Medicine:Fragile X syndrome

From HandWiki
Short description: X-linked dominant genetic disorder

Fragile X syndrome
Other namesMartin–Bell syndrome,[1]
Escalante syndrome
Boy with protruding ears, a characteristic of fragile X syndrome
SpecialtyMedical genetics, pediatrics, psychiatry
SymptomsIntellectual disability, long and narrow face, large ears, flexible fingers, autistic behavior, large testicles[1]
ComplicationsSeizures[1]
Usual onsetNoticeable by age 2[1]
DurationLifelong[2]
CausesGenetic (X-linked dominant)
Diagnostic methodGenetic testing[2]
TreatmentSupportive care, early interventions[2]
Frequency1 in 4,000 (males), 1 in 8,000 (females)[1]

Fragile X syndrome (FXS) is a genetic neurodevelopmental disorder.[1] 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.[3][4] Physical features may include a long and narrow face, large ears, flexible fingers, and large testicles.[1] About a third of those affected have features of autism such as problems with social interactions and delayed speech.[1] Hyperactivity is common, and seizures occur in about 10%.[1] Males are usually more affected than females.[1]

This disorder and finding of fragile X syndrome has an X-linked dominant inheritance.[5] It is typically caused by an expansion of the CGG triplet repeat within the FMR1 (fragile X messenger ribonucleoprotein 1) gene on the X chromosome.[1] This results in silencing (methylation) of this part of the gene and a deficiency of the resultant protein (FMRP), which is required for the normal development of connections between neurons.[1] Diagnosis requires genetic testing to determine the number of CGG repeats in the FMR1 gene.[6] Normally, there are between 5 and 40 repeats; fragile X syndrome occurs with more than 200.[1] 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.[1] Testing for premutation carriers may allow for genetic counseling.[6]

There is no cure or approved medications for treating the condition.[7][2] Early intervention is recommended, as it provides the most opportunity for developing a full range of skills.[8] These interventions may include special education, occupational therapy, speech therapy, physical therapy, or behavioral therapy.[2][9] Medications may be used to treat associated anxiety, seizures, mood problems, aggressive behavior, or ADHD.[10] Fragile X syndrome tends to show more symptoms on affected males since females have another X chromosome which can compensate for the damaged one.[4][11]

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.[7]

Signs and symptoms

Prominent characteristics of the syndrome include an elongated face and large or protruding ears.

Aside from intellectual disability, prominent characteristics of the syndrome may include an elongated face, large or protruding ears, flat feet, larger testes (macroorchidism), and low muscle tone.[12][13] Recurrent otitis media (middle ear infection) and sinusitis is common during early childhood. Speech may be cluttered or nervous. Behavioral characteristics may include 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.[14]

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.[15] 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.[16][17]

Physical phenotype

  • Large, protruding ears (both)
  • Long face (vertical maxillary excess)
  • High-arched palate (related to the above)
  • 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.[18][7]
  • Postpubescent macroorchidism (large testicles in males after puberty)[19]
  • Hypotonia (low muscle tone)[20][21]

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.[13] 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.[13][22]

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.[22]

Individuals with FXS often demonstrated language and communicative problems.[23] This may be related to muscle function of the mouth and frontal-lobe deficits.[23]

Autism

Fragile X syndrome is the most common genetic cause of autism.[7][12][24] This finding has resulted in medical screening for FMR1 mutation in individuals who present with autism.[12] 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.[24]

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.[24] When both autism and FXS are present, a greater language deficit and lower IQ is observed as compared to children with only FXS.[25]

Genetic mouse models of FXS have also been shown to have autistic-like behaviors.[26][27][28][29][30]

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.[31] 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.[24] Social anxiety in individuals with FXS is related to challenges with face encoding, the ability to recognize a face that one has seen before.[32]

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.[24][31] 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.[24]

Females with FXS frequently display shyness, social anxiety and social avoidance or withdrawal.[13] 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.[33]

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.[12][31] Children with fragile X have very short attention spans, are 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.[31]



Individuals with fragile X-associated tremor/ataxia syndrome (FXTAS) are likely to experience combinations of dementia, mood, and anxiety disorders. 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.[34]

