The abnormal misfolded isoform of prion protein (PrPd; "d" for disease) is considered a... more The abnormal misfolded isoform of prion protein (PrPd; "d" for disease) is considered as a surrogate marker for infectivity in the transmissible spongiform encephalopathies (TSEs) or prion diseases, including Creutzfeldt-Jakob disease (CJD). In this experiment, we used intraocular inoculation to study PrPd deposition in the visual system of the brain of mice infected with the Fujisaki (K.Fu) strain of Gerstmann-Sträussler-Scheinker (GSS) disease. We report here that PrPd is deposited in the superior colliculus following contralateral intraocular inoculation and thus follows neuronal connections when it spreads into the brain. Until 26 weeks postinoculation, no PrPd-specific immunostaining was observed in the brain. At 27 weeks postinoculation, PrPd targeted to the contralateral superior colliculus as delicate granular synaptic deposits located in the superficial part of this structure. As already reported, a few spongiform vacuoles were visible in the same area by conventi...
The epidemics of classical bovine spongiform encephalopathy (BSE) and variant Creutzfeldt-Jakob d... more The epidemics of classical bovine spongiform encephalopathy (BSE) and variant Creutzfeldt-Jakob disease (vCJD) related to BSE-infected food are coming to an end. The decline in concern about these diseases may invite complacency and questions whether surveillance for human prion diseases is still necessary. This article reviews the main points of surveillance and why it is still needed: animal sources for human prion infection other than BSE cannot be excluded; the potentially increasing circulation of prions between humans by blood, blood products and medical procedures; the prevalence of vCJD prion carriers in the UK; and the scientific study of prion diseases as paradigm for other neurodegenerative diseases with "prion-like" spread of pathological proteins. We conclude that continuation of detailed surveillance of human prion disorders would be prudent in view of all these points that deserve clarification.
Pathological accumulation of abnormally phosphorylated tau protein in astrocytes is a frequent, b... more Pathological accumulation of abnormally phosphorylated tau protein in astrocytes is a frequent, but poorly characterized feature of the aging brain. Its etiology is uncertain, but its presence is sufficiently ubiquitous to merit further characterization and classification, which may stimulate clinicopathological studies and research into its pathobiology. This paper aims to harmonize evaluation and nomenclature of aging-related tau astrogliopathy (ARTAG), a term that refers to a morphological spectrum of astroglial pathology detected by tau immunohistochemistry, especially with phosphorylation-dependent and 4R isoform-specific antibodies. ARTAG occurs mainly, but not exclusively, in individuals over 60 years of age. Tau-immunoreactive astrocytes in ARTAG include thorn-shaped astrocytes at the glia limitans and in white matter, as well as solitary or clustered astrocytes with perinuclear cytoplasmic tau immunoreactivity that extends into the astroglial processes as fine fibrillar or ...
Annals of clinical and translational neurology, 2014
To identify the prevalence of MRI features of Binswanger's disease (BD), specifically MRI wit... more To identify the prevalence of MRI features of Binswanger's disease (BD), specifically MRI with diffuse white matter lesions and scattered multiple lacunes (BD-MRI), and to describe neurological features and pathological outcomes of a community-based cohort study. Of 697 participants (all 75 years old), 503 completed neurological examinations at baseline and were followed-up every 30 months thereafter with MRIs, the mini-mental state examination (MMSE) and the Unified Parkinson Disease Rating Scale-Motor Section (UPDRSM). Data from participants with BD-MRI were compared with those from participants with predominant white matter lesions (WML-MRI), scattered multiple lacunes (ML-MRI), or normal MRIs. Fourteen BD-MRI patients (2.8%) were detected at baseline. The mean MMSE scores in the BD-MRI, WML-MRI, ML-MRI, and normal MRIs groups were 26.4, 28.2, 28.4, and 28.5, respectively, and the mean UPDRSM scores were 9.1, 1.3, 3.1, and 1.7, respectively. At the 30-month follow-up, mortali...
