Foundations · Year 1 · from Foundations
Case 3: Fragile X Syndrome (X-Linked with CGG Repeat Expansion)
Clinical Image
Source: Wikipedia - Fragile X syndrome - CC BY-SA 3.0
Case Presentation
A 3-year-old boy is referred for evaluation of developmental delay and speech regression. He spoke his first words at 12 months but has since lost language skills and now has only 10 single words. He exhibits repetitive behaviors, poor eye contact, and hand flapping, raising concern for autism spectrum disorder. Physical examination reveals a long face, prominent ears, and macroorchidism (large testes) is noted. His maternal grandfather has a progressive tremor and balance problems. Genetic testing reveals >200 CGG repeats in the 5' UTR of the FMR1 gene, confirming fragile X syndrome. The genetic counselor explains: normal individuals have <55 repeats; premutation carriers (55-200 repeats) have normal intelligence but may develop fragile X-associated tremor/ataxia syndrome (FXTAS) in later life, particularly males, explaining the grandfather's symptoms. Full mutations (>200 repeats) occur when premutation alleles expand during maternal transmission, causing methylation and silencing of FMR1. The loss of FMRP protein (which regulates synaptic plasticity) causes the cognitive and behavioral features. Testing reveals his mother carries a premutation, explaining how she is unaffected but transmitted a full mutation to her son. The family is referred to early intervention services.
Key Learning Points
- Fragile X syndrome results from CGG repeat expansion (>200) in the 5' UTR of FMR1; massive expansion causes DNA methylation and gene silencing, eliminating FMRP protein expression
- Premutation carriers (55-200 repeats) are at risk for fragile X-associated tremor/ataxia syndrome (FXTAS) and, in females, premature ovarian insufficiency; the premutation can expand to full mutation during female meiosis
- The inheritance pattern is complex: unaffected carrier females can have affected sons; the phenotype is worse in males due to hemizygosity (only one X chromosome)