels do not appear to be increased in premutation carriers younger than 30 years, although the small
number of women in this group precludes any conclusions. Finally, levels of inhibin, an indicator of ovarian
reserve, were not altered in premutation carriers, although the same subjects displayed earlier ages of
menopause than did controls.46
More endocrinology work has been reported on
males with fragile X syndrome. Alterations in endocrine
regulation associated with full mutations in males are
widely reported but the results vary greatly with no consistent pattern of endocrine changes.75–85 Thus, it is not
clear if the irregularities seen in premutation females are
unique to premutations or are part of a spectrum of the
endocrine problems seen in full mutation males.
MODELS
Several models have been proposed to explain the role
of FMR1 in ovarian function. Fryns, in his initial 1986
report, speculated that fragile X carriers suffer from a
breakdown in the regulation of the cortico-hypothalamic-pituitary axis. An alteration in the feedback mechanism between the ovaries and the brain could result in
the higher FSH levels observed in fragile X carriers,
thus resulting in increased twinning and faster depletion
Table 3 Prevalence of Fragile X Premutation Carriers Among Females with POF
Population
POF
Australia
Greece
Italy
Italy
United Kingdom
United Kingdom
United States
0/21*
Familial POF
Sporadic POF
Controls
1/7
0/16
0/100
4/33
3/23
4/50
0/17
2/73
3/106
2/244
0/16
1/107
7/108
*POF cases who were also mothers of twins.
Ref.
62
54
102
52
51
53
60
161
162
SEMINARS IN REPRODUCTIVE MEDICINE/VOLUME 19, NUMBER 2 2001
of the oocyte pool. In support of this model, FMRP is
expressed in the cortex and the thalamus,86–89 both of
which have significant neural inputs into the hypothalamus. More studies of fragile X carriers over a wider
range of ages to determine when the altered FSH levels
first appear may lend clues to whether the increased
FSH levels are a cause or a result of early ovarian depletion. To date, only three premutation carriers under the
age of 30 years have been examined, and although they
did not have the increased FSH levels seen in older premutation carriers,74 this number is too small to draw
any conclusions.
Other models focus on the potential role of
FMRP in the ovary itself. FMRP is expressed in germ
cell development, in both primordial germ cells in the
fetus86,90,91 and in the granulosa cells of developing follicles in adults.88 Decreased expression of FMRP from
premutation alleles during germ cell proliferation may
adversely affect the number of oocytes produced, thus
reducing the available pool in adults.51 Alternatively, the
presence of the premutation tract itself may have some
adverse effects on germ cells, perhaps destabilizing meiotic arrest or increasing the attrition rate, again causing
a more rapid depletion of the germ cell pool.51 Finally, a
model involving a selection against germ cells in which
the premutation has expanded to full mutations, also reducing the germ cell pool, has been proposed.51
A selection model is supported by an unusual inheritance pattern of fragile X syndrome. Affected patients always inherit the expanded repeat from their
mothers and premutation-carrying males always pass on
premutation alleles to their children.3,92 Furthermore,
affected full mutation males produce sperm with only
premutation alleles,93 and although full mutation germ
cells are present in developing male fetuses, these are
gradually replaced with premutation-bearing germ
cells.91 This could be due to a proliferation advantage of
FMRP-producing cells or to a selection against male
germ cells with large trinucleotide repeat expansions.
The latter model is supported by a similar phenomenon
of maternal bias for large expansions in two other trinucleotide repeat disorders, myotonic dystrophy and
Friedereich’s ataxia.94 Proliferation of germ cells with
large repeat tracts may be influenced by the presence of
an altered chromatin conformation associated with full
mutation alleles.95 Myotonic dystrophy and Friedereich’s ataxia differ from fragile X syndrome in that
larger paternal expansions (up to 2000 repeats) are observed in the two former cases, while the FMR1 repeat
does not appear to be greater than around 120 repeats in
sperm,96–99 which does not even approach the maximum
premutation length, suggesting that a selection for
FMRP-producing germ cells is an additional factor in
fragile X patients.
The apparent lack of a similar phenomenon in
females may be due to the X-linked nature of FMR1. In
females, selection against germ cells with an expanded
full mutation allele on the active X chromosome may
reduce the germ cell pool, and expansion on the inactive
X chromosome may allow passage of full mutation alleles to offspring. As the probability of expansion to full
mutation range is directly correlated with the number of
repeats,3 this model would predict a negative correlation
between premutation repeat size and age at menopause.
