Fragile X-associated primary ovarian insufficiency (FXPOI) is the most common genetic cause of

premature ovarian failure Primary ovarian insufficiency (POI), also called premature ovarian insufficiency and premature ovarian failure, is the partial or total loss of reproductive and hormonal function of the ovaries before age 40 because of follicular ( egg produc ...

in women with a normal karyotype 46, XX. The expansion of a CGG repeat in the 5' untranslated region of the ''FMR1'' gene from the normal range of 5-45 repeats to the premutation range of 55-199 CGGs leads to risk of FXPOI for ovary-bearing individuals. About 1:150-1:200 women in the US population carry a premutation. Women who carry an ''FMR1'' premutation have a roughly 20% risk of being diagnosed with FXPOI, compared to 1% for the general population, and an 8-15% risk of developing the neurogenerative tremor/ataxia disorder (FXTAS). ''FMR1'' premutation women are also at increased risk of having a child with a CGG repeat that is expanded to >200 repeats (a full mutation). Individuals with a full mutation, unlike the premutation, produce little to no mRNA or protein from the ''FMR1'' gene and have

fragile X syndrome Fragile X syndrome (FXS) is a genetic neurodevelopmental disorder. The average IQ in males with FXS is under 55, while affected females tend to be in the borderline to normal range, typically around 70–85. Physical features may include a lo ...

as a result.

Clinical diagnosis

Primary ovarian insufficiency requires that a diagnosis be made before the age of 40, since it is considered premature relative to the average age of

menopause Menopause, also known as the climacteric, is the time when Menstruation, menstrual periods permanently stop, marking the end of the Human reproduction, reproductive stage for the female human. It typically occurs between the ages of 45 and 5 ...

of 51 in the US. The two criteria are the repeated elevation of the

follicle stimulating hormone Follicle-stimulating hormone (FSH) is a gonadotropin, a glycoprotein polypeptide hormone. FSH is synthesized and secreted by the gonadotropic cells of the anterior pituitary gland and regulates the development, growth, pubertal maturation, ...

(FSH), which increases dramatically when a woman enters menopause, and the loss of

menstruation Menstruation (also known as a period, among other colloquial terms) is the regular discharge of blood and Mucous membrane, mucosal tissue from the endometrium, inner lining of the uterus through the vagina. The menstrual cycle is characterized ...

for at least 4–6 months. In ''FMR1'' premuation carriers, the likelihood of receiving a clinical diagnosis of FXPOI is about 20% and increased FSH levels and altered menstrual cycles become particularly evident between 30 and 40 years of age. Even if

menses Menstruation (also known as a period, among other colloquial terms) is the regular discharge of blood and Mucous membrane, mucosal tissue from the endometrium, inner lining of the uterus through the vagina. The menstrual cycle is characterized ...

are lost, women diagnosed with FXPOI may experience a spontaneous "escape"

ovulation Ovulation is an important part of the menstrual cycle in female vertebrates where the egg cells are released from the ovaries as part of the ovarian cycle. In female humans ovulation typically occurs near the midpoint in the menstrual cycle and ...

. This means that there is some chance for conception, around 10%, even if menstruation has been absent for extended periods in women with FXPOI. Women planning to conceive before the cessation of periods are often encouraged to consult a

genetic counselor Genetic counseling is the process of investigating individuals and families affected by or at risk of genetic disorders to help them understand and adapt to the medical, psychological and familial implications of genetic contributions to disease. ...

or medical geneticist to understand their risk for having a child with fragile X syndrome.

Genetics

The ''FMR1'' premutation is commonly identified using reflexive

genetic testing Genetic testing, also known as DNA testing, is used to identify changes in DNA sequence or chromosome structure. Genetic testing can also include measuring the results of genetic changes, such as RNA analysis as an output of gene expression, or ...

after identification of a child with fragile X syndrome found in a family. This genetic diagnosis accounts for 10-15% of women who will receive an FXPOI diagnosis. Women may also experience

infertility In biology, infertility is the inability of a male and female organism to Sexual reproduction, reproduce. It is usually not the natural state of a healthy organism that has reached sexual maturity, so children who have not undergone puberty, whi ...

and receive genetic testing in the course of reproductive care. Roughly 1-3% of FXPOI cases are identified through this process. FXPOI is the most common known genetic cause of ovarian insufficiency for women with a normal chromosome number (46, XX). It accounts for 5-10% of these cases of

