ABSTRACT
BACKGROUND AND PURPOSE: Akinetic mutism is thought to be an appropriate therapeutic end-point in patients with sporadic Creutzfeldt-Jakob disease (sCJD). However, prognostic factors for akinetic mutism are unclear and clinical signs or symptoms that precede this condition have not been defined. The goal of this study was to identify prognostic factors for akinetic mutism and to clarify the order of clinical sign and symptom development prior to its onset. METHODS: The cumulative incidence of akinetic mutism and other clinical signs and symptoms was estimated based on Japanese CJD surveillance data (455 cases) collected from 2003 to 2008. A proportional hazards model was used to identify prognostic factors for the time to onset of akinetic mutism and other clinical signs and symptoms. RESULTS: Periodic synchronous discharges on electroencephalography were present in the majority of cases (93.5%). The presence of psychiatric symptoms or cerebellar disturbance at sCJD diagnosis was associated with the development of akinetic mutism [hazard ratio (HR) 1.50, 95% confidence interval (CI) 1.14-1.99, and HR 2.15, 95% CI1.61-2.87, respectively]. The clinical course from cerebellar disturbance to myoclonus or akinetic mutism was classified into three types: (i) direct path, (ii) path via pyramidal or extrapyramidal dysfunction and (iii) path via psychiatric symptoms or visual disturbance. CONCLUSIONS: The presence of psychiatric symptoms or cerebellar disturbance increased the risk of akinetic mutism of sCJD cases with probable MM/MV subtypes. Also, there appear to be sequential associations in the development of certain clinical signs and symptoms of this disease.
Subject(s)
Creutzfeldt-Jakob Syndrome/diagnosis , Adult , Aged , Aged, 80 and over , Akinetic Mutism/epidemiology , Akinetic Mutism/etiology , Cerebellar Diseases/complications , Cerebellar Diseases/epidemiology , Creutzfeldt-Jakob Syndrome/epidemiology , Creutzfeldt-Jakob Syndrome/physiopathology , Disease Progression , Electroencephalography , Female , Humans , Incidence , Magnetic Resonance Imaging , Male , Mental Disorders/complications , Mental Disorders/epidemiology , Middle Aged , Myoclonus/epidemiology , Myoclonus/etiology , Predictive Value of Tests , PrognosisABSTRACT
BACKGROUND: It is not known whether the clinical course of Japanese sporadic Creutzfeldt-Jakob disease (sCJD) cases differs from that of Caucasian sCJD cases. PATIENTS AND METHODS: To investigate the clinical course of Japanese sCJD, clinical findings from 29 patients with Japanese MM1-type sCJD were retrospectively evaluated and compared to Caucasian sCJD findings. RESULTS: Survival of Japanese MM1-type sCJD up to the time of akinetic mutism state is similar to that of Caucasian subjects. However, the total disease duration of Japanese patients was approximately three times longer. CONCLUSIONS: The present observations indicate that Japanese sCJD cases generally show a longer disease duration because of the longer survival period after reaching the akinetic mutism state.
Subject(s)
Akinetic Mutism/ethnology , Akinetic Mutism/etiology , Creutzfeldt-Jakob Syndrome/complications , Creutzfeldt-Jakob Syndrome/ethnology , Age of Onset , Aged , Aged, 80 and over , Asian People , Creutzfeldt-Jakob Syndrome/mortality , Disease Progression , Female , Humans , Male , Middle Aged , Retrospective Studies , Time , White PeopleABSTRACT
Identification of the localization of human T lymphotrophic virus type I (HTLV-I) proviral DNA in the central nervous system (CNS) is crucial to the understanding of the pathogenesis of HTLV-I-associated myelopathy (HAM)/tropical spastic paraparesis (TSP) pathogenesis. We have developed a sensitive detection method, called two-step polymerase chain reaction (PCR) in situ hybridization, which enabled us to detect the HTLV-I proviral DNA in paraffin-embedded spinal cord tissue sections from HAM/TSP patients. HTLV-I proviral DNA was detected only in the nucleus of lymphocytes that had infiltrated into the spinal cord. However, no proviral DNA was amplified in any neuronal cells, including neurons and glial cells. This indicates that the demyelination of the spinal cord by HTLV-I as a result of viral infection of oligodendrocytes or neuronal cells is unlikely. The T cell receptor V beta gene sequence from lymphocytes in the spinal cord lesions taken from the same HAM/TSP autopsy cases revealed unique and restricted CDR3 motifs, CASSLXG(G) (one-letter amino acid. X is any amino acid), CASSPT(G), and CASSGRL which are similar to those described in T cells from brain lesions of multiple sclerosis (MS) and in a rat T cell clone derived from experimental allergic encephalomyelitis (EAE) lesions. The present results suggest that T cells containing restricted V beta CDR3 motifs, which are also found in MS and EAE, become activated upon HTLV-I infection and infiltrate into the spinal cord lesions of HAM/TSP patients.
