View source for Fragile X syndrome

{{short description|X-linked dominant genetic disorder}}
{{cs1 config|name-list-style=vanc}}
{{Infobox medical condition
| name = Fragile X syndrome
| image = Fragx-2.jpg
| caption = Boy with protruding ears, a characteristic of fragile X syndrome
| field = [[Medical genetics]], [[pediatrics]], [[psychiatry]]
| synonyms = Martin–Bell syndrome,<ref name=NIH2012GHR/><br />Escalante syndrome
| symptoms = [[Intellectual disability]], long and narrow face, large ears, flexible fingers, autistic behavior, [[macroorchidism|large testicles]]<ref name=NIH2012GHR/>
| complications = [[Seizure]]s<ref name=NIH2012GHR/>
| onset = Noticeable by age 2<ref name=NIH2012GHR/>
| duration = Lifelong<ref name=CDC2017/>
| types = 
| causes = [[Genetic disorder|Genetic]] ([[X-linked dominant]])
| risks = 
| diagnosis = [[Genetic testing]]<ref name=CDC2017/>
| differential = 
| prevention = 
| treatment = [[Supportive care]], early interventions<ref name=CDC2017/>
| medication = 
| prognosis = 
| frequency = 1 in 4,000 (males), 1 in 8,000 (females)<ref name=NIH2012GHR/>
| deaths = 
}}
<!-- Definition and symptoms -->

'''Fragile X syndrome''' ('''FXS''') is a [[genetic disorder|genetic]] [[neurodevelopmental disorder]].<ref name="NIH2012GHR">{{cite web|url=https://medlineplus.gov/genetics/condition/fragile-x-syndrome/|title=fragile X syndrome|date=April 2012|website=Genetics Home Reference|url-status=live|archive-url=https://web.archive.org/web/20161009162713/https://ghr.nlm.nih.gov/condition/fragile-x-syndrome|archive-date=9 October 2016|access-date=7 October 2016}}</ref> The average [[Intelligence quotient|IQ]] in males with FXS is under 55, while affected females tend to be in the borderline to normal range, typically around 70–85.<ref>{{cite journal | vauthors = Raspa M, Wheeler AC, Riley C | title = Public Health Literature Review of Fragile X Syndrome | journal = Pediatrics | volume = 139 | issue = Suppl 3 | pages = S153–S171 | date = June 2017 | pmid = 28814537 | pmc = 5621610 | doi = 10.1542/peds.2016-1159C }}</ref><ref name = data>{{Cite news|url=https://www.cdc.gov/ncbddd/fxs/data.html|title=Data and Statistics Fragile X Syndrome (FXS)|date=2018-08-09|work=Centers for Disease Control and Prevention|access-date=2018-11-05|language=en-us|archive-date=2019-10-13|archive-url=https://web.archive.org/web/20191013033336/https://www.cdc.gov/ncbddd/fxs/data.html|url-status=live}}</ref> Physical features may include a long and [[narrow face]], large ears, flexible fingers, and [[macroorchidism|large testicles]].<ref name=NIH2012GHR/> About a third of those affected have features of [[autism]] such as problems with social interactions and delayed speech.<ref name=NIH2012GHR/> [[Hyperactivity]] is common, and [[seizure]]s occur in about 10%.<ref name=NIH2012GHR/> Males are usually more affected than females.<ref name=NIH2012GHR/>

<!-- Cause and diagnosis -->
This disorder and finding of fragile X syndrome has an [[X-linked dominant inheritance]].<ref>{{cite web |title=Fragile X syndrome |url=https://medlineplus.gov/genetics/condition/fragile-x-syndrome/#inheritance |website=MedlinePlus |publisher=NIH |access-date=15 February 2025 |ref=MedlinePlusNIH}}</ref> It is typically caused by an expansion of the [[Nucleobase|CGG]] [[Trinucleotide repeat disorder|triplet repeat]] within the ''[[FMR1]]'' (fragile X messenger ribonucleoprotein 1) [[gene]] on the [[X chromosome]].<ref name="NIH2012GHR" /> This results in silencing ([[DNA methylation|methylation]]) of this part of the gene and a deficiency of the resultant [[protein]] (FMRP), which is required for the normal development of [[synapse|connections between neurons]].<ref name="NIH2012GHR" /> Diagnosis requires [[genetic testing]] to determine the number of CGG repeats in the ''FMR1'' gene.<ref name="ACMG2016" /> Normally, there are between 5 and 40 repeats; fragile X syndrome occurs with more than 200.<ref name="NIH2012GHR" /> A [[premutation]] is said to be present when the gene has between 55 and 200 repeats; females with a premutation have an increased risk of having an affected child.<ref name=NIH2012GHR/> Testing for premutation carriers may allow for [[genetic counseling]].<ref name=ACMG2016>{{cite web|title=Technical Standards and Guidelines for Fragile X|url=https://www.acmg.net/Pages/ACMG_Activities/stds-2002/fx.htm|website=www.acmg.net|access-date=10 May 2017|date=2006|url-status=live|archive-url=https://web.archive.org/web/20161012163824/http://www.acmg.net/Pages/ACMG_Activities/stds-2002/fx.htm|archive-date=12 October 2016}}</ref>

<!-- Treatment and epidemiology -->
There is no cure or approved medications for treating the condition.<ref name="Hagerman 2025">{{cite journal |last1=Hagerman |first1=Randi Jenssen |last2=Hagerman |first2=Paul J. |title=The Spectrum of Fragile X Disorders |journal=New England Journal of Medicine |date=17 July 2025 |volume=393 |issue=3 |pages=281–288 |doi=10.1056/NEJMra2300487 |pmid=40673587 }}</ref><ref name=CDC2017>{{cite web|title= What is Fragile X Syndrome?|url=https://www.cdc.gov/ncbddd/fxs/facts.html|website= National Center on Birth Defects and Developmental Disabilities |location = US | publisher = Centers for Disease Control and Prevention|access-date=10 May 2017|language=en-us|date=3 June 2022 |url-status=live|archive-url=https://web.archive.org/web/20170510171238/https://www.cdc.gov/ncbddd/fxs/facts.html|archive-date=10 May 2017}}</ref> Early intervention is recommended, as it provides the most opportunity for developing a full range of skills.<ref name=NIH2016Tx>{{Cite web|url=https://www.nichd.nih.gov/health/topics/fragilex/conditioninfo/treatments|title=What are the treatments for Fragile X syndrome?|website=www.nichd.nih.gov|access-date=2016-11-21|url-status=live|archive-url=https://web.archive.org/web/20161121233205/https://www.nichd.nih.gov/health/topics/fragilex/conditioninfo/Pages/treatments.aspx|archive-date=2016-11-21}}</ref> These interventions may include [[special education]], [[occupational therapy]], [[speech therapy]], [[physical therapy]], or [[behavioral therapy]].<ref name=CDC2017/><ref>{{cite web|title=Therapy Treatments|url=https://www.nichd.nih.gov/health/topics/fragilex/conditioninfo/therapytreatments|website=NICHD|access-date=10 May 2017|url-status=live|archive-url=https://web.archive.org/web/20170505024156/https://www.nichd.nih.gov/health/topics/fragilex/conditioninfo/Pages/therapytreatments.aspx|archive-date=5 May 2017}}</ref> Medications may be used to treat associated [[anxiety]], [[seizure]]s, mood problems, aggressive behavior, or [[ADHD]].<ref>{{cite web|title=Medication Treatments|url=https://www.nichd.nih.gov/health/topics/fragilex/conditioninfo/medicationtreatments|website=NICHD|access-date=10 May 2017|url-status=live|archive-url=https://web.archive.org/web/20170505024215/https://www.nichd.nih.gov/health/topics/fragilex/conditioninfo/Pages/medicationtreatments.aspx|archive-date=5 May 2017}}</ref> Fragile X syndrome tends to show more symptoms on affected males since females have another X chromosome which can compensate for the damaged one.<ref name = data/><ref>{{Cite web |title=What is Fragile-X syndrome? |url=https://www.yourgenome.org/theme/what-is-fragile-x-syndrome/ |access-date=2025-03-25 |website=@yourgenome · Science website |language=en-GB}}</ref>

