Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics

In the paper

“Identified in 1991 by positional cloning (8), the FMR1 gene is characterized by the presence of a polymorphic CGG triplet sequence in the 5′ UTR (8, 9).”

What the sources say

• Not checked yetcites [8] source
• Not checked yetcites [9] source

In the paper

“Due to compensation by the unaffected X chromosome, only one-third of female carriers with a full mutation (FM) have ID; the majority have normal IQ, although learning difficulties and emotional problems are common (7).”

What the sources say

• Not checked yetcites [7] source

In the paper

“Normal alleles have a number of CGG repeats, ranging from 5 to 54, with a mode of 30.”

In the paper

“Expansion in this triplet sequence gives rise to FXS, which is the prototype of unstable triplet expansion disorders.”

In the paper

“This boundary is missing in FM alleles, and the cytosines upstream of the CGG repeat become methylated around the thirteenth week of embryonic development (16).”

What the sources say

• Not checked yetcites [16] source

In the paper

“Normal alleles are also methylated in the FMR1 promoter region but not in close proximity to the CGG repeat, which seems to be a “boundary” in the normal allele that prevents methylation from spreading.”

In the paper

“Estimates report that FXS affects approximately 1 in 2,500 to 5,000 men and 1 in 4,000 to 6,000 women (2, 3).”

What the sources say

• Not checked yetcites [2] source
• Not checked yetcites [3] source

In the paper

“FXS is caused by mutations in the FMR1 gene, which is located on the X chromosome and whose locus at Xq27.3 coincides with the folate-sensitive fragile site (4, 5).”

What the sources say

• Not checked yetcites [4] Fryns, 1984, Acta Paediatr Scand Suppl.
• Not checked yetcites [5] source

In the paper

“Premutation (PM) alleles have a number of CGG repeats, ranging from 55 to 200.”

In the paper

“FMRP has been detected in P bodies and stress granules as well, where it forms translationally silent preinitiation complexes (64) (Figure 2).”

What the sources say

• Not checked yetcites [64] source

In the paper

“These epigenetic changes promote a heterochromatic configuration that excludes the binding of specific transcription factors (19), thus turning gene expression off (20).”

What the sources say

• Not checked yetcites [19] source
• Not checked yetcites [20] source

In the paper

“High-throughput screenings supported by accompanying small scale studies have revealed that a wide array of neuronal mRNAs, with a large proportion encoding for presynaptic and postsynaptic proteins, is deregulated in the absence of FMRP, suggesting that concerted alteration of many proteins contributes to the FXS phenotype (62).”

What the sources say

• Not checked yetcites [62] De Rubeis, 2012, Adv Exp Med Biol. source

In the paper

“In addition to altered methylation status, FXS alleles show deacetylation of histones H3 and H4, reduced methylation of lysine 4 (K4), and increased methylation of lysine 9 (K9) on histone H3 (18).”

What the sources say

• Not checked yetcites [18] source

In the paper

“Of note, some alleles remain partially or even fully unmethylated (UFM), despite containing >200 CGG repeats, but the differences in methylation status are poorly understood.”

In the paper

“The behavior of boys with FXS typically includes attention deficit hyperactivity disorder (ADHD), with significant impulsivity and anxiety, as well as behaviors that include repetitive language, hand biting, hand stereotypies, rocking, and sometimes head banging (24,25).”

What the sources say

• Not checked yetcites [24] source
• Not checked yetcites [25] Sullivan, 2006, Am J Med Genet A. source

In the paper

“A child with FXS is often described as hyperaroused; an imbalance of the excitatory and inhibitory synaptic pathways described in the “From RNA metabolism to synaptic receptor dysfunction” section may contribute to such a clinical phenotype.”

In the paper

“FMRP is an RNA-binding protein, and, despite its clear shuttling from the nucleus to the cytoplasm (59,60), only the cytoplasmic function of FMRP has been well characterized.”

What the sources say

• Not checked yetcites [59] source
• Not checked yetcites [60] source

In the paper

“acetylation of histones H3 and H4 and methylation of lysine 9 on H3 of UFM alleles are more similar to those of FM alleles, while the level of methylation of lysines 4 and 27 on H3 are more similar to that of normal alleles (18,22).”

What the sources say

• Not checked yetcites [18] source
• Not checked yetcites [22] source

In the paper

“PM prevalence was found to be different in various ethnic groups; it was higher in people of mixed European descent compared with that in African American and Hispanic people (for both males and females) and shows a higher incidence for PM compared with that in previous studies (34,35).”

What the sources say

• Not checked yetcites [34] source
• Not checked yetcites [35] source

In the paper

“FMRP regulates stability, subcellular transport, and translation of neuronal mRNAs encoding for proteins involved the in synaptic structure and function (58,(65)(66)(67).”

What the sources say

• Not checked yetcites [58] source
• Not checked yetcites [65] source
• Not checked yetcites [66] source

In the paper

“The fragile X mutation is the most common single genetic cause of autism, occurring in 1% to 6% of boys with ASD (7).”