Subject(s)
DNA, Viral/analysis , Human T-lymphotropic virus 1/genetics , Paraparesis, Tropical Spastic/microbiology , Proviruses/genetics , Receptors, Antigen, T-Cell, alpha-beta/genetics , Spinal Cord/microbiology , Adult , Aged , Amino Acid Sequence , Base Sequence , Female , Humans , Lymphocyte Activation , Male , Middle Aged , Molecular Sequence Data , Paraparesis, Tropical Spastic/immunology , Paraparesis, Tropical Spastic/pathology , Spinal Cord/immunology , Spinal Cord/pathologyABSTRACT
Treatment with intraventricular pentosan polysulphate (PPS) might be beneficial in patients with Creutzfeldt-Jakob disease. We report a 68-year-old woman with sporadic Creutzfeldt-Jakob disease who received continuous intraventricular PPS infusion (1-120 microg/kg/day) for 17 months starting 10 months after the onset of clinical symptoms. Treatment with PPS was well tolerated but was associated with a minor, transient intraventricular hemorrhage and a non-progressive collection of subdural fluid. The patient's overall survival time was well above the mean time expected for the illness but still within the normal range. Post-mortem examination revealed that the level of abnormal protease-resistant prion protein in the brain was markedly decreased compared with levels in brains without PPS treatment. These findings suggest that intraventricular PPS infusion might modify the accumulation of abnormal prion proteins in the brains of patients with sporadic Creutzfeldt-Jakob disease.
Subject(s)
Brain/metabolism , Creutzfeldt-Jakob Syndrome/drug therapy , Creutzfeldt-Jakob Syndrome/metabolism , Neuroprotective Agents/therapeutic use , Pentosan Sulfuric Polyester/therapeutic use , Prions/metabolism , Aged , Brain/diagnostic imaging , Brain/drug effects , Creutzfeldt-Jakob Syndrome/diagnostic imaging , Fatal Outcome , Female , Humans , Neuroprotective Agents/administration & dosage , Pentosan Sulfuric Polyester/administration & dosage , Time Factors , Tomography, X-Ray Computed , Treatment OutcomeABSTRACT
The phosphorylation of the human estrogen receptor (ER) serine residue at position 118 is required for full activity of the ER activation function 1 (AF-1). This Ser118 is phosphorylated by mitogen-activated protein kinase (MAPK) in vitro and in cells treated with epidermal growth factor (EGF) and insulin-like growth factor (IGF) in vivo. Overexpression of MAPK kinase (MAPKK) or of the guanine nucleotide binding protein Ras, both of which activate MAPK, enhanced estrogen-induced and antiestrogen (tamoxifen)-induced transcriptional activity of wild-type ER, but not that of a mutant ER with an alanine in place of Ser118. Thus, the activity of the amino-terminal AF-1 of the ER is modulated by the phosphorylation of Ser118 through the Ras-MAPK cascade of the growth factor signaling pathways.
