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BACKGROUND AND CLINICAL INFORMATION:
Head
Summary:
This
is the most common form of inherited mental retardation. It affects both male
and female. The fragile site is on chromosome Xq27.3 where the fragile
X mental retardation 1 (FMR1) gene
locates. The molecular defect involves the presence of a large amplification of
a trinucleotide CGG tandem repeat, often with methylation that leads to
silicencing of the gene, in the untranslated area. The fragile site appears as a
gap at Xq27, and the chromosome is apt to break from a triradial at this point.
The FMR protein coded by the gene is a mRNA binding protein that
modulates RNA translation. Clinically, most male carriers are mentally retarded
and also have macro-orchidism, high forehead, prominent nose, and large
protruding ears. Most heterozygous female carriers are normal but with slight
mental retardation.
Severely mentally retarded female carriers have also been described.
There are no consistent changes of the CNS associated with this syndrome,
however, abnormal dentritic morphology has been described in several cases.
Incidence:
Fragile X syndrome is the most common inherited
cause of mental retardation; the second most common chromosomal disorder
associated with developmental disability.
Sex: Fragile
X syndrome affects both male and females. However, females are less severely
affected because they have two X chromosomes (affected heterogous female).
Clinical
features:
Molecular
pathology:
The
FMR1 Gene: The
fragile site is on chromosome Xq27.3 where the FMR1 gene locates. The
molecular defect involves the presence of a large amplification of a
trinucleotide CGG tandem repeat, often with methylation of the gene, in the
untranslated area. In
most cases the disease is caused by the methylation-induced transcriptional
silencing of the fragile X mental retardation 1 (FMR1) gene and
leads to the loss of protein product fragile X mental retardation protein (FMRP).
The
fragile site appears as a gap at Xq27, and the chromosome is apt to break
from a triradial at this point.
FMR
protein:
FMRP is an RNA binding protein that associates with translating
polyribosomes as part of a large messenger ribonucleoprotein (mRNP) and
modulates the translation of its RNA ligands.
Pathogenesis: Experimental evidence suggest that the FMRP is involved in synapse function and plasticity.
Cytogenetics: The fragile changes can be demonstrated with
cytogenetics. In addition to FMR1 gene, mutations can be found in FRAXE (a
mutation slightly distal to the FMR1 gene and also has a CGG repeat) and FRAXF
mutation (about 0.6 kb distal to the FRAXE gene and also has a CGG repeat) in a
small number of patients. Therefore, testing with PCR for mutation of FMR1 gene
is recommended.
CGG
repeat: At the 5’-end of the gene is a CGG repeat that varies from 6
to 54 repeats (average 29-30) in normal population. The CGG repeats are
usually punctuated by an AGG repeat at every 9 to 10 repeats. These AGG
repeats serve as anchors to stabilize the CGG repeats and one or more of
them are missing in carriers. Expansion to a full multation only occurs when
a female with the abnormal expansion passes on the mutations to her
offsprings.
Phenotypic-genotypic
correlation: The higher the number of CGG repeats in the mother, the
more likely the chance that the offsprings will have the full mutation.
Patients with fragile X syndrome, there is abnormal expansion of the CGG
repeats. These repeats are transcribed but not translated into protein. The
clinical pictures are related to the size of the repeats.
| Number of Repeats | Phenotype |
| 40-55 repeats | These patients are phenotypically normal but genetically in the gray zone in particular if one or more of the AGG repeats is missing. |
| 55-200 repeats | They are carriers for fragile X syndrome and do not have cognitive involvement. The repeats are usually unmethylated and the FMR1 protein produced is normal. |
| Over 230 repeats | Full mutation for fragile X
syndrome and usually have methylation of the gene which prevents
transcription and translation of the gene into FMR1 protein. |
Some non-specific changes including enlargement of the hippocampus have been described but the findings are not very reproducible.
No consistent macroscopic pathologic changes have been documented in the limited cases of autopsy studies.
HISTOPATHOLOGY AND IMMUNOHISTOCHEMISTRY:
Head
No consistent histopathologicchanges ahve been documented in the limited cases of autopsy studies.
O'Donnell WT, Warren ST. A decade of molecular studies of fragile x syndrome. Annu Rev Neurosci. 2002;25:315-38.
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Background Neuroimaging Gross Pathology Histopathology & Immunohistochemistry Reference