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1.
Neurosci Res ; 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31669371

RESUMO

Exosomes contain many proteins associated with neurodegenerative diseases. To identify new candidate biomarkers and proteins associated with amyotrophic lateral sclerosis (ALS), we performed liquid chromatography-tandem mass spectrometry proteomic analysis of exosome-enriched fractions isolated from cerebrospinal fluid (CSF) of sporadic ALS patients using gel filtration chromatography. Proteomic data revealed that three proteins were increased and 11 proteins were decreased in ALS patients. The protein with the greatest increase in exosome-enriched fractions of CSF derived from ALS was novel INHAT repressor (NIR), which is closely associated with nucleolar function. By immunohistochemical analysis, we found that NIR was reduced in the nucleus of motor neurons in ALS patients. Our results demonstrate the potential utility of our methodology for proteomic analysis of CSF exosomes and suggest that nucleolar stress might play a role in sporadic ALS pathogenesis through the dysfunction of NIR.

2.
Nat Genet ; 51(8): 1215-1221, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31332381

RESUMO

Neuronal intranuclear inclusion disease (NIID) is a progressive neurodegenerative disease that is characterized by eosinophilic hyaline intranuclear inclusions in neuronal and somatic cells. The wide range of clinical manifestations in NIID makes ante-mortem diagnosis difficult1-8, but skin biopsy enables its ante-mortem diagnosis9-12. The average onset age is 59.7 years among approximately 140 NIID cases consisting of mostly sporadic and several familial cases. By linkage mapping of a large NIID family with several affected members (Family 1), we identified a 58.1 Mb linked region at 1p22.1-q21.3 with a maximum logarithm of the odds score of 4.21. By long-read sequencing, we identified a GGC repeat expansion in the 5' region of NOTCH2NLC (Notch 2 N-terminal like C) in all affected family members. Furthermore, we found similar expansions in 8 unrelated families with NIID and 40 sporadic NIID cases. We observed abnormal anti-sense transcripts in fibroblasts specifically from patients but not unaffected individuals. This work shows that repeat expansion in human-specific NOTCH2NLC, a gene that evolved by segmental duplication, causes a human disease.

3.
Neurobiol Dis ; 130: 104516, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31229688

RESUMO

Spinocerebellar ataxia 42 (SCA42) is a neurodegenerative disorder recently shown to be caused by c.5144G > A (p.Arg1715His) mutation in CACNA1G, which encodes the T-type voltage-gated calcium channel CaV3.1. Here, we describe a large Japanese family with SCA42. Postmortem pathological examination revealed severe cerebellar degeneration with prominent Purkinje cell loss without ubiquitin accumulation in an SCA42 patient. To determine whether this mutation causes ataxic symptoms and neurodegeneration, we generated knock-in mice harboring c.5168G > A (p.Arg1723His) mutation in Cacna1g, corresponding to the mutation identified in the SCA42 family. Both heterozygous and homozygous mutants developed an ataxic phenotype from the age of 11-20 weeks and showed Purkinje cell loss at 50 weeks old. Degenerative change of Purkinje cells and atrophic thinning of the molecular layer were conspicuous in homozygous knock-in mice. Electrophysiological analysis of Purkinje cells using acute cerebellar slices from young mice showed that the point mutation altered the voltage dependence of CaV3.1 channel activation and reduced the rebound action potentials after hyperpolarization, although it did not significantly affect the basic properties of synaptic transmission onto Purkinje cells. Finally, we revealed that the resonance of membrane potential of neurons in the inferior olivary nucleus was decreased in knock-in mice, which indicates that p.Arg1723His CaV3.1 mutation affects climbing fiber signaling to Purkinje cells. Altogether, our study shows not only that a point mutation in CACNA1G causes an ataxic phenotype and Purkinje cell degeneration in a mouse model, but also that the electrophysiological abnormalities at an early stage of SCA42 precede Purkinje cell loss.