There is no evidence of such a correlation, but this relationship may be obscured by other genetic and environmental factors affecting age at menopause. Furthermore, the timing of expansion from premutation to full
mutation range during oogenesis has not been elucidated; consequently, it not possible to draw conclusions
about the impact of premutation and full mutation
alleles in germ cells.
More problematic is the apparent lack of association between full mutation alleles and ovarian dysfunction. One possible explanation is that X inactivation selects for inactivation of full mutation alleles, thereby
silencing the effect of the lack of FMRP on germ cells
that is evident in males with no such compensatory
mechanism. Premutation-expressing oocytes, on the
other hand, may have enough FMRP to escape this silencing but not enough for completely normal function
at a later stage in development. Another mechanism is
suggested by the observations that premutation cells
produce more FMR1 messenger RNA (mRNA) than
do normal cells100 (A. Kenneson et al, submitted). As a
consequence, increased FMR1 mRNA is a molecular
phenotype that distinguishes premutation alleles from
both full mutations, which are not transcribed, and normal alleles. The enhanced transcription of FMR1, and
consequent high level of FMR1 message, may act as a
sink for transcription factors, translation factors, or
CGG-binding proteins, with an ultimately detrimental
effect on germ cells.
The cosegregation of POF and premutations in
some families and the lack of POF in other fragile X
families suggest that ovarian function is adversely affected by only a subset of premutation alleles. This
model could partially account for the discrepant results
of the various association studies between POF and
fragile X mutations as the various study groups may differ in the proportion of alleles that are associated with
POF. Differences between the POF and non-POF premutation alleles could be due to linkage disequilibrium
with a nearby POF-causing mutation or to variations in
the structure of the repeat itself, such as AGG interruption pattern or length of pure CGG tracts. Such
changes may be responsible for subtle, but critical,
changes in FMRP level. Other confounding factors
could include modifying genes, perhaps also affecting
FMRP levels, as well as the various genetic and environmental factors known to affect age at menopause.
Whatever the mechanism of the association between
THE FEMALE AND THE FRAGILE X REVIEWED/KENNESON, WARREN
FMR1 and ovarian function, the challenges raised by
the differing results in various populations reflect
the complexity at work in this particular genotypephenotype relationship.
REFERENCES
1. Lehrke RG (1974). X-linked mental retardation and verbal
disability. In: Bergsma D, ed. Birth Defects: Original Article
Series. New York: The National Foundation; 1981:1–100
2. Martin JP, Bell J. A pedigree of mental defect showing sexlinkage. J Neurol Psychiatry 1943;6:154–157
3. Fu YH, Kuhl DP, Pizzuti A, et al. Variation of the CGG repeat at the fragile X site results in genetic instability: resolution of the Sherman paradox. Cell 1991;67:1047–1058
4. Rousseau F, Heitz D, Biancalana V, et al. Direct diagnosis by
DNA analysis of the fragile X syndrome of mental retardation. N Engl J Med 1991;325:1673–1681
5. Sutcliffe JS, Nelson DL, Zhang F, et al. DNA methylation
represses FMR-1 transcription in fragile X syndrome. Hum
Mol Genet 1992;1:397–400
6. Pieretti PC, Sismani C, Hettinger JA, et al. Absence of expression of the FMR-1 gene in fragile X syndrome. Cell
1991;66:817–822
7. Albright SG, Lachiewicz AM, Tarleton JC, et al. Fragile X
phenotype in a patient with a large de novo deletion in
Xq27-q28. Am J Med Genet 1994;51:294–297
8. Hirst M, Grewel P, Flannery A, et al. Two new cases of
FMR1 deletion associated with mental impairment. Am J
Hum Genet 1995;56:67–74
9. Kooy RF, D’Hooge R, Reyniers E. Transgenic mouse model
for the fragile X syndrome. Am J Med Genet 1996;64:
241–245
10. Mannermaa A, Pulkkinen L, Kajanoja E, Ryynanen M,
Saarikoski S. Deletion in the FMR1 gene in a fragile-X
male. Am J Med Genet 1996;64:293–295
11. Paradee W, Melikian HE, Rasmussen DL, Kenneson A,
Conn PJ, Warren ST. Fragile X mouse: strain effects of
knock-out phenotype and evidence suggesting deficient
amygdala function. Neuroscience 1999;94:185–192
12. Tarleton J, Richie R, Schwartz C, Rao K, Aylsworth AS,
Lachiewicz A. An extensive de novo deletion removing
FMR1 in a patient with mental retardation and the fragile X
syndrome phenotype. Hum Mol Genet 1993;2:1973–1974
13. Warren ST, Nelson DL. Advances in molecular analysis of
fragile X syndrome. JAMA 1994;271:536–542
14. Brown WT, Friedman E, Jenkins EC, et al. Association of
the fragile X syndrome with autism. Lancet 1982;1:100
15. Brown WT, Jenkins EC, Friedman E, et al. Autism is associated with fragile X syndrome. J Autism Dev Disord 1982;
12:303–308
16. Fisch GS. Is autism associated with the fragile X syndrome?
Am J Med Genet 1992;43:47–55
17. Reiss AL, Freund L. Fragile X syndrome, DSM-III-R, and
autism. J Am Acad Child Adolesc Psychiatry 1990;29:
885–891
18. Fisch GS Holden JJ, Simensen R, et al. Is fragile X syndrome a pervasive developmental disability? Am J Med
Genet 1994;51:346–352
19. Reiss AL, Hagerman RJ, Vinogradov S, Abrams M, King
RJ. Psychiatric disability in female carriers of the fragile X
chromosome. Arch Gen Psychiatry 1988;45:25–30
20. Freund LS, Resii AL, Abrams MT. Psychiatric disorders
associated with fragile X in the young female. Pediatrics
1993;91:321–329
21. Franke P, Maier W, Hautzinger M, et al. Fragile-X carrier
females: evidence for a distinct psychopathological phenotype? Am J Med Genet 1996;64:334–339
22. Rousseau F, Heitz D, Tarleton J, et al. A multi-center study
on genotype-phenotype correlations in the fragile X syndrome, using direct diagnosis with probe StB12.3: the first
2,253 cases. Am J Hum Genet 1994;55:225–237
23. Snow K, Doud LK, Hagerman R, Pergolizzi RG, Erster
SH, Thibodeau SN. Analysis of a CGG sequence at the
FMR-1 locus in fragile X families and in the general population. Am J Hum Genet 1993;53:1217–1228
24. Sobesky WE, Hull CE, Hagerman RJ. Symptoms of schizotypal personality disorder in fragile X women. J Am Acad
Child Adolesc Psychiatry 1994;33:247–255
25. Thompson NM, Gulley ML, Rogeness GA, et al. Neurobehavioral characteristics of CGG amplification status in fragile X females. Am J Med Genet 1994;54:378–383
26. Franke P, Leboyer M, Gansicke M, et al. Genotype-phenotype relationship in female carriers of the permutation and
full mutation of the FMR-1. Psychiatry Res 1998;80:113–
127
27. Sobesky WE, Taylor AK, Pennington BF, et al. Molecular/
clinical correlations in females with fragile X. Am J Med
Genet 1996;64:340–345
28. Dorn MB, Mazzocco MM, Hagerman RJ. Behavioral and
psychiatric disorders in adult male carriers of fragile X. J Am
Acad Child Adolesc Psychiatry 1994;33:256–264
29. Hull C, Hagerman RJ. A study of the physical, behavioral,
and medical phenotype, including anthropometric measures,
of females with fragile X syndrome. Am J Dis Child 1993;
147:1236–1241
30. Loesch DZ, Hay DA, Mulley J. Transmitting males and carrier females in fragile X: revisited. Am J Med Genet 1994;
51:392–399
31. Riddle JE, Ceema A, Sobesky WE, et al. Phenotypic involvement in females with the FM-1 gene mutation. Am J
Ment Retard 1998;102:590–601
32. Fryns JP. The female and the fragile X: a study of 144 obligate female carriers. Am J Med Genet 1986;23:157–169
33. Centers for Disease Control. State-specific variation in twin
births: United States, 1992–1994. MMWR Morb Mortal
Wkly Rep 1997;46:121–125
34. Lykken DT, Bouchard TJJ, McGue M, Tellegen A. Minnesota Twin Family Study: The Minnesota Twin Family
Registry: Some Initial Findings. Minneapolis: University of
Minnesota; 2000
35. Meyers C, Adam R, Dungan J, Pregner V. Aneuploidy in
twin gestations: when is maternal age advanced? Obstet Gynecol 1997;89:248–251
36. Moore KL. The Developing Human: Clinical Oriented
Embryology. Philadelphia: WB Saunders; 1988
37. Cronister A, Schreiner R, Wittenberger M, Amiri K,
Harris K, Hagerman RJ. Heterozygous fragile X females:
historical, physical, cognitive, and cytogenetic features. Am J
Med Genet 1991;38:269–274
38. Krauss CM, Turksoy N, Atkins L, McLaughlin C,
Brown LG, Page DC. Familial premature ovarian failure
due to an interstitial deletion of the long arm of the X chromosome. N Engl J Med 1987;317:125–131
39. Powell CM, Taggart RT, Drumheller TC, Wangsa DC, Nelson LM, White BJ. Molecular and cytogenetic studies of an
163
164
SEMINARS IN REPRODUCTIVE MEDICINE/VOLUME 19, NUMBER 2 2001
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
X;autosome translocation in a patient with premature ovarian failure and review of the literature. Am J Med Genet
1994;52:19–26
Schwartz C, Fitch N, Phelan MC, Richer C-L, Steveson R.
