Fragile X syndrome

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. 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. 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. • Hypotonia (low muscle tone) 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. 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. Individuals with FXS often demonstrated language and communicative problems. This may be related to muscle function of the mouth and frontal-lobe deficits. Genetic mouse models of FXS have also been shown to have autistic-like behaviors. 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. 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. 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. 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. 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. In larger study populations the frequency varies between 13% and 18%, 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). The number of CGG repeats correlates with penetrance and age of onset, but it is not a linear relationship. 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. FXPOI is the most common cause of hereditary primary ovarian insufficiency. FMRP also occupies sites on meiotic chromosomes and regulates the dynamics of the DNA damage response machinery during spermatogenesis. == Causes ==

'' 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. Although this accounts for over 98% of cases, FXS can also occur as a result of point mutations affecting FMR1. 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. 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. 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. The first complete DNA sequence of the repeat expansion in someone with the full mutation was generated by scientists in 2012 using SMRT sequencing. Inheritance Fragile X syndrome has traditionally been considered an X-linked recessive condition with variable expressivity and possibly reduced penetrance. 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. Due to this, male children often have a greater degree of symptoms than their mothers. 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. 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). While more common in males than females, recent studies reveal how females are affected. 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. Most individuals have less than 44 CGG repeats. 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. Female carriers often show little to no physical phenotype, but have an increased risks for premature ovarian failure (FXPOI) and lowered bone density. 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. == Pathophysiology ==

FMRP is found throughout the body, but in highest concentrations within the brain and testes. Connectome changes have long been suspected to be involved in the sensory pathophysiology and most recently a range of circuit alterations have been shown, involving structurally increased local connectivity and functionally decreased long-range connectivity. In addition, FMRP has been implicated in several signalling pathways that are being targeted by a number of drugs undergoing clinical trials. The group 1 metabotropic glutamate receptor (mGluR) pathway, which includes mGluR1 and mGluR5, is involved in mGluR-dependent long term depression (LTD) and long term potentiation (LTP), both of which are important mechanisms in learning. ==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. 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. Since the 1990s, more sensitive molecular techniques have been used to determine carrier status. == Management ==

There is no cure for the underlying defects of FXS. Everyday Living 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. 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. However, some adults are able to achieve independence through support and accommodations. 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'''. 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. 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. ADHD, which affects the majority of boys and 30% of girls with FXS, is frequently treated using stimulants. 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. Anxiety, as well as mood and obsessive-compulsive symptoms, may be treated using SSRIs, although these can also aggravate hyperactivity and cause disinhibited behavior. 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. == 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. 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. 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. There is also early evidence for the efficacy of arbaclofen, a GABAB agonist, in improving social withdrawal in individuals with FXS and ASD. 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. 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. ==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). In 1969, Herbert Lubs first sighted an unusual "marker X chromosome" in association with intellectual disability. 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. Continued advocacy later won him an honour through the FRAXA Research Foundation in December 1998. ==See also==