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.[25]

Neurology

Individuals with FXS are at a higher risk of developing seizures, with rates between 10% and 40% reported in the literature.[35] In larger study populations the frequency varies between 13% and 18%,[13][35] consistent with a recent survey of caregivers which found that 14% of males and 6% of females experienced seizures.[35] The seizures tend to be partial, are generally not frequent, and are amenable to treatment with medication. Individuals who are carriers of premutation alleles are at risk for developing fragile X-associated tremor/ataxia syndrome (FXTAS), a progressive neurodegenerative disease.[15][36] 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.[36]

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.[37]

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).[15][36] The number of CGG repeats correlates with penetrance and age of onset, but it is not a linear relationship.[38][15] 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.[39][40] 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 eggs through "escape" ovulation.[41][42] FXPOI is the most common cause of hereditary primary ovarian insufficiency.[7] There is not specific treatment for FXPOI, but hormonal therapy is recommended as a treatment, as for other women with primary ovarian insufficiency.[7]

In women with infertility, and a family history of infertility, there is a 7% risk of FXPOI so genetic testing is recommended.[7]

FMRP is a chromatin-binding protein that functions in the DNA damage response.[43][44] FMRP also occupies sites on meiotic chromosomes and regulates the dynamics of the DNA damage response machinery during spermatogenesis.[43]

Causes

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 Fragile X Messenger Ribonucleoprotein 1 (FMR1) gene on the X chromosome, most commonly an increase in the number of CGG trinucleotide repeats in the 5' untranslated region of FMR1.[15][36] Mutation at that site is found in 1 out of about every 2000 males and 1 out of about every 259 females. Incidence of the disorder itself is about 1 in every 3600 males and 1 in 4000–6000 females.[45] Although this accounts for over 98% of cases, FXS can also occur as a result of point mutations affecting FMR1.[15][36]

In unaffected individuals, the FMR1 gene contains 5–44 repeats of the sequence CGG, most commonly 29 or 30 repeats.[15][36][46] 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.[12][46][47] In these individuals with a repeat expansion greater than 200, there is methylation of the CGG repeat expansion and FMR1 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.[48]

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.[49] The first complete DNA sequence of the repeat expansion in someone with the full mutation was generated by scientists in 2012 using SMRT sequencing.[50]

Inheritance

Fragile X syndrome has traditionally been considered an X-linked recessive condition with variable expressivity and possibly reduced penetrance.[13] 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.[51] 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.[15] This tendency for future generations to be affected at a higher frequency became known as the Sherman paradox after its description in 1985.[15][52] Due to this, male children often have a greater degree of symptoms than their mothers.[53]

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.[15][36] Incidentally, males with a full mutation only pass on premutations to their daughters.[36] 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.[36][46] 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. Repeat expansion is considered to be a consequence of strand slippage either during DNA replication or DNA repair synthesis.[54]

Carriers

Clinical and diagnostic testing taken from a 2025 study reported that around 31% women who are a carrier for the FMR1 premutation were later diagnosed with FXTAS (Fragile X-Associated Tremor/Ataxia Syndrome).[55] While more common in males than females, recent studies reveal how females are affected.[55] In addition to premutation carriers being at risk for FXTAS, they are also at risk for a variety of other medical conditions. Female carriers are more at risk for thyroid disease, hypertension and chronic muscle pain than the general population.[56] Female carriers are also more at risk of having migraines than male carriers. The most common health condition found in premutation carriers are neuropsychiatric disorders.[56] Anxiety disorder, ADHD and depression are common in carriers. Depression is associated with CGG repeats and premutation carriers have around 55-200 CGG repeats.[57] Most individuals have less than 44 CGG repeats.[58]   Some males with the premutation show traits of Fragile-X including an increased size in testicles, social impairment, delays in speech and language, and hyperactivity. Traits also include wider outer canthal distance and developmental delays.[59] Female carriers often show little to no physical phenotype, but have an increased risks for premature ovarian failure (FXPOI) and lowered bone density.[60]

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.[61]