Fragile X syndrome is the most common cause of inherited [[intellectual disability]], affecting an estimated 1 per 4,000 people. It is also the most common single gene cause of autism.<ref name="Hagerman 2025"/>

==Signs and symptoms==
[[Image:Fragx-1.jpg|thumb|upright=1.3|Prominent characteristics of the syndrome include an elongated face and large or protruding ears.]]
Most young children do not show any physical signs of FXS.<ref name=autogenerated1>{{Cite web|url=https://www.nichd.nih.gov/health/topics/fragilex/conditioninfo/commonsymptoms|title=What are the symptoms of Fragile X syndrome?|website=www.nichd.nih.gov|access-date=2016-11-21|url-status=live|archive-url=https://web.archive.org/web/20161121234507/https://www.nichd.nih.gov/health/topics/fragilex/conditioninfo/Pages/commonsymptoms.aspx|archive-date=2016-11-21}}</ref> It is not until puberty that physical features of FXS begin to develop.<ref name=autogenerated1 /> Aside from intellectual disability, prominent characteristics of the syndrome may include an elongated face, large or [[protruding ear]]s, flat feet, larger testes ([[macroorchidism]]), and [[low muscle tone]].<ref name=McLennan/><ref name=Garber/> Recurrent [[otitis media]] (middle ear infection) and [[sinusitis]] is common during early childhood. Speech may be [[cluttered speech|cluttered]] or nervous. Behavioral characteristics may include [[Stereotypy|stereotypic movements]] (e.g., hand-flapping) and atypical social development, particularly shyness, limited [[eye contact]], memory problems, and difficulty with face encoding. Some individuals with fragile X syndrome also meet the diagnostic criteria for [[autism]].<ref>{{Cite web |title=Fragile X and Autism {{!}} Fragile X Society {{!}} UK |url=https://www.fragilex.org.uk/fragile-x-and-autism |access-date=2022-09-07 |website=fragilex |language=en}}</ref>

Males with a full mutation display virtually complete [[penetrance]] and will therefore almost always display symptoms of FXS, while females with a full mutation generally display a penetrance of about 50% as a result of having a second, normal X chromosome.<ref name=Santoro/> Females with FXS may have symptoms ranging from mild to severe, although they are generally less affected than males due to variability in X-inactivation.<ref>{{cite journal | vauthors = Bartholomay KL, Lee CH, Bruno JL, Lightbody AA, Reiss AL | title = Closing the Gender Gap in Fragile X Syndrome: Review on Females with FXS and Preliminary Research Findings | journal = Brain Sciences | volume = 9 | issue = 1 | page = 11 | date = January 2019 | pmid = 30642066 | pmc = 6356553 | doi = 10.3390/brainsci9010011 | doi-access = free }}</ref><ref>{{Cite web |last=CDC |date=2022-06-03 |title=What is Fragile X Syndrome (FXS)? {{!}} CDC |url=https://www.cdc.gov/ncbddd/fxs/facts.html |access-date=2022-11-04 |website=Centers for Disease Control and Prevention |language=en-us}}</ref>

===Physical phenotype===
* Large, [[protruding ears]] (both)
* Long face ([[vertical maxillary excess]])
* [[High-arched palate]] (related to the above)
* [[Hypermobility (joints)|Hyperextensible finger joints]]
* Hyperextensible thumbs ('double-jointed')
* [[Flat feet]]
* Soft skin, sometimes described as velvety (especially on the palms) or redundant skin on the back of the hands.<ref name="Lubala 2018">{{cite journal |last1=Lubala |first1=TK |last2=Lumaka |first2=A |last3=Kanteng |first3=G |last4=Mutesa |first4=L |last5=Mukuku |first5=O |last6=Wembonyama |first6=S |last7=Hagerman |first7=R |last8=Luboya |first8=ON |last9=Lukusa Tshilobo |first9=P |title=Fragile X checklists: A meta-analysis and development of a simplified universal clinical checklist. |journal=Molecular Genetics & Genomic Medicine |date=6 April 2018 |volume=6 |issue=4 |pages=526–32 |doi=10.1002/mgg3.398 |pmid=29624914|pmc=6081230 }}</ref><ref name="Hagerman 2025" />
* Postpubescent [[macroorchidism]] (large testicles in males after puberty)<ref>{{cite book| vauthors = Jordan JA, Regezi JJ, Sciubba RC |title=Oral pathology: clinical pathologic correlations|year=2008|publisher=Saunders/Elsevier|location=St. Louis, Mo.|isbn=978-1-4160-4570-0|edition=5th|chapter=15}} Section on fragile X syndrome{{page needed|date=December 2013}}</ref>
* [[Hypotonia]] (low muscle tone)<ref>{{cite journal | vauthors = Nichols C, Nichols D |title=Fragile X Syndrome: Implications for Physical Education |journal=Palaestra |date=1 June 2019 |volume=33 |issue=3}}</ref><ref name=book2>{{cite book | vauthors = Goldstein S, Reynolds CR |title=Handbook of neurodevelopmental and genetic disorders in children |location=New York |publisher=Guilford Press |year=1999 |isbn=978-1-57230-448-2}}{{page needed|date=December 2013}}</ref>

===Intellectual development===
Individuals with FXS may present anywhere on a continuum from [[learning disabilities]] in the context of a normal [[intelligence quotient]] (IQ) to severe [[intellectual disability]], with an average IQ of 40 in males who have complete silencing of the ''FMR1'' gene.<ref name=Garber>{{cite journal | vauthors = Garber KB, Visootsak J, Warren ST | title = Fragile X syndrome | journal = European Journal of Human Genetics | volume = 16 | issue = 6 | pages = 666–672 | date = June 2008 | pmid = 18398441 | pmc = 4369150 | doi = 10.1038/ejhg.2008.61 }}</ref> Females, who tend to be less affected, generally have an IQ which is normal or borderline with learning difficulties. The main difficulties in individuals with FXS are with working and short-term memory, [[executive function]], visual memory, visual-spatial relationships, and mathematics, with verbal abilities being relatively unaffected.<ref name=Garber/><ref name=Hall/>

Data on intellectual development in FXS are limited. However, there is some evidence that standardized IQ decreases over time in the majority of cases, apparently as a result of slowed intellectual development. A longitudinal study looking at pairs of siblings where one child was affected and the other was not found that affected children had an intellectual learning rate which was 55% slower than unaffected children.<ref name=Hall>{{cite journal | vauthors = Hall SS, Burns DD, Lightbody AA, Reiss AL | title = Longitudinal changes in intellectual development in children with Fragile X syndrome | journal = Journal of Abnormal Child Psychology | volume = 36 | issue = 6 | pages = 927–939 | date = August 2008 | pmid = 18347972 | pmc = 4820329 | doi = 10.1007/s10802-008-9223-y }}</ref>

Individuals with FXS often demonstrated language and communicative problems.<ref name=":0">{{Cite journal| vauthors = Abbeduto L, Hagerman RJ |date=1997|title=Language and communication in fragile X syndrome |journal= Mental Retardation and Developmental Disabilities Research Reviews |language=en |volume=3 |issue=4 |pages=313–322 |doi=10.1002/(SICI)1098-2779(1997)3:4<313::AID-MRDD6>3.0.CO;2-O|issn=1098-2779}}</ref> This may be related to muscle function of the mouth and frontal-lobe deficits.<ref name=":0" />

=== Autism ===
Fragile X syndrome is the most common genetic cause of autism.<ref name="Hagerman 2025" /><ref name=McLennan/><ref name=Bud/> This finding has resulted in medical screening for FMR1 mutation in individuals who present with autism.<ref name=McLennan/> Of those with fragile X syndrome, prevalence of concurrent [[autism spectrum disorder]] (ASD) has been estimated to be between 15 and 60%, with the variation due to differences in diagnostic methods and the high frequency of autistic features in individuals with fragile X syndrome not meeting the DSM criteria for an ASD.<ref name=Bud/>

