Fragile X-associated primary ovarian insufficiency

Last updated
Fragile X-associated primary ovarian insufficiency
Other namespremature ovarian failure
Pronunciation
  • fax-poi
Specialty Genetics, reproductive endocrinology
Symptoms Elevated follicle stimulating hormone (FSH) and loss of menstrual cycles before age 40
CausesFMR1 premutation
Diagnostic method genetic testing
Treatmentinfertility: may use assisted reproductive technologies risk of FMR1 premutation expansion: genetic testing for CGG repeat expansion in embryos or fetuses

Fragile X-associated primary ovarian insufficiency (FXPOI) is the most common genetic cause of premature ovarian failure in women with a normal karyotype 46,XX. [1] 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. [2] About 1:150-1:200 women in the US population carry a premutation. [3] 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). [4] [5] 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). [6] Individuals with a full mutation, unlike the premutation, produce little to no mRNA or protein from the FMR1 gene and have fragile X syndrome as a result.

Contents

Clinical diagnosis

Primary ovarian insufficiency requires that a diagnosis be made prior to the age of 40, since it is considered premature relative to the average age of menopause of 51 in the US. [7] The two criteria are the repeated elevation of the follicle stimulating hormone (FSH), which increases dramatically when a woman enters menopause, and the loss of menstruation for at least 4–6 months. [8] 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. [4] Even if menses are lost, women diagnosed with FXPOI may experience a spontaneous "escape" ovulation. This means that there is some chance for conception, around 10%, even if menstruation has been absent for extended periods in women with FXPOI. [9] Women planning to conceive before the cessation of periods are often encouraged to consult a genetic counselor or medical geneticist to understand their individual risk for having a child with fragile X syndrome.

Genetics

The FMR1 premutation is commonly identified using reflexive genetic testing 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 a FXPOI diagnosis. [9] Women may also experience infertility and receive genetic testing in the course of reproductive care. Roughly 1-3% of FXPOI cases are identified through this process. [9]

FXPOI is the most common known genetic cause of ovarian insufficiency for women with a normal chromosome number (46,XX) and accounts for 5-10% of these cases of premature ovarian failure. [10] 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. [11] Women with highest risk of POI have 70-100 CGG repeats, meaning there is a non-linear association between CGG-repeat size and FXPOI risk. [7] [12] 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. [13] 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 fragile X syndrome. [14] [15]

Though the greatest risks for female carriers of an FMR1 premuation are developing POI and having a child with fragile X syndrome, there are other possible neurological and neuropsychiatric conditions that may occur. [16] [17] Roughly 8-15% of female premutation carriers will develop the late-onset neurodegenerative tremor/ataxia disorder FXTAS. [16] 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, autoimmune dysfunction, and neuromuscular pain. [17] [18] [19] [20] The prevalence of depression and anxiety in premutation females is, notably, higher than that observed in premutation males. [21] 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. [22] 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 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. [23] 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. [14] [23] Expansion from a premutation to full mutation only occurs within the egg cells of a female premutation carrier. [23] [24] Additional factors influencing the stability of FMR1 premutation alleles are the presence of AGG interruptions. [25] 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. [23] [14] [25] 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. [14] [23] [26]

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 are available. The National Fragile X Foundation is a private foundation that focuses on raising awareness about fragile X-associated disorders, research, and treatments. [27] 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. [28]

Related Research Articles

A microsatellite is a tract of repetitive DNA in which certain DNA motifs are repeated, typically 5–50 times. Microsatellites occur at thousands of locations within an organism's genome. They have a higher mutation rate than other areas of DNA leading to high genetic diversity. Microsatellites are often referred to as short tandem repeats (STRs) by forensic geneticists and in genetic genealogy, or as simple sequence repeats (SSRs) by plant geneticists.

<span class="mw-page-title-main">Fragile X syndrome</span> X-linked dominant genetic disorder

Fragile X syndrome (FXS) is a genetic neurodevelopmental disorder characterized by mild-to-moderate intellectual disability. The average IQ in males with FXS is under 55, while about two thirds of affected females are intellectually disabled. Physical features may include a long and narrow face, large ears, flexible fingers, and large testicles. About a third of those affected have features of autism such as problems with social interactions and delayed speech. Hyperactivity is common, and seizures occur in about 10%. Males are usually more affected than females.

In genetics, anticipation is a phenomenon whereby as a genetic disorder is passed on to the next generation, the symptoms of the genetic disorder become apparent at an earlier age with each generation. In most cases, an increase in the severity of symptoms is also noted. Anticipation is common in trinucleotide repeat disorders, such as Huntington's disease and myotonic dystrophy, where a dynamic mutation in DNA occurs. All of these diseases have neurological symptoms. Prior to the understanding of the genetic mechanism for anticipation, it was debated whether anticipation was a true biological phenomenon or whether the earlier age of diagnosis was related to heightened awareness of disease symptoms within a family.