Pathophysiology

FMRP is found throughout the body, but in highest concentrations within the brain and testes.[12][15] 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.[12][15][62] Connectome changes have long been suspected to be involved in the sensory pathophysiology[63] and most recently a range of circuit alterations have been shown, involving structurally increased local connectivity and functionally decreased long-range connectivity.[64]


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.[65]

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 sites" (discontinuity of staining in the region of the trinucleotide repeat) on the long arm of the X chromosome.[66] 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.[67]


Prenatal testing with chorionic villus sampling or amniocentesis allows diagnosis of FMR1 mutation while the fetus is in utero and appears to be reliable.[13]

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.[68]

Management

There is no cure for the underlying defects of FXS.[2] 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.[69]

Daily routine

Individuals with full mutation Fragile-X Syndrome may experience challenges in daily living. Individuals with FXS often benefit from consistent routines and predictability, as this reduces anxiety.[70] Some individuals with FXS may experience limited social skills as well as social anxiety which makes it hard for them to form close bonds with others. Everyday activities such as traveling, making purchases at a store and interacting with peers may be difficult.[70]  Individuals may experience difficulties in achieving functional independence. Independent living skills and employment capabilities are typically limited.[71] However, some adults are able to achieve independence through support and accommodations.[71]

Developmental delays

Infants with Fragile-X Syndrome may experience hypotonia, feeding problems and vomiting, but all developmental delays are subtle.[72] By a year, language delays begin to be noticeable. These delays are followed by an increased amount of tantrums and irritability as an individual approaches 3 years old. By the time children with FXS reach school age, they face significant learning challenges including verbal comprehension, working memory and understanding complex language.[72] By adolescence, social challenges increase as well as aggression, anxiety and irritability. Going into adulthood, FXS individuals require support in daily living and mental health may worsen.[72]

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.[13] For co-morbid disorders with FXS, antidepressants such as selective serotonin reuptake inhibitors (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 seizures 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.[13] 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.[73] 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.[69] While metformin may reduce body weight in persons with fragile X syndrome, it is uncertain whether it improves neurological or psychiatric symptoms.[74]

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.[75]

ADHD, which affects the majority of boys and 30% of girls with FXS, is frequently treated using stimulants.[12] 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.[31] Anxiety, as well as mood and obsessive-compulsive symptoms, may be treated using SSRIs, although these can also aggravate hyperactivity and cause disinhibited behavior.[13][31] 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 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.[76]

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.[7]

Research into the etiology of FXS has given rise to many attempts at drug discovery.[77] 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 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.[12][78][79] 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.[12][80] There is also early evidence for the efficacy of arbaclofen, a GABAB agonist, in improving social withdrawal in individuals with FXS and ASD.[12][24] 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 controlled trials to support its use.[12] 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.[7]

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).[81] In 1969, Herbert Lubs first sighted an unusual "marker X chromosome" in association with intellectual disability.[82] 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.[83] Continued advocacy later won him an honour through the FRAXA Research Foundation in December 1998.[84]

Research in 2020 suggested that Idiocy and Imbecility (1877) by William Wotherspoon Ireland contained the earliest depiction of a person with FXS.[85]