Proceedings of the National Academy of Sciences, 1998
The clinicopathological phenotype of the Gerstmann–Sträussler–Scheinker disease (GSS) variant lin... more The clinicopathological phenotype of the Gerstmann–Sträussler–Scheinker disease (GSS) variant linked to the codon 102 mutation in the prion protein (PrP) gene (GSS P102L) shows a high heterogeneity. This variability also is observed in subjects with the same prion protein gene PRNP haplotype and is independent from the duration of the disease. Immunoblot analysis of brain homogenates from GSS P102L patients showed two major protease-resistant PrP fragments (PrP-res) with molecular masses of ≈21 and 8 kDa, respectively. The 21-kDa fragment, similar to the PrP-res type 1 described in Creutzfeldt–Jakob disease, was found in five of the seven subjects and correlated with the presence of spongiform degeneration and “synaptic” pattern of PrP deposition whereas the 8-kDa fragment, similar to those described in other variants of GSS, was found in all subjects in brain regions showing PrP-positive multicentric amyloid deposits. These data further indicate that the neuropathology of prion dis...
Background: Viral encephalitis is a medical emergency. The prognosis depends mainly on the patho... more Background: Viral encephalitis is a medical emergency. The prognosis depends mainly on the pathogen and host immunologic state. Correct immediate diagnosis and introduction of symptomatic and specific therapy has a dramatic influence upon survival and reduces the extent of permanent brain injury.Methods: We searched the literature from 1966 to 2009. Recommendations were reached by consensus. Where there was lack of evidence but consensus was clear, we have stated our opinion as good practice points.Recommendations: Diagnosis should be based on medical history and examination followed by CSF analysis for protein and glucose levels, cellular analysis, and identification of the pathogen by polymerase chain reaction amplification (recommendation level A) and serology (level B). Neuroimaging, preferably by MRI, is essential (level B). Lumbar puncture can follow neuroimaging when immediately available, but if this cannot be performed immediately, LP should be delayed only under unusual...
Viral encephalitis is a medical emergency. The spectrum of brain involvement and the prognosis ar... more Viral encephalitis is a medical emergency. The spectrum of brain involvement and the prognosis are dependent mainly on the specific pathogen and the immunological state of the host. Although specific therapy is limited to only several viral agents, correct immediate diagnosis and introduction of symptomatic and specific therapy has a dramatic influence upon survival and reduces the extent of permanent brain injury in survivors. We searched MEDLINE (National Library of Medicine) for relevant literature from 1966 to May 2004. Review articles and book chapters were also included. Recommendations are based on this literature based on our judgment of the relevance of the references to the subject. Recommendations were reached by consensus. Where there was lack of evidence but consensus was clear we have stated our opinion as good practice points. Diagnosis should be based on medical history, examination followed by analysis of cerebrospinal fluid for protein and glucose contents, cellula...
ABSTRACT Phenotypic heterogeneity in sporadic Creutzfeldt-Jakob disease (sCJD) is well documented... more ABSTRACT Phenotypic heterogeneity in sporadic Creutzfeldt-Jakob disease (sCJD) is well documented, but there is not yet a systematic classification of the disease variants. In a previous study, we showed that the polymorphic codon 129 of the prion protein gene (PRNP), and two types of protease-resistant prion protein (PrPSc) with distinct physicochemical properties, are major determinants of these variants. To define the full spectrum of variants, we have examined a series of 300 sCJD patients. Clinical features, PRNP genotype, and PrPSc properties were determined in all subjects. In 187, we also studied neuropathological features and immunohistochemical pattern of PrPSc deposition. Seventy percent of subjects showed the classic CJD phenotype, PrPSc type 1, and at least one methionine allele at codon 129; 25% of cases displayed the ataxic and kuru-plaque variants, associated to PrPSc type 2, and valine homozygosity or heterozygosity at codon 129, respectively. Two additional variants, which included a thalamic form of CJD and a phenotype characterized by prominent dementia and cortical pathology, were linked to PrPSc type 2 and methionine homozygosity. Finally, a rare phenotype characterized by progressive dementia was linked to PrPSc type 1 and valine homozygosity. The present data demonstrate the existence of six phenotypic variants of sCJD. The physicochemical properties of PrPSc in conjunction with the PRNP codon 129 genotype largely determine this phenotypic variability, and allow a molecular classification of the disease variants. Ann Neurol 1999;46:224–233
Deposition of alpha-synuclein in the brain is a hallmark of Lewy body disorders. Alpha-synuclein ... more Deposition of alpha-synuclein in the brain is a hallmark of Lewy body disorders. Alpha-synuclein has been considered to show prion-like properties. Prion diseases can be transmitted by the transplantation of cadaveric dura mater causing iatrogenic Creutzfeldt-Jakob disease. Recent observations of amyloid-β deposition in dural grafts support the seeding properties of amyloid-β. Here we assessed the presence of alpha-synuclein in dura mater samples as a potential transmissible seed source. We immunostained 32 postmortem dura mater samples; 16 cases with Lewy-body disorder (LBD) showing different pathology stages and 16 non-LBD cases for phosphorylated (Ser129) and disease-associated (5G4) alpha-synuclein. Disease-associated alpha-synuclein aggregates were identified in intradural nerve fibres and associated with a vessel in a single LBD-Braak stage 4 case. We conclude that alpha-synuclein is detectable, although rarely, in dura mater samples in patients with LBD. The risk of potential...