Subject(s)
Calcium-Calmodulin-Dependent Protein Kinases/metabolism , Receptors, Estrogen/metabolism , Serine/metabolism , Transcriptional Activation , Amino Acid Sequence , Animals , Cell Line , Enzyme Activation , Epidermal Growth Factor/pharmacology , Estradiol/analogs & derivatives , Estradiol/pharmacology , Estrogen Antagonists/pharmacology , Humans , Mitogen-Activated Protein Kinase Kinases , Molecular Sequence Data , Mutation , Phosphorylation , Polyunsaturated Alkamides , Protein Kinases/metabolism , Protein Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins c-raf , Proto-Oncogene Proteins p21(ras)/metabolism , Receptors, Estrogen/chemistry , Receptors, Estrogen/genetics , Recombinant Fusion Proteins/metabolism , Somatomedins/pharmacology , Tamoxifen/analogs & derivatives , Tamoxifen/pharmacology , Transcriptional Activation/drug effects , TransfectionABSTRACT
We identified and characterized a novel rat vitamin D receptor isoform (rVDR1), which retains intron 8 of the canonical VDR (rVDR0) during alternative splicing. In this isoform protein directed by the stop codon in this newly identified exon, a part of the ligand binding domain (86 amino acids) is truncated at the C-terminal end but contains 19 extra amino acids. The rVDR1 transcript was expressed at a level 1/15 to 1/20 of that of rVDR0 in the kidney and intestine in adult rats but not in embryos. The recombinant rVDR1 protein showed no ligand binding activity. Homo- and heterodimers of the recombinant rVDR0 and rVDR1 proteins bound to a consensus vitamin D response element (VDRE) but not to consensus response elements for thyroid hormone and retinoic acid. However, unlike rVDR0, rVDR1 did not form a heterodimeric complex with RXR on the VDRE. A transient expression assay showed that this isoform acted as a dominant negative receptor against rVDR0 transactivation. Interestingly, the dominant negative activities of rVDR1 differed among VDREs. Thus, the present study indicates that this new VDR isoform negatively modulates the vitamin D signaling pathway, through a particular set of target genes.
Subject(s)
Alternative Splicing , Introns , Receptors, Calcitriol/genetics , Receptors, Calcitriol/physiology , Vitamin D/metabolism , Amino Acid Sequence , Animals , Base Sequence , Calcitriol/metabolism , Chloramphenicol O-Acetyltransferase/biosynthesis , Embryo, Mammalian , HeLa Cells , Humans , Intestinal Mucosa/metabolism , Kidney/metabolism , Molecular Sequence Data , Oligonucleotide Probes , Polymerase Chain Reaction , Rats , Receptors, Calcitriol/biosynthesis , Receptors, Retinoic Acid/physiology , Recombinant Fusion Proteins/metabolism , Restriction Mapping , Retinoid X Receptors , Signal Transduction , Transcription Factors/physiology , Transcription, Genetic , TransfectionABSTRACT
Fatty acid synthetase was isolated from the Harderian gland of guinea-pig. The fatty acids synthesized by the purified enzyme were analyzed by mass fragmentography. The purified enzyme had an inherent capacity to utilize methylmalonyl-CoA and synthesize methyl-branched fatty acids. Physicochemical studies indicated that an active enzyme was a dimer, consisted of two subunits of Mr = 2.5 X 10(5). The negatively stained enzyme had an electron micrographic image of an ellipsoidal contour with a continuous middle cleft along the major axis. The major and minor axes were approximately equal to 220 and 150 A, respectively. In a dimer, the subunit had a rod-like structure about 220 A long and 50 A wide. The enzyme was inactivated and dissociated into subunits by incubation at 0 degree C. The inactivated enzyme was fully reactivated by raising the temperature of the solution. The relationship between the quaternary structure of the enzyme and the occurrence of enzymatic activity was studied by high-performance liquid chromatography. Neither active monomers nor inactive dimers were found in inactivation and reactivation processes. The initial velocity of reactivation was proportional to the enzyme concentration over a concentration range of 160-800 micrograms/ml, indicating that the rate-determining step in the reactivation reaction was unimolecular.
