Neuropathologic features in the hippocampus and cerebellum of three older men with fragile X syndrome

Abstract

BackgroundFragile X syndrome (FXS) is the most common inherited form of intellectual disability, and is the most common single-gene disorder known to be associated with autism. Despite recent advances in functional neuroimaging and our understanding of the molecular pathogenesis, only limited neuropathologic information on FXS is available.MethodsNeuropathologic examinations were performed on post-mortem brain tissue from three older men (aged 57, 64 and 78 years) who had received a clinical or genetic diagnosis of FXS. In each case, physical and cognitive features were typical of FXS, and one man was also diagnosed with autism. Guided by reports of clinical and neuroimaging abnormalities of the limbic system and cerebellum of individuals with FXS, the current analysis focused on neuropathologic features present in the hippocampus and the cerebellar vermis.ResultsHistologic and immunologic staining revealed abnormalities in both the hippocampus and cerebellar vermis. Focal thickening of hippocampal CA1 and irregularities in the appearance of the dentate gyrus were identified. All lobules of the cerebellar vermis and the lateral cortex of the posterior lobe of the cerebellum had decreased numbers of Purkinje cells, which were occasionally misplaced, and often lacked proper orientation. There were mild, albeit excessive, undulations of the internal granular cell layer, with patchy foliar white matter axonal and astrocytic abnormalities. Quantitative analysis documented panfoliar atrophy of both the anterior and posterior lobes of the vermis, with preferential atrophy of the posterior lobule (VI to VII) compared with age-matched normal controls.ConclusionsSignificant morphologic changes in the hippocampus and cerebellum in three adult men with FXS were identified. This pattern of pathologic features supports the idea that primary defects in neuronal migration, neurogenesis and aging may underlie the neuropathology reported in FXS.

Hippocampal dysfunction and cognitive impairment in Fragile-X Syndrome

“…Furthermore, the use of different measurement techniques, ranging from magnetic resonance imaging (MRI) (Reiss et al, 1994, Jakala et al, 1997, Kates et al, 1997, physical examination of post-mortem specimens to voxel-based morphometry (Hoeft et al, 2008) make direct comparisons between the studies difficult. More recently, one study has reported focal thickening (due to an increased pyramidal cell number) of the CA1 and an irregular appearance of the DG hippocampal sub-region in older FXS patients (Greco et al, 2011). This irregular appearance of the DG may reflect the mild cell loss and associated astrogliosis and microgliosis that have been reported in the CA4/hilar sub-region (Brown et al, 2001).…”

Deficiency of Adult Neurogenesis in the Ts65Dn Mouse Model of Down Syndrome

“…Alteration of neurogenesis in neurodevelopmental disorders were studied to a lesser extent in DS (Contestabile et al, 2007;Guidi et al, 2008Guidi et al, , 2010, autism spectrum disorders (Greco et al, 2011;Wegiel et al, 2010), including Rett syndrome (Ronnett et al, 2003). Studies to understand the neurobiology of DS have benefited from the ability to examine mouse models of the disorder Kleschevnikov et al, 2004;Popov et al, 2011).…”

Gene expression profiles in the cerebellum of transgenic mice over expressing the human FMR1 gene with CGG repeats in the normal range

“…Loss of expression of the FMR1 gene by increased CGG trinucleotide repeats (<200) in the 5'UTR causes the most frequent inherited form of mental retardation (fragile X syndrome, FXS), whereas carriers of premutation alleles (55-200 CGG triplet repeats) may present a specific late-onset neurodegenerative disorder characterized by tremor, ataxia, parkinsonism, and intellectual decline (fragile X-associated tremor ataxia syndrome, FXTAS) (Hagerman et al, 2001;Hagerman and Hagerman, 2004a;Jacquemont et al, 2007;Costa et al, 2011;Greco et al, 2011). Neurohistological studies on the brain of premutation carriers have demonstrated neuronal degeneration in the cerebellum and the presence of eosinophilic intranuclear inclusions in both neurons and astroglia (Jacquemont et al, 2003;Greco et al, 2006;Wenzel et al, 2010).…”