摘要:

We present new data on the original Austrian kindred with Gerstmann‐Sträussler‐Scheinker disease (GSS) which encompasses currently 221 members in 9 generations. The mode of inheritance is autosomal dominant. Predominant clinical features are slowly progressive ataxia and late impairment of higher cerebral functins. In contrast, a recent case with proven P102L mutation of the PRNP gene had rapidly developing dementia and severe cortical damage indistinguishable from the clinicopathological phenotype of Creutzfeldt‐Jakob disease (CJD). PRNP codon 129 was homozygous for methionine in both the historic and recent cases. Neuropathology confirms spongiosis of variable degree and numerous protease resistant / prion protein (PrP) amyloid plaques scattered throughout most of the brain as constant features in this family. Some amyloid deposits are surrounded by dystrophic neurites with accumulation of phosphorylated neurofilaments and abnormal organelles, reminiscent of Alzheimer‐type plaques. Severe telencephalic damage and a synaptic‐type fine granular immunoreactivity in laminar distribution in the cortex with anti‐PrP after hydrated autoclaving of sections were seen only in the recent patient. In conclusion, factors in addition to the PRNP genotype at codons 102 and 129 must play a role in determining clinicopathological characteristics of this inherited brain

ISSN:1015-6305    

DOI:10.1111/j.1750-3639.1995.tb00596.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

Neuronal loss is a salient yet poorly understood feature in the pathology of transmissible spongiform encephalopathies (prion diseases). Cell culture experiments with neurotoxic prion protein fragments suggest that neuronal cell death in these diseases may be due to apoptosis. To test this hypothesis invivowe used thein situend‐labeling (ISEL) technique and electron microscopy to study cell death in an experimental scrapie system in the mouse. ISEL, which relies on the incorporation of labeled nucleotides in fragmented DNA by terminal transferase, showed labeled nuclei in the brains and retinae of mice infected with the 79A strain of scrapie, whereas no labeling was observed in control animals. In the retina the highest numbers of labeled nuclei were found in the outer nuclear layer 120 days post infection followed by massive cell loss in this layer. In the brain, labeled nuclei were mainly found in the granular layer of the cerebellum of terminally ill mice. This corresponded to the presence of small dark nuclei with condensed and occasionally fragmented chromatin at the light and electron microscopical levels. Our results support the hypothesis that neuronal loss in spongiform encephalopathies is due to apoptosis. This may explain the almost complete absence of inflammatory response in prion diseases in the face of widespread neuronal cell death, and may also have therapeutic implications in the futur

ISSN:1015-6305    

DOI:10.1111/j.1750-3639.1995.tb00597.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

Tissues from 9 horses and 1 donkey suffering from natural Borna disease were investigated immunomorphologically. Lymphocytic inflammatory reactions and increased expressions of MHC class I and class II antigen were found in the brain as well as in the trigeminal and olfactory system. Perivascular inflammatory infiltrates were dominated by CD4+ T cells, whereas the majority of CD8+ T cells were disseminated intraparenchymally. No evidence of inflammation was found in the retina. Borna disease virus proteins and nucleic acids were present in the hippocampus, thalamus and medulla oblongata in all 10 animals, in the cerebral cortex, retina, trigeminal ganglion and nerve in 9, in the olfactory epithelium in 6 and in roots and proximal parts of large peripheral nerves in 3. No evidence of infection was found in the autonomic nervous system, lung, heart, liver, kidney or gut. BDV‐ proteins and nucleic acids were even more abundant in the trigeminal system than in the olfactory system, suggesting that infection may have occured via the trigeminal nerv

ISSN:1015-6305    

DOI:10.1111/j.1750-3639.1995.tb00598.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

ISSN:1015-6305    

DOI:10.1111/j.1750-3639.1995.tb00599.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

The Hereditary Motor and Sensory Neuropathies (HMSNs) are well known to be clinically, morphologically, and genetically heterogeneous. Yet, recent advances in the cellular and molecular biology of the peripheral nervous system coupled with remarkable progress in human and mouse genetics have provided a framework that has profoundly changed our understanding of the pathogenesis of these diseases. It now appears that most of the HMSNs are related to mutations affecting genes encoding Schwann cell proteins, specifically the Peripheral Myelin Protein PMP22, Myelin Protein Zero, and one of the gap junction proteins, connexin‐32. Accordingly, these findings are discussed in the context of the clinical and pathologic features of the human HMSNs, but are interpreted in the context of basic research findings on the cellular and molecular biology of the peripheral nervous system derived fromin vivoandin vitrostudies in spontaneously‐occurring and genetically engineered animal models for the HM

ISSN:1015-6305    

DOI:10.1111/j.1750-3639.1995.tb00600.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

The twitcher is a naturally‐occurring mouse mutant caused by an abnormality in the gene coded for galactosylceramidase. It is therefore genetically equivalent to human globoid cell leukodystrophy (Krabbe disease). Affected mice develop clinical symptoms at the onset of the active myelination period and, if untreated, die by 35± days. The pathology is very similar to that in human disease. Toxicity of galactosylsphingosine (psychosine) that accumulates abnormally in the nervous system is considered to be primarily responsible for the pathogenesis. Transplantation of bone marrow cells from normal donors is partially effective and triples the life span of affected mice to 100± days with evidence of remyelination in the CNS. The mutation responsible for the twitcher mutant has recently been identified. It is expected that this model will be useful for basic studies on treatment of this group of genetic disorders affecting the brain through transgenic and/or gene therapy approac