Subject(s)
Fatty Acid Synthases/metabolism , Harderian Gland/enzymology , Lacrimal Apparatus/enzymology , Amino Acids/analysis , Animals , Circular Dichroism , Fatty Acid Synthases/antagonists & inhibitors , Fatty Acid Synthases/isolation & purification , Guinea Pigs , Macromolecular Substances , Microscopy, Electron , Protein ConformationABSTRACT
Limited proteolysis and electron microscopic observation of fatty acid synthetase from the Harderian gland of guinea pig was performed to elucidate the higher-order structures of this multifunctional protein. Staphylococcus aureus V8 protease dissected the 250,000 Mr subunit of fatty acid synthetase into 120,000, 70,000, 35,000 and 30,000 Mr fragments, which were aligned in this order from the NH2 terminus. Some of the protease-resistant fragments produced with elastase, trypsin and lysyl endopeptidase were purified and fragment-specific antibodies (A40L, A33E and A25T) were prepared. A25T and A33F specifically bound the 35,000 and 30,000 Mr fragments, and A40L recognized the region between the 120,000 and 70,000 Mr fragments. Electron microscopic studies employing rotary shadowing, unidirectional shadowing and negative staining revealed that the overall dimension of the enzyme was 22 nm x 15 nm x 7 nm, and that two elongated subunits mainly composed of three subregions were in contact with each other at a few, three at most, points with two holes between them. The outer two attachment sites were often not in contact, indicating a certain flexibility of subunits at their ends. Immunocomplexes composed of fatty acid synthetase and fragment-specific antibodies were isolated and observed under the electron microscope. The attachment sites of A40L and A33E were located at the end of the minor and the major axes of the ellipsoidal contour of the molecule, respectively. Based on these results, the three-dimensional structure of animal fatty acid synthetase is discussed.
Subject(s)
Fatty Acid Synthases/metabolism , Harderian Gland/metabolism , Lacrimal Apparatus/metabolism , Amino Acid Sequence , Animals , Antibodies/metabolism , Binding Sites , Guinea Pigs , Hydrolysis , Immunoblotting , Microscopy, Electron , Molecular Sequence DataABSTRACT
Clinico-pathological phenotypes of patients with prion diseases were compared with their PrP genotypes and transmission rate to mice. Sporadic and iatrogenic CJD patients without mutation and familial CJD patients with E200K showed uniform clinico-pathological features, synaptic-type deposition of PrPCJD and high rate of transmission of the disease to mice. GSS patients with P102L showed long duration of ataxia, numerous plaques in cerebellar cortex and transmitted the disease to mice in only one third of inoculated cases. Other mutations such as P105L, A117V, Y145stop, V180I, M232R and various insertions have particular phenotypes, distinct distribution patterns of PrPCJD, and untransmitted or inconclusive transmission to mice. Polymorphism at codon 129 may modify the phenotypes and transmission rate to mice. Therefore, prion diseases have a wide range from infectious disease to non-infectious, hereditary metabolic disease.
Subject(s)
Creutzfeldt-Jakob Syndrome/genetics , Creutzfeldt-Jakob Syndrome/transmission , Prion Diseases/genetics , Prion Diseases/transmission , Prions/metabolism , Animals , Humans , Immunohistochemistry , Mice , Mutation , Point Mutation , PrPSc Proteins/analysis , PrPSc Proteins/metabolism , Prion Diseases/pathology , Prions/analysisABSTRACT
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 functions. 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 amyloidosis.
Subject(s)
Gerstmann-Straussler-Scheinker Disease/genetics , Gerstmann-Straussler-Scheinker Disease/pathology , Adult , Austria , Base Sequence , Brain/pathology , Female , Genotype , Humans , Male , Middle Aged , Molecular Sequence Data , Pedigree , PhenotypeABSTRACT
Urocortin is a recently identified neuropeptide of the CRF family in the mammalian brain, but its expression in human tissue has been little studied. In this study, we examined urocortin expression in human anterior pituitary gland and pituitary adenomas by RIA, high performance liquid chromatography, immunohistochemistry, messenger ribonucleic acid (mRNA) in situ hybridization, and reverse transcriptase-PCR. Immunoreactive urocortin concentrations in normal pituitary tissue extract were 103.25 +/- 39.05 ng/g wet wt (mean +/- SEM; n = 4), and their levels were all significantly higher than those in other portions of central nervous system of the same subjects. High performance liquid chromatography analysis of human pituitary extract demonstrated a single peak corresponding to that