4.
Intern Med ; 58(18): 2715-2719, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31178479

RESUMO

A 24-year-old Japanese man exhibited slowly progressive gait disturbance from childhood to young adulthood. Physical and physiological examinations showed the involvement of both upper and lower motor neurons, fulfilling the diagnostic criteria for amyotrophic lateral sclerosis (ALS). Mild cognitive impairment and subclinical sensory involvement were also observed. A genetic analysis revealed novel compound heterozygous mutations, c.767C>T (p.Thr256Ile) and c.800A>G (p.Asp267Gly), in the vaccinia-related kinase 1 gene (VRK1). This is the first report of a Japanese patient with a motor neuron disease phenotype caused by VRK1 mutations. This diagnosis should be considered in atypical cases of juvenile-onset and slowly progressive types of motor neuron disease.

5.
Mult Scler ; 24(11): 1514-1516, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29671689

RESUMO

Steroid pulse therapy with methylprednisolone (mPSL) succinate ester is the most common treatment for neuromyelitis optica (NMO); no cases of anaphylaxis have been reported to date. Here, we report two cases of anaphylactic shock induced by mPSL pulse therapy in patients with NMO and concurrent systemic lupus erythematosus. Both patients had received several courses of mPSL pulse therapy without any problems previously. Repeated mPSL pulse therapy and comorbid humoral autoimmune disease might increase the risk of anaphylaxis. Corticosteroids without succinate esters should be considered as an alternative therapy to prevent anaphylaxis.

6.
Cerebellum ; 17(5): 525-530, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29687291

RESUMO

Spinocerebellar ataxia type 21 (SCA21) is a rare subtype of autosomal dominant cerebellar ataxias, which was first identified in a French family and has been reported almost exclusively in French ancestry so far. We here report the first Japanese family with SCA21, in which all affected members examined carried a heterozygous c.509C > T:p.Pro170Leu variant in TMEM240. Their clinical features were summarized as a slowly progressive ataxia of young-adult onset (5-48 years) associated with various degree of psychomotor retardation or cognitive impairment. The MR images revealed atrophy in the cerebellum, but not in the cerebrum or brainstem. These clinical findings were consistent with those in the original French families with SCA21. Neuropathological findings in one autopsied patient showed a prominent decrease of cerebellar Purkinje cells, but no specific abnormalities outside the cerebellum.


Assuntos
Cerebelo/patologia , Degenerações Espinocerebelares/patologia , Degenerações Espinocerebelares/fisiopatologia , Adulto , Idoso , Cerebelo/diagnóstico por imagem , Família , Feminino , Humanos , Japão , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Fenótipo , Degenerações Espinocerebelares/genética , Degenerações Espinocerebelares/psicologia
7.
J Neurol Sci ; 385: 99-104, 2018 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-29406924

RESUMO

BACKGROUND: In dementia with Lewy bodies (DLB) and Parkinson's disease with dementia (PDD), it is still debated whether white matter hyperintensities (WMH) on MRI reflect atherosclerotic cerebrovascular changes or Alzheimer's disease (AD)-related pathology such as cerebral amyloid angiopathy. To examine AD-related pathology in DLB and PDD, we compared the severity of WMH and medial temporal lobe atrophy among patients with DLB, PDD, non-demented PD (PDND), and AD. METHODS: We retrospectively studied sex- and age-matched outpatients with AD, DLB, PDD, and PDND, as well as subjects without central nervous system disorders as normal controls (n=50 each). All subjects underwent 1.5-T MRI examinations, and WMH detected by T2-weighted images or fluid-attenuated inversion recovery images were semiquantified according to the Fazekas method. Medial temporal lobe atrophy (MTA) was visually assessed by the MTA score. RESULTS: WMH were more prominent in AD, DLB, and PDD patients than in PDND patients and normal controls (NCs). DLB as well as AD showed more severe WMH than PDD. Visual assessment of medial temporal lobe atrophy showed that AD patients had the most severe atrophy, followed by DLB, PDD, and PDND patients, and NC subjects in that order. MTA scores showed significant correlations with WMH severity. CONCLUSION: Our results indicated that DLB was more similar to AD than to PDD in terms of MRI findings, suggesting that WMH in DLB may reflect mainly AD-related pathology rather than atherosclerotic cerebrovascular changes.