. Not all women who are carriers for an ''FMR1'' premutation allele, an expansion of the CGG repeat in the ''FMR1'' gene to 55-199 repeats, will be diagnosed with FXPOI. About 20% of premutation carriers will be diagnosed, but this risk represents a significant increase over the general population who have a roughly 1% risk of POI. Women with the highest risk of POI have 70-100 CGG repeats, meaning there is a non-linear association between CGG-repeat size and FXPOI risk. This relationship is different than the linear association seen between CGG repeat size and age of onset of FXTAS. Other variations in premutation alleles, like AGG interruptions within the CGG repeats, are not correlated with risk of a FXPOI diagnosis. The AGG interruptions are correlated with the risk that the premutation-length allele could expand in the oocyte, or egg cell, and lead to a child with

Pathophysiology

In the context of FXPOI, two main hypotheses explain the underlying molecular mechanisms. One proposes an mRNA toxic gain-of-function effect, while the other suggests a protein-based mechanism. In the latter, repeat-associated non-AUG (RAN) translation produces an abnormal protein, FMRpolyG, which may contribute to cellular dysfunction.

Risk of developing other premutation-related diagnoses

Though the greatest risks for female carriers of an ''FMR1'' premutation are developing POI and having a child with fragile X syndrome, there are other possible

neurological Neurology (from , "string, nerve" and the suffix -logia, "study of") is the branch of medicine dealing with the diagnosis and treatment of all categories of conditions and disease involving the nervous system, which comprises the brain, the s ...

and

neuropsychiatric conditions A mental disorder, also referred to as a mental illness, a mental health condition, or a psychiatric disability, is a behavioral or mental pattern that causes significant distress or impairment of personal functioning. A mental disorder is ...

that may occur. Roughly 8-15% of female premutation carriers will develop the late-onset

neurodegenerative A neurodegenerative disease is caused by the progressive loss of neurons, in the process known as neurodegeneration. Neuronal damage may also ultimately result in their death. Neurodegenerative diseases include amyotrophic lateral sclerosis, mul ...

tremor/ataxia disorder FXTAS. More recently, increased interest in neurological features and cognition of female premutation carriers has suggested a broader range of neuropsychiatric conditions associated with premutation-sized CGG repeats. Women with an ''FMR1'' premutation exhibit higher incidences of depression,

anxiety Anxiety is an emotion characterised by an unpleasant state of inner wikt:turmoil, turmoil and includes feelings of dread over Anticipation, anticipated events. Anxiety is different from fear in that fear is defined as the emotional response ...

, autoimmune dysfunction, and neuromuscular pain. The prevalence of depression and anxiety in premutation females is, notably, higher than that observed in premutation males. Interpretation of studies that examine women with a premutation, who may have complex and challenging needs, is difficult since it is unclear whether the premutation leads to increased anxiety and depression or it is increased environmental stressors within the home. Research to understand these differences between males and females with the same genetic change is developing, but there are no studies that point to a definitive driver of these differences.

Expansion of a premutation to full mutation

An additional challenge for women with an ''FMR1'' premutation is determining the risk for having a child with fragile X syndrome.

Epidemiological Epidemiology is the study and analysis of the distribution (who, when, and where), patterns and Risk factor (epidemiology), determinants of health and disease conditions in a defined population, and application of this knowledge to prevent dise ...

data show that the risk of a premutation allele (55-199 CGGs) expanding to a full mutation (>200 CGGs) increases as the length of the CGG tract grows. This risk assessment for expansion to a full mutation is critical for women, but not men, with a premutation since the premutation allele in males does not show large expansion and transmission through generations. Expansion from a premutation to full mutation only occurs within the

egg cell The egg cell or ovum (: ova) is the female Reproduction, reproductive cell, or gamete, in most anisogamous organisms (organisms that reproduce sexually with a larger, female gamete and a smaller, male one). The term is used when the female game ...

s of a female premutation carrier. Additional factors influencing the stability of ''FMR1'' premutation alleles are the presence of AGG interruptions. The loss of 1 or 2 AGG interruptions in the 5' region of the CGG repeat allele leads to increased likelihood that a premutation will expand to a full mutation from one generation to the next. Studies have also indicated that increasing maternal age may be a contributor to increased risk of expansion of a premutation to a full mutation, but the molecular mechanism through which this expansion process occurs are not yet understood.

Resources

Individuals with ''FMR1''-related disorders and families have access to several communities to find support groups and information about ongoing research and new therapies. Concise information designed for patients, families, or people outside of medical fields is available. The National Fragile X Foundation raises awareness about fragile X-associated disorders, research, and treatments. The FRAXA Research Foundation is another resource for families and is primarily focused on funding and helping amplify research and treatment options for fragile X to the community.

References

External links

* * {{cite web , title = National Fragile X Foundation , url=https://fragilex.org/ , location = Washington, DC Genetic diseases and disorders Reproduction Women's health Genetic anomalies X-linked dominant disorders Endocrine diseases