of the expected chromatographic mobility of synthetic human urocortin-(1-40). Urocortin-immunoreactive cells were detected in the anterior pituitary gland. Neither urocortin-immunoreactive nerve fibers nor cells were detected in the posterior lobe. Immunostaining in serial mirror tissue sections revealed that 76.55 +/- 3.06% of urocortin-immunoreactive cells expressed GH immunoreactivity, whereas 22.25 +/- 3.02% and less than 1% of urocortin-immunoreactive cells expressed PRL and ACTH, respectively. mRNA hybridization signals of urocortin were also detected in urocortin-immunopositive pituitary cells. The reverse transcriptase-PCR analysis demonstrated a 145-bp RNA band corresponding to that of the expected length of urocortin in all cases of normal pituitary glands examined (n = 3). We also immunostained urocortin in 52 cases of human anterior pituitary adenomas, including GH-producing adenomas (n = 14), ACTH-producing adenomas (n = 13), PRL-producing adenomas (n = 11), and nonfunctioning hormonally inactive adenomas (n = 14). No urocortin immunoreactivity was detected in these adenoma cells, except for one case of GH-producing adenoma and one case of nonfunctioning adenoma. We also performed mRNA in situ hybridization in 27 adenomas. No hybridization signals were detected in these adenomas, except in two cases. The results described above indicated that urocortin is synthesized in human anterior pituitary cells and may play an important role in biological features of normal pituitary gland, possibly as an autocrine or a paracrine regulator
Subject(s)
Adenoma/metabolism , Corticotropin-Releasing Hormone/genetics , Gene Expression , Pituitary Gland, Anterior/metabolism , Pituitary Neoplasms/metabolism , Adult , Aged , Brain Chemistry , Chromatography, High Pressure Liquid , Corticotropin-Releasing Hormone/analysis , Female , Humans , Immunohistochemistry , In Situ Hybridization , Male , Middle Aged , Polymerase Chain Reaction , RNA, Messenger/analysis , RNA-Directed DNA Polymerase , Radioimmunoassay , Tissue Distribution , UrocortinsABSTRACT
We have analyzed the cis-regulatory regions in the 5' flanking DNA of the Drosophila melanogaster choline acetyltransferase (ChAT; E.C. 2.3.1.6) gene by using germline transformants. These transformants are carrying wild-type ChAT cDNA fused to different lengths of 5' flanking sequence of the ChAT gene. Appropriate genetic crosses were used to introduce the transgene into animals with a presumptive null genetic background for endogenous ChAT. Expression of ChAT protein could thus be attributed exclusively to the transgene. Using a monoclonal antibody against Drosophila ChAT, we have investigated the spatial distribution of transgenic ChAT and compared it to the normal distribution of ChAT protein in wild-type animals. The brains of 7.4 kb cDNA transformants showed a ChAT expression pattern similar to that of wild-type animals in the first- and second-order sensory neuropil but reduced expression in other highly ordered neuropil. Several lines that were transformed with 1.2 kb or 0.8 kb of 5' flanking DNA demonstrated relatively normal expression in sensory neuropil. In addition, these lines also showed ectopic expression in higher order neuropil. In the optic lobe, the expression pattern directed by 7.4 kb of 5' flanking DNA was very similar to that of wild-type ChAT expression. In contrast, 1.2 kb or 0.8 kb transformants showed reduced levels of expression and a more limited pattern of distribution in the optic lobe. Our results suggest that the 5' flanking DNA of the ChAT gene can be divided into several separable positive and negative regulatory regions, which define various subsets of cholinergic neurons in the nervous system.
Subject(s)
Choline O-Acetyltransferase/genetics , DNA, Complementary/genetics , Drosophila melanogaster/enzymology , Gene Expression Regulation, Enzymologic/physiology , Regulatory Sequences, Nucleic Acid , Transformation, Genetic , Animals , Animals, Genetically Modified , Behavior, Animal/physiology , Choline O-Acetyltransferase/analysis , Genes, Reporter , Immunohistochemistry , Optic Lobe, Nonmammalian/enzymology , Phenotype , Reference ValuesABSTRACT
A 53-year-old man with nonfamilial prealbumin-type amyloid polyneuropathy had severe motor, sensory, and autonomic polyneuropathy, beginning at age 48 years. These clinical features closely resembled familial amyloid polyneuropathy (FAP), but abnormal serum prealbumin levels, specific to FAP (Japanese type), were not detected by radioimmunoassay; DNA sequence for prealbumin was normal. Thus, the diagnosis of FAP was excluded. A possible diagnosis of systemic senile amyloidosis was also considered.