8.
J Hum Genet ; 63(4): 417-423, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29403087

RESUMO

Autosomal recessive cerebellar ataxias (ARCAs) are clinically and genetically heterogeneous neurological disorders. Through whole-exome sequencing of Japanese ARCA patients, we identified three index patients from unrelated families who had biallelic mutations in ERCC4. ERCC4 mutations have been known to cause xeroderma pigmentosum complementation group F (XP-F), Cockayne syndrome, and Fanconi anemia phenotypes. All of the patients described here showed very slowly progressive cerebellar ataxia and cognitive decline with choreiform involuntary movement, with young adolescent or midlife onset. Brain MRI demonstrated atrophy that included the cerebellum and brainstem. Of note, cutaneous symptoms were very mild: there was normal to very mild pigmentation of exposed skin areas and/or an equivocal history of pathological sunburn. However, an unscheduled DNA synthesis assay of fibroblasts from the patient revealed impairment of nucleotide excision repair. A similar phenotype was very recently recognized through genetic analysis of Caucasian cerebellar ataxia patients. Our results confirm that biallelic ERCC4 mutations cause a cerebellar ataxia-dominant phenotype with mild cutaneous symptoms, possibly accounting for a high proportion of the genetic causes of ARCA in Japan, where XP-F is prevalent.


Assuntos
Ataxia Cerebelar/diagnóstico , Ataxia Cerebelar/genética , Proteínas de Ligação a DNA/genética , Genes Dominantes , Mutação , Fenótipo , Adulto , Idade de Início , Idoso , Alelos , Sequência de Aminoácidos , Substituição de Aminoácidos , Encéfalo/anormalidades , Encéfalo/diagnóstico por imagem , Análise Mutacional de DNA , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Imagem por Ressonância Magnética , Masculino , Linhagem
9.
J Neuroinflammation ; 15(1): 46, 2018 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-29454354

RESUMO

BACKGROUND: Although inflammation in the central nervous system is responsible for multiple neurological diseases, the lack of appropriate biomarkers makes it difficult to evaluate inflammatory activities in these diseases. Therefore, a new biomarker reflecting neuroinflammation is required for accurate diagnosis, appropriate therapy, and comprehension of pathogenesis of these neurological disorders. We previously reported that the cerebrospinal fluid (CSF) concentration of lateral olfactory tract usher substance (LOTUS), which promotes axonal growth as a Nogo receptor 1 antagonist, negatively correlates with disease activity in multiple sclerosis, suggesting that variation in LOTUS reflects the inflammatory activities and is a useful biomarker to evaluate the disease activity. To extend this observation, we analyzed the variation of LOTUS in the CSF of patients with bacterial and viral meningitis, which are the most common neuroinflammatory diseases. METHODS: CSF samples were retrospectively obtained from patients with meningitis (n = 40), who were followed up by CSF study at least twice, and from healthy controls (n = 27). Patients were divided into bacterial (n = 14) and viral meningitis (n = 18) after exclusion of eight patients according to the criteria of this study. LOTUS concentrations, total protein levels, and CSF cell counts in the acute and recovery phases were analyzed chronologically. We also used lipopolysaccharide-injected mice as a model of neuroinflammation to evaluate LOTUS mRNA and protein expression in the brain. RESULTS: Regardless of whether meningitis was viral or bacterial, LOTUS concentrations in the CSF of patients in acute phase were lower than those of healthy controls. As the patients recovered from meningitis, LOTUS levels in the CSF returned to the normal range. Lipopolysaccharide-injected mice also exhibited reduced LOTUS mRNA and protein expression in the brain. CONCLUSIONS: CSF levels of LOTUS correlated inversely with disease activity in both bacterial and viral meningitis, as well as in multiple sclerosis, because neuroinflammation downregulated LOTUS expression. Our data strongly suggest that variation of CSF LOTUS is associated with neuroinflammation and is useful as a biomarker for a broader range of neuroinflammatory diseases.

