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

Claudia M. Greco, Celestine S. Navarro, Michael R. Hunsaker, Izumi Maezawa, John F. Shuler, Flora Tassone, Mary Delany, Jacky W. Au, Robert F Berman, Lee-Way Jin, Cynthia Schumann, Paul J Hagerman, Randi J Hagerman

Research output: Contribution to journalArticle

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Abstract

Background: Fragile 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. Methods. Neuropathologic 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. Results: Histologic 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. Conclusions: Significant 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.

Original languageEnglish (US)
Article number2
JournalMolecular Autism
Volume2
Issue number1
DOIs
StatePublished - 2011

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Fragile X Syndrome
Cerebellum
Hippocampus
Autistic Disorder
Atrophy
Limbic System
Functional Neuroimaging
Purkinje Cells
Neurogenesis
Dentate Gyrus
Neuroimaging
Intellectual Disability
Staining and Labeling
Brain
Genes

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Developmental Neuroscience
  • Developmental Biology
  • Molecular Biology

Cite this

Neuropathologic features in the hippocampus and cerebellum of three older men with fragile X syndrome. / Greco, Claudia M.; Navarro, Celestine S.; Hunsaker, Michael R.; Maezawa, Izumi; Shuler, John F.; Tassone, Flora; Delany, Mary; Au, Jacky W.; Berman, Robert F; Jin, Lee-Way; Schumann, Cynthia; Hagerman, Paul J; Hagerman, Randi J.

In: Molecular Autism, Vol. 2, No. 1, 2, 2011.

Research output: Contribution to journalArticle

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AU - Shuler, John F.

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AB - Background: Fragile 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. Methods. Neuropathologic 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. Results: Histologic 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. Conclusions: Significant 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.

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