Although individuals with FXS have difficulties in forming friendships, those with FXS and ASD characteristically also have difficulties with reciprocal conversation with their peers. Social withdrawal behaviors, including avoidance and indifference, appear to be the best predictors of ASD in FXS, with avoidance appearing to be correlated more with social anxiety while indifference was more strongly correlated to ASD.<ref name=Bud/> When both autism and FXS are present, a greater language deficit and lower IQ is observed as compared to children with only FXS.<ref name=book>Hagerman, Randi J., and Paul J. Hagerman. ''Fragile X syndrome: diagnosis, treatment, and research''. 3, illustrated ed. Baltimore, MD: JHU P, 2002.{{page needed|date=December 2013}}</ref>

Genetic [[Animal model|mouse models]] of FXS have also been shown to have autistic-like behaviors.<ref>{{cite journal | vauthors = Pietropaolo S, Guilleminot A, Martin B, D'Amato FR, Crusio WE | title = Genetic-background modulation of core and variable autistic-like symptoms in Fmr1 knock-out mice | journal = PLOS ONE | volume = 6 | issue = 2 | article-number = e17073 | date = February 2011 | pmid = 21364941 | pmc = 3043074 | doi = 10.1371/journal.pone.0017073 | doi-access = free | bibcode = 2011PLoSO...617073P | author-link5 = Wim Crusio }}</ref><ref>{{cite journal | vauthors = Bernardet M, Crusio WE | title = Fmr1 KO mice as a possible model of autistic features | journal = TheScientificWorldJournal | volume = 6 | pages = 1164–1176 | date = September 2006 | pmid = 16998604 | pmc = 5917219 | doi = 10.1100/tsw.2006.220 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Mineur YS, Huynh LX, Crusio WE | title = Social behavior deficits in the Fmr1 mutant mouse | journal = Behavioural Brain Research | volume = 168 | issue = 1 | pages = 172–175 | date = March 2006 | pmid = 16343653 | doi = 10.1016/j.bbr.2005.11.004 | s2cid = 45731129 }}</ref><ref>{{cite journal | vauthors = Spencer CM, Alekseyenko O, Hamilton SM, Thomas AM, Serysheva E, Yuva-Paylor LA, Paylor R | title = Modifying behavioral phenotypes in Fmr1KO mice: genetic background differences reveal autistic-like responses | journal = Autism Research | volume = 4 | issue = 1 | pages = 40–56 | date = February 2011 | pmid = 21268289 | pmc = 3059810 | doi = 10.1002/aur.168 }}</ref><ref>{{cite journal | vauthors = Spencer CM, Graham DF, Yuva-Paylor LA, Nelson DL, Paylor R | title = Social behavior in Fmr1 knockout mice carrying a human FMR1 transgene | journal = Behavioral Neuroscience | volume = 122 | issue = 3 | pages = 710–715 | date = June 2008 | pmid = 18513141 | doi = 10.1037/0735-7044.122.3.710 }}</ref>

===Social interaction===
FXS is characterized by [[social anxiety]], including poor eye contact, gaze aversion, prolonged time to commence social interaction, and challenges forming peer relationships.<ref name=Tranfaglia/> Social anxiety is one of the most common features associated with FXS, with up to 75% of males in one series characterized as having excessive shyness and 50% having panic attacks.<ref name=Bud/> Social anxiety in individuals with FXS is related to challenges with face encoding, the ability to recognize a face that one has seen before.<ref>{{cite journal | vauthors = Holsen LM, Dalton KM, Johnstone T, Davidson RJ | title = Prefrontal social cognition network dysfunction underlying face encoding and social anxiety in fragile X syndrome | journal = NeuroImage | volume = 43 | issue = 3 | pages = 592–604 | date = November 2008 | pmid = 18778781 | pmc = 2598775 | doi = 10.1016/j.neuroimage.2008.08.009 }}</ref>

It appears that individuals with FXS are interested in social interaction and display greater empathy than groups with other causes of intellectual disability, but display anxiety and withdrawal when placed in unfamiliar situations with unfamiliar people.<ref name=Bud/><ref name=Tranfaglia/> This may range from mild social withdrawal, which is predominantly associated with shyness, to severe social withdrawal, which may be associated with co-existing autism spectrum disorder.<ref name=Bud/>

Females with FXS frequently display shyness, social anxiety and social avoidance or withdrawal.<ref name=Garber/> In addition, premutation in females has been found to be associated with social anxiety.

Individuals with FXS showed decreased ability to recruit more areas of the brain for more complex working memory or problem solvings tasks as seen on [[functional MRI]].<ref>{{cite journal | vauthors = Lightbody AA, Reiss AL | title = Gene, brain, and behavior relationships in fragile X syndrome: evidence from neuroimaging studies | journal = Developmental Disabilities Research Reviews | volume = 15 | issue = 4 | pages = 343–352 | date = 2009 | pmid = 20014368 | pmc = 4354896 | doi = 10.1002/ddrr.77 | publisher = Wiley | oclc = 175296472 }}</ref>

=== Mental health ===
[[Attention deficit hyperactivity disorder]] (ADHD) is found in the majority of males with FXS and 30% of females, making it the most common psychiatric diagnosis in those with FXS.<ref name=McLennan/><ref name=Tranfaglia>{{cite journal | vauthors = Tranfaglia MR | title = The psychiatric presentation of fragile x: evolution of the diagnosis and treatment of the psychiatric comorbidities of fragile X syndrome | journal = Developmental Neuroscience | volume = 33 | issue = 5 | pages = 337–348 | year = 2011 | pmid = 21893938 | doi = 10.1159/000329421 | s2cid = 207554509 | doi-access = free }}</ref> Children with fragile X have very short attention spans, are [[hyperactivity|hyperactive]], and show hypersensitivity to visual, auditory, tactile, and [[olfactory]] stimuli. These children have difficulty in large crowds due to the loud noises and this can lead to tantrums due to [[hyperarousal]]. Hyperactivity and disruptive behavior peak in the preschool years and then gradually decline with age, although inattentive symptoms are generally lifelong.<ref name=Tranfaglia/>

Aside from the characteristic social phobia features, a range of other anxiety symptoms are very commonly associated with FXS, with symptoms typically spanning a number of psychiatric diagnoses but not fulfilling any of the criteria in full.<ref name=Tranfaglia/> Children with FXS pull away from light touch and can find textures of materials to be irritating. Transitions from one location to another can be difficult for children with FXS. Behavioral therapy can be used to decrease the child's sensitivity in some cases.<ref name=book2/> Behaviors such as hand flapping and biting, as well as aggression, can be an expression of anxiety.{{citation needed|date=August 2021}}

[[Perseveration]] is a common communicative and behavioral characteristic in FXS. Children with FXS may repeat a certain ordinary activity over and over. In speech, the trend is not only in repeating the same phrase but also talking about the same subject continually. Cluttered speech and [[self-talk]] are commonly seen. Self-talk includes talking with oneself using different tones and pitches.<ref name=book2/> Although only a minority of FXS cases will meet the criteria for [[obsessive–compulsive disorder]] (OCD), a significant majority will have symptoms of obsession. However, as individuals with FXS generally find these behaviors pleasurable, unlike individuals with OCD, they are more frequently referred to as stereotypic behaviors.{{citation needed|date=September 2021}}

Mood symptoms in individuals with FXS rarely meet diagnostic criteria for a major mood disorder as they are typically not of sustained duration.<ref name=Tranfaglia/> Instead, these are usually transient and related to stressors, and may involve labile (fluctuating) mood, irritability, self-injury and aggression.{{citation needed|date=July 2022}}

Individuals with [[fragile X-associated tremor/ataxia syndrome]] (FXTAS) are likely to experience combinations of [[dementia]], [[mood disorder|mood]], and [[anxiety disorder]]s. Males with the ''FMR1'' premutation and clinical evidence of FXTAS were found to have increased occurrence of [[somatization]], [[obsessive–compulsive disorder]], interpersonal sensitivity, depression, phobic anxiety, and [[psychoticism]].<ref>{{cite journal | vauthors = Bourgeois JA, Cogswell JB, Hessl D, Zhang L, Ono MY, Tassone F, Farzin F, Brunberg JA, Grigsby J, Hagerman RJ | display-authors = 6 | title = Cognitive, anxiety and mood disorders in the fragile X-associated tremor/ataxia syndrome | journal = General Hospital Psychiatry | volume = 29 | issue = 4 | pages = 349–356 | year = 2007 | pmid = 17591512 | pmc = 3991490 | doi = 10.1016/j.genhosppsych.2007.03.003 }}</ref>