10.
Am J Pathol ; 188(2): 507-514, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29128563

RESUMO

Mutations in the MATR3 gene have been identified as a cause of familial amyotrophic lateral sclerosis, but involvement of the matrin 3 (MATR3) protein in sporadic amyotrophic lateral sclerosis (SALS) pathology has not been fully assessed. We immunohistochemically analyzed MATR3 pathology in the spinal cords of SALS and control autopsy specimens. MATR3 immunostaining of the motor neuron nuclei revealed two distinct patterns: mild and strong staining. There were no differences in the ratio of mild versus strong nuclear staining between the SALS and control cases. MATR3-containing neuronal cytoplasmic inclusions (NCIs) were observed in 60% of SALS cases. Most motor neurons with MATR3-positive NCIs exhibited a mild nuclear staining pattern. Although 16.8% of NCIs positive for transactivating response region DNA-binding protein 43 (TDP-43) were estimated as double-labeled by MATR3, no MATR3-positive or TDP-43-negative NCIs were observed. Although a previous study found that MATR3-positive NCIs are present only in cases with C9orf72 hexanucleotide repeat expansion, ubiquitin-positive granular NCIs were not observed in the cerebellum, which have been reported as specific to C9orf72-related ALS. Six ALS cases were confirmed to be negative for the GGGGCC hexanucleotide. Our results reveal that MATR3 is a component of TDP-43-positive NCIs in motor neurons, even in SALS, and indicate the broader involvement of MATR3 in ALS pathology and the heterogeneity of TDP-43-positive NCIs.

11.
Intern Med ; 54(12): 1547-52, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26073248

RESUMO

A 71-year-old immunocompetent man developed cognitive decline and gait disturbance. Brain magnetic resonance imaging (MRI) revealed bilateral diffuse leukoencephalopathy without a mass lesion. An analysis of the cerebrospinal fluid (CSF) showed elevated levels of interleukin (IL)-10. The condition of the patient progressively deteriorated, and intravenous high-dose steroids proved ineffective. Detection of non-destructive, diffusely infiltrating, large B-cell lymphoma in biopsy and autopsy specimens led to a diagnosis of lymphomatosis cerebri (LC). On serial MRI, the basal ganglia and white matter lesions increased in parallel with the levels of IL-10. These findings suggest that the IL-10 level in the CSF may represent a potentially useful biomarker for the early diagnosis and monitoring of the disease progression in LC.


Assuntos
Biomarcadores Tumorais/líquido cefalorraquidiano , Neoplasias Encefálicas/líquido cefalorraquidiano , Transtornos Cognitivos/líquido cefalorraquidiano , Transtornos Neurológicos da Marcha/líquido cefalorraquidiano , Interleucina-10/líquido cefalorraquidiano , Linfoma de Células B/líquido cefalorraquidiano , Idoso , Autopsia , Biópsia , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/patologia , Transtornos Cognitivos/etiologia , Progressão da Doença , Evolução Fatal , Transtornos Neurológicos da Marcha/etiologia , Humanos , Linfoma de Células B/complicações , Linfoma de Células B/patologia , Imagem por Ressonância Magnética , Masculino
12.
Ann Clin Transl Neurol ; 2(4): 417-26, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25909086

RESUMO

OBJECTIVE: Glucocerebrosidase gene (GBA) variants that cause Gaucher disease are associated with Parkinson disease (PD) and dementia with Lewy bodies (DLB). To investigate the role of GBA variants in multiple system atrophy (MSA), we analyzed GBA variants in a large case-control series. METHODS: We sequenced coding regions and flanking splice sites of GBA in 969 MSA patients (574 Japanese, 223 European, and 172 North American) and 1509 control subjects (900 Japanese, 315 European, and 294 North American). We focused solely on Gaucher-disease-causing GBA variants. RESULTS: In the Japanese series, we found nine carriers among the MSA patients (1.65%) and eight carriers among the control subjects (0.89%). In the European series, we found three carriers among the MSA patients (1.35%) and two carriers among the control subjects (0.63%). In the North American series, we found five carriers among the MSA patients (2.91%) and one carrier among the control subjects (0.34%). Subjecting each series to a Mantel-Haenszel analysis yielded a pooled odds ratio (OR) of 2.44 (95% confidence interval [CI], 1.14-5.21) and a P-value of 0.029 without evidence of significant heterogeneity. Logistic regression analysis yielded similar results, with an adjusted OR of 2.43 (95% CI 1.15-5.37) and a P-value of 0.022. Subtype analysis showed that Gaucher-disease-causing GBA variants are significantly associated with MSA cerebellar subtype (MSA-C) patients (P = 7.3 × 10(-3)). INTERPRETATION: The findings indicate that, as in PD and DLB, Gaucher-disease-causing GBA variants are associated with MSA.