Subject(s)
Amyloidosis/physiopathology , Peripheral Nervous System Diseases/physiopathology , Prealbumin/metabolism , Electromyography , Humans , Japan , Male , Middle Aged , Sural Nerve/pathologyABSTRACT
BACKGROUND: Many reported cases of iatrogenic Creutzfeldt-Jakob disease (CJD) developed after grafting cadaveric dura mater contaminated with CJD prions (dura-associated CJD). They are known to be clinicopathologically similar to sporadic CJD. We report herein 2 autopsy cases of dura-associated CJD with atypical clinicopathological features. PATIENTS: Two patients presented with progressive ataxia and mental deterioration 10 or 11 years after neurosurgical treatment with cadaveric dural grafting, which led to their deaths at 8 and 17 months, respectively, after onset. RESULTS: The cases were clinically atypical in exhibiting no or late occurrence of myoclonus and periodic synchronous discharges on electroencephalographic studies. They were pathologically unique in several aspects. The most striking feature was the presence of many prion protein (PrP) plaques in multiple areas in the brain. Some of them were the "florid" type surrounded by a zone of spongiform changes known to be a hallmark for the new variant CJD. The distribution of spongiform degeneration was also unique in that it was intense in the thalamus, basal ganglia, and the dentate nuclei of the cerebellum but milder in the cerebrum. There were no mutations in the PrP gene of the patients. There was no major difference in the size and glycoform pattern between the abnormal isoform of PrP extracted from the brain tissue from the dura-associated cases of CJD and that from a sporadic case of CJD. CONCLUSIONS: These 2 cases are clinicopathologically distinct from typical dura-associated cases of CJD. They may be a subtype with florid-type plaques in dura-associated CJD.
Subject(s)
Creutzfeldt-Jakob Syndrome/etiology , Dura Mater/transplantation , Iatrogenic Disease , Aged , Autopsy , Brain/pathology , Cadaver , Creutzfeldt-Jakob Syndrome/pathology , Female , Humans , Male , Prions/geneticsABSTRACT
Fatal familial insomnia (FFI), or familial selective thalamic degeneration with a mutation at codon 178 of the prion protein (PrP) gene, is a rapidly progressive autosomal dominant disease characterized by progressive insomnia, dysautonomia, and myoclonus. We report here the clinical and postmortem findings as well as genomic analysis in a first non-Western case with FFI. This patient also clinically had cognitive impairments such as memory disturbance, delirium, and hallucinations, along with insomnia, dysautonomia, and myoclonus. This case implies a worldwide distribution of FFI and also highlights the need for more aggressive clinical application of genomic analysis of the PrP gene and polysomnographic study in patients with insomnia and cognitive impairments.
Subject(s)
Prion Diseases/genetics , Prions/genetics , Humans , Japan , Male , Middle Aged , MutationABSTRACT
Kuru plaques are the pathologic hallmark in Gerstmann-Sträussler syndrome (GSS). To demonstrate that prion protein (PrP) is a component of kuru plaque cores, we fractionated and sequenced kuru plaque core derived peptides, following digestion with Achromobacter lyticus protease I. We identified 3 PrP-derived peptides by reverse-phase high-performance liquid chromatography and found a fragment of digests derived from a missense variant of PrP. The variant PrP was also present in the prion rod fraction in patients with GSS. This substitution may play a major role in cerebral amyloidogenesis.
Subject(s)
Gerstmann-Straussler-Scheinker Disease/metabolism , Viral Proteins/metabolism , Amino Acid Sequence , Chromatography, High Pressure Liquid/methods , Creutzfeldt-Jakob Syndrome/metabolism , Creutzfeldt-Jakob Syndrome/pathology , Genetic Variation , Gerstmann-Straussler-Scheinker Disease/pathology , Humans , PrPSc Proteins , Prions/metabolism , Viral Proteins/geneticsABSTRACT
Sporadic Creutzfeldt-Jakob disease (CJD) with 129M/M, and iatrogenic and familial CJD with E200K and M232R, showed similar clinicopathologic features, a synaptic type deposition of PrPCJD, and high transmission frequencies to mice. Sporadic patients with 129M/V or 129V/V, and mutation cases with V180I, showed slightly different features and low or null transmission frequencies to mice. Hereditary cases with P102L, P105L, A117V, Y145stop, and insertions had different features but all demonstrated a long clinical duration and the presence of PrP plaques. The experimental transmission to mice of these mutant forms was difficult, except for one-third of the cases with P102L. CJD and related diseases, even those that are hereditary, may thus be divided into two different groups, those that are easily transmissible and those that are either difficult to transmit or nontransmissible.