=== Vision ===
Ophthalmologic problems include [[strabismus]]. This requires early identification to avoid [[amblyopia]]. Surgery or patching are usually necessary to treat strabismus if diagnosed early. Refractive errors in patients with FXS are also common.<ref name=book/>

=== Neurology ===
Individuals with FXS are at a higher risk of developing [[seizure]]s, with rates between 10% and 40% reported in the literature.<ref name=Seizures>{{cite journal | vauthors = Berry-Kravis E, Raspa M, Loggin-Hester L, Bishop E, Holiday D, Bailey DB | title = Seizures in fragile X syndrome: characteristics and comorbid diagnoses | journal = American Journal on Intellectual and Developmental Disabilities | volume = 115 | issue = 6 | pages = 461–472 | date = November 2010 | pmid = 20945999 | doi = 10.1352/1944-7558-115.6.461 }}</ref> In larger study populations the frequency varies between 13% and 18%,<ref name=Garber/><ref name=Seizures/> consistent with a recent survey of caregivers which found that 14% of males and 6% of females experienced seizures.<ref name=Seizures/> The seizures tend to be [[Partial seizure|partial]], are generally not frequent, and are amenable to treatment with medication.{{citation needed|date=July 2022}}

Individuals who are carriers of premutation alleles are at risk for developing [[FXTAS|fragile X-associated tremor/ataxia syndrome]] (FXTAS), a progressive neurodegenerative disease.<ref name=Santoro/><ref name=Peprah/> It is seen in approximately half of male carriers over the age of 70, while penetrance in females is lower. Typically, onset of [[tremor]] occurs in the sixth decade of life, with subsequent progression to [[ataxia]] (loss of coordination) and gradual cognitive decline.<ref name=Peprah/>

=== Working memory ===
From their 40s onward, males with FXS begin developing progressively more severe problems in performing tasks that require the central executive of [[working memory]]. Working memory involves the temporary storage of information 'in mind', while processing the same or other information. Phonological memory (or verbal working memory) deteriorates with age in males, while visual-spatial memory is not found to be directly related to age. Males often experience an impairment in the functioning of the [[phonological loop]]. The CGG length is significantly correlated with central executive and the visual–spatial memory. However, in a premutation individual, CGG length is only significantly correlated with the central executive, not with either phonological memory or visual–spatial memory.<ref>{{cite journal | vauthors = Cornish KM, Kogan CS, Li L, Turk J, Jacquemont S, Hagerman RJ | title = Lifespan changes in working memory in fragile X premutation males | journal = Brain and Cognition | volume = 69 | issue = 3 | pages = 551–558 | date = April 2009 | pmid = 19114290 | pmc = 4158922 | doi = 10.1016/j.bandc.2008.11.006 }}</ref>

=== Fertility ===
About 20% of women who are carriers for the fragile X premutation are affected by [[Fragile X-associated primary ovarian insufficiency]] (FXPOI), which is defined as [[primary ovarian insufficiency]], which is menopause occurring before 40 years of age (average age at menopause is 51 years old in the US).<ref name=Santoro>{{cite journal | vauthors = Santoro MR, Bray SM, Warren ST | title = Molecular mechanisms of fragile X syndrome: a twenty-year perspective | journal = Annual Review of Pathology | volume = 7 | pages = 219–245 | year = 2012 | pmid = 22017584 | doi = 10.1146/annurev-pathol-011811-132457 }}</ref><ref name=Peprah>{{cite journal | vauthors = Peprah E | title = Fragile X syndrome: the FMR1 CGG repeat distribution among world populations | journal = Annals of Human Genetics | volume = 76 | issue = 2 | pages = 178–191 | date = March 2012 | pmid = 22188182 | pmc = 3288311 | doi = 10.1111/j.1469-1809.2011.00694.x }}</ref> The number of CGG repeats correlates with [[penetrance]] and age of onset, but it is not a linear relationship.<ref>{{cite journal | vauthors = Sullivan AK, Marcus M, Epstein MP, Allen EG, Anido AE, Paquin JJ, Yadav-Shah M, Sherman SL | display-authors = 6 | title = Association of FMR1 repeat size with ovarian dysfunction | journal = Human Reproduction | volume = 20 | issue = 2 | pages = 402–412 | date = February 2005 | pmid = 15608041 | doi = 10.1093/humrep/deh635 | doi-access = free }}</ref><ref name=Santoro/> However primary ovarian insufficiency is more common in premutation carriers than in women with the full mutation, and the highest risk for FXPOI is observed in women with between 70-100 repeats.<ref>{{cite journal | vauthors = Allen EG, Charen K, Hipp HS, Shubeck L, Amin A, He W, Nolin SL, Glicksman A, Tortora N, McKinnon B, Shelly KE, Sherman SL | display-authors = 6 | title = Refining the risk for fragile X-associated primary ovarian insufficiency (FXPOI) by FMR1 CGG repeat size | language = English | journal = Genetics in Medicine | volume = 23 | issue = 9 | pages = 1648–1655 | date = September 2021 | pmid = 33927378 | pmc = 8460441 | doi = 10.1038/s41436-021-01177-y }}</ref><ref name=Bibi>{{cite journal | vauthors = Bibi G, Malcov M, Yuval Y, Reches A, Ben-Yosef D, Almog B, Amit A, Azem F | display-authors = 6 | title = The effect of CGG repeat number on ovarian response among fragile X premutation carriers undergoing preimplantation genetic diagnosis | journal = Fertility and Sterility | volume = 94 | issue = 3 | pages = 869–874 | date = August 2010 | pmid = 19481741 | doi = 10.1016/j.fertnstert.2009.04.047 | doi-access = free }}</ref> FXPOI is one of three Fragile X-associated Disorders (FXD) caused by changes in the FMR1 gene. FXPOI affects female premutation carriers, of which is caused by the FMR1 gene, when their ovaries are not functioning properly. Women with FXPOI may exhibit changes in menstrual cycles and have changes in hormone levels but not be considered menopausal. Women with FXPOI still have the chance to get pregnant in about 10% of cases, because their ovaries occasionally release viable [[Egg cell|eggs]] through "escape" ovulation.<ref>{{cite journal | vauthors = Sherman SL, Curnow EC, Easley CA, Jin P, Hukema RK, Tejada MI, Willemsen R, Usdin K | display-authors = 6 | title = Use of model systems to understand the etiology of fragile X-associated primary ovarian insufficiency (FXPOI) | journal = Journal of Neurodevelopmental Disorders | volume = 6 | issue = 1 | article-number = 26 | date = 2014 | pmid = 25147583 | pmc = 4139715 | doi = 10.1186/1866-1955-6-26 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Hipp HS, Charen KH, Spencer JB, Allen EG, Sherman SL | title = Reproductive and gynecologic care of women with fragile X primary ovarian insufficiency (FXPOI) | journal = Menopause | volume = 23 | issue = 9 | pages = 993–999 | date = September 2016 | pmid = 27552334 | pmc = 4998843 | doi = 10.1097/GME.0000000000000658 }}</ref> FXPOI is the most common cause of hereditary primary ovarian insufficiency.<ref name="Hagerman 2025" /> There is not specific treatment for FXPOI, but hormonal therapy is recommended as a treatment, as for other women with primary ovarian insufficiency.<ref name="Hagerman 2025" />

In women with infertility, and a family history of infertility, there is a 7% risk of FXPOI so genetic testing is recommended.<ref name="Hagerman 2025" />