13.
J Voice ; 29(3): 273-80, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25795370

RESUMO

BACKGROUND: The precise comparison of the voice characteristics of Parkinson disease (PD) patients with age-matched normal subjects is still one of the important research projects. The present study aimed at comparing the voice characteristics in sustained phonations of PD patients with an age-matched control group. METHODS: The subjects were 30 Japanese PD patients (15 males and 15 females). The control group consisted of 30 age-matched normal Japanese subjects (15 males and 15 females). Each subject was required to phonate into a mouthpiece attached to Vocal Function Analyzer (PS-77E; Nagashima Medical Instrumental Corporation, Tokyo, Japan) with the airway interruption system, and expiratory lung pressure, mean flow rate, fundamental frequency and intensity of voice, and pitch range were measured. Maximum phonation time was also assessed. RESULTS: The highest pitch level was significantly lower in the PD group than that of the control group in both sexes, whereas the lowest pitch level was significantly higher in the PD group only in males. In both sexes, the pitch range was significantly narrower in the PD group than in the control group. There was no significant difference in intensity, mean flow rate, expiratory pressure, or maximum phonation time between the two groups, for both males and females. CONCLUSION: Only remarkable difference in the voice characteristics between PD patients and age-matched normal elderlies was limited to the narrowing of the pitch range in PD patients. The restriction in pitch regulation in PD patients was considered to be because of difficulty in reciprocal control of the laryngeal muscles secondary to latent rigidity.


Assuntos
Doença de Parkinson/complicações , Fonação , Acústica da Fala , Distúrbios da Voz/etiologia , Qualidade da Voz , Acústica/instrumentação , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Desenho de Equipamento , Expiração , Feminino , Humanos , Japão , Músculos Laríngeos/fisiopatologia , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/diagnóstico , Doença de Parkinson/fisiopatologia , Pressão , Fatores Sexuais , Processamento de Sinais Assistido por Computador , Medida da Produção da Fala/instrumentação , Distúrbios da Voz/diagnóstico , Distúrbios da Voz/fisiopatologia
14.
Brain Nerve ; 66(8): 927-46, 2014 Aug.
Artigo em Japonês | MEDLINE | ID: mdl-25082315

RESUMO

Intravascular lymphoma (IVL) is a rare form of malignant lymphoma characterized by the selective growth of lymphoma cells within the lumina of vessels, without the involvement of adjacent parenchymal tissue. IVL is predominantly of B-cell lineage, but cases of T-cell or natural killer cell lineage have been described occasionally, predominantly involving the skin. IVL usually affects elderly patients with a poor performance status, elevated serum lactic dehydrogenase levels, anemia, and B symptoms. The clinical presentation varies in different geographical areas, particularly between patients diagnosed in Europe and Asia. In European countries, the Western variant of IVL mainly involves the central nervous system and skin; in particular, there is a "cutaneous variant" limited to the skin. In Asian countries, the Asian variant of IVL predominantly accompanies hemophagocytic syndrome. Identification of this disease is difficult because it presents with non-specific clinical symptoms. Although organ biopsies are mandatory for accurate IVL diagnosis, no standard procedure has been established. An additional random skin biopsy may be useful to diagnose IVL at an early stage. Early diagnosis and treatment can improve the outcome of IVL patients following treatment with rituximab-containing chemotherapy.


Assuntos
Linfoma/patologia , Neoplasias Vasculares/patologia , Biópsia , Neoplasias Encefálicas/diagnóstico , Progressão da Doença , Humanos , Linfoma/diagnóstico , Neoplasias Cutâneas/diagnóstico , Neoplasias Vasculares/diagnóstico
15.
Orphanet J Rare Dis ; 9: 118, 2014 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-25053188

