Fragile X
Epidemiology and
Etiology:
- 2nd
most common genetic cause of mental retardation (after trisomy 21)
- Males
>> females
Common sites:
Gross features:
- Variable
features
- Macrocephaly
- Long
face
- Large
mandible
- Large everted ears
- Macro-orchidism (post-pubertal) (90%)
- Features
of connective tissue disorder in some:
- Hyperextensible joints
- High
arched palate
- Mitral
valve prolapse
Histologic
features:
Immunophenotype:
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Marker:
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Sensitivity:
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Specificity:
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Molecular features:
- Familial
mental retardation 1 (FMR-1)
gene trinucleotide repeat
expansion (99%)
- Loss
of function related to methylation of promoter
due to trinucleotide repeat expansion in
non-translated 5’ region of gene
- FMRP
regulates the translation of mRNAs at synapses of neurons
- Trinucleotide repeat expansion (CGG)
- Normally
6-44 repeats
- 45-54
repeats: “intermediate”
- Transmitting
males and carrier females: 55-200 repeats (pre-mutations)
- Affected
individuals: 200-4000 repeats (full mutation)
- PCR
is used to test for mutation
- Carrier
males transmit the pre-mutation to their daughters with small changes in
repeat number
- Carrier
females transmit with a high probability of a dramatic amplification of
repeats
- 20%
of males with the (pre)mutation are not affected and pass the mutation
to all their daughters (transmitting males)
- 50%
of females with full mutation are affected (mental retardation)
- Anticipation:
- Features
worsen with each successive generation
- FMR-1
point mutation or deletion (1%)
- Cells
cultured in a folate deficient medium:
- Discontinuity
of staining or constriction in Xq (fragile
site)
Other features:
- Mental
retardation
- Intermediate
status
- no
increased risk of affected child in the next generation
- May
be associated with Fragile X syndrome in future generations
- Permutation
(55-200 repeats)
- Individual
is not usually affected by fragile X syndrome
- Risk
of affected offspring
- Risk
of FXTAS
- Major
diagnostic criteria:
- Intention
tremor/gait ataxia
- White
matter lesions on MRI
- Minor
signs:
- Parkinsonism
- Memory
deficits
- Cognitive
function deficits
- Penetrance is age-related
- Risk
of POF
- Expressivity
is variable
- Severity
of disease cannot be assessed prenatally
References:
·
Kumar V, Fausto N, Abbas
A. Robbins & Cotran Pathologic Basis of Disease,
Seventh Edition. 7th ed. Saunders; 2004.