<span class="mw-page-title-main">Non-Mendelian inheritance</span> Type of pattern of inheritance

Non-Mendelian inheritance is any pattern in which traits do not segregate in accordance with Mendel's laws. These laws describe the inheritance of traits linked to single genes on chromosomes in the nucleus. In Mendelian inheritance, each parent contributes one of two possible alleles for a trait. If the genotypes of both parents in a genetic cross are known, Mendel's laws can be used to determine the distribution of phenotypes expected for the population of offspring. There are several situations in which the proportions of phenotypes observed in the progeny do not match the predicted values.

In genetics, trinucleotide repeat disorders, a subset of microsatellite expansion diseases, are a set of over 30 genetic disorders caused by trinucleotide repeat expansion, a kind of mutation in which repeats of three nucleotides increase in copy numbers until they cross a threshold above which they cause developmental, neurological or neuromuscular disorders. In addition to the expansions of these trinucleotide repeats, expansions of one tetranucleotide (CCTG), five pentanucleotide, three hexanucleotide, and one dodecanucleotide (CCCCGCCCCGCG) repeat cause 13 other diseases. Depending on its location, the unstable trinucleotide repeat may cause defects in a protein encoded by a gene; change the regulation of gene expression; produce a toxic RNA, or lead to production of a toxic protein. In general, the larger the expansion the faster the onset of disease, and the more severe the disease becomes.

The Sherman paradox was a term used to describe the anomalous pattern of inheritance found in fragile X syndrome. The phenomenon is also referred to as anticipation or dynamic mutation.

<span class="mw-page-title-main">FMR1</span> Human protein and coding gene

FMR1 is a human gene that codes for a protein called fragile X messenger ribonucleoprotein, or FMRP. This protein, most commonly found in the brain, is essential for normal cognitive development and female reproductive function. Mutations of this gene can lead to fragile X syndrome, intellectual disability, premature ovarian failure, autism, Parkinson's disease, developmental delays and other cognitive deficits. The FMR1 premutation is associated with a wide spectrum of clinical phenotypes that affect more than two million people worldwide.

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 dysfunction or early loss of eggs. POI can be seen as part of a continuum of changes leading to menopause that differ from age-appropriate menopause in the age of onset, degree of symptoms, and sporadic return to normal ovarian function. POI affects approximately 1 in 10,000 women under age 20, 1 in 1,000 women under age 30, and 1 in 100 of those under age 40. A medical triad for the diagnosis is amenorrhea, hypergonadotropism, and hypoestrogenism.

A trinucleotide repeat expansion, also known as a triplet repeat expansion, is the DNA mutation responsible for causing any type of disorder categorized as a trinucleotide repeat disorder. These are labelled in dynamical genetics as dynamic mutations. Triplet expansion is caused by slippage during DNA replication, also known as "copy choice" DNA replication. Due to the repetitive nature of the DNA sequence in these regions, 'loop out' structures may form during DNA replication while maintaining complementary base pairing between the parent strand and daughter strand being synthesized. If the loop out structure is formed from the sequence on the daughter strand this will result in an increase in the number of repeats. However, if the loop out structure is formed on the parent strand, a decrease in the number of repeats occurs. It appears that expansion of these repeats is more common than reduction. Generally, the larger the expansion the more likely they are to cause disease or increase the severity of disease. Other proposed mechanisms for expansion and reduction involve the interaction of RNA and DNA molecules.

<span class="mw-page-title-main">CGGBP1</span> Protein-coding gene in humans

CGG triplet repeat-binding protein 1 is a protein that in humans is encoded by the CGGBP1 gene.

<span class="mw-page-title-main">Fragile X-associated tremor/ataxia syndrome</span>

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder most frequently seen in male premutation carriers of Fragile X syndrome (FXS) over the age of 50. The main clinical features of FXTAS include problems of movement with cerebellar gait ataxia and action tremor. Associated features include parkinsonism, cognitive decline, and dysfunction of the autonomic nervous system. FXTAS is found in Fragile X "premutation" carriers, which is defined as a trinucleotide repeat expansion of 55-200 CGG repeats in the Fragile X mental retardation-1 (FMR1) gene. 4-40 CGG repeats in this gene is considered normal, while individual with >200 repeats have full Fragile X Syndrome.