What the sources say

• Not checked yetcites [7] source

In the paper

“Among the recurrent problems that may occur in children before 2 years of age are hypotonia, delayed motor milestones, hand flapping, poor eye contact, frequent emesis and/or otitis media, and irritability.”

In the paper

“In addition, the majority of women with FM often do not have ID, and they are frequently diagnosed with FM following the diagnosis of FXS in their children.”

In the paper

“As a consequence, gene transcription is inhibited, leading to the absence of its protein product FMRP (17).”

What the sources say

• Not checked yetcites [17] source

In the paper

“The results of a pilot newborn screening (NBS) study for FXS in the United States, based on the screening of 11,217 newborns, indicated that the observed prevalence of a PM allele is 1:188 in females and 1:480 in males, while the prevalence of gray-zone alleles (45-54 CGG repeats) is 1:70 in females and 1:107 in males (33).”

What the sources say

• Not checked yetcites [33] Tassone F, et al. Newborn screening in fragile X syndrome: prevalence and allele distribution of the FMR1 gene. Paper presented at: American College of Medical Genetics Annual Clinical Genetics Meeting; July 26, 2012; Charlotte, North Carolina, USA. http://www.fragilex.org/community/international-fragile-x-conference/miami2012/agenda/ . Accessed October 19, 2012.

In the paper

“FXTAS (Figure 1) has been reported to affect approximately 46% of male and 17% of female adult carriers (28).”

What the sources say

• Not checked yetcites [28] source

In the paper

“Approximately 30% of boys with FXS meet the diagnostic criteria for autism, and these children have the lowest developmental and adaptive behavior scores of those with FXS.”

In the paper

“A late diagnosis may occur for older patients who may have undergone genetic testing prior to the 1991 discovery of the FMR1 gene (8) or for patients that carry a mild form of the disease, showing atypical symptoms as often occurs for the UFM alleles.”

What the sources say

• Not checked yetcites [8] source

In the paper

“effects on other methylated genes cannot be excluded.”

In the paper

“Recently, the striatal enriched protein tyrosine phosphatase (STEP) has been shown to be upregulated in FXS, and genetic reduction of STEP diminished seizures and restored selected social and nonsocial anxiety-related behaviors in the Fmr1 KO mice (94).”

What the sources say

• Not checked yetcites [94] Goebel-Goody, 2012, Genes Brain Behav. source

In the paper

“While the action of 5-azadC appears to be specific in the context of the FMR1 gene, as shown by its lack of effect on the methylated sequence upstream of the FMR1 boundary (G.Neri, unpublished observations), effects on other methylated genes cannot be excluded.”

What the sources say

• Not checked yetcites G.Neri, unpublished observations

In the paper

“The molecular signaling pathways orchestrating protein synthesis, spine shape, and synaptic plasticity, such as mTOR and ERK (Figure 2), are also impaired in FXS (72,(87)(88)(89), possibly because some FMRP target mRNAs encode members of second messenger cascades converging on ERK (88,89).”

What the sources say

• Not checked yetcites [72] source
• Not checked yetcites [87] Hoeffer, 2012, Genes Brain Behav. source
• Not checked yetcites [88] source

In the paper

“Moreover, it is presumed to be effective only on dividing cells, which excludes postmitotic neurons.”

In the paper

“A significant amelioration of the hyperactivity and adaptive behavior of drug-treated boys (compared with those treated with placebo) was observed; however, the methylation state of FMR1 did not change, and the expression of the gene did not increase (100).”

What the sources say

• Not checked yetcites [100] Torrioli, 2008, Am J Med Genet A. source

In the paper

“This receptor unbalance results in enhanced mGluR-long-term depression (mGluR-LTD), the most commonly studied forms of hippocampal synaptic plasticity.”

In the paper

“Expression of a dominant-negative mutant of PAK in the forebrain of Fmr1 KO mice led to an improvement of several behavioral abnormalities, such as impaired locomotor activity, stereotypical anxiety, and trace fear conditioning, suggesting that the PAK signaling pathway could also represent a bona fide site for therapeutic intervention (93).”

What the sources say

• Not checked yetcites [93] source

In the paper

“Reactivation was accompanied not only by DNA demethylation but also by changes in the epigenetic code of histones H3 and H4 (97).”

What the sources say

• Not checked yetcites [97] source

In the paper

“Upon receptor activation, the FMRPmediated translational block is released, possibly due to changes (86) in its phosphorylation status, and protein synthesis can ensue.”

What the sources say

• Not checked yetcites [86] source

In the paper

“Because STEP acts on at least three molecules (ERK1/2, NMDA, and AMPA) affected in FXS, strategies to inhibit STEP activity may be considered for treating patients with FXS.”

What the sources say

• Not checked yetcites [94] Goebel-Goody, 2012, Genes Brain Behav. source

In the paper

“Because both mouse models have upregulated mTOR pathway activity, the authors propose that normal synaptic plasticity and cognition occur within an optimal range of mGluRmediated protein synthesis, such that deviations in either direction can lead to shared behavioral impairments.”

