Fragile X Syndrome

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Introduction

X-Linked recessive (affected father)

ICD-10: Q99.2 Fragile X chromosome Fragile X syndrome  ICD-11 LD55 Fragile X chromosome


Fragile X Syndrome (Mental Retardation, X-linked, associated with marXq28, X-linked mental retardation and macroorchidism, Marker X syndrome, Martin-Bell syndrome).

Fragile X Syndrome (FXS) is the most common form of inherited mental retardation and autism. The condition is caused by a loss of the functional fragile X mental retardation protein (FMRP) an RNA-binding protein that can regulate the translation of specific mRNAs. There are several suggested additional roles for this protein including synaptic development and function[1] and in adult neurogenesis.[2]

The normal FMR1 functional gene can contain a trinucleotide sequence (CGG) repeated between 6 to 44 times. Expansion of this sequence (55 to 200 repeats) in an unmethylated form that generates an unstable sequence. This leads to repression of FMR1 transcription and subsequent decreased protein levels in the brain.



Links: Neural Abnormalities | Neural System Development | 2011 Student Project - Fragile X Syndrome | Fragile X Association of Australia


Genetic Links: genetic abnormalities | maternal age | Trisomy 21 | Trisomy 18 | Trisomy 13 | Trisomy X | trisomy mosaicism | Monosomy | Fragile X | Williams | Alagille | Philadelphia chromosome | mitochondria | VACTERL | hydatidiform mole | epigenetics | Prenatal Diagnosis | Neonatal Diagnosis | meiosis | mitosis | International Classification of Diseases | genetics


Diagnosis Links: Prenatal Diagnosis | pregnancy test | amniocentesis | chorionic villus sampling | ultrasound | Alpha-Fetoprotein | Pregnancy-associated plasma protein-A | Fetal Blood Sampling | Magnetic Resonance Imaging | Computed Tomography | Non-Invasive Prenatal Testing | Fetal Cells in Maternal Blood | Preimplantation Genetic Screening | Comparative Genomic Hybridization | Genome Sequencing | Neonatal Diagnosis | Category:Prenatal Diagnosis | Fetal Surgery | Classification of Diseases | Category:Neonatal Diagnosis

Some Recent Findings

FMR1 gene silencing
FMR1 developmental gene silencing[3]
Fragile X syndrome EEG analysis method[4]
  • Review - Reevaluation of FMR1 Hypermethylation Timing in Fragile X Syndrome[3] "Fragile X syndrome (FXS) is one of the most common heritable forms of cognitive impairment. It results from a fragile X mental retardation protein (FMRP) protein deficiency caused by a CGG repeat expansion in the 5'-UTR of the X-linked FMR1 gene. Whereas in most individuals the number of CGGs is steady and ranges between 5 and 44 units, in patients it becomes extensively unstable and expands to a length exceeding 200 repeats (full mutation). Interestingly, this disease is exclusively transmitted by mothers who carry a premutation allele (55-200 CGG repeats). When the CGGs reach the FM range, they trigger the spread of abnormal DNA methylation, which coincides with a switch from active to repressive histone modifications. This results in epigenetic gene silencing of FMR1 presumably by a multi-stage, developmentally regulated process. The timing of FMR1 hypermethylation and transcription silencing is still hotly debated. There is evidence that hypermethylation varies considerably between and within the tissues of patients as well as during fetal development, thus supporting the view that FMR1 silencing is a post-zygotic event that is developmentally structured. On the other hand, it may be established in the female germ line and transmitted to the fetus as an integral part of the mutation. This short review summarizes the data collected to date concerning the timing of FMR1 epigenetic gene silencing and reassess the evidence in favor of the theory that gene inactivation takes place by a developmentally regulated process around the 10th week of gestation."
  • Review - How common are challenging behaviours amongst individuals with Fragile X Syndrome?[5] "Fragile X Syndrome (FXS) appears to be associated with an increased risk for engaging in challenging behaviour, particularly self-injury, relative to those with mixed aetiology learning disabilities. ... It is hoped that this comprehensive overview of data on this clinically significant topic will help to inform and drive future investigation to understand and provide effective intervention for the benefit of those with FXS."
  • Resting-state EEG oscillatory dynamics in fragile x syndrome: abnormal functional connectivity and brain network organization[4] "Disruptions in functional connectivity and dysfunctional brain networks are considered to be a neurological hallmark of neurodevelopmental disorders. ...Here we used resting-state EEG to characterize functional brain connectivity and brain network organization in eight males with fragile X syndrome (FXS) and 12 healthy male controls. ...A decrease in global functional connectivity was observed in FXS males for upper alpha and beta frequency bands. For theta oscillations, we found increased connectivity in long-range (fronto-posterior) and short-range (frontal-frontal and posterior-posterior) clusters. Graph theoretical analysis yielded evidence of increased path length in the theta band, suggesting that information transfer between brain regions is particularly impaired for theta oscillations in FXS. These findings are discussed in terms of aberrant maturation of neuronal oscillatory dynamics, resulting in an imbalance in excitatory and inhibitory neuronal circuit activity."
More recent papers  
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Search term: Fragile X Syndrome

