On average, the menopause occurs at the age of 50 years,1 with 1 % of women continuing to menstruate beyond the age of 60 years and 1% whose menopause occurs before 40 years. Arbitrarily, a menopause before the age of 40 years is defined as 'premature'. Premature ovarian failure may be caused by any process which reduces the number of oocytes within the ovary. In the embryo, germ cells first appear in the urogenital ridge. These germ cells then migrate to the primitive ovary. Once within the ovary, the germ cells multiply to form 3.5 million potential oocytes in each ovary (Fig. 1). From this time, oocytes are held in suspended animation - meiosis - until required for ovulation perhaps 40 years later. If a woman were to ovulate every month throughout her reproductive life, then she would use fewer than 500 eggs - a tiny proportion of the original 7 million (0.007%). Thus, if a woman were to prevent ovulation, say by taking the combined oral contraceptive

/pdf/premature-ovarian-failure-27iznvee62.pdf

Premature ovarian failure

We present a series of 26 patients, all >50 years of age, who are carriers of the fragile X premutation and are affected by a multisystem, progressive neurological disorder. The two main clinical features of this new syndrome are cerebellar ataxia and/or intention tremor, which were chosen as clinical inclusion criteria for this series. Other documented symptoms were short-term memory loss, executive function deficits, cognitive decline, parkinsonism, peripheral neuropathy, lower limb proximal muscle weakness, and autonomic dysfunction. Symmetrical regions of increased T2 signal intensity in the middle cerebellar peduncles and adjacent cerebellar white matter are thought to be highly sensitive for this neurologic condition, and their presence is the radiological inclusion criterion for this series. Molecular findings include elevated mRNA and low-normal or mildly decreased levels of fragile X mental retardation 1 protein. The clinical presentation of these patients, coupled with a specific lesion visible on magnetic resonance imaging and with neuropathological findings, affords a more complete delineation of this fragile X premutation–associated tremor/ataxia syndrome and distinguishes it from other movement disorders.

Fragile X Premutation Tremor/Ataxia Syndrome: Molecular, Clinical, and Neuroimaging Correlates

Fragile X syndrome (FXS) is the leading inherited form of intellectual disability and autism spectrum disorder, and patients can present with severe behavioural alterations, including hyperactivity, impulsivity and anxiety, in addition to poor language development and seizures. FXS is a trinucleotide repeat disorder, in which >200 repeats of the CGG motif in FMR1 leads to silencing of the gene and the consequent loss of its product, fragile X mental retardation 1 protein (FMRP). FMRP has a central role in gene expression and regulates the translation of potentially hundreds of mRNAs, many of which are involved in the development and maintenance of neuronal synaptic connections. Indeed, disturbances in neuroplasticity is a key finding in FXS animal models, and an imbalance in inhibitory and excitatory neuronal circuits is believed to underlie many of the clinical manifestations of this disorder. Our knowledge of the proteins that are regulated by FMRP is rapidly growing, and this has led to the identification of multiple targets for therapeutic intervention, some of which have already moved into clinical trials or clinical practice.

Fragile X syndrome

FMR1 and the fragile X syndrome: Human genome epidemiology review

ContextPremutation expansions (55-200 CGG repeats) of the fragile X mental
retardation 1 (FMR1) gene are frequent in the general
population, with estimated prevalences of 1 per 259 females and 1 per 813
males. Several articles have recently described the presence of late-onset
neurological symptoms in male carriers of premutation (FMR1) alleles. The main clinical features described in this newly identified
syndrome are cerebellar ataxia and intention tremor. Additional documented
symptoms include short-term memory loss, executive functional deficits, cognitive
decline, parkinsonism, peripheral neuropathy, lower-limb proximal muscle weakness,
and autonomic dysfunction.ObjectiveTo study the penetrance of the fragile X–associated tremor/ataxia
syndrome (FXTAS) among premutation carriers.Design, Setting, and ParticipantsFamily-based study of 192 individuals (premutation carriers and controls)
whose families belong to the Northern or Southern California Fragile X Associations.
Data were collected (March 2002-April 2003) through a survey and a standardized
neurological examination, which was videotaped and subsequently scored in
a blinded fashion.Main Outcome MeasuresPenetrance of intention tremor and ataxia among adult carriers (aged
≥50 years) of premutation expansions of the FMR1 gene.ResultsData from the survey of 192 individuals demonstrated an age-related
penetrance of the combination of reported intention tremor and gait ataxia
in male carriers (17%, 38%, 47%, and 75% [lower-bound estimates] for participants
aged 50-59, 60-69, 70-79, and ≥80 years, respectively). The male carrier
group had an age-adjusted 13-fold increased risk (95% confidence interval,
3.9-25.4; P = .003) of combined intention tremor
and gait ataxia when compared with male controls. The clinical examination
data from 93 individuals demonstrated that male carriers experienced more
difficulties on each of 3 standardized neurological rating scales compared
with controls (P<.05). Female carrier scores were
also higher than those of female controls (P<.05)
on 2 of the 3 neurological rating scales, but no participant was identified
with probable or definite FXTAS.ConclusionsThe study demonstrates that older male carriers of premutation alleles
of the FMR1 gene are at high risk of developing FXTAS.
Since male premutation carriers are relatively common in the general population,
older men with ataxia and intention tremor should be screened for the FMR1 mutation, especially if these signs are accompanied
by parkinsonism, autonomic dysfunction, or cognitive decline, regardless of
family history.

