Fragile X syndrome
Fragile X syndrome (FXS) is a genetic disorder characterized by mild-to-moderate intellectual disability.[1] The average IQ in males with FXS is under 55, while about two thirds of affected females are intellectually disabled.[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]
Fragile X syndrome
Martin–Bell syndrome,[1]
Escalante syndrome
Intellectual disability, long and narrow face, large ears, flexible fingers, large testicles[1]
Noticeable by age 2[1]
Lifelong[2]
Supportive care, early interventions[2]
1 in 4,000 (males), 1 in 8,000 (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.[2] Early intervention is recommended, as it provides the most opportunity for developing a full range of skills.[6] These interventions may include special education, speech therapy, physical therapy, or behavioral therapy.[2][7] Medications may be used to treat associated seizures, mood problems, aggressive behavior, or 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]
Pathophysiology[edit]
FMRP is found throughout the body, but in highest concentrations within the brain and testes.[11][14] 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.[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 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.[11][14] 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.[11][14][29] 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.
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[edit]
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.[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.
Since the 1990s, more sensitive molecular techniques have been used to determine carrier status.[58] 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.[12] 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 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.
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]
Pharmacological therapy[edit]
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.[65] 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.[11][66][67] 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.[11][68] There is also early evidence for the efficacy of 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[edit]
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]