<pubmed limit=5>Fragile X Syndrome</pubmed>

Older papers  
  • Consistency between research and clinical diagnoses of autism among boys and girls with fragile X syndrome[6] "Prior research suggests that 60-74% of males and 16-45% of females with fragile X syndrome (FXS) meet criteria for autism spectrum disorder (ASD) in research settings. However, relatively little is known about the rates of clinical diagnoses in FXS and whether such diagnoses are consistent with those performed in a research setting using gold standard diagnostic tools. ...ASD in FXS may be under-diagnosed in clinical/educational settings, which raises questions regarding access to ASD-related services."
  • Nuclear Fragile X Mental Retardation Protein is localized to Cajal bodies[7] "Using a new generation of anti-FMRP antibodies and recombinant expression, we show here that the most commonly expressed human FMRP isoforms (ISO1 and 7) do not localize to the nucleus. Instead, specific FMRP isoforms 6 and 12 (ISO6 and 12), containing a novel C-terminal domain, were the only isoforms that localized to the nuclei in cultured human cells. These isoforms localized to specific p80-coilin and SMN positive structures that were identified as Cajal bodies. The Cajal body localization signal was confined to a 17 amino acid stretch in the C-terminus of human ISO6 and is lacking in a mouse Iso6 variant. As FMRP is an RNA-binding protein, its presence in Cajal bodies suggests additional functions in nuclear post-transcriptional RNA metabolism. Supporting this hypothesis, a missense mutation (I304N), known to alter the KH2-mediated RNA binding properties of FMRP, abolishes the localization of human FMRP ISO6 to Cajal bodies. These findings open unexplored avenues in search for new insights into the pathophysiology of Fragile X Syndrome."
  • Genetic Counseling and Testing for FMR1 Gene Mutations: Practice Guidelines of the National Society of Genetic Counselors[8] "Fragile X syndrome (FXS) is one of several clinical disorders associated with mutations in the X-linked Fragile X Mental Retardation-1 (FMR1) gene. With evolving knowledge about the phenotypic consequences of FMR1 transcription and translation, sharp clinical distinctions between pre- and full mutations have become more fluid. The complexity of the issues surrounding genetic testing and management of FMR1-associated disorders has increased; and several aspects of genetic counseling for FMR1 mutations remain challenging, including risk assessment for intermediate alleles and the widely variable clinical prognosis for females with full mutations. FMR1 mutation testing is increasingly being offered to women without known risk factors, and newborn screening for FXS is underway in research-based pilot studies. Each diagnosis of an FMR1 mutation has far-reaching clinical and reproductive implications for the extended family."
  • Synaptic NMDA receptor-mediated currents in anterior piriform cortex are reduced in the adult fragile X mouse[9] "Fragile X syndrome is a neurodevelopmental condition caused by the transcriptional silencing of the fragile X mental retardation 1 (FMR1) gene. The Fmr1-KO mouse exhibits age-dependent deficits in long term potentiation (LTP) at association (ASSN) synapses in anterior piriform cortex (APC)."

International Classification of Diseases

The International Classification of Diseases (ICD) World Health Organization's classification used worldwide as the standard diagnostic tool for epidemiology, health management and clinical purposes. This includes the analysis of the general health situation of population groups. It is used to monitor the incidence and prevalence of diseases and other health problems. Within this classification "congenital malformations, deformations and chromosomal abnormalities" are (Q00-Q99) but excludes "inborn errors of metabolism" (E70-E90).

Q99 Other chromosome abnormalities, not elsewhere classified

  • Q99.2 Fragile X chromosome Fragile X syndrome

ICD-10

Fragile X-associated Tremor

(Ataxia Syndrome) A mainly male adult-onset condition that causes tremor and affects balance and memory in some "carriers" of the Fragile X gene. Because of the adult onset, this can be mistaken for a range of other neurological disorders including Parkinson's and Alzheimer's disease.