See also

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 "fragile X syndrome". April 2012. https://medlineplus.gov/genetics/condition/fragile-x-syndrome/. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 "What is Fragile X Syndrome?" (in en-us). US: Centers for Disease Control and Prevention. 3 June 2022. https://www.cdc.gov/ncbddd/fxs/facts.html. 
  3. ↑ "Public Health Literature Review of Fragile X Syndrome". Pediatrics 139 (Suppl 3): S153–S171. June 2017. doi:10.1542/peds.2016-1159C. PMID 28814537. 
  4. ↑ 4.0 4.1 "Data and Statistics Fragile X Syndrome (FXS)" (in en-us). Centers for Disease Control and Prevention. 2018-08-09. https://www.cdc.gov/ncbddd/fxs/data.html. 
  5. ↑ "Fragile X syndrome". NIH. https://medlineplus.gov/genetics/condition/fragile-x-syndrome/#inheritance. 
  6. ↑ 6.0 6.1 "Technical Standards and Guidelines for Fragile X". 2006. https://www.acmg.net/Pages/ACMG_Activities/stds-2002/fx.htm. 
  7. ↑ 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8 Hagerman, Randi Jenssen; Hagerman, Paul J. (17 July 2025). "The Spectrum of Fragile X Disorders". New England Journal of Medicine 393 (3): 281–288. doi:10.1056/NEJMra2300487. PMID 40673587. 
  8. ↑ "What are the treatments for Fragile X syndrome?". https://www.nichd.nih.gov/health/topics/fragilex/conditioninfo/treatments. 
  9. ↑ "Therapy Treatments". https://www.nichd.nih.gov/health/topics/fragilex/conditioninfo/therapytreatments. 
  10. ↑ "Medication Treatments". https://www.nichd.nih.gov/health/topics/fragilex/conditioninfo/medicationtreatments. 
  11. ↑ "What is Fragile-X syndrome?" (in en-GB). https://www.yourgenome.org/theme/what-is-fragile-x-syndrome/. 
  12. ↑ 12.00 12.01 12.02 12.03 12.04 12.05 12.06 12.07 12.08 12.09 12.10 12.11 "Fragile x syndrome". Current Genomics 12 (3): 216–224. May 2011. doi:10.2174/138920211795677886. PMID 22043169. 
  13. ↑ 13.00 13.01 13.02 13.03 13.04 13.05 13.06 13.07 13.08 13.09 "Fragile X syndrome". European Journal of Human Genetics 16 (6): 666–672. June 2008. doi:10.1038/ejhg.2008.61. PMID 18398441. 
  14. ↑ "Fragile X and Autism | Fragile X Society | UK" (in en). https://www.fragilex.org.uk/fragile-x-and-autism. 
  15. ↑ 15.00 15.01 15.02 15.03 15.04 15.05 15.06 15.07 15.08 15.09 15.10 15.11 "Molecular mechanisms of fragile X syndrome: a twenty-year perspective". Annual Review of Pathology 7: 219–245. 2012. doi:10.1146/annurev-pathol-011811-132457. PMID 22017584. 
  16. ↑ "Closing the Gender Gap in Fragile X Syndrome: Review on Females with FXS and Preliminary Research Findings". Brain Sciences 9 (1): 11. January 2019. doi:10.3390/brainsci9010011. PMID 30642066. 
  17. ↑ CDC (2022-06-03). "What is Fragile X Syndrome (FXS)? | CDC" (in en-us). https://www.cdc.gov/ncbddd/fxs/facts.html. 
  18. ↑ Lubala, TK; Lumaka, A; Kanteng, G; Mutesa, L; Mukuku, O; Wembonyama, S; Hagerman, R; Luboya, ON et al. (6 April 2018). "Fragile X checklists: A meta-analysis and development of a simplified universal clinical checklist.". Molecular Genetics & Genomic Medicine 6 (4): 526–32. doi:10.1002/mgg3.398. PMID 29624914. 
  19. ↑ "15". Oral pathology: clinical pathologic correlations (5th ed.). St. Louis, Mo.: Saunders/Elsevier. 2008. ISBN 978-1-4160-4570-0.  Section on fragile X syndrome
  20. ↑ "Fragile X Syndrome: Implications for Physical Education". Palaestra 33 (3). 1 June 2019. 
  21. ↑ Handbook of neurodevelopmental and genetic disorders in children. New York: Guilford Press. 1999. ISBN 978-1-57230-448-2. 
