A neuropsychological investigation of male premutation carriers of fragile X syndrome

Neuropsychologia. 2004;42(14):1934-47. doi: 10.1016/j.neuropsychologia.2004.05.002.

Abstract

It is currently thought that fragile X syndrome (FraX; the most common inherited form of learning disability) results from having more than 200 cytosine-guanine-guanine (CGG) trinucleotide repeats, with consequent methylation of the fragile X mental retardation (FMR1) gene and loss of FMR1 protein (FMRP). It was also considered that premutation carriers (with 55-200 CGG repeats) are unaffected, although a tremor/ataxia syndrome has recently been described in older adult male carriers. We reported that premutation expansion of CGG trinucleotide repeats affects brain anatomy, which, together with other studies, indicates that the molecular model for FraX needs modification. However, there are few studies on the cognitive ability of adult male premutation carriers. Thus, we selected 20 male premutation carriers on the basis of their genetic phenotype, and compared them to 20 male controls matched on age, IQ and handedness. We investigated intellectual functioning, executive function, memory, attention, visual and spatial perception, and language and pragmatics. The premutation carriers had significant impairments on tests of executive function (Verbal Fluency, Trail Making Test and Tower of London) and memory (Names sub-test of the Doors and People, Verbal Paired Associates Immediate Recall and Visual Paired Associates Delayed Recall sub-tests of the WMS-R, and Category Fluency Test for natural kinds). We therefore suggest that CGG trinucleotide repeats in the premutation range affect specific neuronal circuits that are concordant with specific neuropsychological deficits; and that these deficits reflect an emerging neuropsychological phenotype of premutation FraX.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Aged
  • Attention
  • Case-Control Studies
  • Chromosomes, Human, X*
  • Fragile X Mental Retardation Protein
  • Fragile X Syndrome / genetics
  • Fragile X Syndrome / metabolism
  • Fragile X Syndrome / physiopathology*
  • Heterozygote*
  • Humans
  • Immunohistochemistry / methods
  • Intelligence / genetics
  • Intelligence Tests
  • Language
  • Male
  • Mental Processes / physiology*
  • Middle Aged
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Neuropsychological Tests*
  • RNA, Messenger / biosynthesis
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction / methods
  • Surveys and Questionnaires
  • Trinucleotide Repeat Expansion / genetics
  • Verbal Behavior / physiology

Substances

  • FMR1 protein, human
  • Nerve Tissue Proteins
  • RNA, Messenger
  • RNA-Binding Proteins
  • Fragile X Mental Retardation Protein