Learning Objectives
- Identify the genetic mechanism of Fragile X, including trinucleotide repeats and methylation.
- Distinguish between inherited and genetic causes of intellectual disability.
- Recognize the clinical triad of macroorchidism, long face, and large ears.
- Understand the difference between premutation and full mutation phenotypes.
1. Genetics & Pathophysiology
Fragile X is an atypical X-linked disorder characterized by the expansion of a trinucleotide repeat in the FMR1 gene.
- The Repeat: (CGG)n expansion occurs during oogenesis.
- The Mechanism: Expansion leads to hypermethylation of cytosine residues, which effectively “silences” the gene (decreased expression).
- Impact: Fragile X is the most common inherited cause of intellectual disability. (Note: Down syndrome is the most common genetic cause, but it is usually sporadic.)
Activity
2. Clinical Manifestations (Full Mutation)
The “Full Mutation” involves >200 repeats. Physical findings are most prominent after puberty.
| Category | Key Clinical Findings |
|---|---|
| Physical | Postpubertal macroorchidism (large testes), long face with large jaw, large everted ears. |
| Neuro-Psych | Intellectual disability, autism, self-mutilation. |
| Connective Tissue | Mitral valve prolapse (MVP), hypermobile joints. |
3. The Premutation (50–200 repeats)
Individuals with the premutation do not show the full syndrome but may present with distinct clinical issues:
- Fragile X-associated Tremor/Ataxia Syndrome (FXTAS): Late-onset progressive neurological decline.
- Primary Ovarian Insufficiency: Early menopause in females.
Activity