  22. ↑ 22.0 22.1 "Longitudinal changes in intellectual development in children with Fragile X syndrome". Journal of Abnormal Child Psychology 36 (6): 927–939. August 2008. doi:10.1007/s10802-008-9223-y. PMID 18347972. 
  23. ↑ 23.0 23.1 "Language and communication in fragile X syndrome" (in en). Mental Retardation and Developmental Disabilities Research Reviews 3 (4): 313–322. 1997. doi:10.1002/(SICI)1098-2779(1997)3:4<313::AID-MRDD6>3.0.CO;2-O. ISSN 1098-2779. 
  24. ↑ 24.0 24.1 24.2 24.3 24.4 24.5 24.6 Budimirovic DB; Kaufmann WE (2011). "What can we learn about autism from studying fragile X syndrome?". Developmental Neuroscience 33 (5): 379–394. doi:10.1159/000330213. PMID 21893949. 
  25. ↑ 25.0 25.1 Hagerman, Randi J., and Paul J. Hagerman. Fragile X syndrome: diagnosis, treatment, and research. 3, illustrated ed. Baltimore, MD: JHU P, 2002.
  26. ↑ "Genetic-background modulation of core and variable autistic-like symptoms in Fmr1 knock-out mice". PLOS ONE 6 (2). February 2011. doi:10.1371/journal.pone.0017073. PMID 21364941. Bibcode: 2011PLoSO...617073P. 
  27. ↑ "Fmr1 KO mice as a possible model of autistic features". TheScientificWorldJournal 6: 1164–1176. September 2006. doi:10.1100/tsw.2006.220. PMID 16998604. 
  28. ↑ "Social behavior deficits in the Fmr1 mutant mouse". Behavioural Brain Research 168 (1): 172–175. March 2006. doi:10.1016/j.bbr.2005.11.004. PMID 16343653. 
  29. ↑ "Modifying behavioral phenotypes in Fmr1KO mice: genetic background differences reveal autistic-like responses". Autism Research 4 (1): 40–56. February 2011. doi:10.1002/aur.168. PMID 21268289. 
  30. ↑ "Social behavior in Fmr1 knockout mice carrying a human FMR1 transgene". Behavioral Neuroscience 122 (3): 710–715. June 2008. doi:10.1037/0735-7044.122.3.710. PMID 18513141. 
  31. ↑ 31.0 31.1 31.2 31.3 31.4 31.5 "The psychiatric presentation of fragile x: evolution of the diagnosis and treatment of the psychiatric comorbidities of fragile X syndrome". Developmental Neuroscience 33 (5): 337–348. 2011. doi:10.1159/000329421. PMID 21893938. 
  32. ↑ "Prefrontal social cognition network dysfunction underlying face encoding and social anxiety in fragile X syndrome". NeuroImage 43 (3): 592–604. November 2008. doi:10.1016/j.neuroimage.2008.08.009. PMID 18778781. 
  33. ↑ "Gene, brain, and behavior relationships in fragile X syndrome: evidence from neuroimaging studies". Developmental Disabilities Research Reviews (Wiley) 15 (4): 343–352. 2009. doi:10.1002/ddrr.77. OCLC 175296472. PMID 20014368. 
  34. ↑ "Cognitive, anxiety and mood disorders in the fragile X-associated tremor/ataxia syndrome". General Hospital Psychiatry 29 (4): 349–356. 2007. doi:10.1016/j.genhosppsych.2007.03.003. PMID 17591512. 
  35. ↑ 35.0 35.1 35.2 "Seizures in fragile X syndrome: characteristics and comorbid diagnoses". American Journal on Intellectual and Developmental Disabilities 115 (6): 461–472. November 2010. doi:10.1352/1944-7558-115.6.461. PMID 20945999. 
  36. ↑ 36.0 36.1 36.2 36.3 36.4 36.5 36.6 36.7 36.8 "Fragile X syndrome: the FMR1 CGG repeat distribution among world populations". Annals of Human Genetics 76 (2): 178–191. March 2012. doi:10.1111/j.1469-1809.2011.00694.x. PMID 22188182. 
  37. ↑ "Lifespan changes in working memory in fragile X premutation males". Brain and Cognition 69 (3): 551–558. April 2009. doi:10.1016/j.bandc.2008.11.006. PMID 19114290. 