Screening

Screening By Country

  • USA - Practice Guidelines of the National Society of Genetic Counselors - original version (2000), updated (2005)[10], latest version (2012).[8]

FMRP and Cajal bodies

Image Fragile X protein ISO6 and Cajal bodies
Fragile X protein ISO6 and Cajal bodies

A recent study has identified specific isoforms of the Fragile X protein (ISO6 and ISO12) are localised to the nuclear Cajal bodies.[7] The authors have postulated a model (shown below) for these specific function in neurons.

Fragile X protein model of function in neurons
FMRP Localization in Neurons Model[7]

Alternative splicing of the primary FMRP transcripts generates either ISO6 FMRP lacking the CRD domain, or ISO1 FMRP containing both NLS and CRD domains.

  • ISO6 is driven to Cajal bodies by transporter proteins.
  • ISO1 interacts with protein partners that lock the NLS and CRD domains and is localized to the perinuclear area to join the nascent mRNPs complexes emerging from the nuclear pores.
  • ISO1 FMRP-mRNPs particles In the cytoplasm associate with the translation machinery or are transported in RNA-granules to micro-domains away from the soma.

Mouse Model

A Mouse Model of the Human Fragile X Syndrome I304N Mutation[11]

"The mental retardation, autistic features, and behavioral abnormalities characteristic of the Fragile X mental retardation syndrome result from the loss of function of the RNA-binding protein FMRP. The disease is usually caused by a triplet repeat expansion in the 5'UTR of the FMR1 gene. This leads to loss of function through transcriptional gene silencing, pointing to a key function for FMRP, but precluding genetic identification of critical activities within the protein. Moreover, antisense transcripts (FMR4, ASFMR1) in the same locus have been reported to be silenced by the repeat expansion. Missense mutations offer one means of confirming a central role for FMRP in the disease, but to date, only a single such patient has been described. This patient harbors an isoleucine to asparagine mutation (I304N) in the second FMRP KH-type RNA-binding domain, however, this single case report was complicated because the patient harbored a superimposed familial liver disease. To address these issues, we have generated a new Fragile X Syndrome mouse model in which the endogenous Fmr1 gene harbors the I304N mutation. These mice phenocopy the symptoms of Fragile X Syndrome in the existing Fmr1-null mouse, as assessed by testicular size, behavioral phenotyping, and electrophysiological assays of synaptic plasticity. I304N FMRP retains some functions, but has specifically lost RNA binding and polyribosome association; moreover, levels of the mutant protein are markedly reduced in the brain specifically at a time when synapses are forming postnatally. These data suggest that loss of FMRP function, particularly in KH2-mediated RNA binding and in synaptic plasticity, play critical roles in pathogenesis of the Fragile X Syndrome and establish a new model for studying the disorder."

References

  1. Bassell GJ & Warren ST. (2008). Fragile X syndrome: loss of local mRNA regulation alters synaptic development and function. Neuron , 60, 201-14. PMID: 18957214 DOI.
  2. Luo Y, Shan G, Guo W, Smrt RD, Johnson EB, Li X, Pfeiffer RL, Szulwach KE, Duan R, Barkho BZ, Li W, Liu C, Jin P & Zhao X. (2010). Fragile x mental retardation protein regulates proliferation and differentiation of adult neural stem/progenitor cells. PLoS Genet. , 6, e1000898. PMID: 20386739 DOI.
  3. 3.0 3.1 Mor-Shaked H & Eiges R. (2018). Reevaluation ofFMR1Hypermethylation Timing in Fragile X Syndrome. Front Mol Neurosci , 11, 31. PMID: 29467618 DOI.
  4. 4.0 4.1 van der Molen MJ, Stam CJ & van der Molen MW. (2014). Resting-state EEG oscillatory dynamics in fragile X syndrome: abnormal functional connectivity and brain network organization. PLoS ONE , 9, e88451. PMID: 24523898 DOI.
  5. Hardiman RL & McGill P. (2018). How common are challenging behaviours amongst individuals with Fragile X Syndrome? A systematic review. Res Dev Disabil , , . PMID: 29525058 DOI.
  6. Klusek J, Martin GE & Losh M. (2014). Consistency between research and clinical diagnoses of autism among boys and girls with fragile X syndrome. J Intellect Disabil Res , 58, 940-52. PMID: 24528851 DOI.
  7. 7.0 7.1 7.2 Dury AY, El Fatimy R, Tremblay S, Rose TM, Côté J, De Koninck P & Khandjian EW. (2013). Nuclear Fragile X Mental Retardation Protein is localized to Cajal bodies. PLoS Genet. , 9, e1003890. PMID: 24204304 DOI.
  8. 8.0 8.1 Finucane B, Abrams L, Cronister A, Archibald AD, Bennett RL & McConkie-Rosell A. (2012). Genetic counseling and testing for FMR1 gene mutations: practice guidelines of the national society of genetic counselors. J Genet Couns , 21, 752-60. PMID: 22797890 DOI.
  9. Gocel J & Larson J. (2012). Synaptic NMDA receptor-mediated currents in anterior piriform cortex are reduced in the adult fragile X mouse. Neuroscience , 221, 170-81. PMID: 22750206 DOI.
  10. McConkie-Rosell A, Finucane B, Cronister A, Abrams L, Bennett RL & Pettersen BJ. (2005). Genetic counseling for fragile x syndrome: updated recommendations of the national society of genetic counselors. J Genet Couns , 14, 249-70. PMID: 16047089 DOI.
  11. Zang JB, Nosyreva ED, Spencer CM, Volk LJ, Musunuru K, Zhong R, Stone EF, Yuva-Paylor LA, Huber KM, Paylor R, Darnell JC & Darnell RB. (2009). A mouse model of the human Fragile X syndrome I304N mutation. PLoS Genet. , 5, e1000758. PMID: 20011099 DOI.