ISSN:1015-6305    

DOI:10.1111/j.1750-3639.1995.tb00601.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

Knowledge about adrenoleukodystrophy (ALD), a disorder which was described first in 1923, has increased greatly during recent years. The principal biochemical abnormality, the presumed enzyme defect, and the gene defect, have been defined. A dietary therapy has been proposed and attracted world‐wide attention through a motion picture. Nevertheless, many questions remain and cannot be answered without a more fundamental understanding of pathology and pathogenesis. This article will provide a review of the history, clinical features, pathology, biochemistry, and the gene defect, and then appraise current efforts to clarify pathogenesis and develop therapeutic approache

ISSN:1015-6305    

DOI:10.1111/j.1750-3639.1995.tb00602.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

The recent history of Pelizaeus‐Merzbacher Disease (PMD) demonstrates paradigmatically the impact of basic biological research on clinical neurology and brain pathology: this rare and peculiar hereditary disease has become one of the best known disorders of its kind, through a cooperative research effort in neuropathology, human genetics, neurochemistry and molecular biology. PMD, a genetic dysmyelination restricted to the CNS, has been identified as a disease that involves the X chromosome‐linked gene for myelin proteolipid protein (PLP), a major structural myelin component. Today more than 30 different mutations in this gene have been defined and associated with PMD or the clinically distinct form X‐linked spastic paraplegia type‐2 (SPG‐2). Improved scanning techniques, specifically the non‐invasive magnetic resonance imaging (MRI), allow its early diagnosis in the heterogeneous group of CNS myelin deficiencies. These remarkable achievements have, at the same time, caused a problem for disease classification. Myelin disorders have been grouped in the past on the basis of clinical and neuropathological criteria, creating a system that has now to be reconciled with molecular

ISSN:1015-6305    

DOI:10.1111/j.1750-3639.1995.tb00603.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

The X chromosome‐linked PLP/DM‐20 gene is the CNS myelin gene most frequently associated with mutations, resulting in dysmyelination in several species including man (Pelizaeus‐Merzbacher disease, X‐linked Spastic Paraplegia). The pathology of most PLP gene mutations is characterized by hypomyelination, glial cell proliferation, increased numbers of microglia, and premature oligodendrocyte death. In most mutants, residual myelin structures have an abnormal ultrastructure and periodicity. Surprisingly, transgenic mice which carry extra copies of the wild type PLP gene show dysmyelination, demonstrating that the PLP gene is dosage sensitive. Pathological changes of transgenic mice vary from the phenotype of natural mutants. Specifically, many Golgi saccules of oligodendrocytes are vacuolated and the cytoplasm contains autophagic vacuoles hinting at a perturbation in protein trafficking. In fact, upon transgenic overexpression PLP becomes a prominent peripheral myelin protein, whereas in normal Schwann cells PLP is restricted from entering the myelin compartment. Surprisingly, transgenic animals which overexpress PLP/DM‐20 at a low level appear normal during early development, but later spontaneously demyelinate. The mechanisms underlying this demyelination phenotype is unknown but an immune‐mediated process has been suggested. All attempts to correct the phenotype of natural PLP mutants, such as jimpy mice, with a wild type transgene have had little effects, indicating a dominant‐negative effect of the mutant gene product. On the other hand, mice with a targeted disruption of the PLP/DM‐20 gene have suprisingly minor clinical signs. This suggests that the lethal phenotype associated with the majority of PLP gene mutations is a complex combination of loss and gain‐of‐function effects of a mu

ISSN:1015-6305    

DOI:10.1111/j.1750-3639.1995.tb00604.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY

摘要:

A large number of genetic mutants that are missing a particular myelin protein or that have an aberrant myelin protein composition have been described. These mutations usually cause dysmyelination in the PNS or CNS. Similarly, the nervous system of animals experimentally altered to block synthesis of myelin proteins have recently been generated that show aberrations in the myelin sheath. For both groups of animals, the numbers of myelinating cells remain relatively stable and glial cell death is minimal. The exception is animals with mutations in the proteolipid protein (PLP) gene which exhibit extensive death of oligodendrocytes (OLs). The degree of OL death in the PLP mutants generally correlates with the amount of dysmyelination. Dying OLs in the PLP mutants exhibit the classical features of apoptotic cells. Programmed cell death (PCD) is often, but not necessarily, manifested by cleavage of DNA into abundant oligonucleosomal fragments. Detection of these abundant DNA fragments was examined in normal and jimpy (jp) mice using the TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) method. In normal spinal cord and brain, at least twice as many cells exhibited DNA fragmentation when compared to numbers of pyknotic glia observed microscopically. In jp spinal cord and brain, roughly onehalf of cells exhibited DNA fragmentation when compared to numbers of pyknotic glia observed microscopically. PCD of cells in normal development involving DNA fragmentation has been previously described and our results support that conclusion. The data obtained from the jp mice suggests that the mechanism of apoptosis due to PLP mutations is somewhat different from that which occurs in normal development.

ISSN:1015-6305    

DOI:10.1111/j.1750-3639.1995.tb00605.x

出版商:Blackwell Publishing Ltd    

年代:1995

数据来源: WILEY