To characterize the brain-infiltrating immune cell repertoire in Rasmussen encephalitis (RE) with... more To characterize the brain-infiltrating immune cell repertoire in Rasmussen encephalitis (RE) with special focus on the subsets, clonality, and their cytokine profile. The immune cell infiltrate of freshly isolated brain tissue from RE was phenotypically and functionally characterized using immunohistology, flow cytometry, and T-cell receptor (TCR) deep sequencing. Identification of clonally expanded T-cell clones (TCCs) was achieved by combining flow cytometry sorting of CD4+ and CD8+ T cells and high-throughput TCR Vβ-chain sequencing. The most abundant brain-infiltrating TCCs were isolated and functionally characterized. We found that CD4+, CD8+, and also γδ T cells infiltrate the brain tissue in RE. Further analysis surprisingly revealed that not only brain-infiltrating CD8+ but also CD4+ T cells are clonally expanded in RE. All 3 subsets exhibited a Tc1/Th1 phenotype characterized by the production of interferon (IFN)-γ and TNF. Broad cytokine profiling at the clonal level showe...
Journal of neuropathology and experimental neurology, 2015
Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the CNS with severe involv... more Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the CNS with severe involvement of the optic nerve and spinal cord. Highly specific serum IgG autoantibodies (NMO-IgG) that react with aquaporin-4 (AQP4), the most abundant CNS water channel protein, are found in patients with NMO. However, in vivo evidence combining the results of AQP4 antibody serum levels and brain pathology is lacking. We report a patient with NMO whose AQP4 antibody levels decreased simultaneously with clinical deterioration caused by the development of a tumor-like brain lesion. In the seminecrotic biopsied brain lesion, there was activated complement complex, whereas only very scattered immunoreactivity to AQP4 protein was detectable. The decrease in serum AQP4 antibody levels and the loss of AQP4 in the tumor-like lesion could represent a "serum antibody-consuming effect" during lesion formation.
Spinal muscular atrophy (SMA) is a neuromuscular disorder in childhood leading to a dramatic loss... more Spinal muscular atrophy (SMA) is a neuromuscular disorder in childhood leading to a dramatic loss of muscle strength. Functional investigations with high-resolution polarography and enzyme measurements of the respiratory chain revealed lowered activities in muscle tissue of SMA patients. To gain a better understanding of this low energy supply we analyzed the amount of mitochondrial DNA (mtDNA) in skeletal muscle of 20 unrelated children with genetically proven SMA and 31 controls. Quantitative Southern blot analysis revealed a severe and homogeneous decrease in the content of muscle mtDNA in relation to nuclear DNA in SMA patients (90.3+/-7.8%), whereas by immunofluorescence no decrease in the number of mitochondria was detected. In addition, a two- to threefold reduction of the nuclear-encoded complex II (succinate dehydrogenase) activity was detected in SMA muscle tissue. Western blot analysis showed a significant reduction of both mitochondrial- and nuclear-encoded cytochrome c ...
We describe a novel transthyretin mutation at codon 18 where Asp is replaced by Gly (D18G) in a H... more We describe a novel transthyretin mutation at codon 18 where Asp is replaced by Gly (D18G) in a Hungarian kindred. This mutation is associated with meningocerebrovascular amyloidosis, producing dementia, ataxia, and spasticity. Fifty different transthyretin mutations are related to amyloid deposition, typically producing a peripheral neuropathy or cardiac dysfunction. These symptoms are absent in this family. Up to now, amyloid-beta (A beta), cystatin C, and prion proteins have been known to be deposited as amyloid in the brain, leading to stroke or dementia. With this report we establish that transthyretin amyloid deposition can also produce central nervous system dysfunction as the major clinical symptom.