RESUMO

BACKGROUND: Only a few prospective studies have determined which clinical symptoms and factors are associated with the disease severity of spinocerebellar ataxia type 6 (SCA6). A multicenter longitudinal cohort study was conducted to clarify both the natural history of SCA6 in Japan and the factors influencing disease progression. METHODS: Patients were consecutively recruited between 2007 and 2008. Scores from the Scale for the Assessment and Rating of Ataxia (SARA) and Barthel Index (BI) were collected prospectively each year. Additionally, data from the Japan intractable diseases research (IDR) registry were collected both retrospectively, from 2003 to 2006, and prospectively, from 2007 to 2010. As a result, we were able to collect 3 years of retrospective data and 4 years of prospective data during the course of 3 yearly visits. RESULTS: Forty-six patients were registered. The follow-up rate of the third year was 93%. The SARA scores worsened significantly each year. Over 3 years, the decline of the SARA scores was 1.33 ± 1.40 points/year. The results of multivariate analysis of the decline of the SARA score were not significant. The IDR scores correlated well with the SARA and BI scores. Kaplan-Meier curves of 7 years of data from the IDR registry illustrated the correlation between the ability to walk and the time course of the disease. CONCLUSIONS: Information regarding the progression of ataxia and the decline in the activities of daily living (ADL) in patients with SCA6 was obtained by a 3-year cohort study and a 7-year IDR study. The decline of the SARA score of patients with SCA6 was 1.33 ± 1.40 points/year. The results elucidate the natural history of SCA6, factors influencing disease severity, and utility of data from the IDR registry of Japan.


Assuntos
Ataxias Espinocerebelares/fisiopatologia , Estudos de Coortes , Humanos , Japão , Estudos Prospectivos , Sistema de Registros
16.
J Neurol ; 261(7): 1381-6, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24781836

RESUMO

Spinocerebellar degeneration (SCD) is a progressive neurodegenerative disorder in which cerebellar ataxia causes motor disability. There are no widely applicable methods for objective evaluation of ataxia in SCD. An objective system to evaluate ataxia is necessary for use in clinical trials of newly developed medication and rehabilitation. The aim of this study was to develop a simple method to quantify the degree of upper-limb ataxia. Forty-nine patients with SCD participated in this study. Patients were instructed to trace an Archimedean spiral template, and the gap between the template spiral and the drawn spiral (gap area; GA) was measured using Image J software. Ataxia was rated using the Scale for the Assessment and Rating of Ataxia (SARA) and cerebellar volume was evaluated in 37 patients using an axial cross-section of magnetic resonance images that were obtained within 6 months of clinical evaluation. Regression analysis was performed to assess the relation between GA and patient age, disease duration, SARA score, and cerebellar volume. GA was significantly related to total SARA score (r = 0.660, p < 0.001), the posture and gait (r = 0.551, p < 0.001), speech (r = 0.527, p < 0.001), hand movements (r = 0.553, p < 0.001), and heel-shin slide (r = 0.367, p = 0.036) SARA subscores, and cerebellar volume (r = 0.577, p < 0.001) but was not related to patient age (r = 0.176, p = 0.227) or disease duration (r = 0.236, p = 0.103). GA is a simple, useful method to objectively quantify the degree of cerebellar ataxia, especially upper-limb ataxia, and can be widely adopted in various settings, including clinical trials.


Assuntos
Ataxia/diagnóstico , Ataxia/etiologia , Degenerações Espinocerebelares/complicações , Extremidade Superior/fisiopatologia , Pesos e Medidas , Adulto , Idoso , Idoso de 80 Anos ou mais , Cerebelo/patologia , Córtex Cerebral/patologia , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença
17.
Brain Pathol ; 24(6): 599-606, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24674145

RESUMO

Spinocerebellar ataxia type 2 (SCA2) is a hereditary neurodegenerative disorder caused by the expansion of the trinucleotide CAG repeats encoding elongated polyglutamine tract in ataxin-2, the SCA2 gene product. Polyglutamine diseases comprise nine genetic entities, including seven different forms of spinocerebellar ataxias, Huntington's disease, and spinal and bulbar muscular atrophy. These are pathologically characterized by neuronal loss and intranuclear aggregates or inclusions of mutant proteins including expanded polyglutamine in selected neuronal groups. Previously, we examined immunolocalization of ubiquitin, expanded polyglutamine (probed by 1C2 antibody), and ataxin-2 in genetically confirmed SCA2 patients. In the present study, we expanded this approach by distinguishing different patterns of subcellular 1C2 immunoreactivity ("granular cytoplasmic," "cytoplasmic and nuclear" and "nuclear with inclusions.") and by quantifying their regional frequencies in three autopsied SCA2 brains at different stage of the disease. Comparison with neuronal loss and gliosis revealed that overall 1C2 immunoreactivity was paralleled with their severity. Furthermore, appearance of granular cytoplasmic pattern corresponded to early stage, cytoplasmic and nuclear pattern to active stage, and nuclear with inclusions pattern to final stage. We conclude that this 1C2-immunoreactive typing may be useful for evaluating the overall severity and extent of affected regions and estimating the neuropathological stage of SCA2.


