Learning Objective: Understand the genetic mechanism, clinical presentation, and distinctive features of Fragile X syndrome, including its inheritance pattern and relationship to trinucleotide repeat expansion.
Inheritance:
X-linked (atypical) inheritance pattern.
Genetic Mechanism:
Trinucleotide repeat expansion (CGG)n in the FMR1 gene → hypermethylation of cytosine residues → reduced gene expression.
Key Facts:
- Most common inherited cause of intellectual disability.
- Down syndrome is the most common genetic cause overall (mostly sporadic).
- Repeat expansion occurs during oogenesis (maternal transmission).
Mutation Classes:
| Type | Repeats | Clinical Features |
|---|---|---|
| Premutation | 50–200 | Tremor, ataxia, primary ovarian insufficiency |
| Full mutation | >200 | Macroorchidism, long face with large jaw, large everted ears, autism, mitral valve prolapse, hypermobile joints |
Characteristic Features:
- Postpubertal macroorchidism (enlarged testes)
- Long face, large jaw, large everted ears
- Autism, mitral valve prolapse, hypermobile joints
- Self-mutilation, which can mimic Lesch-Nyhan syndrome
