title: Autopsy study of cerebellar degeneration in siblings with ataxia-telangiectasia-like disorder.
abstract: Ataxia-telangiectasia-like disorder (ATLD) is caused by mutations of the MRE11 gene and is characterized by cerebellar ataxia, increased frequency of chromosomal translocations and hypersensitivity to ionizing radiation. ATLD is a rare genetic disease and the associated pathological changes in the brain are unclear. Here, we report the neuropathological findings in the first cases of genetically confirmed ATLD in a pair of Japanese male siblings. Magnetic resonance imaging studies performed during infancy revealed that both subjects had cerebellar atrophy. They died of pulmonary cancer at 9 and 16 years. The siblings had the same compound heterozygous mutations of the MRE11 gene. Brain autopsy demonstrated mild and severe cerebellar atrophy in the vermis and medial part of the hemispheres, oral to the horizontal fissure, respectively. Nuclear immunoreactivity for MRE11 was absent in neurons of cerebellar cortex, cerebral cortex, basal ganglia and midbrain, whereas being widespread in normal control brains. Immunoreactivity for the DNA oxidative stress marker, 8-hydroxy-2'-deoxyguanosine, was identified in nuclei of granule cells and Bergmann glial cells. The combination of MRE11 deficiency and DNA oxidative injury might have led to selective cerebellar degeneration.
authors.affiliation: Division of Neurology, Saitama Children's Medical Center, 2100, Magome, Iwatsuki-ku, Saitama, Saitama 339-8551, Japan.
authors.forename: Daiju
authors.initials: D
authors.lastname: Oba
authors.forename: Masaharu
authors.initials: M
authors.lastname: Hayashi
authors.forename: Motoyuki
authors.initials: M
authors.lastname: Minamitani
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Hamano
authors.forename: Naoki
authors.initials: N
authors.lastname: Uchisaka
authors.forename: Akira
authors.initials: A
authors.lastname: Kikuchi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kishimoto
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Takagi
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Morio
authors.forename: Shuki
authors.initials: S
authors.lastname: Mizutani
mesh_terms: D000293:Adolescent; D044466:Asian People; D001260:Ataxia Telangiectasia / Q000150:complications / Q000235:genetics / Q000473:pathology; D001284:Atrophy; D001344:Autopsy; D001479:Basal Ganglia / Q000378:metabolism / Q000473:pathology; D002525:Cerebellar Cortex / Q000378:metabolism / Q000473:pathology; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D002648:Child; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D017809:Fatal Outcome; D006579:Heterozygote; D006801:Humans; D007223:Infant; D008175:Lung Neoplasms / Q000209:etiology; D000076228:MRE11 Homologue Protein; D008297:Male; D008636:Mesencephalon / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology; D035781:Siblings; D013132:Spinocerebellar Degenerations / Q000150:complications / Q000235:genetics / Q000473:pathology
chemical_list: D004268:DNA-Binding Proteins; C121766:MRE11 protein, human; D000076228:MRE11 Homologue Protein