https://jamanetwork.com/journals/jama/articlepdf/198088/joc31090.pdf

Penetrance of the Fragile X–Associated Tremor/Ataxia Syndrome in a Premutation Carrier Population

We have conducted a multicenter obstetrical and gynecological survey of women in fragile X families. Included in the study were 131 gene carriers (39 with a full mutation and 92 with a premutation) and 109 noncarriers. Analysis indicated that higher numbers of fragile X gene carriers reported having irregular menses and other gynecological complications. As a group they also experienced cessation of menses prior to age 40 years at a significantly higher rate. The data appear to indicate that the FMR1 gene may play a role in the development and proliferation of oogonia. © 1994 Wiley-Liss, Inc.

Obstetrical and gynecological complications in fragile X carriers: a multicenter study.

We collected data on growth, psychomotor development, speech and language development, and intellectual function on a cohort of 100 males with the fragile X chromosome and 95 carrier females. The data include information on prenatal growth (33 males), growth during the preadult years (32 males), psychomotor development during the first 2 years (25 males), speech and language development (15 males and 5 females), and intellectual function (93 males, 33 females, and 10 obligate carriers who were cytogenetically normal). Birth measurements appeared normal when plotted on the Usher/McLean curves of newborn infants (mean head circumference - OFC - at 40th centile, length at 60th centile and weight at 55th centile). Following birth, OFC rose above the 50th percentile and continued above average throughout the preadult years, whereas average length was above average for the first 5 years only and weight did not deviate from the normal mean. Psychomotor development lagged behind the norm from birth with affected males requiring nearly twice as long as expected to sit alone, walk unassisted, and say first words clearly. All males and females studied had significant language delay; all except one male had abnormalities of articulation. All on whom a clear voice sample was obtained had low voice pitch, and 80% had a hoarse or harsh quality of voice. Five males had word repetitions or perseverative speech during the preadult years. The mean IQ of the 93 males studied was 33 and regression analysis demonstrated a decrease in intellectual performance with age. Four fifths of the female carriers who expressed the fra(X) had intellectual performance in the mentally retarded range and showed similar decrease in performance with age. Obligate female carriers who did not express the fra(X) site had normal IQs (IQ 102 +/- 13.3).

Fragile X syndrome: growth, development, and intellectual function

Individuals in South Carolina with the Fragile X [ fra(X) ] or Martin-Bell syndrome have been ascertained by referral for evaluation of facial abnormalities, macroorchidism or mental deficit; by screening patients in residential and day programs for the mentally retarded; and by family follow up after an index case has been identified. Between 1982 and 1987, 100 positive fra(X) males were diagnosed. Of these, 35 were residents of residential facilities for the mentally retarded representing 2.5% of the population of institutionalized males. Another 23 were found in community day programs for the mentally retarded. Of these 58 cases, 28 (48%) were ascertained by screening for the craniofacial characteristics of the Martin-Bell syndrome, namely long face, midface hypoplasia, prominent forehead, large mandible and large simple pinnae. Although this screening procedure proved to be productive, it was found that the craniofacial traits of long face, midface hypoplasia, large jaw and simple pinnae were found less frequently in black fra(X) positive males and in prepubertal boys of both races.

Fragile X syndrome: incidence, clinical and cytogenetic findings in the black and white populations of South Carolina.

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Papers

Obstetrical and gynecological complications in fragile X carriers: a multicenter study.

Fragile X syndrome: growth, development, and intellectual function

Fragile X syndrome: incidence, clinical and cytogenetic findings in the black and white populations of South Carolina.