Fragile X

From Ganfyd

Introduction

Fragile X mental retardation syndrome is a major cause of learning disability associated with a trinucleotide repeat expansion. The premutation state is also associated with clinical features, called Fragile X tremor/ataxia syndrome (FXTAS). Called Fragile X because under certain growth conditions, the chromosome has a tendency to break at this site (called the FRAXA site, to differentiate from other fragile sites on the X chromosome also associated with mental retardation, FRAXE and FRAXF).

Epidemiology

• Most common heritable cause of mental retardation in males
• Second most common genetic cause of mental impairment after trisomy 21

Clinical Features

• Moderate to severe mental retardation (average IQ 42)
  • Speech delay
  • Autism
  • ADHD
• Macroorchidism (evident post-pubertally)
• Distinct facies
  • Long face
  • Large ears
  • Prominent jaw
  • High arched palate
• Tall stature
• Hypermobility
  • Mitral valve prolapse
• Epilepsy (20%)

Cause

The problem is usually an expansion of trinucleotide repeat sequences at Xq27.3, affecting the FMR1 gene with (CGG)_n repeat expansion of more than 200 repeats. Although the full syndrome is seen in males, females can be mildly affected, as can male carriers (about 50% show clinical features). The FMR1 genes produces the FMRP protein, which interacts with the mGluR5 glutamate receptor. Absence leads to long term depression in brain synapses.

Genetic counselling

Tricky, since you must consider the spectrum of clinical manifestations seen with different numbers of trinucleotide repeats. The expansion anticipates in females carriers, not in males.

Fragile X tremor/ataxia syndrome

(FXTAS) Associated with premutations in the FMR1 gene with (CGG)_n repeat expansion of 55 to 200 repeats. Presents as late as the sixth decade in men, with:

• Progressive intention tremor
• Parkinsonism
• Cognitive decline
• Generalized cerebral atrophy on MRI
• Male impotence

In women, associated with premature ovarian failure.