The abnormal misfolded isoform of prion protein (PrPd; "d" for disease) is considered a... more The abnormal misfolded isoform of prion protein (PrPd; "d" for disease) is considered as a surrogate marker for infectivity in the transmissible spongiform encephalopathies (TSEs) or prion diseases, including Creutzfeldt-Jakob disease (CJD). In this experiment, we used intraocular inoculation to study PrPd deposition in the visual system of the brain of mice infected with the Fujisaki (K.Fu) strain of Gerstmann-Sträussler-Scheinker (GSS) disease. We report here that PrPd is deposited in the superior colliculus following contralateral intraocular inoculation and thus follows neuronal connections when it spreads into the brain. Until 26 weeks postinoculation, no PrPd-specific immunostaining was observed in the brain. At 27 weeks postinoculation, PrPd targeted to the contralateral superior colliculus as delicate granular synaptic deposits located in the superficial part of this structure. As already reported, a few spongiform vacuoles were visible in the same area by conventi...
The epidemics of classical bovine spongiform encephalopathy (BSE) and variant Creutzfeldt-Jakob d... more The epidemics of classical bovine spongiform encephalopathy (BSE) and variant Creutzfeldt-Jakob disease (vCJD) related to BSE-infected food are coming to an end. The decline in concern about these diseases may invite complacency and questions whether surveillance for human prion diseases is still necessary. This article reviews the main points of surveillance and why it is still needed: animal sources for human prion infection other than BSE cannot be excluded; the potentially increasing circulation of prions between humans by blood, blood products and medical procedures; the prevalence of vCJD prion carriers in the UK; and the scientific study of prion diseases as paradigm for other neurodegenerative diseases with "prion-like" spread of pathological proteins. We conclude that continuation of detailed surveillance of human prion disorders would be prudent in view of all these points that deserve clarification.
Pathological accumulation of abnormally phosphorylated tau protein in astrocytes is a frequent, b... more Pathological accumulation of abnormally phosphorylated tau protein in astrocytes is a frequent, but poorly characterized feature of the aging brain. Its etiology is uncertain, but its presence is sufficiently ubiquitous to merit further characterization and classification, which may stimulate clinicopathological studies and research into its pathobiology. This paper aims to harmonize evaluation and nomenclature of aging-related tau astrogliopathy (ARTAG), a term that refers to a morphological spectrum of astroglial pathology detected by tau immunohistochemistry, especially with phosphorylation-dependent and 4R isoform-specific antibodies. ARTAG occurs mainly, but not exclusively, in individuals over 60 years of age. Tau-immunoreactive astrocytes in ARTAG include thorn-shaped astrocytes at the glia limitans and in white matter, as well as solitary or clustered astrocytes with perinuclear cytoplasmic tau immunoreactivity that extends into the astroglial processes as fine fibrillar or ...
Annals of clinical and translational neurology, 2014
To identify the prevalence of MRI features of Binswanger's disease (BD), specifically MRI wit... more To identify the prevalence of MRI features of Binswanger's disease (BD), specifically MRI with diffuse white matter lesions and scattered multiple lacunes (BD-MRI), and to describe neurological features and pathological outcomes of a community-based cohort study. Of 697 participants (all 75 years old), 503 completed neurological examinations at baseline and were followed-up every 30 months thereafter with MRIs, the mini-mental state examination (MMSE) and the Unified Parkinson Disease Rating Scale-Motor Section (UPDRSM). Data from participants with BD-MRI were compared with those from participants with predominant white matter lesions (WML-MRI), scattered multiple lacunes (ML-MRI), or normal MRIs. Fourteen BD-MRI patients (2.8%) were detected at baseline. The mean MMSE scores in the BD-MRI, WML-MRI, ML-MRI, and normal MRIs groups were 26.4, 28.2, 28.4, and 28.5, respectively, and the mean UPDRSM scores were 9.1, 1.3, 3.1, and 1.7, respectively. At the 30-month follow-up, mortali...