[[FMR1|FMRP]] is a [[chromatin]]-binding protein that functions in the [[DNA damage (naturally occurring)|DNA damage]] response.<ref name="pmid24813610">{{cite journal | vauthors = Alpatov R, Lesch BJ, Nakamoto-Kinoshita M, Blanco A, Chen S, Stützer A, Armache KJ, Simon MD, Xu C, Ali M, Murn J, Prisic S, Kutateladze TG, Vakoc CR, Min J, Kingston RE, Fischle W, Warren ST, Page DC, Shi Y | display-authors = 6 | title = A chromatin-dependent role of the fragile X mental retardation protein FMRP in the DNA damage response | journal = Cell | volume = 157 | issue = 4 | pages = 869–881 | date = May 2014 | pmid = 24813610 | pmc = 4038154 | doi = 10.1016/j.cell.2014.03.040 }}</ref><ref name="pmid29796988">{{cite journal | vauthors = Dockendorff TC, Labrador M | title = The Fragile X Protein and Genome Function | journal = Molecular Neurobiology | volume = 56 | issue = 1 | pages = 711–721 | date = January 2019 | pmid = 29796988 | doi = 10.1007/s12035-018-1122-9 | s2cid = 44159474 }}</ref> FMRP also occupies sites on [[meiosis|meiotic]] [[chromosome]]s and regulates the dynamics of the DNA damage response machinery during [[spermatogenesis]].<ref name="pmid24813610" />

== Causes ==
[[Image:Fmr1.jpeg|left|upright=1.25|thumb|Location of the ''[[FMR1]]'' gene on the [[X chromosome]]]]
Fragile X syndrome is a [[genetic disorder]] which occurs as a result of a [[mutation]] of the [[FMR1|''Fragile X Messenger Ribonucleoprotein 1'']] (''FMR1'') [[gene]] on the [[X chromosome]], most commonly an increase in the number of CGG [[Trinucleotide repeat disorders|trinucleotide repeats]] in the [[Five prime untranslated region|5' untranslated region]] of ''FMR1''.<ref name=Santoro/><ref name=Peprah/> Mutation at that site is found in 1 out of about every 2000 [[male]]s and 1 out of about every 259 [[female]]s. Incidence of the disorder itself is about 1 in every 3600 males and 1 in 4000–6000 females.<ref>{{cite web|url=https://www.who.int/genomics/public/geneticdiseases/en/index2.html|title=Monogenic diseases|work=Human Genomics in Global Health|publisher=World Health Organization|access-date=2020-10-04|archive-date=2012-10-20|archive-url=https://web.archive.org/web/20121020153249/http://www.who.int/genomics/public/geneticdiseases/en/index2.html|url-status=live}}</ref> Although this accounts for over 98% of cases, FXS can also occur as a result of point mutations affecting ''FMR1''.<ref name=Santoro/><ref name=Peprah/>

In unaffected individuals, the ''FMR1'' gene contains 5–44 repeats of the sequence CGG, most commonly 29 or 30 repeats.<ref name=Santoro/><ref name=Peprah/><ref name=guidelines>{{cite journal | vauthors = Maddalena A, Richards CS, McGinniss MJ, Brothman A, Desnick RJ, Grier RE, Hirsch B, Jacky P, McDowell GA, Popovich B, Watson M, Wolff DJ | display-authors = 6 | title = Technical standards and guidelines for fragile X: the first of a series of disease-specific supplements to the Standards and Guidelines for Clinical Genetics Laboratories of the American College of Medical Genetics. Quality Assurance Subcommittee of the Laboratory Practice Committee | journal = Genetics in Medicine | volume = 3 | issue = 3 | pages = 200–205 | year = 2001 | pmid = 11388762 | pmc = 3110344 | doi = 10.1097/00125817-200105000-00010 }}</ref> Between 45 and 54 repeats is considered a "grey zone", with a premutation [[allele]] generally considered to be between 55 and 200 repeats in length. Individuals with fragile X syndrome have a full mutation of the ''FMR1'' allele, with over 200 CGG repeats.<ref name=McLennan>{{cite journal | vauthors = McLennan Y, Polussa J, Tassone F, Hagerman R | title = Fragile x syndrome | journal = Current Genomics | volume = 12 | issue = 3 | pages = 216–224 | date = May 2011 | pmid = 22043169 | pmc = 3137006 | doi = 10.2174/138920211795677886 }}</ref><ref name=guidelines/><ref>{{cite journal | vauthors = Nolin SL, Brown WT, Glicksman A, Houck GE, Gargano AD, Sullivan A, Biancalana V, Bröndum-Nielsen K, Hjalgrim H, Holinski-Feder E, Kooy F, Longshore J, Macpherson J, Mandel JL, Matthijs G, Rousseau F, Steinbach P, Väisänen ML, von Koskull H, Sherman SL | display-authors = 6 | title = Expansion of the fragile X CGG repeat in females with premutation or intermediate alleles | journal = American Journal of Human Genetics | volume = 72 | issue = 2 | pages = 454–464 | date = February 2003 | pmid = 12529854 | pmc = 379237 | doi = 10.1086/367713 }}</ref> In these individuals with a repeat expansion greater than 200, there is [[methylation]] of the CGG repeat expansion and ''FMR1'' [[Promoter (genetics)|promoter]], leading to the silencing of the ''FMR1'' gene and a lack of its product.

This methylation of ''FMR1'' in chromosome band Xq27.3 is believed to result in constriction of the X chromosome which appears 'fragile' under the microscope at that point, a phenomenon that gave the syndrome its name. One study found that FMR1 silencing is mediated by the FMR1 mRNA. The FMR1 mRNA contains the transcribed CGG-repeat tract as part of the 5' untranslated region, which hybridizes to the complementary CGG-repeat portion of the FMR1 gene to form an RNA·DNA duplex.<ref name="Colak">{{cite journal | vauthors = Colak D, Zaninovic N, Cohen MS, Rosenwaks Z, Yang WY, Gerhardt J, Disney MD, Jaffrey SR | display-authors = 6 | title = Promoter-bound trinucleotide repeat mRNA drives epigenetic silencing in fragile X syndrome | journal = Science | volume = 343 | issue = 6174 | pages = 1002–1005 | date = February 2014 | pmid = 24578575 | pmc = 4357282 | doi = 10.1126/science.1245831 | bibcode = 2014Sci...343.1002C }}</ref>

A subset of people with intellectual disability and symptoms resembling fragile X syndrome are found to have point mutations in ''FMR1.'' This subset lacked the CGG repeat expansion in ''FMR1'' traditionally associated with fragile X syndrome.<ref>{{cite journal | vauthors = Sitzmann AF, Hagelstrom RT, Tassone F, Hagerman RJ, Butler MG | title = Rare FMR1 gene mutations causing fragile X syndrome: A review | journal = American Journal of Medical Genetics. Part A | volume = 176 | issue = 1 | pages = 11–18 | date = January 2018 | pmid = 29178241 | pmc = 6697153 | doi = 10.1002/ajmg.a.38504 }}</ref> The first complete DNA sequence of the repeat expansion in someone with the full mutation was generated by scientists in 2012 using [[SMRT sequencing]].<ref>{{cite journal |display-authors=6 |vauthors=Loomis EW, Eid JS, Peluso P, Yin J, Hickey L, Rank D, McCalmon S, Hagerman RJ, Tassone F, Hagerman PJ |date=January 2013 |title=Sequencing the unsequenceable: expanded CGG-repeat alleles of the fragile X gene |journal=Genome Research |volume=23 |issue=1 |pages=121–128 |doi=10.1101/gr.141705.112 |pmc=3530672 |pmid=23064752}}</ref>

=== Inheritance ===
Fragile X syndrome has traditionally been considered an [[X-linked recessive inheritance|X-linked recessive]] condition with variable expressivity and possibly reduced [[penetrance]].<ref name=Garber/> The likelihood of transmission depends on the parent's sex, the X chromosome carrying the mutation, and the number of CGG repeats in the premutation.

