Fragile X results in apparently normal neurological development, with the effects becoming apparent during early learning (age 3-5). This disease is one of several CAG expansion diseases.
In the general population we all carry a limited copy of this nuceotide sequence, it is only when the copy number increases that the encoded protein (FRP, Fragile X Protein) is decreased in neuronal expression.
Page Links: Introduction | Some Recent Findings | Symptoms | FMR Protein | Diagnostic Testing | References | WWW Links | Glossary
See also: Neural System - Abnormal Development
Yun SW, Platholi J, Flaherty MS, Fu W, Kottmann AH, Toth M. Fmrp is required for the establishment of the startle response during the critical period of auditory development. Brain Res. 2006 Aug 1; "The startle response was first detectable at the end of the 2nd postnatal week in wild-type mice. The amplitude of startle response showed a substantial increase until the 4th postnatal week followed by a further but moderate increase up to adulthood." ...Although the onset and amplitude of the startle response were not altered in fmr1 KO mice until the 3rd-4th postnatal week, beyond this age it failed to develop further resulting in an overall response deficit in adult KO mice."
Castren M. Differentiation of neuronal cells in fragile x syndrome. Cell Cycle. 2006 Jul;5(14):1528-30. Epub 2006 Jul 17. "The absence of fragile X mental retardation protein caused an increased number of new-born cells in the subventricular region of the embryonic mouse brain and substantial aberrances in the differentiation of both human and mouse neural stem cells in vitro."
Castren M, Tervonen T, Karkkainen V, Heinonen S, Castren E, Larsson K, Bakker CE, Oostra BA, Akerman K. Altered differentiation of neural stem cells in fragile X syndrome. Proc Natl Acad Sci U S A. 2005 Dec 6;102(49):17834-9. "The differentiation of fragile X neurospheres into neuronal and glial cells differed from the differentiation of control neurospheres..." "...These results demonstrate substantial alterations in the early maturation of FMRP-deficient neural stem cells in fragile X syndrome and in the fmr1-KO mice."
cognitive defect
hyperactivity
seizures
sensory abnormalities - increased sensitivity to auditory, tactile, visual, and olfactory stimuli
FMRP is an RNA-binding protein encoded by the Fmr1 gene.
In mammals there are also 2 homologs of FMRP:
fragile X related protein 1 (FXR1P)
fragile X related protein 2 (FXR2P) - in mice, Fxr2 disruption produces learning and memory deficits
The text below is an excerpt from the Policy Statement of the American College of Medical Genetics (July 28, 1994), the current policy may differ from that shown below.
Individuals for Whom Testing Should Be Considered
Population Screening
Population carrier screening is not recommended at this time except as part of a well-defined clinical research protocol. The DNA test is very accurate, but it is important to ensure that effective means are in place to adequately inform tested populations of the meaning and implications of results. The nature of the FMR1 mutation and its inheritance are complex, and testing necessitates appropriate follow-up counseling.
(More? Policy Statement: American College of Medical Genetics Fragile X Syndrome: Diagnostic and Carrier Testing)
Australia
Fragile X Association of Australia
USA
National Institute of Child Health and Human Development (NICHD) Facts About Fragile X Syndrome
Policy Statement: American College of Medical Genetics Fragile X Syndrome: Diagnostic and Carrier Testing
The National Fragile X Foundation
United Kingdom
Canada
Reviews | Articles | Search NCBI Bookshelf | Search PubMed | Glossary
Reviews
Garber K, Smith KT, Reines D, Warren ST. Transcription, translation and fragile X syndrome. Curr Opin Genet Dev. 2006 Jun;16(3):270-5. Epub 2006 May 2.
Vanderklish PW, Edelman GM. Differential translation and fragile X syndrome. Genes Brain Behav. 2005 Aug;4(6):360-84.
Zalfa F, Bagni C. Molecular insights into mental retardation: multiple functions for the Fragile X mental retardation protein? Curr Issues Mol Biol. 2004 Jul;6(2):73-88.