Subject(s)
Creutzfeldt-Jakob Syndrome/genetics , Creutzfeldt-Jakob Syndrome/transmission , Zoonoses , Adult , Age of Onset , Aged , Animals , Brain Tissue Transplantation/adverse effects , Codon , Creutzfeldt-Jakob Syndrome/physiopathology , Cricetinae , Electroencephalography , Female , Genotype , Guinea Pigs , Homozygote , Humans , Iatrogenic Disease , Male , Mice , Middle Aged , Point Mutation , Prions/analysis , Rats , Time FactorsABSTRACT
We report the first Japanese case of familial Creutzfeldt-Jakob disease (CJD) with the heterozygous point mutation at codon 200 of the prion protein gene. This suggests that the mutation is not race-specific. The clinical and pathologic features of this case are not different from those of sporadic CJD without point mutations. Some healthy members of the family also carry the same mutation in the autosomal dominant inheritance expression.
Subject(s)
Creutzfeldt-Jakob Syndrome/genetics , Point Mutation , Prions/genetics , Adolescent , Adult , Cerebellum/metabolism , Cerebellum/pathology , Codon , Creutzfeldt-Jakob Syndrome/pathology , DNA/blood , Deoxyribonucleases, Type II Site-Specific , Female , Genetic Variation , Humans , Immunohistochemistry , Japan , Lymphocytes/metabolism , Lysine , Male , Middle Aged , Pedigree , Polymerase Chain Reaction , PrPSc Proteins , Prions/analysisABSTRACT
Using immunostaining with anti-prion protein (PrP) antiserum, we detected numerous kuru plaques in the brain of a 24-year-old man with Gerstmann-Sträussler-Scheinker syndrome. Immunoreactivity on Western blotting of the protease-resistant PrP fraction from the frozen brain was weak. PrP gene analysis showed substitution of alanine to valine in codon 117 but no substitution in codon 102. As the experimental transmission of the disease to mice was negative, a pathogen of a relatively low infectivity may cause the disease in predisposed family members.
Subject(s)
Gerstmann-Straussler-Scheinker Disease/physiopathology , Adult , Alleles , Blotting, Western , Genes , Gerstmann-Straussler-Scheinker Disease/metabolism , Gerstmann-Straussler-Scheinker Disease/transmission , Humans , Immunohistochemistry/methods , Male , Molecular Biology , PrPSc Proteins , Prions/genetics , Prions/metabolism , Staining and Labeling , Viral Proteins/genetics , Viral Proteins/metabolismABSTRACT
OBJECTIVE: To clarify a clinical and neuropathologic phenotype of an inherited prion disease associated with a missense mutation at codon 105 in the prion protein (PrP) gene that was originally described as a variant of Gerstmann-Sträussler-Scheinker disease demonstrating spastic paraparesis. METHODS: Two siblings from a Japanese family are described. PrP gene analyses, neuropathologic studies with immunohistochemistry, and Western blot analysis of the PrP were performed. RESULTS: Both patients showed a missense (proline-->leucine) mutation at codon 105 and a methionine/valine polymorphism at codon 129 of the PrP gene. Clinically, Patient 1 presented with progressive spastic paraparesis, ataxia, and dementia. Patient 2, the sister of Patient 1, showed prominent action myoclonus and dementia. Neuropathologically, multiple PrP-positive amyloid plaques and diffuse PrP deposition in the deep cortical layers were found in the cerebral cortex with primarily frontal dominant atrophy in both patients. Tau-positive pathologic structures including neurofibrillary tangles, neuropil threads, and dystrophic neurites around the plaques were abundant in the brain of Patient 2. In contrast, the tau pathology was scarce in Patient 1. Western blot analysis of the brain showed different patterns of detergent-insoluble PrP fragments between the patients. CONCLUSIONS: Despite the identical codon 105 mutation and codon 129 polymorphism of the PrP gene, remarkable clinical and neuropathologic differences, and PrP heterogeneity were present between the affected siblings. The phenotypic variability might be related to PrP heterogeneity.