Proceedings of the National Academy of Sciences, 1998
The clinicopathological phenotype of the Gerstmann–Sträussler–Scheinker disease (GSS) variant lin... more The clinicopathological phenotype of the Gerstmann–Sträussler–Scheinker disease (GSS) variant linked to the codon 102 mutation in the prion protein (PrP) gene (GSS P102L) shows a high heterogeneity. This variability also is observed in subjects with the same prion protein gene PRNP haplotype and is independent from the duration of the disease. Immunoblot analysis of brain homogenates from GSS P102L patients showed two major protease-resistant PrP fragments (PrP-res) with molecular masses of ≈21 and 8 kDa, respectively. The 21-kDa fragment, similar to the PrP-res type 1 described in Creutzfeldt–Jakob disease, was found in five of the seven subjects and correlated with the presence of spongiform degeneration and “synaptic” pattern of PrP deposition whereas the 8-kDa fragment, similar to those described in other variants of GSS, was found in all subjects in brain regions showing PrP-positive multicentric amyloid deposits. These data further indicate that the neuropathology of prion dis...
Background: Viral encephalitis is a medical emergency. The prognosis depends mainly on the patho... more Background: Viral encephalitis is a medical emergency. The prognosis depends mainly on the pathogen and host immunologic state. Correct immediate diagnosis and introduction of symptomatic and specific therapy has a dramatic influence upon survival and reduces the extent of permanent brain injury.Methods: We searched the literature from 1966 to 2009. Recommendations were reached by consensus. Where there was lack of evidence but consensus was clear, we have stated our opinion as good practice points.Recommendations: Diagnosis should be based on medical history and examination followed by CSF analysis for protein and glucose levels, cellular analysis, and identification of the pathogen by polymerase chain reaction amplification (recommendation level A) and serology (level B). Neuroimaging, preferably by MRI, is essential (level B). Lumbar puncture can follow neuroimaging when immediately available, but if this cannot be performed immediately, LP should be delayed only under unusual...
Viral encephalitis is a medical emergency. The spectrum of brain involvement and the prognosis ar... more Viral encephalitis is a medical emergency. The spectrum of brain involvement and the prognosis are dependent mainly on the specific pathogen and the immunological state of the host. Although specific therapy is limited to only several viral agents, correct immediate diagnosis and introduction of symptomatic and specific therapy has a dramatic influence upon survival and reduces the extent of permanent brain injury in survivors. We searched MEDLINE (National Library of Medicine) for relevant literature from 1966 to May 2004. Review articles and book chapters were also included. Recommendations are based on this literature based on our judgment of the relevance of the references to the subject. Recommendations were reached by consensus. Where there was lack of evidence but consensus was clear we have stated our opinion as good practice points. Diagnosis should be based on medical history, examination followed by analysis of cerebrospinal fluid for protein and glucose contents, cellula...
ABSTRACT Phenotypic heterogeneity in sporadic Creutzfeldt-Jakob disease (sCJD) is well documented... more ABSTRACT Phenotypic heterogeneity in sporadic Creutzfeldt-Jakob disease (sCJD) is well documented, but there is not yet a systematic classification of the disease variants. In a previous study, we showed that the polymorphic codon 129 of the prion protein gene (PRNP), and two types of protease-resistant prion protein (PrPSc) with distinct physicochemical properties, are major determinants of these variants. To define the full spectrum of variants, we have examined a series of 300 sCJD patients. Clinical features, PRNP genotype, and PrPSc properties were determined in all subjects. In 187, we also studied neuropathological features and immunohistochemical pattern of PrPSc deposition. Seventy percent of subjects showed the classic CJD phenotype, PrPSc type 1, and at least one methionine allele at codon 129; 25% of cases displayed the ataxic and kuru-plaque variants, associated to PrPSc type 2, and valine homozygosity or heterozygosity at codon 129, respectively. Two additional variants, which included a thalamic form of CJD and a phenotype characterized by prominent dementia and cortical pathology, were linked to PrPSc type 2 and methionine homozygosity. Finally, a rare phenotype characterized by progressive dementia was linked to PrPSc type 1 and valine homozygosity. The present data demonstrate the existence of six phenotypic variants of sCJD. The physicochemical properties of PrPSc in conjunction with the PRNP codon 129 genotype largely determine this phenotypic variability, and allow a molecular classification of the disease variants. Ann Neurol 1999;46:224–233
Deposition of alpha-synuclein in the brain is a hallmark of Lewy body disorders. Alpha-synuclein ... more Deposition of alpha-synuclein in the brain is a hallmark of Lewy body disorders. Alpha-synuclein has been considered to show prion-like properties. Prion diseases can be transmitted by the transplantation of cadaveric dura mater causing iatrogenic Creutzfeldt-Jakob disease. Recent observations of amyloid-β deposition in dural grafts support the seeding properties of amyloid-β. Here we assessed the presence of alpha-synuclein in dura mater samples as a potential transmissible seed source. We immunostained 32 postmortem dura mater samples; 16 cases with Lewy-body disorder (LBD) showing different pathology stages and 16 non-LBD cases for phosphorylated (Ser129) and disease-associated (5G4) alpha-synuclein. Disease-associated alpha-synuclein aggregates were identified in intradural nerve fibres and associated with a vessel in a single LBD-Braak stage 4 case. We conclude that alpha-synuclein is detectable, although rarely, in dura mater samples in patients with LBD. The risk of potential...