Two sisters with a distal deletion at the Xq26/Xq27 interface: DNA studies indicate that the gene locus for factor IX
is present. Hum Genet 1987;76:54–57
Skibsted L, Welsh H, Niebuhr. X long-arm deletions: a review of non-mosaic cases studied with banding techniques.
Hum Genet 1994;67:1–5
Veneman TF, Beverstock GC, Exalto N, Mollevanger P. Premature menopause because of an inherited deletion in the
long arm on the X-characterization. Fertil Steril 1991;55:
631–633
Partington MW, Moore DY, Turner GM. Confirmation of
early menopause in fragile X carriers. Am J Med Genet
1996;64:370–372
Tizzano EF, Baiget M. High proportion of twins in carriers
of fragile X syndrome. J Med Genet 1992;29:599
Sherman SL, Turner G, Sheffield L, Laing S, Robinson H.
Investigation of the twinning rate in families with the fragile
X syndrome. Am J Med Genet 1988;30:625–631
Murray A, Ennis S, MacSwiney F, Webb J, Morton NE. Reproductive and menstrual history of females with fragile X
expansions. Eur J Hum Genet 2000;8:247–252
Allingham-Hawkins DJ, Babul-Hirji R, Chitayat D, et al.
Fragile X premutations is a significant risk factor for premature ovarian failure: the International Collaborative POF in
Fragile X Study—preliminary data. Am J Med Genet 1999;
83:322–325
Schwartz CE, Dean J, Howard-Peebles PN, et al. Obstetrical and gynecological complications in fragile X carriers: a
multi-center study. Am J Med Genet 1994;51:400–402
Uzielli MLG, Guarducci S, Lapi E, et al. Premature ovarian
failure (POF) and fragile X premutation females: from POF
to fragile X carrier identification, from fragile X carrier diagnosis to POF association data. Am J Med Genet 1999;84:
300–303
Conway GS, Hettiarachi S, Murray A, Jacobs PA. Fragile X
premutations in familial premature ovarian failure. Lancet
1995;346:309–310
Conway GS, Payne NN, Webb J, Murray A, Jacobs PA.
Fragile X premutation screening in women with premature
ovarian failure. Hum Reprod 1998;13:1184–1187
Marozzi A, Vegetti W, Manfredini E, et al. Association between idiopathic premature ovarian failure and fragile X
premutations. Hum Reprod 2000;15:197–202
Murray A, Webb J, Grimley S, Conway G, Jacobs P. Studies
of FRAXA and FRAXE in women with premature menopause. J Med Genet 1998;35:637–640
Syrrou M, Georgiou I, Patsalis PC, Bouba I, Adonakis G,
Pagoulatos GN. Fragile X permutation and (TA)n estrogen
receptor polymorphism in women with ovarian dysfunction.