What the sources say

• Not checked yetcites [92] source

In the paper

“Elevation of the glutamate receptors mGluR1 and mGluR5 and the reduced insertion of AMPA receptors into the postsynaptic membrane are two of the central mechanics of impaired synaptic plasticity in FXS: such a dysregulated signaling is the basis of mGluR theory (75).”

What the sources say

• Not checked yetcites [75] source

In the paper

“The strategy of restoring FMR1 gene activity, which is based on the presence of the intact FMR1 coding sequence, targets potentially reversible epigenetic changes, primarily DNA methylation.”

In the paper

“FMRP activity is regulated in response to metabotropic glutamate receptors (mGluRs) (78), 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl) propanoic acid (AMPA) receptors (79), γ-aminobutyric acid (GABA) receptors (76,80,81), N-methyl-d-aspartate (NMDA) receptors (82)(83)(84), and the tyrosine kinase or BDNF/NT-3 growth factor (TrkB) receptors (85).”

What the sources say

• Not checked yetcites [78] source
• Not checked yetcites [79] source
• Not checked yetcites [76] source
• Not checked yetcites [80] source
• Not checked yetcites [81] source

In the paper

“Two possible approaches are presently being considered for a substantial treatment of FXS: (a) reactivation of the affected gene and (b) compensating for the lack of FMRP.”

In the paper

“Because the mouse model recapitulates morphological changes and behavioral deficits seen in human patients, these molecular insights have led clinicians to design targeted treatments (see below).”

In the paper

“In the absence of FMRP, there is an increase in the synthesis of several proteins involved in cytoskeleton remodeling and receptor internalization (i.e., Arc) (Figure 2) as well as reduction of other proteins due to a reduced stability of their mRNAs (i.e., GABA-R subunits).”

In the paper

“The resulting 50% reduction in mGluR5 protein levels in the offspring led to the correction of typical FXS phenotypic features, including spine dysmorphogenesis and audiogenic seizures, and restored mGluR-LTD (90).”

What the sources say

• Not checked yetcites [90] source

In the paper

“The GABA receptor system has also been reported as downregulated in FXS, partially due to destabilization of the mRNAs encoding the GABA receptor subunits (76,80,113).”

What the sources say

• Not checked yetcites [76] source
• Not checked yetcites [80] source
• Not checked yetcites [113] source

In the paper

“No significant improvement in the primary outcome measure or in secondary measures of language, attention/executive function, or behavior was observed when compared with placebo, possibly due to the potency or dosage of CX516 used (105).”

What the sources say

• Not checked yetcites [105] source

In the paper

“Treatment of young mice with minocycline, a broad-spectrum antibiotic, had a dual effect: increased phosphorylation of GluR1 and subsequent membrane insertion of AMPA receptors (124)”

What the sources say

• Not checked yetcites [124] source

In the paper

“Acamprosate, a molecule used to maintain abstinence from alcohol, is able to block NMDA-R as well as activate GABA A -R and was recently tested in three young adult patients with FXS, who showed global benefit (as rated by the CGI-I scale) and marked communication improvement (115).”

What the sources say

• Not checked yetcites [115] source

In the paper

“Treatment of Fmr1 KO mice with the mGluR antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) (Figure 3B) resulted in suppression of the audiogenic seizure phenotype (106) and rescue of dendritic spine morphology in the Fmr1 KO mouse (107).”

What the sources say

• Not checked yetcites [106] source
• Not checked yetcites [107] source

In the paper

“and mice demonstrated improvements in anxiety and in a cognitive task (125).”

What the sources say

• Not checked yetcites [125] source

In the paper

“The third tested compound is valproic acid (101), which is already known as a reactivator of silenced genes (102) that appeared to be a weak reactivator of FM (103).”

What the sources say

• Not checked yetcites [101] source
• Not checked yetcites [102] source
• Not checked yetcites [103] source

In the paper

“Long term use of a similar mGluR5 antagonist, CTEC, in adult animals corrected elevated hippocampal LTD, protein synthesis, spine dysmorphogenesis, overactive ERK and mTOR signaling, and partially corrected macroorchidism (108).”

What the sources say

• Not checked yetcites [108] source

In the paper

“Fenobam, used in the past for anxiety treatment (109), was recently tested in adults with FXS (37).Beneficial effects such as reduced anxiety and hyperarousal, improved prepulse inhibition of startle, and better accuracy on a continuous performance task were also reported.”

What the sources say

• Not checked yetcites [37] source

In the paper

“Intriguingly, in this small trial, improvements in inappropriate speech, stereotypic behavior, and hyperactivity and efficacy have been reported in adults with FXS who have a fully methylated FM allele but not in those with mosaicism (36).”

What the sources say

• Not checked yetcites [36] Jacquemont, 2011, Sci Transl Med. source

In the paper

“FMRP is also required for neural stem and progenitor cell proliferation, differentiation, and survival, suggesting additional mechanisms that could explain certain features of the disease (136).”

What the sources say

• Not checked yetcites [136] source