Articles
Search NCBI Bookshelf: Fragile X | Genes and Disease - Fragile X
Search PubMed: Search August 2006 "Fragile X" 3,853 reference articles of which 600 were reviews.
Search term = Fragile X
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These developmental abnormalities usually involve only small DNA mutations affecting individual or a few genes, two exceptions are the major chromosomal abnormalities usualy trisomy; trisomy 21 (Down syndrome) and trisomy 18 (Edwards syndrome) (also trisomy 9, 13, 15). Note that the occurance of chromosomal abnormalities also increases with increasing maternal age. There are many pamphlets providing information about prenatal diagnosis (see NSW State Health Publication Checking your baby's health before birth).
Alcohol "Fetal Alcohol Syndrome"
Infection
cytomegalovirus
Trauma
These links require online access to Merck Manuals on Women's Health Issues. http://www.merck.com/mrkshared/mmanual_home2/sec22/sec22.jsp
Risk Factors Present Before Pregnancy
Risk Factors That Develop During Pregnancy
Diseases that complicate Pregnancy
Problems Affecting the Fetus or Newborn
Mitral Valve Prolapse
High Blood Pressure
Anemias
Kidney Disease
Infectious Disease
Diabetes
Thyroid
Liver
Asthma
Systemic Lupus Erythematosus
Rheumatoid Arthritis
Myasthenia Gravis
Idiopathic Thrombocytopenic Purpura
<Surgery During Pregnancy
Relate to lifestyle, environment and nutrition. Some examples of this form of abnormality are the impact of excess alcohol on neural development (Fetal alcohol syndrome), viral infection (rubella) at a critical stage of development, inadequate dietry folate intake (neural tube defects), effects of prescription drugs (Thalidomide- limb development) and even maternal endocrine function (thyroid development).
In addition to these obvious maternally-derived abnormalities, there is growing evidence that the interuterine environment has a strong influence on later postnatal health. This theory is based on the early statistical analysis of disease/longevity in babies with low birth weights in England by Barker, and has been called the "Barker Hypothesis". (More? Barker Hypothesis)
Sudden Infant Death Syndrome (SIDS)
Malnutrition
Infection
Trauma
see also Normal Childhood Development
Each section of the notes covering early development and specific systems contain references to specific abnormalities (on Page 2 of each notes section). The best source for Australian statistical data is the Australian Institute of Health and Welfare National Perinatal Statistics Unit, UNSW which publishes "Congenital Malformations Australia" every 2 years. Be aware that some congenital abnormalities, by their nature, affect multiple systems. In the USA, the Center for Disease Control (CDC) keeps and publishes relevant statistical information. A very difficult issue in abnormal development are the many different Ethical implications.
This current page is a link to Normal and Abnormal Development and Population Data.
You should look at normal development. Development Notes
Alternatively, go on to look at Systematic Development of organs and tissues.
For those wanting to see dynamic processes of development (and have a reasonably quick connection) then the Movies pages are good for watching changes occur.
The study of human development has relied extensively on studying the process in other model animals. For those wanting to see the process of development in other species then the other embryos pages are a good start.
Home Page
Embryo stages
Fetal Dev
Dev Notes 1
Dev Notes 2
System Notes
Acknowledgements
Movies
Audio
Class Notes
Serial Images
K12 Students
Abnormal Development
Fragile X
Embryology in the News
Histology
Site Map
School of Med Sci
UNSW Medicine
University of NSW
UNSW Cell Biology
NCBI Books
Dev Biol (Gilbert)
How and why do things go wrong in development?
Abnormalities in human development can be due to many different maternal factors, this page gives a few starting points to look at this topic.
The page links to internal resources coving specific topics and also uses the online Merck Manuals, which cover this topic with some excellent short summaries.
Please email Dr Mark Hill if you wish to make a comment about this current project.