NCBI Bookshelf

  • Clinical Methods 3rd ed. Walker, H.K.; Hall, W.D.; Hurst, J.W.; editors Stoneham (MA): Butterworth Publishers; c1990 Table - Recognizable Genetic Conditions
  • Modern Genetic Analysis Griffiths, Anthony J.F.; Gelbart, William M.; Miller, Jeffrey H.; Lewontin, Richard C. New York: W. H. Freeman & Co.; c1999.
  • Introduction to Genetic Analysis 7th ed. Griffiths, Anthony J.F.; Miller, Jeffrey H.; Suzuki, David T.; Lewontin, Richard C.; Gelbart, William M. New York: W. H. Freeman & Co.; c1999.

Reviews

Mor-Shaked H & Eiges R. (2018). Reevaluation ofFMR1Hypermethylation Timing in Fragile X Syndrome. Front Mol Neurosci , 11, 31. PMID: 29467618 DOI.

van de Vondervoort II, Gordebeke PM, Khoshab N, Tiesinga PH, Buitelaar JK, Kozicz T, Aschrafi A & Glennon JC. (2013). Long non-coding RNAs in neurodevelopmental disorders. Front Mol Neurosci , 6, 53. PMID: 24415997 DOI.

Lubs HA, Stevenson RE & Schwartz CE. (2012). Fragile X and X-linked intellectual disability: four decades of discovery. Am. J. Hum. Genet. , 90, 579-90. PMID: 22482801 DOI.

Fung LK, Quintin EM, Haas BW & Reiss AL. (2012). Conceptualizing neurodevelopmental disorders through a mechanistic understanding of fragile X syndrome and Williams syndrome. Curr. Opin. Neurol. , 25, 112-24. PMID: 22395002 DOI.

Paluszkiewicz SM, Martin BS & Huntsman MM. (2011). Fragile X syndrome: the GABAergic system and circuit dysfunction. Dev. Neurosci. , 33, 349-64. PMID: 21934270 DOI.

Tranfaglia MR. (2011). The psychiatric presentation of fragile x: evolution of the diagnosis and treatment of the psychiatric comorbidities of fragile X syndrome. Dev. Neurosci. , 33, 337-48. PMID: 21893938 DOI.

Hersh JH & Saul RA. (2011). Health supervision for children with fragile X syndrome. Pediatrics , 127, 994-1006. PMID: 21518720 DOI.

Krueger DD & Bear MF. (2011). Toward fulfilling the promise of molecular medicine in fragile X syndrome. Annu. Rev. Med. , 62, 411-29. PMID: 21090964 DOI.

Articles

Haessler F, Gaese F, Colla M, Huss M, Kretschmar C, Brinkman M, Schieb H, Peters H, Elstner S & Pittrow D. (2013). EXPLAIN Fragile-X: an explorative, longitudinal study on the characterization, treatment pathways, and patient-related outcomes of Fragile X Syndrome. BMC Psychiatry , 13, 339. PMID: 24354947 DOI.

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Cite this page: Hill, M.A. (2019, May 23) Embryology Fragile X Syndrome. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Fragile_X_Syndrome

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