Document Detail


Features of cell death in brain and liver, the target tissues of progressive neuronal degeneration of childhood with liver disease (Alpers-Huttenlocher disease).
MedLine Citation:
PMID:  12721699     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Alpers-Huttenlocher disease (AHD) is a rare encephalopathy of infancy and childhood characterized by myoclonic seizures and progressive neurological deterioration, usually associated with signs and symptoms of liver dysfunction. There is no biological marker of the disease, and ultimate diagnosis still relies on pathological examination. Features of clinical progression and pathological findings suggest AHD to be secondary to a genetically determined disorder of mitochondrial function. We report on four AHD patients and focus on their pathological features in brain, liver and muscle. Liver and muscle biopsy specimens were examined using histochemical markers of the oxidative pathways, probes to immunodetect molecules of the apoptotic cascades and electron microscopy. In liver (but not in muscle) biopsy samples, activated caspases were detected by immunohistochemistry: foci of caspase-9-positive cells were seen in a child affected with chronic, progressive fibrosis. In an 18-year-old boy, who suffered from valproic acid-associated acute hepatitis, caspase-3 cells were clustered among the necrotic foci and the foamy cells. In both patients electron microscopy revealed apoptotic nuclei. Normal muscle biopsy specimens were observed in two children, 2 and 8 years-old respectively; in the 18-year-old patient cytochrome oxidase-negative fibers as well as ultrastructural findings of mitochondrial abnormalities were observed. In no patient was there biochemical evidence of impaired oxidative metabolism. Neuropathological examination of the brains of two patients (13 months and 19 years old, respectively) showed focal distribution of the lesions affecting the telencephalic cortex and, to a lesser extent, subcortical gray nuclei. Along with the necrotizing lesions, characterized by neuronal loss, neuropil microcysts and newly formed vessels, we also observed acutely shrunken neurons and features of apoptotic cell death in the cerebral cortex only. Severe neuronal loss without necrotizing features was observed in the cerebellar cortex. The presence of both anoxic and apoptotic nuclei in brain and liver, the target tissues of the disease, is consistent with the hypothesis that abnormal activation of mitochondrion-related cell death pathways might be involved in the pathogenesis of AHD.
Authors:
Alessandro Simonati; Massimiliano Filosto; Chiara Savio; Giuliano Tomelleri; Paola Tonin; Bernardo Dalla Bernardina; Nicolo' Rizzuto
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Publication Detail:
Type:  Case Reports; Journal Article; Research Support, Non-U.S. Gov't     Date:  2003-04-30
Journal Detail:
Title:  Acta neuropathologica     Volume:  106     ISSN:  0001-6322     ISO Abbreviation:  Acta Neuropathol.     Publication Date:  2003 Jul 
Date Detail:
Created Date:  2003-05-29     Completed Date:  2003-08-11     Revised Date:  2007-11-09    
Medline Journal Info:
Nlm Unique ID:  0412041     Medline TA:  Acta Neuropathol     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  57-65     Citation Subset:  IM    
Affiliation:
Department of Neurological and Visual Sciences, Section of Neurology, Policlinico GB Rossi, University of Verona, P.le LA Scuro 1, 37134 Verona, Italy. alessandro.simonati@univr.it
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MeSH Terms
Descriptor/Qualifier:
Adolescent
Adult
Age of Onset
Apoptosis
Biopsy / methods
Brain / metabolism,  pathology*,  ultrastructure
Caspase 3
Caspase 9
Caspases / metabolism
Cell Death
Child, Preschool
DNA-Binding Proteins / metabolism
Diffuse Cerebral Sclerosis of Schilder / complications,  pathology*
Disease Progression
Humans
In Situ Nick-End Labeling / methods
Infant
Lipids / analysis
Liver Diseases / complications,  enzymology,  pathology*
Male
Microscopy, Electron
Muscles / pathology
Nerve Degeneration / pathology*
Staining and Labeling
Viral Proteins / metabolism
Chemical
Reg. No./Substance:
0/Cox protein, Enterobacteria phage P2; 0/DNA-Binding Proteins; 0/Lipids; 0/Viral Proteins; EC 3.4.22.-/CASP3 protein, human; EC 3.4.22.-/CASP9 protein, human; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspase 9; EC 3.4.22.-/Caspases

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