Jiro Idezuka

Anti-aquaporin 4 antibody in selected Japanese multiple sclerosis patients with long spinal cord lesions:

Multiple sclerosis (MS) in Asian populations is often characterized by the selective involvement of the optic nerve (ON) and spinal cord (SP) (OSMS) in contrast to classic MS (CMS), where frequent lesions are observed in the cerebrum, cerebellum or brainstem. In Western countries, inflammatory demyelinating disease preferentially involving the ON and SP is called neuromyelitis optica (NMO). Recently, Lennon et al. discovered that NMO-IgG, shown to bind to aquaporin 4 (AQP4), could be a specific marker of NMO and also of Japanese OSMS whose clinical features were identical to NMO having long spinal cord lesions extending over three vertebral segments (LCL). To examine this antibody in larger populations of Japanese OSMS patients in order to know its epidemiological and clinical spectra, we established an immunohistochemical detection system for the anti-AQP4 antibody (AQP4-Ab) using the AQP4-transfected human embryonic kidney cell line (HEK-293) and confirmed AQP4-Ab positivity together with the immunohistochemical staining pattern of NMO-IgG in approximately 60% of Japanese OSMS patients with LCL. Patients with OSMS without LCL and those with CMS were negative for this antibody. Our results accorded with those of Lennon et al. suggest that Japanese OSMS with LCL may have an underlying pathogenesis in common with NMO. Multiple Sclerosis 2007; 13: 850—855. http://msj.sagepub.com

Patients Homozygous and Heterozygous for SNCA Duplication in a Family With Parkinsonism and Dementia

BACKGROUND Multiplication of the alpha-synuclein gene (SNCA) (OMIM 163890) has been identified as a causative mutation in hereditary Parkinson disease or dementia with Lewy bodies. OBJECTIVE To determine the genetic, biochemical, and neuropathologic characteristics of patients with autopsy-confirmed autosomal dominant Lewy body disease, with particular reference to the dosage effects of SNCA. DESIGN Four-generation family study. SETTING Academic research. Patients We fractionated samples extracted from frozen brain tissues of 4 patients for biochemical characterization, followed by immunoblot analysis. MAIN OUTCOME MEASURES We determined the dosages of SNCA and its surrounding genes by quantitative polymerase chain reaction analysis. RESULTS Quantitative polymerase chain reaction analysis revealed that 3 patients were heterozygous for SNCA duplication and 1 patient was homozygous for SNCA duplication. The homozygous patient showed earlier age at onset and earlier death, with more severe cognitive impairment than the heterozygous patients. Biochemical analysis revealed that phosphorylated alpha-synuclein accumulated in the sarkosyl-insoluble urea-extracted fraction of the brains of the patients. CONCLUSIONS Pathologically confirmed Lewy body disease clinically characterized by progressive parkinsonism and cognitive dysfunction is caused by SNCA duplication. The homozygous patient demonstrated the most severe phenotype, suggesting that SNCA dosage has a considerable effect on disease phenotype even within a family. SNCA duplication results in the hyperaccumulation of phosphorylated alpha-synuclein in the brains of patients.

Cytotoxic T cells react with recombinant Yo protein from a patient with paraneoplastic cerebellar degeneration and anti-Yo antibody

Antibodies against autologous tumor cells and neurons are found in the sera or cerebrospinal fluid of patients with paraneoplastic neurological syndromes. Attempts to produce animal models by passive transfer or active immunization, however, have failed, and there is no direct evidence that antibodies cause neuronal damage. Previously, we found that patients with paraneoplastic cerebellar degeneration (PCD) and anti-Yo antibody tested had HLA A24. We now have studied cytotoxic T cell activity in peripheral blood that reacts with recombinant Yo protein when autologous dendritic cells are used as the target. Results suggest that cytotoxic T cells are involved in Purkinje cell loss in PCD.

Failure to detect cytotoxic T cell activity against recombinant yo protein using autologous dendritic cells as the target in a patient with paraneoplastic cerebellar degeneration and anti-yo antibody

Paraneoplastic neurological syndromes are believed to be autoimmune neuronal degenerations that develop in some patients with systemic cancer. Although a high titer of anti-Yo antibody has been found in the sera and cerebrospinal fluid of patients with paraneoplastic cerebellar degeneration (PCD), the role of anti-Yo antibody in Purkinje cell loss has not been shown. Previously we found that all of nine Japanese patients with PCD who harbored anti-Yo antibody had HLA A24. In this present study we have examined cytotoxic T cell (CTL) activity against recombinant Yo protein in peripheral blood of a patient with PCD and anti-Yo antibody using autologous dendritic cells as the target. We did not detect CTL activity against Yo protein, though, this study does not exclude the possibility of the involvement of CTL in the development of PCD.

Long-term disability and prognosis in dentatorubral-pallidoluysian atrophy: A correlation with CAG repeat length†

Dentatorubral‐pallidoluysian atrophy (DRPLA) is a rare autosomal dominant neurodegenerative disorder caused by CAG repeat expansion. Previous studies demonstrated that the onset of DRPLA is closely associated with CAG repeat length. However, the natural history of DRPLA has not yet been evaluated. We here retrospectively investigated the factors that determine the disease milestones and prognosis in 183 Japanese patients genetically diagnosed with DRPLA. We determined the age at onset, age at which each of the subsequent clinical manifestations appeared, age at becoming wheelchair‐bound, and age at death. Kaplan‐Meier analysis revealed that the patients with CAG repeats larger than the median length of 65 repeats developed each of the clinical features of DRPLA at a younger age than those with <65 repeats. The patients became wheelchair‐bound at a median age of 33 years (n = 61; range, 3–77 years) and died at a median age of 49 years (n = 23; range, 18–80 years). The ages at becoming wheelchair‐bound and at death strongly correlated with the expanded CAG repeat length. Moreover, the patients with ≥65 CAG repeats showed a more severe long‐term disability and a poorer prognosis. In contrast, the rate of progression after the onset did not correlate with CAG repeat length. The CAG repeat length may have a considerable effect on not only the disease onset but also the disease milestones and prognosis in DRPLA patients. These effects of CAG repeat length may be relevant in designing future clinical therapeutic trials.

Improvement of symptoms following epileptic convulsion in a patient with Parkinson's disease

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