Am J Med Genet 1999;84:306–309
Rousseau F, Rouillard P, Morel ML, Khandjian EW, Morgan K. Prevalence of carriers of premutation-size alleles of
the FMR1 gene, and implications for the population genetics of the fragile X syndrome. Am J Hum Genet 1995;57:
1006–1018
Spence WC, Black SH, Fallon L, et al. Molecular fragile X
screening in normal populations. Am J Med Genet 1996;64:
181–183
Driscoll G, Clark J, Elakis G, Turner G. Early menopause in
a family carrying a fragile X permutation. Aust N Z J Med
2000;30:86–88
58. Layman LL, Gupta J, Xie J, Song M, Das S. Fragile X
FMR1 premutation alleles with premature ovarian failure in
families with at least one full mutation. Am J Hum Genet
1998;63(suppl):A334
59. Vianna-Morgante AM, Costa SS, Pares AS, Verreschi IT.
FRAXA premutation associated with premature ovarian
failure. Am J Med Genet 1996;64:373–375
60. Kenneson A, Cramer DE, Warren ST. Fragile X premutations are not a major cause of early menopause. Am J Hum
Genet 1997;61:1362–1369
61. Marozzi A, Dalpra L, Ginelli E, Tibiletti MG, Crosignani
PG. FRAXA premutations are not a cause of familial premature ovarian failure. Hum Reprod 1999;14:573–575
62. Martin NG, Healey SC, Pangan TS, Heath AC, Turner G.
Do mothers of dizygotic twins have earlier menopause? A
role for fragile X? Am J Med Genet 1997;69:114–116
63. Sherman SL, Meadows KL, Ashley AE. Examination of
factors that influence the expansion of the fragile X mutation in a subset of conceptuses from known carrier females.
Am J Med Genet 1996;64:256–260
64. Hunscheind RDL, Sistermans EA, Thomas CMG, et al.
Imprinting effect in premature ovarian failure confined to
paternally inherited fragile X permutations. Am J Hum
Genet 2000;66:413–418
65. Murray A, Ennis S, Morton N. No evidence of parent of
origin influencing premature ovarian failure in fragile X premutation carriers. Am J Hum Genet 2000;67:253–254
66. Vianna-Morgante AM, Costa SS. Premature ovarian failure
is associated with maternally and paternally inherited premutation in Brazilian families with fragile X. Am J Hum
Genet 2000;67:254–255
67. Sherman SL. Premature ovarian failure among fragile X permutation carriers: parent-of-origin effect? Am J Hum Genet
2000;67:11–13
68. Butler MG, Najjar JL. Do some patients with fragile X syndrome have precocious puberty? Am J Med Genet 1988;31:
779–781
69. Moore PS, Chudley AE, Winter JS. True precocious puberty
in a girl with the fragile X syndrome. Am J Med Genet
1990;37:265–267
70. Burgess B, Partington M, Turner G, Robinson J. Normal age
of menarche in fragile X syndrome. Am J Med Genet 1996;
64:376
71. Black SH. Preimplantation genetic diagnosis. Curr Opin
Pediatr 1994;6:712–716
72. Howard-Peebles PN. Successful pregnancy in a fragile X
carrier by donor egg. Am J Med Genet 1996;64:377
73. Braat DDM, Smits APT, Thomas CMG. Menstrual disorders and endocrine profiles in fragile X carriers prior to
40 years of age: a pilot study. Am J Med Genet 1999;83:
327–328
74. Murray A, Webb J, MacSwiney F, Shipley EL, Morton
NE, Conway GS. Serum concentrations of follicle stimulating hormone may predict premature ovarian failure in
FRAXA premutation women. Hum Reprod 1999;14:
1217–1218
75. Berkowitz GD, Wilson DP, Carpenter NJ, Brown TR,
Migeon CJ. Gonadal function in men with the MartinBell (fragile X) syndrome. Am J Med Genet 1986;23:
227–239
76. Bregman JD, Leckman JF, Ort SI. Thyroid function in fragile X syndrome males. Yale J Biol Med 1990;63:293–299
77. Cantu JM, Scaglia HE, Medina M, et al. Inherited congenital normofunctional testicular hyperplasia and mental deficiency. Hum Genet 1976;33:23–33
THE FEMALE AND THE FRAGILE X REVIEWED/KENNESON, WARREN
78. McDermott A, Walters R, Howell RT, Gardner A. Fragile
X chromosome: clinical and cytogenetic studies on cases
from seven families. J Med Genet 1993;20:169–178
79. Moore PS, Chudley AE, Winter JS. Pituitary-gonadal axis
in pubertal boys with fragile X syndrome Am J Med Genet
1991;39:374–375
80. Nielsen KB, Tommerup N, Dyggve HV, Schou C. Macroorchidism and fragile X in mentally retarded males: clinical,
cytogenetic, and some hormonal investigations in mentally
retarded males, including two with the fragile site of Xq28,
fra(X)(q28). Hum Genet 1982;61:113–117
81. O’Hare JP, O’Brien IA, Arendt J, et al. Does melatonin deficiency cause the enlarged genitalia of the fragile X syndrome? Clin Endocrinol 1986;24:327–333
82. Ruvalcaba RH, Myhre SA, Roosen-Runge EC, Beckwith
JB. X-linked mental deficiency megalotestes syndrome.