Due to [[genetic anticipation]] and [[X-inactivation]] in females, the inheritance of Fragile X syndrome does not follow the usual pattern of X-linked dominant inheritance, and some scholars have proposed discontinuing labeling X-linked disorders as dominant or recessive.<ref>{{cite journal | vauthors = Dobyns WB, Filauro A, Tomson BN, Chan AS, Ho AW, Ting NT, Oosterwijk JC, Ober C | display-authors = 6 | title = Inheritance of most X-linked traits is not dominant or recessive, just X-linked | journal = American Journal of Medical Genetics. Part A | volume = 129A | issue = 2 | pages = 136–143 | date = August 2004 | pmid = 15316978 | doi = 10.1002/ajmg.a.30123 | s2cid = 42108591 }}</ref> Males with a full mutation are usually affected and infertile, while carrier females have a 50% chance of passing on the mutation.

Before the ''FMR1'' gene was discovered, analysis of pedigrees showed the presence of male carriers who were asymptomatic, with their grandchildren affected by the condition at a higher rate than their siblings suggesting that [[genetic anticipation]] was occurring.<ref name=Santoro/> This tendency for future generations to be affected at a higher frequency became known as the [[Sherman paradox]] after its description in 1985.<ref name=Santoro/><ref>{{cite journal | vauthors = Sherman SL, Jacobs PA, Morton NE, Froster-Iskenius U, Howard-Peebles PN, Nielsen KB, Partington MW, Sutherland GR, Turner G, Watson M | display-authors = 6 | title = Further segregation analysis of the fragile X syndrome with special reference to transmitting males | journal = Human Genetics | volume = 69 | issue = 4 | pages = 289–299 | year = 1985 | pmid = 3838733 | doi = 10.1007/BF00291644 | s2cid = 23299935 }}</ref> Due to this, male children often have a greater degree of symptoms than their mothers.<ref name=Marco>{{cite journal | vauthors = Marco EJ, Skuse DH | title = Autism-lessons from the X chromosome | journal = Social Cognitive and Affective Neuroscience | volume = 1 | issue = 3 | pages = 183–193 | date = December 2006 | pmid = 18985105 | pmc = 2555419 | doi = 10.1093/scan/nsl028 }}</ref>

The explanation for this phenomenon is that male carriers pass on their premutation to all of their daughters, with the length of the ''FMR1'' CGG repeat typically not increasing during [[meiosis]], the cell division that is required to produce sperm.<ref name=Santoro/><ref name=Peprah/> Incidentally, males with a full mutation only pass on premutations to their daughters.<ref name=Peprah/> However, females with a full mutation are able to pass this full mutation on, so theoretically there is a 50% chance that a child will be affected.<ref name=Peprah/><ref name=guidelines/> In addition, the length of the CGG repeat frequently does increase during meiosis in female premutation carriers due to instability and so, depending on the length of their premutation, they may pass on a full mutation to their children who will then be affected. [[trinucleotide repeat expansion|Repeat expansion]] is considered to be a consequence of [[strand slippage]] either during [[DNA replication]] or [[DNA repair]] synthesis.<ref name="pmid25608779">{{cite journal | vauthors = Usdin K, House NC, Freudenreich CH | title = Repeat instability during DNA repair: Insights from model systems | journal = Critical Reviews in Biochemistry and Molecular Biology | volume = 50 | issue = 2 | pages = 142–167 | date = 2015 | pmid = 25608779 | pmc = 4454471 | doi = 10.3109/10409238.2014.999192 }}</ref>

==== Mosaicism ====
Mosaicism refers to cases where individuals have both full mutation and premutation copies. Mosaicism can result from instability in the CGG repeats, and affected individuals may show classic symptoms, although some evidence suggests higher intellectual abilities compared to those with a full mutation.<ref>{{Cite journal |last1=Mineur |first1=Yann S. |last2=Sluyter |first2=Frans |last3=de Wit |first3=Sanne |last4=Oostra |first4=Ben A. |last5=Crusio |first5=Wim E. |date=2002 |title=Behavioral and neuroanatomical characterization of the ''Fmr1'' knockout mouse |journal=Hippocampus |volume=12 |issue=1 |pages=39–46 |doi=10.1002/hipo.10005 |pmid=11918286 |s2cid=35472224 |issn=1050-9631}}</ref>

== Pathophysiology ==
FMRP is found throughout the body, but in highest concentrations within the brain and testes.<ref name=McLennan/><ref name=Santoro/> It appears to be primarily responsible for selectively binding to around 4% of [[mRNA]] in mammalian brains and transporting it out of the cell nucleus and to the [[synapses]] of [[neurons]]. Most of these mRNA targets have been found to be located in the [[dendrites]] of neurons, and brain tissue from humans with FXS and mouse models shows abnormal [[dendritic spines]], which are required to increase contact with other neurons. The subsequent abnormalities in the formation and function of synapses and development of neural circuits result in impaired [[neuroplasticity]], an integral part of memory and learning.<ref name=McLennan/><ref name=Santoro/><ref>{{cite journal | vauthors = Bassell GJ, Warren ST | title = Fragile X syndrome: loss of local mRNA regulation alters synaptic development and function | journal = Neuron | volume = 60 | issue = 2 | pages = 201–214 | date = October 2008 | pmid = 18957214 | pmc = 3691995 | doi = 10.1016/j.neuron.2008.10.004 }}</ref> [[Connectome]] changes have long been suspected to be involved in the sensory pathophysiology<ref>{{cite journal | vauthors = Bureau I, Shepherd GM, Svoboda K | title = Circuit and plasticity defects in the developing somatosensory cortex of FMR1 knock-out mice | journal = The Journal of Neuroscience | volume = 28 | issue = 20 | pages = 5178–5188 | date = May 2008 | pmid = 18480274 | pmc = 2696604 | doi = 10.1523/JNEUROSCI.1076-08.2008 | author3-link = Karel Svoboda (scientist) }}</ref> and most recently a range of circuit alterations have been shown, involving structurally increased local connectivity and functionally decreased long-range connectivity.<ref>{{cite journal | vauthors = Haberl MG, Zerbi V, Veltien A, Ginger M, Heerschap A, Frick A | title = Structural-functional connectivity deficits of neocortical circuits in the Fmr1 (-/y) mouse model of autism | journal = Science Advances | volume = 1 | issue = 10 | article-number = e1500775 | date = November 2015 | pmid = 26702437 | pmc = 4681325 | doi = 10.1126/sciadv.1500775 | bibcode = 2015SciA....1E0775H }}</ref>

In addition, FMRP has been implicated in several signalling pathways that are being targeted by a number of drugs undergoing clinical trials. The [[Metabotropic glutamate receptor#Group I|group 1 metabotropic glutamate receptor]] (mGluR) pathway, which includes [[Metabotropic glutamate receptor 1|mGluR1]] and [[Metabotropic glutamate receptor 5|mGluR5]], is involved in mGluR-dependent [[long term depression]] (LTD) and [[long term potentiation]] (LTP), both of which are important mechanisms in learning.<ref name=McLennan/><ref name=Santoro/> The lack of FMRP, which represses mRNA production and thereby protein synthesis, leads to exaggerated LTD. FMRP also appears to affect [[dopamine]] pathways in the prefrontal cortex which is believed to result in the attention deficit, hyperactivity and impulse control problems associated with FXS.<ref name=McLennan/><ref name=Santoro/><ref name=Tranfaglia/> The downregulation of [[GABA]] pathways, which serve an inhibitory function and are involved in learning and memory, may be a factor in the anxiety symptoms which are commonly seen in FXS.{{citation needed|date=August 2021}}

Research in a mouse model of FSX shows that cortical neurons receive reduced sensory information (hyposensitivity), contrary to the common assumption that these neurons are hypersensitive, accompanied by enhanced contextual information, accumulated from previous experiences. Therefore, these results suggest that the hypersensitive phenotype of affected individuals might arise from mismatched contextual input onto these neurons.<ref>{{cite journal |vauthors=Mitchell DE, Miranda-Rottmann S, Blanchard MG, Araya R |date=January 2023 |title=Altered integration of excitatory inputs onto the basal dendrites of layer 5 pyramidal neurons in a mouse model of Fragile X Syndrome |journal=PNAS |volume=120 |issue=2 |article-number=e2208963120 |doi=10.1073/pnas.2208963120|doi-access=free |pmid=36595706 |pmc=9926222 |bibcode=2023PNAS..12008963M }}</ref>

==Diagnosis==
Clinical diagnosis relies on identifying a variant of FMR1 associated with decreased function alongside moderate to severe intellectual impairment, particularly in males or moderate in females. Diagnostic tests include PCR to analyze the number of CGG repeats, Southern blot analysis, and examination of AGG trinucleotides in the FMR1 gene region.