  38. ↑ "Association of FMR1 repeat size with ovarian dysfunction". Human Reproduction 20 (2): 402–412. February 2005. doi:10.1093/humrep/deh635. PMID 15608041. 
  39. ↑ "Refining the risk for fragile X-associated primary ovarian insufficiency (FXPOI) by FMR1 CGG repeat size" (in English). Genetics in Medicine 23 (9): 1648–1655. September 2021. doi:10.1038/s41436-021-01177-y. PMID 33927378. 
  40. ↑ "The effect of CGG repeat number on ovarian response among fragile X premutation carriers undergoing preimplantation genetic diagnosis". Fertility and Sterility 94 (3): 869–874. August 2010. doi:10.1016/j.fertnstert.2009.04.047. PMID 19481741. 
  41. ↑ "Use of model systems to understand the etiology of fragile X-associated primary ovarian insufficiency (FXPOI)". Journal of Neurodevelopmental Disorders 6 (1). 2014. doi:10.1186/1866-1955-6-26. PMID 25147583. 
  42. ↑ "Reproductive and gynecologic care of women with fragile X primary ovarian insufficiency (FXPOI)". Menopause 23 (9): 993–999. September 2016. doi:10.1097/GME.0000000000000658. PMID 27552334. 
  43. ↑ 43.0 43.1 "A chromatin-dependent role of the fragile X mental retardation protein FMRP in the DNA damage response". Cell 157 (4): 869–881. May 2014. doi:10.1016/j.cell.2014.03.040. PMID 24813610. 
  44. ↑ "The Fragile X Protein and Genome Function". Molecular Neurobiology 56 (1): 711–721. January 2019. doi:10.1007/s12035-018-1122-9. PMID 29796988. 
  45. ↑ "Monogenic diseases". Human Genomics in Global Health. World Health Organization. https://www.who.int/genomics/public/geneticdiseases/en/index2.html. 
  46. ↑ 46.0 46.1 46.2 "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". Genetics in Medicine 3 (3): 200–205. 2001. doi:10.1097/00125817-200105000-00010. PMID 11388762. 
  47. ↑ "Expansion of the fragile X CGG repeat in females with premutation or intermediate alleles". American Journal of Human Genetics 72 (2): 454–464. February 2003. doi:10.1086/367713. PMID 12529854. 
  48. ↑ "Promoter-bound trinucleotide repeat mRNA drives epigenetic silencing in fragile X syndrome". Science 343 (6174): 1002–1005. February 2014. doi:10.1126/science.1245831. PMID 24578575. Bibcode: 2014Sci...343.1002C. 
  49. ↑ "Rare FMR1 gene mutations causing fragile X syndrome: A review". American Journal of Medical Genetics. Part A 176 (1): 11–18. January 2018. doi:10.1002/ajmg.a.38504. PMID 29178241. 
  50. ↑ "Sequencing the unsequenceable: expanded CGG-repeat alleles of the fragile X gene". Genome Research 23 (1): 121–128. January 2013. doi:10.1101/gr.141705.112. PMID 23064752. 
  51. ↑ "Inheritance of most X-linked traits is not dominant or recessive, just X-linked". American Journal of Medical Genetics. Part A 129A (2): 136–143. August 2004. doi:10.1002/ajmg.a.30123. PMID 15316978. 
  52. ↑ "Further segregation analysis of the fragile X syndrome with special reference to transmitting males". Human Genetics 69 (4): 289–299. 1985. doi:10.1007/BF00291644. PMID 3838733. 
  53. ↑ "Autism-lessons from the X chromosome". Social Cognitive and Affective Neuroscience 1 (3): 183–193. December 2006. doi:10.1093/scan/nsl028. PMID 18985105. 
  54. ↑ "Repeat instability during DNA repair: Insights from model systems". Critical Reviews in Biochemistry and Molecular Biology 50 (2): 142–167. 2015. doi:10.3109/10409238.2014.999192. PMID 25608779. 
