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Detailed information of FRAGILE X SYNDROME
FRAGILE X SYNDROME
DEFINITION:
An inherited disorder characterized by mental retardation, macro-orchidism,
and a fragile X chromosome site on cytogenetic analysis.
EPIDEMIOLOGY:
- prevalence: 1:1,250 males and 1:2,500 females
- age of onset:
- risk factors:
- familial - fits neither dominant or recessive X-linked
inheritance patterns (carrier frequency for females: 1:500)
- chrom.#: Xq27.3
- gene: Fragile X Mental Retardation-1 (FMR-1) gene
- M:F (1:0.7)
PATHOGENESIS:
- the Fragile X Syndrome belongs to a growing family of
disorders where the genetic mutation involves unstable
trinucleotide repeats (C_G):
- in this family of disorders, the number of repeats tends to
increase with succeeding generations ("genetic anticipation")
- in the Fragile Syndrome:
- in 1991, three groups isolated the FMR-1 gene and an
unstable part of the gene was identified characterized by
numerous repeats of single trinucleotide sequences containing
the bases cytosine and guanine (CGG)
- in normal individuals, there are between 10-50 CGG repeats
but in those with Fragile X Syndrome, there may be between
200-2000 CGG repeats
- the function of the FMR-1 gene product is unknown but may
be a putative RNA binding protein
2. Genetic Defect
- genetic defect -> amplification of the sequence of unstable
trinucleotide repeats (CGG) in the 5' region of the gene to
greater than 200 -> promotes methylation of regulatory sequences
within this sequence (CpG islands) -> turns off FMR-1 gene
expression -> lack of gene product -> variable phenotypic
expression in males and females
- amplification of the premutation allele occurs only through
female gametogenesis
- males with a premutation allele will pass this allele on to
all of his daughters who will be phenotypically normal but all
of the daughters children will be at risk of having affected
children
- the number of CGG repeats may affect the phenotype and risk
for amplification to the full mutation allele:
CLINICAL FEATURES:
- ranges from profound to normal IQ with learning
disabilities
- mental impairment is low for premutation carriers
2. Developmental Delay
2. Genitourinary Manifestations
- found in 80-90% of affected males after puberty
- testes usually not enlarged prior to puberty
- one or both testes may be of normal size
- normal testicular function
3. Dysmorphic Features
- large head - prominent mandible
- long, thin face - prominent forehead
- large ears +/- low set, posteriorly rotated, poorly
formed
2. Connective Tissue Manifestations
- hyperextension of fingers
- mild-to-moderate pectus excavatum
- floppy mitral valve (in 80% over the age of 18)
2. Females
- 50% impaired due to unfavourable X chromosome
inactivation
2. Developmental Delay
2. Dysmorphic Features
- mild craniofacial and connective tissue manifestations
INVESTIGATIONS:
- diagnostic
- the fragile X chromosome site at Xq27.3 is induced under
folic acid or thymidine-deficient culture conditions using
lymphocytes
2. Molecular Analysis
- the size of CGG amplification and the degree of methylation
of the associated CpG islands can be estimated by Southern blot
analysis of genomic DNA or by the PCR
MANAGEMENT:
- no treatment for underlying disorder
- the degree of intellectual impairment will determine the
extent of educational and speech and language intervention
2. Prognosis
- normal life span
- integration into society depends upon the degree of
intellectual impairment
INTERNET LINKS:
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Pediatric Database - FRAGILE X SYNDROME
Pediatric Organization - Pedbase [at] Gmail.com