Assuntos
Encéfalo/fisiopatologia , Núcleo Celular/metabolismo , Citoplasma/metabolismo , Neurônios/fisiologia , Ataxias Espinocerebelares/fisiopatologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Ataxinas , Atrofia , Encéfalo/patologia , Núcleo Celular/patologia , Citoplasma/patologia , Progressão da Doença , Feminino , Gliose/patologia , Gliose/fisiopatologia , Humanos , Imuno-Histoquímica , Corpos de Inclusão Intranuclear/metabolismo , Corpos de Inclusão Intranuclear/patologia , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/metabolismo , Neurônios/patologia , Peptídeos/metabolismo , Ataxias Espinocerebelares/patologia , Ubiquitina/metabolismo
18.
Intern Med ; 52(14): 1629-33, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23857099

RESUMO

Autosomal recessive cerebellar ataxias and autosomal recessive hereditary spastic paraplegias are clinically and genetically heterogeneous disorders with diverse neurological and non-neurological features. We herein describe a Japanese patient with a slowly progressive form of ataxia and spastic paraplegia. Using whole exome sequencing, we identified a novel homozygous frameshift mutation in SPG7, encoding paraplegin, in this patient. This is the first report of an SPG7 mutation in the Japanese population. For disorders previously undetected in a particular population, or unrecognized/atypical phenotypes, exome sequencing may facilitate molecular diagnosis.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Deficiência Intelectual/genética , Metaloendopeptidases/genética , Espasticidade Muscular/genética , Mutação/genética , Atrofia Óptica/genética , Paraplegia/genética , Paraplegia Espástica Hereditária/genética , Ataxias Espinocerebelares/genética , ATPases Associadas a Diversas Atividades Celulares , Exoma/genética , Homozigoto , Humanos , Deficiência Intelectual/diagnóstico , Masculino , Pessoa de Meia-Idade , Espasticidade Muscular/diagnóstico , Atrofia Óptica/diagnóstico , Paraplegia/diagnóstico , Linhagem , Análise de Sequência de DNA/métodos , Paraplegia Espástica Hereditária/diagnóstico , Ataxias Espinocerebelares/diagnóstico
19.
Brain Nerve ; 65(3): 257-65, 2013 Mar.
Artigo em Japonês | MEDLINE | ID: mdl-23475517

RESUMO

In amyotrophic lateral sclerosis (ALS), 5% of cases are familial, and most of the remaining cases are sporadic. In familial ALS, many causative genes have been identified during the last 20 years of the golden age of genetics. In particular, the recent discovery of a hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9orf72) has had a large impact on ALS research, as this mutation is the most frequent cause of familial ALS in Europe and the US. However, the relative rarity of this mutation in Japan and Asia suggests the need to identify further other causative genes of familial ALS. In this regard, the advent of next-generation sequencing technology is expected to accelerate the identification of novel genes. In addition, next-generation sequencing will supersede Sanger sequencing in the molecular diagnosis of familial ALS. A number of genome-wide association studies (GWAS) have been conducted to identify the disease-susceptibility genes of sporadic ALS. In 1,305 Japanese ALS samples, the ZNF512B gene was associated with susceptibility to ALS. This gene has been shown to be one of the prognostic factors in sporadic ALS. Although GWAS that are based on the 'common disease-common variants hypothesis' have successfully revealed many disease-susceptibility genes, including ZNF512B, in sporadic ALS, the odds ratios associated with these risk alleles are generally low. The next challenge in ALS research is to use next-generation sequencing techniques to identify disease-relevant alleles with large effect sizes based on the 'common disease-multiple rare variants hypothesis'.


Assuntos
Esclerose Amiotrófica Lateral/genética , Ligação Genética/genética , Privacidade Genética , Genoma Humano , Estudo de Associação Genômica Ampla , Esclerose Amiotrófica Lateral/diagnóstico , Humanos , Mutação
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