  55. ↑ 55.0 55.1 McGatlin, Kristen; Shafer, Robin L.; Unruh, Kathryn E.; Stevens, Cassandra J.; Peterson, Sophia G.; Dubinsky, Richard M.; Lee, Andrea P.; Tassone, Flora et al. (2025-11-04). "Reduced Sensorimotor, Working Memory, and Episodic Memory Abilities in Aging Female FMR1 Premutation Carriers with and Without Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS)" (in en). Genes 16 (11): 1331. doi:10.3390/genes16111331. ISSN 2073-4425. PMID 41300783. 
  56. ↑ 56.0 56.1 Tassanakijpanich, Nattaporn; Hagerman, Randi J.; Worachotekamjorn, Juthamas (June 2021). "Fragile X premutation and associated health conditions: A review" (in en). Clinical Genetics 99 (6): 751–760. doi:10.1111/cge.13924. ISSN 0009-9163. PMID 33443313. https://onlinelibrary.wiley.com/doi/10.1111/cge.13924. 
  57. ↑ Tassanakijpanich, Nattaporn; Hagerman, Randi J.; Worachotekamjorn, Juthamas (June 2021). "Fragile X premutation and associated health conditions: A review" (in en). Clinical Genetics 99 (6): 751–760. doi:10.1111/cge.13924. ISSN 0009-9163. PMID 33443313. https://onlinelibrary.wiley.com/doi/10.1111/cge.13924. 
  58. ↑ Villate, Olatz; Ibarluzea, Nekane; Maortua, Hiart; de la Hoz, Ana Belén; Rodriguez-Revenga, Laia; Izquierdo-Álvarez, Silvia; Tejada, María Isabel (2020-07-14). "Effect of AGG Interruptions on FMR1 Maternal Transmissions". Frontiers in Molecular Biosciences 7. doi:10.3389/fmolb.2020.00135. ISSN 2296-889X. PMID 32766278. 
  59. ↑ "Entry - #300624 - FRAGILE X SYNDROME; FXS - OMIM - (OMIM.ORG)" (in en-us). https://www.omim.org/entry/300624?search=fragile%20x%20carriers&highlight=carrier,fragile,x. 
  60. ↑ Allen, Emily Graves; Charen, Krista; Hipp, Heather S.; Shubeck, Lisa; Amin, Ashima; He, Weiya; Nolin, Sarah L.; Glicksman, Anne et al. (2021-09-01). "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. ISSN 1098-3600. PMID 33927378. 
  61. ↑ Mineur, Yann S.; Sluyter, Frans; de Wit, Sanne; Oostra, Ben A.; Crusio, Wim E. (2002). "Behavioral and neuroanatomical characterization of the Fmr1 knockout mouse". Hippocampus 12 (1): 39–46. doi:10.1002/hipo.10005. ISSN 1050-9631. PMID 11918286. 
  62. ↑ "Fragile X syndrome: loss of local mRNA regulation alters synaptic development and function". Neuron 60 (2): 201–214. October 2008. doi:10.1016/j.neuron.2008.10.004. PMID 18957214. 
  63. ↑ "Circuit and plasticity defects in the developing somatosensory cortex of FMR1 knock-out mice". The Journal of Neuroscience 28 (20): 5178–5188. May 2008. doi:10.1523/JNEUROSCI.1076-08.2008. PMID 18480274. 
  64. ↑ "Structural-functional connectivity deficits of neocortical circuits in the Fmr1 (-/y) mouse model of autism". Science Advances 1 (10). November 2015. doi:10.1126/sciadv.1500775. PMID 26702437. Bibcode: 2015SciA....1E0775H. 
  65. ↑ "Altered integration of excitatory inputs onto the basal dendrites of layer 5 pyramidal neurons in a mouse model of Fragile X Syndrome". PNAS 120 (2). January 2023. doi:10.1073/pnas.2208963120. PMID 36595706. Bibcode: 2023PNAS..12008963M. 
  66. ↑ "Visualizing carrier status: fragile X syndrome and genetic diagnosis since the 1940s". Endeavour 36 (2): 77–84. June 2012. doi:10.1016/j.endeavour.2011.12.002. PMID 22257912. https://zenodo.org/record/894526. Retrieved 2018-04-20. 
  67. ↑ Sharif, Abid (2012). Practice Guidelines for Molecular Diagnosis of Fragile X Syndrome. https://www.acgs.uk.com/media/10768/frx_bpg_final_nov_2014.pdf. 
  68. ↑ "How do health care providers diagnose Fragile X syndrome?". US: NIH. 2021-08-25. https://www.nichd.nih.gov/health/topics/fragilex/conditioninfo/diagnosis. 