To characterize the brain-infiltrating immune cell repertoire in Rasmussen encephalitis (RE) with... more To characterize the brain-infiltrating immune cell repertoire in Rasmussen encephalitis (RE) with special focus on the subsets, clonality, and their cytokine profile. The immune cell infiltrate of freshly isolated brain tissue from RE was phenotypically and functionally characterized using immunohistology, flow cytometry, and T-cell receptor (TCR) deep sequencing. Identification of clonally expanded T-cell clones (TCCs) was achieved by combining flow cytometry sorting of CD4+ and CD8+ T cells and high-throughput TCR Vβ-chain sequencing. The most abundant brain-infiltrating TCCs were isolated and functionally characterized. We found that CD4+, CD8+, and also γδ T cells infiltrate the brain tissue in RE. Further analysis surprisingly revealed that not only brain-infiltrating CD8+ but also CD4+ T cells are clonally expanded in RE. All 3 subsets exhibited a Tc1/Th1 phenotype characterized by the production of interferon (IFN)-γ and TNF. Broad cytokine profiling at the clonal level showe...
Journal of neuropathology and experimental neurology, 2015
Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the CNS with severe involv... more Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the CNS with severe involvement of the optic nerve and spinal cord. Highly specific serum IgG autoantibodies (NMO-IgG) that react with aquaporin-4 (AQP4), the most abundant CNS water channel protein, are found in patients with NMO. However, in vivo evidence combining the results of AQP4 antibody serum levels and brain pathology is lacking. We report a patient with NMO whose AQP4 antibody levels decreased simultaneously with clinical deterioration caused by the development of a tumor-like brain lesion. In the seminecrotic biopsied brain lesion, there was activated complement complex, whereas only very scattered immunoreactivity to AQP4 protein was detectable. The decrease in serum AQP4 antibody levels and the loss of AQP4 in the tumor-like lesion could represent a "serum antibody-consuming effect" during lesion formation.
Spinal muscular atrophy (SMA) is a neuromuscular disorder in childhood leading to a dramatic loss... more Spinal muscular atrophy (SMA) is a neuromuscular disorder in childhood leading to a dramatic loss of muscle strength. Functional investigations with high-resolution polarography and enzyme measurements of the respiratory chain revealed lowered activities in muscle tissue of SMA patients. To gain a better understanding of this low energy supply we analyzed the amount of mitochondrial DNA (mtDNA) in skeletal muscle of 20 unrelated children with genetically proven SMA and 31 controls. Quantitative Southern blot analysis revealed a severe and homogeneous decrease in the content of muscle mtDNA in relation to nuclear DNA in SMA patients (90.3+/-7.8%), whereas by immunofluorescence no decrease in the number of mitochondria was detected. In addition, a two- to threefold reduction of the nuclear-encoded complex II (succinate dehydrogenase) activity was detected in SMA muscle tissue. Western blot analysis showed a significant reduction of both mitochondrial- and nuclear-encoded cytochrome c ...
We describe a novel transthyretin mutation at codon 18 where Asp is replaced by Gly (D18G) in a H... more We describe a novel transthyretin mutation at codon 18 where Asp is replaced by Gly (D18G) in a Hungarian kindred. This mutation is associated with meningocerebrovascular amyloidosis, producing dementia, ataxia, and spasticity. Fifty different transthyretin mutations are related to amyloid deposition, typically producing a peripheral neuropathy or cardiac dysfunction. These symptoms are absent in this family. Up to now, amyloid-beta (A beta), cystatin C, and prion proteins have been known to be deposited as amyloid in the brain, leading to stroke or dementia. With this report we establish that transthyretin amyloid deposition can also produce central nervous system dysfunction as the major clinical symptom.
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