[[Cytogenetic]] analysis for fragile X syndrome was first available in the late 1970s when diagnosis of the syndrome and carrier status could be determined by culturing cells in a folate deficient medium and then assessing for "[[fragile site]]s" (discontinuity of staining in the region of the trinucleotide repeat) on the long arm of the X chromosome.<ref name="Hogan">{{cite journal | vauthors = Hogan AJ | title = Visualizing carrier status: fragile X syndrome and genetic diagnosis since the 1940s | journal = Endeavour | volume = 36 | issue = 2 | pages = 77–84 | date = June 2012 | pmid = 22257912 | doi = 10.1016/j.endeavour.2011.12.002 | url = https://zenodo.org/record/894526 | access-date = 2018-04-20 | url-status = live | archive-url = https://web.archive.org/web/20191105204324/https://zenodo.org/record/894526 | archive-date = 2019-11-05 }}</ref> This technique proved unreliable, however, as the fragile site was often seen in less than 40% of an individual's cells. This was not as much of a problem in males, but in female carriers, where the fragile site could generally only be seen in 10% of cells, the mutation often could not be visualised.<ref>{{Cite journal |last=Sharif |first=Abid |date=2012 |title=Practice Guidelines for Molecular Diagnosis of Fragile X Syndrome |url=https://www.acgs.uk.com/media/10768/frx_bpg_final_nov_2014.pdf |journal=}}</ref>

Since the 1990s, more [[Sensitivity and specificity|sensitive]] molecular techniques have been used to determine carrier status.<ref name=Hogan/> The fragile X abnormality is now directly determined by analysis of the number of CGG repeats using [[polymerase chain reaction]] (PCR) and methylation status using [[Southern blot]] analysis.<ref name=Garber/> By determining the number of CGG repeats on the X chromosome, this method allows for more accurate assessment of risk for premutation carriers in terms of their own risk of fragile X associated syndromes, as well as their risk of having affected children. Because this method only tests for expansion of the CGG repeat, individuals with FXS due to [[missense mutations]] or [[Deletion (genetics)|deletions]] involving ''FMR1'' will not be diagnosed using this test and should therefore undergo sequencing of the FMR1 gene if there is clinical suspicion of FXS.{{citation needed|date=September 2021}}

Prenatal testing with [[chorionic villus sampling]] or [[amniocentesis]] allows diagnosis of FMR1 mutation while the fetus is in utero and appears to be reliable.<ref name=Garber/>

Early diagnosis of fragile X syndrome or carrier status is important for providing early intervention in children or fetuses with the syndrome, and allowing genetic counselling with regards to the potential for a couple's future children to be affected. Most parents notice delays in speech and language skills, difficulties in social and emotional domains as well as sensitivity levels in certain situations with their children.<ref>{{Cite web|url=https://www.nichd.nih.gov/health/topics/fragilex/conditioninfo/diagnosis|title=How do health care providers diagnose Fragile X syndrome?|website=  National Institute of Child Health and Human Development |publisher =NIH|location = US | date = 2021-08-25 |access-date=2016-11-21|url-status=live|archive-url=https://web.archive.org/web/20161121234354/https://www.nichd.nih.gov/health/topics/fragilex/conditioninfo/Pages/diagnosed.aspx|archive-date=2016-11-21}}</ref>

== Management ==
There is no cure for the underlying defects of FXS.<ref name=CDC2017/> Management of FXS may include [[speech therapy]], [[behavioral therapy]], [[occupational therapy]], [[special education]], or individualised educational plans, and, when necessary, treatment of physical abnormalities. Persons with fragile X syndrome in their family histories are advised to seek [[genetic counseling]] to assess the likelihood of having children who are affected, and how severe any impairments may be in affected descendants.<ref name="Hagerman et al 2009">{{cite journal | vauthors = Hagerman RJ, Berry-Kravis E, Kaufmann WE, Ono MY, Tartaglia N, Lachiewicz A, Kronk R, Delahunty C, Hessl D, Visootsak J, Picker J, Gane L, Tranfaglia M | display-authors = 6 | title = Advances in the treatment of fragile X syndrome | journal = Pediatrics | volume = 123 | issue = 1 | pages = 378–390 | date = January 2009 | pmid = 19117905 | pmc = 2888470 | doi = 10.1542/peds.2008-0317 }}</ref>

=== Medication ===
Current trends in treating the disorder include medications for symptom-based treatments that aim to minimize the secondary characteristics associated with the disorder. If an individual is diagnosed with FXS, genetic counseling for testing family members at risk for carrying the full mutation or premutation is a critical first-step. Due to a higher prevalence of FXS in boys, the most commonly used medications are stimulants that target hyperactivity, impulsivity, and attentional problems.<ref name=Garber/> For co-morbid disorders with FXS, antidepressants such as [[selective serotonin reuptake inhibitor]]s (SSRIs) are utilized to treat the underlying anxiety, obsessive-compulsive behaviors, and mood disorders. Following antidepressants, antipsychotics such as [[risperidone]] and [[quetiapine]] are used to treat high rates of self-injurious, aggressive and aberrant behaviors in this population (Bailey Jr et al., 2012). Anticonvulsants are another set of pharmacological treatments used to control [[seizure]]s as well as mood swings in 13%–18% of individuals with FXS. Drugs targeting the mGluR5 (metabotropic glutamate receptors) that are linked with synaptic plasticity are especially beneficial for targeted symptoms of FXS.<ref name=Garber/> Lithium is also currently being used in clinical trials with humans, showing significant improvements in behavioral functioning, adaptive behavior, and verbal memory. Few studies suggested using folic acid, but more researches are needed due to the low quality of that evidence.<ref>{{cite journal | vauthors = Rueda JR, Ballesteros J, Guillen V, Tejada MI, Solà I | title = Folic acid for fragile X syndrome | journal = The Cochrane Database of Systematic Reviews | issue = 5 | article-number = CD008476 | date = May 2011 | pmid = 21563169 | doi = 10.1002/14651858.CD008476.pub2 }}</ref> Alongside pharmacological treatments, environmental influences such as home environment and parental abilities as well as behavioral interventions such as speech therapy, sensory integration, etc. all factor in together to promote adaptive functioning for individuals with FXS.<ref name="Hagerman et al 2009"/> While metformin may reduce body weight in persons with fragile X syndrome, it is uncertain whether it improves neurological or psychiatric symptoms.<ref>{{cite journal | vauthors = Gantois I, Popic J, Khoutorsky A, Sonenberg N | title = Metformin for Treatment of Fragile X Syndrome and Other Neurological Disorders | journal = Annual Review of Medicine | volume = 70 | pages = 167–181 | date = January 2019 | pmid = 30365357 | doi = 10.1146/annurev-med-081117-041238 | s2cid = 53093694 | url = https://escholarship.mcgill.ca/concern/articles/2j62s977h | doi-access = free }}</ref>

Current pharmacological treatment centers on managing problem behaviors and psychiatric symptoms associated with FXS. However, as there has been very little research done in this specific population, the evidence to support the use of these medications in individuals with FXS is poor.<ref>{{cite journal | vauthors = Rueda JR, Ballesteros J, Tejada MI | title = Systematic review of pharmacological treatments in fragile X syndrome | journal = BMC Neurology | volume = 9 | article-number = 53 | date = October 2009 | pmid = 19822023 | pmc = 2770029 | doi = 10.1186/1471-2377-9-53 | doi-access = free }}</ref>

[[ADHD]], which affects the majority of boys and 30% of girls with FXS, is frequently treated using [[stimulants]].<ref name=McLennan/> However, the use of stimulants in the fragile X population is associated with a greater frequency of adverse events including increased anxiety, irritability and mood lability.<ref name=Tranfaglia/> Anxiety, as well as mood and obsessive-compulsive symptoms, may be treated using [[SSRIs]], although these can also aggravate hyperactivity and cause disinhibited behavior.<ref name=Garber/><ref name=Tranfaglia/> [[Atypical antipsychotics]] can be used to stabilise mood and control aggression, especially in those with comorbid ASD. However, monitoring is required for metabolic side effects including weight gain and diabetes, as well as movement disorders related to [[Extrapyramidal symptoms|extrapyramidal side effects]] such as [[tardive dyskinesia]]. Individuals with coexisting seizure disorder may require treatment with [[anticonvulsants]].

