Fragile X syndrome

Source: Wikipedia, the free encyclopedia.
Fragile X syndrome
Other namesMartin–Bell syndrome,
Supportive care, early interventions[2]
Frequency1 in 4,000 (males), 1 in 8,000 (females)[1]

Fragile X syndrome (FXS) is a

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.[1] 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.[5] 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.[5]

There is no cure.

ADHD.[8] 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][9]

Signs and symptoms

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.

autism.[13]

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.[14] 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.[15][16]

Physical phenotype

Intellectual development

Individuals with FXS may present anywhere on a continuum from

executive function, visual memory, visual-spatial relationships, and mathematics, with verbal abilities being relatively unaffected.[12][20]

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.[20]

Individuals with FXS often demonstrated language and communicative problems.[21] This may be related to muscle function of the mouth and frontal-lobe deficits.[21]

Autism

Fragile X syndrome co-occurs with autism in many cases and is a suspected genetic cause of the autism in these cases.

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.[22]

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.[22] When both autism and FXS are present, a greater language deficit and lower IQ is observed as compared to children with only FXS.[23]

Genetic

mouse models of FXS have also been shown to have autistic-like behaviors.[24][25][26][27][28]

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.[29] 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.[22] Social anxiety in individuals with FXS is related to challenges with face encoding, the ability to recognize a face that one has seen before.[30]

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.[22][29] 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.[22]

Females with FXS frequently display shyness, social anxiety and social avoidance or withdrawal.[12] In addition, premutation in females has been found to be associated with social anxiety.

Female individuals with FXS show decreased activation in the prefrontal regions of the brain.[31][citation needed]

Mental health

hyperarousal. Hyperactivity and disruptive behavior peak in the preschool years and then gradually decline with age, although inattentive symptoms are generally lifelong.[29]

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.[29] 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.[19] Behaviors such as hand flapping and biting, as well as aggression, can be an expression of anxiety.[citation needed]

self-talk are commonly seen. Self-talk includes talking with oneself using different tones and pitches.[19] 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
]

Mood symptoms in individuals with FXS rarely meet diagnostic criteria for a major mood disorder as they are typically not of sustained duration.[29] Instead, these are usually transient and related to stressors, and may involve labile (fluctuating) mood, irritability, self-injury and aggression.[citation needed]

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.[32]

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.[23]

Neurology

Individuals with FXS are at a higher risk of developing

partial, are generally not frequent, and are amenable to treatment with medication.[citation needed
]

Individuals who are carriers of premutation alleles are at risk for developing

fragile X-associated tremor/ataxia syndrome (FXTAS), a progressive neurodegenerative disease.[14][34] 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.[34]

Working memory

From their 40s onward, males with FXS begin developing progressively more severe problems in performing tasks that require the central executive of

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.[35]

Fertility

About 20% of women who are carriers for the fragile X premutation are affected by

premature menopause 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 the risk of FXPOI.[37][38] Fragile X-associated primary ovarian insufficiency (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.[39][40]

FMRP is a chromatin-binding protein that functions in the DNA damage response.[41][42] FMRP also occupies sites on meiotic chromosomes and regulates the dynamics of the DNA damage response machinery during spermatogenesis.[41]

Causes

Location of the FMR1 gene on the X chromosome

Fragile X syndrome is a

trinucleotide repeats in the 5' untranslated region of FMR1.[14][34] 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.[43] Although this accounts for over 98% of cases, FXS can also occur as a result of point mutations affecting FMR1.[14][34]

In unaffected individuals, the FMR1 gene contains 5–44 repeats of the sequence CGG, most commonly 29 or 30 repeats.[14][34][44] 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.[11][44][45] 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.[46]

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.

SMRT sequencing.[48]

Inheritance

Fragile X syndrome has traditionally been considered an X-linked dominant condition with variable expressivity and possibly reduced penetrance.[12] The likelihood of transmission depends on the parent's gender, the X chromosome carrying the mutation, and the number of CGG repeats in the premutation.

Due to

Groningen University Hospital have had an abstract published in the American Journal of Medical Genetics that proposes discontinuing labeling X-linked disorders as dominant or recessive.[49]
Males with a full mutation are usually affected and infertile, while carrier females have a 50% chance of passing 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.[14] This tendency for future generations to be affected at a higher frequency became known as the Sherman paradox after its description in 1985.[14][50] Due to this, male children often have a greater degree of symptoms than their mothers.[51]

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

strand slippage either during DNA replication or DNA repair synthesis.[52]

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.[53]

Pathophysiology

FMRP is found throughout the body, but in highest concentrations within the brain and testes.

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.[11][14][54] Connectome changes have long been suspected to be involved in the sensory pathophysiology[55] and most recently a range of circuit alterations have been shown, involving structurally increased local connectivity and functionally decreased long-range connectivity.[56]

In addition, FMRP has been implicated in several signalling pathways that are being targeted by a number of drugs undergoing clinical trials. The

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
]

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.[57]

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.

fragile sites" (discontinuity of staining in the region of the trinucleotide repeat) on the long arm of the X chromosome.[58] 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.[citation needed
]

Since the 1990s, more

missense mutations or 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
]

Prenatal testing with chorionic villus sampling or amniocentesis allows diagnosis of FMR1 mutation while the fetus is in utero and appears to be reliable.[12]

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.[59]

Management

There is no cure for the underlying defects of FXS.

