U01.01.055 Fragile X syndrome

Fragile X syndrome is an X-linked dominant disorder caused by a trinucleotide repeat expansion in the FMR1 gene, leading to hypermethylation and decreased gene expression. It is the most common inherited cause of intellectual disability.

Etiology

Key Genetic Features

Gene: FMR1 gene on the X chromosome.
Mutation: Expansion of the trinucleotide repeat (CGG)n.
Pathophysiology:
- Hypermethylation of the FMR1 gene.
- Suppressed gene expression and loss of function of the fragile X mental retardation protein (FMRP).

Inheritance Pattern

X-linked dominant:
- Both males and females can be affected.
- Males are typically more severely affected due to the absence of a second normal X chromosome.

Clinical Features

System	Findings
Neurological	Intellectual disability, autism
Facial features	Long face, large jaw, large everted ears
Reproductive	Post-pubertal macroorchidism (enlarged testes)
Cardiovascular	Mitral valve prolapse
Musculoskeletal	Hypermobile joints

Mechanism of Trinucleotide Repeat Expansion

Repeat Sequence: CGG trinucleotide.
When Expansion Occurs: During oogenesis (maternal meiosis).
Threshold for Pathology: Over 200 CGG repeats lead to the full mutation.

Differential Diagnosis

Condition	Key Differentiating Features
Down syndrome	Most common genetic cause of intellectual disability (sporadic in most cases). Fragile X is the most common inherited cause.
Autism spectrum disorder (ASD)	Behavioral features overlap but lacks macroorchidism and characteristic facial findings.

Points to Remember

Inheritance: X-linked dominant; males show more severe symptoms.
Key Genetic Mechanism: Trinucleotide repeat expansion (CGG) in the FMR1 gene leads to hypermethylation and loss of gene function.
Clinical Features: Intellectual disability, macroorchidism, long face, large jaw, large everted ears, and mitral valve prolapse.
Testing: DNA analysis showing CGG repeats confirms the diagnosis.
Reproductive Aspect: Expansion occurs during maternal meiosis (oogenesis).

Learning Tip for USMLE Step 1

Focus on the trinucleotide repeat disorders, comparing them with Huntington disease (CAG), myotonic dystrophy (CTG), and Friedreich ataxia (GAA).
Fragile X syndrome’s unique features—macroorchidism, long face, and hypermethylation—set it apart from other intellectual disabilities.

USMLE Step 1 Review Series

Curriculum