Brain Advance Access originally published online on January 21, 2004
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Brain, Vol. 127, No. 3, 591-601, 2004
© 2004 Guarantors of Brain
doi: 10.1093/brain/awh069
Differential impact of the FMR1 gene on visual processing in fragile X syndrome
1 Department of Psychology, 2 Department of Educational Psychology and Neurology and Neurosurgery, 3 McGill Vision Research, Department of Ophthalmology, 4 Departments of Pediatrics and Human Genetics, McGill University 5 Departments of Neurology and Neurosurgery and Human Genetics, McGill University and the Montreal Neurological Hospital and Institute, Montreal, Québec and 6 Departments of Psychiatry and Physiology, Queen’s University, Kingston, Ontario, Canada
Correspondence to: Avi Chaudhuri Department of Psychology, McGill University, 1205 Dr Penfield Avenue, Montréal, Québec H3A 1B1, Canada. E-mail: avi{at}psych.mcgill.ca
Fragile X syndrome (FXS) is the most common form of heritable mental retardation, affecting 
1 in 4000 males. The syndrome arises from expansion of a trinucleotide repeat in the 5'-untranslated region of the fragile X mental retardation 1 (FMR1) gene, leading to methylation of the promoter sequence and lack of the fragile X mental retardation protein (FMRP). Affected individuals display a unique neurobehavioural phenotype that includes striking visual-motor deficits. Here we provide neurobiological and behavioural evidence that supports the hypothesis that these visual-motor deficits are attributable to a magnocellular (M) visual pathway impairment. Immunohistochemical staining of a lateral geniculate nucleus (LGN) of a normal human male revealed high FMRP basal expression selectively within the M layers, suggesting an increased susceptibility of these neurons to the lack of FMRP as occurs in FXS. Similar staining of monkey LGNs for quantification purposes revealed that the difference is not an artefact of cell size differences between M and parvocellular (P) neurons. Further, Nissl staining of the LGNs of a male FXS patient revealed alaminar nuclei comprised of a homogenous population of small sized neurons, providing anatomical and morphological support for the idea that an M pathway pathology exists in FXS. Consistent with these neurobiological data, we have found that male patients with FXS have reduced sensitivity for psychophysical stimuli that probe the M pathway but not for those that probe the P pathway, a complementary visual stream that performs a separate set of early visual operations. Finally, male patients with FXS performed poorly on a global motion task but not on a form perception task, suggesting that the M pathway thalamic deficit may have a selective impact on cortical visual functioning in the parietal lobe, which is known to be a major recipient of M pathway afferents via the primary visual cortex. Together, these findings provide the first evidence that the loss of a single gene product, FMRP, in humans leads to abnormal neuroanatomical morphology of the LGN and a concomitant selective visual deficit of the M pathway.
Key Words: fragile X syndrome; psychophysics; histology; LGN; FMR1
Abbreviations: CA= chronological age; DS = dorsal stream; FMR1 = fragile X mental retardation 1 gene; FMRP = fragile X mental retardation protein; FXS = fragile X syndrome; LGN = lateral geniculate nucleus; M = magnocellular; MA = verbal mental age; P = parvocellular; VS = ventral stream; PBS = phosphate-buffered saline
Received September 3, 2003. Revised October 25, 2003. Accepted October 25, 2003.
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