JAMA 1977;238:1646–1650
83. Turner G, Eastman C, Casey J, McLeay A, Procopius P,
Tyrner B. X-linked mental retardation associated with
macro-orchidism. J Med Genet 1975;12:367–371
84. Venter PA, Op’t Hof J, Coetzee DJ. The Martin-Bell syndrome in South Africa. Am J Med Genet 1986;23:597–610
85. Wilson DP, Carpenter NJ, Berkowitz G. Thyroid function
in men with fragile X–linked MR. Am J Med Genet 1988;
31:733–734
86. Abitol M, Menini C, Delezoide AL, Rhyner T, Vekemans
M, Mallet J. Nucleus basalis magnocellularis and hippocampus are the major sites of FMR-1 expression in the human
fetal brain. Nat Genet 1993;4:147–153
87. Hergersberg M, Mastuo K, Gassman M, et al. Tissue-specific expression of a FMR1/beta-galactosidase fusion gene
in transgenic mice. Hum Mol Genet 1995;4:359–366
88. Hinds HL, Ashley CT, Sutcliffe JS, et al. Tissue specific
expression of FMR-1 provides evidence for a functional role
in fragile X syndrome [published erratum appears in Nat
Genet 1995;5:312] Nat Genet 1993;3:36–43
89. Tamanini F, Willemsen R, van Unen L, et al. Differential
expression of FMR1, FXR1 and FXR2 proteins in human
brain and testis. Hum Mol Genet 1997;6:1315–1322
90. Bachner D, Manca A, Steinbach P, et al. Enhanced expression of the murine FMR1 gene during germ cell prolifera-
91.
92.
93.
94.
95.
96.
97.
98.
99.
100.
101.
102.
tion suggests a special function in both the male and the female gonad. Hum Mol Genet 1993;2:2043–2050
Malter HE, Iber JC, Willemsen R, et al. Characterization of
the full fragile X syndrome mutation in fetal gametes. Nat
Genet 1997;15:165–169
Oberle I, Rousseau F, Heitz D, et al. Instability of a 550 base
pair DNA segment and abnormal methylation in fragile X
syndrome. Science 1991;252:1097–1102
Reyniers E, Vits L, De Boulle K, et al. The full mutation in
the FMR-1 gene of male fragile X patients is absent in their
sperm. Nat Genet 1993;4:143–146
Pianese L, Cavalcanti F, De Michele G, et al. The effect of
parental gender on the GAA dynamic mutation in the
FRDA gene. Am J Hum Genet 1997;60:460–463
Eberhart DE, Warren ST. Nuclease sensitivity of permeabilized cells confirms altered chromatin formation at the fragile X locus. Somat Cell Mol Genet 1996;22:435–441
Ashley-Koch AE, Robinson H, Glicksman AE, et al. Examination of factors associated with instability of the FMR1
CGG repeat. Am J Hum Genet 1998;63:776–785
Fisch GS, Snow K, Thibodeau SN, et al. The fragile X syndrome permutation in carriers and its effect on mutation size
in offspring. Am J Hum Genet 1995;56:1147–1155
Nolin SL, Lewis FA III, Ye LL. Familial transmission of the
FMR1 CGG repeat. Am J Hum Genet 1996;59:1252–1261
Nolin SL, Houck GE Jr, Gargano AD, et al. FMR1 CGGrepeat instability in single-sperm and lymphocytes of
fragile-X permutation males. Am J Hum Genet 1999;65:
680–688
Tassone F, Hagerman RJ, Taylor AK, Gane LW, Godfry TE, Hagerman PJ. Elevated levels of FMR1 mRNA in
carrier males: a new mechanism of involvement in the fragile-X syndrome. Am J Hum Genet 2000;66:6–15
Turner G, Eastman C, Wake S, Martin N. Dizygous twinning and premature menopause in fragile X syndrome.
Lancet 1994;344:1500
Vianna-Morgante AM. Twinning and premature ovarian
failure in premutation fragile X carriers. Am J Med Genet
1999;83:326
165