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.[60]

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.[12] 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.[12] 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.[61] 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.[60] While metformin may reduce body weight in persons with fragile X syndrome, it is uncertain whether it improves neurological or psychiatric symptoms.[62]

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.[63]

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.[64]

Pharmacological therapy

Fragile X syndrome is the most "translated" human neurodevelopmental disorder under study. Hence, research into the etiology of FXS has given rise to many attempts at drug discovery.

arbaclofen, a GABAB agonist, in improving social withdrawal in individuals with FXS and ASD.[11][22] 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.[11]

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).[69] In 1969, Herbert Lubs first sighted an unusual "marker X chromosome" in association with intellectual disability.[70] 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.[71] Continued advocacy later won him an honour through the FRAXA Research Foundation in December 1998.[72]

See also

References

  1. ^ a b c d e f g h i j k l m n o p "fragile X syndrome". Genetics Home Reference. April 2012. Archived from the original on 9 October 2016. Retrieved 7 October 2016.
  2. ^ a b c d e f "What is Fragile X Syndrome?". National Center on Birth Defects and Developmental Disabilities. US: Centers for Disease Control and Prevention. 3 June 2022. Archived from the original on 10 May 2017. Retrieved 10 May 2017.
  3. PMID 28814537
    .
  4. ^ a b "Data and Statistics Fragile X Syndrome (FXS)". Centers for Disease Control and Prevention. 2018-08-09. Archived from the original on 2019-10-13. Retrieved 2018-11-05.
  5. ^ a b "Technical Standards and Guidelines for Fragile X". www.acmg.net. 2006. Archived from the original on 12 October 2016. Retrieved 10 May 2017.
  6. ^ "What are the treatments for Fragile X syndrome?". www.nichd.nih.gov. Archived from the original on 2016-11-21. Retrieved 2016-11-21.
  7. ^ "Therapy Treatments". NICHD. Archived from the original on 5 May 2017. Retrieved 10 May 2017.
  8. ^ "Medication Treatments". NICHD. Archived from the original on 5 May 2017. Retrieved 10 May 2017.
  9. ^ "What is Fragile-X syndrome?". @yourgenome · Science website. Retrieved 2023-07-15.
  10. ^ a b "What are the symptoms of Fragile X syndrome?". www.nichd.nih.gov. Archived from the original on 2016-11-21. Retrieved 2016-11-21.
  11. ^
    PMID 22043169
    .
  12. ^
    PMID 18398441
    .
  13. ^ "Fragile X and Autism | Fragile X Society | UK". fragilex. Retrieved 2022-09-07.
  14. ^
    PMID 22017584
    .
  15. PMID 30642066
    .
  16. ^ CDC (2022-06-03). "What is Fragile X Syndrome (FXS)? | CDC". Centers for Disease Control and Prevention. Retrieved 2022-11-04.
  17. ISBN 978-1-4160-4570-0. Section on fragile X syndrome[page needed
    ]
  18. ^ Nichols C, Nichols D (1 June 2019). "Fragile X Syndrome: Implications for Physical Education". Palaestra. 33 (3).
  19. ^
    ISBN 978-1-57230-448-2.[page needed
    ]
  20. ^
    PMID 18347972
    .
  21. ^
    ISSN 1098-2779
    .
  22. ^
    PMID 21893949
    .
  23. ^ a b Hagerman, Randi J., and Paul J. Hagerman. Fragile X syndrome: diagnosis, treatment, and research. 3, illustrated ed. Baltimore, MD: JHU P, 2002.[page needed]
  24. PMID 21364941
    .
  25. PMID 16998604
    .
  26. S2CID 45731129
    .
  27. PMID 21268289
    .
  28. PMID 18513141
    .
  29. ^
    S2CID 207554509
    .
  30. PMID 18778781
    .
  31. PMID 20014368
    .
  32. PMID 17591512
    .
  33. ^
    PMID 20945999
    .
  34. ^
    PMID 22188182
    .
  35. PMID 19114290
    .
  36. PMID 15608041
    .
  37. PMID 33927378
    .
  38. PMID 19481741
    .
  39. PMID 25147583
    .
  40. PMID 27552334
    .
  41. ^
    PMID 24813610
    .
  42. S2CID 44159474
    .
  43. ^ "Monogenic diseases". Human Genomics in Global Health. World Health Organization. Archived from the original on 2012-10-20. Retrieved 2020-10-04.
  44. ^
    PMID 11388762
    .
  45. PMID 12529854
    .
  46. PMID 24578575
    .
  47. PMID 29178241
    .
  48. PMID 23064752
    .
  49. S2CID 42108591
    .
  50. S2CID 23299935
    .
  51. PMID 18985105
    .
  52. PMID 25608779
    .
  53. S2CID 35472224
    .
  54. PMID 18957214
    .
  55. PMID 18480274
    .
  56. PMID 26702437
    .
  57. PMID 36595706
    .
  58. ^
    PMID 22257912. Archived
    from the original on 2019-11-05. Retrieved 2018-04-20.
  59. ^ "How do health care providers diagnose Fragile X syndrome?". National Institute of Child Health and Human Development. US: NIH. 2021-08-25. Archived from the original on 2016-11-21. Retrieved 2016-11-21.
  60. ^
    PMID 19117905
    .
  61. PMID 21563169
    .
  62. S2CID 53093694
    .
  63. PMID 19822023
    .
  64. PMID 23949824
    .
  65. PMID 28400977
    .
  66. PMID 18093519
    .
  67. PMID 20303363
    .
  68. S2CID 258330291
    .
  69. PMID 21611430
    .
  70. PMID 5794013
    .
  71. PMID 3901755
    .
  72. ^ "FRAXA Member Update (three issues: Spring 1999, Summer 1999, Fall 1999)" (PDF) (newsletter). Newburyport, Massachusetts: FRAXA Research Foundation. Archived (PDF) from the original on 2010-12-15. Retrieved 2017-12-14.

External links

Wikimedia Commons has media related to Fragile X syndrome.
Retrieved from "https://en.wikipedia.org/w/index.php?title=Fragile_X_syndrome&oldid=1194432631"