== Prognosis ==
A 2013 review stated that life expectancy for FXS was 12 years lower than the general population and that the causes of death were similar to those found for the general population.<ref>{{cite journal | vauthors = Coppus AM | title = People with intellectual disability: what do we know about adulthood and life expectancy? | journal = Developmental Disabilities Research Reviews | volume = 18 | issue = 1 | pages = 6–16 | date = 2013-08-01 | pmid = 23949824 | doi = 10.1002/ddrr.1123 }}</ref>

== Pharmacological therapy ==
There are no pharmacologic therapies approved specifically for fragile X syndrome. Medications are sometimes used to treat the co-morbidities that often accompany FXS, including seizures, anxiety, or disruptive behaviors.<ref name="Hagerman 2025" />

Research into the etiology of FXS has given rise to many attempts at drug discovery.<ref>{{cite journal | vauthors = Duy PQ, Budimirovic DB | title = Fragile X Syndrome: Lessons Learned from the Most Translated Neurodevelopmental Disorder in Clinical Trials | journal = Translational Neuroscience | volume = 8 | issue = 1 | pages = 7–8 | date = January 2017 | pmid = 28400977 | pmc = 5382936 | doi = 10.1515/tnsci-2017-0002 }}</ref> The increased understanding of the molecular mechanisms of disease in FXS has led to the development of therapies targeting the affected pathways. Evidence from mouse models shows that mGluR5 [[Receptor antagonist|antagonists]] (blockers) can rescue dendritic spine abnormalities and seizures, as well as cognitive and behavioral problems, and may show promise in the treatment of FXS.<ref name=McLennan/><ref>{{cite journal | vauthors = Dölen G, Osterweil E, Rao BS, Smith GB, Auerbach BD, Chattarji S, Bear MF | title = Correction of fragile X syndrome in mice | journal = Neuron | volume = 56 | issue = 6 | pages = 955–962 | date = December 2007 | pmid = 18093519 | pmc = 2199268 | doi = 10.1016/j.neuron.2007.12.001 }}</ref><ref name="pmid20303363">{{cite journal | vauthors = Dölen G, Carpenter RL, Ocain TD, Bear MF | title = Mechanism-based approaches to treating fragile X | journal = Pharmacology & Therapeutics | volume = 127 | issue = 1 | pages = 78–93 | date = July 2010 | pmid = 20303363 | doi = 10.1016/j.pharmthera.2010.02.008 }}</ref> Two new drugs, AFQ-056 ([[mavoglurant]]) and [[dipraglurant]], as well as the repurposed drug [[fenobam]] are currently undergoing human trials for the treatment of FXS.<ref name=McLennan/><ref name=Cole>{{cite journal | vauthors = Cole P | title = Mavoglurant | journal = Drugs of the Future | year = 2012 | volume = 37 | issue = 1 | pages = 7–12 | doi = 10.1358/dof.2012.037.01.1772147| s2cid = 258330291 }}</ref> There is also early evidence for the efficacy of [[arbaclofen]], a GABA<sub>B</sub> agonist, in improving social withdrawal in individuals with FXS and ASD.<ref name=McLennan/><ref name=Bud>{{cite journal |author1=Budimirovic DB  |author2=Kaufmann WE | title = What can we learn about autism from studying fragile X syndrome? | journal = Developmental Neuroscience | volume = 33 | issue = 5 | pages = 379–394 | year = 2011 | pmid = 21893949 | pmc = 3254037 | doi = 10.1159/000330213 }}</ref> In addition, there is evidence from mouse models that [[minocycline]], an antibiotic used for the treatment of [[acne]], rescues abnormalities of the dendrites. An open trial in humans has shown promising results, although there is currently no evidence from [[Randomized controlled trial|controlled trials]] to support its use.<ref name=McLennan/> [[Zatolmilast]], a [[phosphodiesterase-4 inhibitor]] works to inhibit [[cyclic adenosine monophosphate]] (cAMP) breakdown, with the resultant higher levels of cAMP in the brain thought to enhance neuronal connectivity. Zatolmilast has shown increased caregiver symptom ratings and increased cognitive scores in those with FXS in a small clinical trial.<ref name="Hagerman 2025" />

==History==
In 1943, British neurologist [[James Purdon Martin]] and British geneticist [[Julia Bell]] described a pedigree of X-linked intellectual disability, without considering the [[macroorchidism]] (larger testicles).<ref>{{cite journal |author1=Martin JP |author2=Bell J | title = A Pedigree of Mental Defect Showing Sex-Linkage | journal = Journal of Neurology and Psychiatry | volume = 6 | issue = 3–4 | pages = 154–157 | date = July 1943 | pmid = 21611430 | pmc = 1090429 | doi = 10.1136/jnnp.6.3-4.154 }}</ref> In 1969, Herbert Lubs first sighted an unusual "marker X chromosome" in association with intellectual disability.<ref>{{cite journal | vauthors = Lubs, HA | title = A marker X chromosome | journal = American Journal of Human Genetics | volume = 21 | issue = 3 | pages = 231–244 | date = May 1969 | pmid = 5794013 | pmc = 1706424 }}</ref> In 1970, Frederick Hecht coined the term "fragile site". And, in 1985, Felix F. de la Cruz outlined extensively the physical, psychological, and cytogenetic characteristics of those with the condition in addition to prospects for therapy.<ref>{{cite journal |author=de la Cruz, FF | title = Fragile X syndrome | journal = American Journal of Mental Deficiency | volume = 90 | issue = 2 | pages = 119–123 | date = September 1985 | pmid = 3901755 }}</ref> Continued advocacy later won him an honour through the FRAXA Research Foundation in December 1998.<ref>{{cite web |url=http://www.fraxa.org/pdf/NEWS1999.pdf |title= FRAXA Member Update (three issues: Spring 1999, Summer 1999, Fall 1999) |access-date=2017-12-14 |type= newsletter |publisher= FRAXA Research Foundation |location= [[Newburyport, Massachusetts]] |url-status=live |archive-url=https://web.archive.org/web/20101215090310/http://fraxa.org/pdf/NEWS1999.pdf |archive-date=2010-12-15 }}</ref>

==See also==
* [[List of syndromes]]
* [[Toxidrome]]
* [[Symptom]]
* [[Sequence (medicine)]]
* [[Characteristics of syndromic ASD conditions]]

== References ==
{{Reflist}}

== External links ==
{{Commons category|Fragile X syndrome}}
* [https://www.cdc.gov/ncbddd/single_gene/fragilex.htm CDC's National Center on Birth Defects and Developmental Disabilities]
* [https://www.ncbi.nlm.nih.gov/books/NBK1384/ Gene Reviews]

{{Medical resources
| DiseasesDB = 4973
| ICD10 = {{ICD10|Q|99|2|q|90}}
| ICD9 = {{ICD9|759.83}}
| OMIM = 300624
| MedlinePlus =001668
| eMedicineSubj =ped
| eMedicineTopic =800
| MeshID =D005600
| Orphanet=908
}}
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{{X-linked disorders}}
{{Trinucleotide repeat disorders}}
{{Disorders of translation and posttranslational modification}}
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[[Category:Genetics of autism]]
[[Category:Syndromes with intellectual disability]]
[[Category:Rare genetic syndromes]]
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[[Category:Syndromes affecting the nervous system]]
[[Category:Syndromes with craniofacial abnormalities]]
[[Category:Trinucleotide repeat disorders]]
[[Category:X-linked dominant disorders]]
[[Category:Neurogenetic disorders]]
[[Category:Wikipedia medicine articles ready to translate]]
[[Category:Syndromic autism]]
[[Category:Syndromes with ADHD]]