<i>BRCA</i> mutation Medical condition

A BRCA mutation is a mutation in either of the BRCA1 and BRCA2 genes, which are tumour suppressor genes. Hundreds of different types of mutations in these genes have been identified, some of which have been determined to be harmful, while others have no proven impact. Harmful mutations in these genes may produce a hereditary breast–ovarian cancer syndrome in affected persons. Only 5–10% of breast cancer cases in women are attributed to BRCA1 and BRCA2 mutations, but the impact on women with the gene mutation is more profound. Women with harmful mutations in either BRCA1 or BRCA2 have a risk of breast cancer that is about five times the normal risk, and a risk of ovarian cancer that is about ten to thirty times normal. The risk of breast and ovarian cancer is higher for women with a high-risk BRCA1 mutation than with a BRCA2 mutation. Having a high-risk mutation does not guarantee that the woman will develop any type of cancer, or imply that any cancer that appears was actually caused by the mutation, rather than some other factor.

<span class="mw-page-title-main">FMR1-AS1 gene</span> Non-coding RNA in the species Homo sapiens

In molecular biology, FMR1 antisense RNA 1 (FMR1-AS1), also known as ASFMR1 or FMR4, is a long non-coding RNA. The FMR1-AS1 gene overlaps, and is antisense to, the CGG repeat region of the FMR1 gene. Its expression is upregulated in fragile X syndrome premutation carriers, and silenced in patients with fragile X syndrome. FMR1-AS1 has an anti-apoptotic function.

Ying-Hui Fu is a Taiwanese-American biologist and human geneticist who has made important contributions to understanding the genetics of many neurological disorders. Her chief discoveries include describing Mendelian sleep phenotypes, identifying causative genes and mutations for circadian rhythm disorders, and characterizing genetic forms of demyelinating degenerative disorders. Fu is currently a professor of neurology at the University of California, San Francisco. She was elected to the US National Academy of Sciences in 2018.

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Stephen T. Warren was an American geneticist and academic. He was the William Patterson Timmie Professor of Human Genetics and the Charles Howard Candler Chair of Human Genetics. He was the former Founding Chairman of the Department of Human Genetics at Emory University School of Medicine. He was an Investigator with the Howard Hughes Medical Institute from 1991 until 2002, when he resigned to found the Human Genetics department. Warren is well known for his work in the field of Human Genetics. His research was focused on the mechanistic understanding of fragile X syndrome, a leading cause of inherited developmental disability and autism. In 2020, Warren stepped down as department chair after 20 years in that position.