  69. ↑ 69.0 69.1 "Advances in the treatment of fragile X syndrome". Pediatrics 123 (1): 378–390. January 2009. doi:10.1542/peds.2008-0317. PMID 19117905. 
  70. ↑ 70.0 70.1 "Daily Living" (in en-US). http://fragilex.org/fxs/topics/daily-life/. 
  71. ↑ 71.0 71.1 Genovese, Ann C.; Butler, Merlin G. (2025-01-25). "Systematic Review: Fragile X Syndrome Across the Lifespan with a Focus on Genetics, Neurodevelopmental, Behavioral and Psychiatric Associations" (in en). Genes 16 (2): 149. doi:10.3390/genes16020149. ISSN 2073-4425. PMID 40004478. 
  72. ↑ 72.0 72.1 72.2 Genovese, Ann C.; Butler, Merlin G. (2025-01-25). "Systematic Review: Fragile X Syndrome Across the Lifespan with a Focus on Genetics, Neurodevelopmental, Behavioral and Psychiatric Associations" (in en). Genes 16 (2): 149. doi:10.3390/genes16020149. ISSN 2073-4425. PMID 40004478. 
  73. ↑ "Folic acid for fragile X syndrome". The Cochrane Database of Systematic Reviews (5). May 2011. doi:10.1002/14651858.CD008476.pub2. PMID 21563169. 
  74. ↑ "Metformin for Treatment of Fragile X Syndrome and Other Neurological Disorders". Annual Review of Medicine 70: 167–181. January 2019. doi:10.1146/annurev-med-081117-041238. PMID 30365357. https://escholarship.mcgill.ca/concern/articles/2j62s977h. 
  75. ↑ "Systematic review of pharmacological treatments in fragile X syndrome". BMC Neurology 9. October 2009. doi:10.1186/1471-2377-9-53. PMID 19822023. 
  76. ↑ "People with intellectual disability: what do we know about adulthood and life expectancy?". Developmental Disabilities Research Reviews 18 (1): 6–16. 2013-08-01. doi:10.1002/ddrr.1123. PMID 23949824. 
  77. ↑ "Fragile X Syndrome: Lessons Learned from the Most Translated Neurodevelopmental Disorder in Clinical Trials". Translational Neuroscience 8 (1): 7–8. January 2017. doi:10.1515/tnsci-2017-0002. PMID 28400977. 
  78. ↑ "Correction of fragile X syndrome in mice". Neuron 56 (6): 955–962. December 2007. doi:10.1016/j.neuron.2007.12.001. PMID 18093519. 
  79. ↑ "Mechanism-based approaches to treating fragile X". Pharmacology & Therapeutics 127 (1): 78–93. July 2010. doi:10.1016/j.pharmthera.2010.02.008. PMID 20303363. 
  80. ↑ "Mavoglurant". Drugs of the Future 37 (1): 7–12. 2012. doi:10.1358/dof.2012.037.01.1772147. 
  81. ↑ Martin JP; Bell J (July 1943). "A Pedigree of Mental Defect Showing Sex-Linkage". Journal of Neurology and Psychiatry 6 (3–4): 154–157. doi:10.1136/jnnp.6.3-4.154. PMID 21611430. 
  82. ↑ "A marker X chromosome". American Journal of Human Genetics 21 (3): 231–244. May 1969. PMID 5794013. 
  83. ↑ de la Cruz, FF (September 1985). "Fragile X syndrome". American Journal of Mental Deficiency 90 (2): 119–123. PMID 3901755. 
  84. ↑ "FRAXA Member Update (three issues: Spring 1999, Summer 1999, Fall 1999)". Newburyport, Massachusetts: FRAXA Research Foundation. https://www.fraxa.org/pdf/NEWS1999.pdf. 
  85. ↑ McKechanie, Andrew G; Lawrie, Stephen M; Stanfield, Andrew C (May 2020). "The never-changing face of fragile X?" (in en). The Lancet Psychiatry 7 (5): e26. doi:10.1016/S2215-0366(20)30127-9. https://linkinghub.elsevier.com/retrieve/pii/S2215036620301279. 
Classification
External resources

Template:Trinucleotide repeat disorders Template:Disorders of translation and posttranslational modification

Template:Nonverbal communication



Retrieved from "https://handwiki.org/wiki/index.php?title=Medicine:Fragile_X_syndrome&oldid=4429147"