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References

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  2. ↑ Allen EG, Charen K, Hipp HS, Shubeck L, Amin A, He W, et al. (September 2021). "Refining the risk for fragile X-associated primary ovarian insufficiency (FXPOI) by FMR1 CGG repeat size". Genetics in Medicine. 23 (9): 1648–1655. doi:10.1038/s41436-021-01177-y. PMC   8460441 . PMID   33927378.
  3. ↑ Seltzer MM, Baker MW, Hong J, Maenner M, Greenberg J, Mandel D (July 2012). "Prevalence of CGG expansions of the FMR1 gene in a US population-based sample". American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics. 159B (5): 589–597. doi:10.1002/ajmg.b.32065. PMC   3391968 . PMID   22619118.
  4. 1 2 Allen EG, Sullivan AK, Marcus M, Small C, Dominguez C, Epstein MP, et al. (August 2007). "Examination of reproductive aging milestones among women who carry the FMR1 premutation". Human Reproduction. 22 (8): 2142–2152. doi: 10.1093/humrep/dem148 . PMID   17588953.
  5. ↑ Berry-Kravis E, Abrams L, Coffey SM, Hall DA, Greco C, Gane LW, et al. (October 2007). "Fragile X-associated tremor/ataxia syndrome: clinical features, genetics, and testing guidelines". Movement Disorders. 22 (14): 2018–30, quiz 2140. doi: 10.1002/mds.21493 . PMID   17618523. S2CID   12559110.
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  12. ↑ Mailick MR, Hong J, Greenberg J, Smith L, Sherman S (December 2014). "Curvilinear association of CGG repeats and age at menopause in women with FMR1 premutation expansions". American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics. 165B (8): 705–711. doi:10.1002/ajmg.b.32277. PMC   4410868 . PMID   25346430.
  13. ↑ Allen EG, Glicksman A, Tortora N, Charen K, He W, Amin A, et al. (2018). "FXPOI: Pattern of AGG Interruptions Does not Show an Association With Age at Amenorrhea Among Women With a Premutation". Frontiers in Genetics. 9: 292. doi: 10.3389/fgene.2018.00292 . PMC   6086008 . PMID   30123240.
  14. 1 2 3 4 Yrigollen CM, Martorell L, Durbin-Johnson B, Naudo M, Genoves J, Murgia A, et al. (2014-07-30). "AGG interruptions and maternal age affect FMR1 CGG repeat allele stability during transmission". Journal of Neurodevelopmental Disorders. 6 (1): 24. doi: 10.1186/1866-1955-6-24 . PMC   4126815 . PMID   25110527.
  15. ↑ Villate O, Ibarluzea N, Maortua H, de la Hoz AB, Rodriguez-Revenga L, Izquierdo-Álvarez S, Tejada MI (2020). "Effect of AGG Interruptions on FMR1 Maternal Transmissions". Frontiers in Molecular Biosciences. 7: 135. doi: 10.3389/fmolb.2020.00135 . PMC   7381193 . PMID   32766278.
  16. 1 2 Jacquemont S, Hagerman RJ, Leehey MA, Hall DA, Levine RA, Brunberg JA, et al. (January 2004). "Penetrance of the fragile X-associated tremor/ataxia syndrome in a premutation carrier population". JAMA. 291 (4): 460–469. doi:10.1001/jama.291.4.460. PMID   14747503.
  17. 1 2 Hagerman RJ, Protic D, Rajaratnam A, Salcedo-Arellano MJ, Aydin EY, Schneider A (2018-11-13). "Fragile X-Associated Neuropsychiatric Disorders (FXAND)". Frontiers in Psychiatry. 9: 564. doi: 10.3389/fpsyt.2018.00564 . PMC   6243096 . PMID   30483160.
  18. ↑ Wheeler AC, Bailey DB, Berry-Kravis E, Greenberg J, Losh M, Mailick M, et al. (December 2014). "Associated features in females with an FMR1 premutation". Journal of Neurodevelopmental Disorders. 6 (1): 30. doi: 10.1186/1866-1955-6-30 . PMC   4121434 . PMID   25097672.
  19. ↑ Mailick MR, Hong J, Movaghar A, DaWalt L, Berry-Kravis EM, Brilliant MH, et al. (October 2021). "Mild Neurological Signs in FMR1 Premutation Women in an Unselected Community-Based Cohort". Movement Disorders. 36 (10): 2378–2386. doi:10.1002/mds.28683. PMC   8597892 . PMID   34117786.
  20. ↑ Allen EG, Charen K, Hipp HS, Shubeck L, Amin A, He W, et al. (2021-10-01). "Predictors of Comorbid Conditions in Women Who Carry an FMR1 Premutation". Frontiers in Psychiatry. 12: 715922. doi: 10.3389/fpsyt.2021.715922 . PMC   8517131 . PMID   34658954.
  21. ↑ Gossett A, Sansone S, Schneider A, Johnston C, Hagerman R, Tassone F, et al. (December 2016). "Psychiatric disorders among women with the fragile X premutation without children affected by fragile X syndrome". American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics. 171 (8): 1139–1147. doi:10.1002/ajmg.b.32496. PMC   6907071 . PMID   27615674.
  22. ↑ Klusek J, Fairchild A, Moser C, Mailick MR, Thurman AJ, Abbeduto L (January 2022). "Family history of FXTAS is associated with age-related cognitive-linguistic decline among mothers with the FMR1 premutation". Journal of Neurodevelopmental Disorders. 14 (1): 7. doi: 10.1186/s11689-022-09415-3 . PMC   8903682 . PMID   35026985.
  23. 1 2 3 4 5 Nolin SL, Glicksman A, Tortora N, Allen E, Macpherson J, Mila M, et al. (July 2019). "Expansions and contractions of the FMR1 CGG repeat in 5,508 transmissions of normal, intermediate, and premutation alleles". American Journal of Medical Genetics. Part A. 179 (7): 1148–1156. doi:10.1002/ajmg.a.61165. PMC   6619443 . PMID   31050164.
  24. ↑ Willemsen R, Levenga J, Oostra BA (September 2011). "CGG repeat in the FMR1 gene: size matters". Clinical Genetics. 80 (3): 214–225. doi:10.1111/j.1399-0004.2011.01723.x. PMC   3151325 . PMID   21651511.
  25. 1 2 Villate O, Ibarluzea N, Maortua H, de la Hoz AB, Rodriguez-Revenga L, Izquierdo-Álvarez S, Tejada MI (2020-07-14). "Effect of AGG Interruptions on FMR1 Maternal Transmissions". Frontiers in Molecular Biosciences. 7: 135. doi: 10.3389/fmolb.2020.00135 . PMC   7381193 . PMID   32766278.
  26. ↑ Tabolacci E, Nobile V, Pucci C, Chiurazzi P (May 2022). "Mechanisms of the FMR1 Repeat Instability: How Does the CGG Sequence Expand?". International Journal of Molecular Sciences. 23 (10): 5425. doi: 10.3390/ijms23105425 . PMC   9141726 . PMID   35628235.
  27. ↑ "National Fragile X Foundation".
  28. ↑ "FRAXA".
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