Yoko Kitagawa

Clinical features of neuromyelitis optica in a large Japanese cohort: comparison between phenotypes

Objective To analyse clinicoepidemiological features of neuromyelitis optica in a large cohort and to compare the differences between onset age, gender and clinical phenotypes. Methods Antiaquaporin-4 antibody (AQP4-ab) levels were tested in 2366 serum samples of patients diagnosed as having central nervous system inflammatory demyelinating disorders by their referring physicians. AQP4-ab was measured by indirect immunofluorescence staining using human AQP4-transfected HEK 293 cells. A blinded analysis was performed and was combined with clinical information. Results A total of 583 patients (91.4% women) were AQP4-ab-positive. The average onset age was 42.9±15.9 years. According to MRI studies, spinal-cord lesions were detected in 85.3% of the patients, longitudinally extensive transverse myelitis in 72.7% and cerebral lesions in 51.1%. Unilateral or bilateral blindness was observed in 16.2% of patients, 19.8% were associated with Sjögren syndrome, and 13.6% were associated with thyroid diseases. Myelin basic protein was detected in the cerebrospinal fluid of 57.5% patients. In addition, men presented with an older onset age, a greater number of brainstem MRI lesions and positive myelin basic protein in the cerebrospinal fluid. All child-onset patients (<15 years, n=9) presented with optic neuritis as the first symptom, while older-onset patients presented with myelitis. Twenty patients initially developed limited brain lesions, and seven of these patients did not develop optic or spinal lesions during the 1–5-year follow-up period. Conclusions The clinical characteristics of AQP4-ab-positive patients were similar. However, optic neuritis was more common in paediatric patients, while myelitis was more common in older patients. A small number of patients exhibited only cerebral, brainstem, or cerebellar lesions during the initial several years and lower Extended Disability Status Scale scores.

Mutation in the CHAC gene in a family of autosomal dominant chorea–acanthocytosis

Writ e Click is restricted to comments about studies published in Neurology ® within the past 8 weeks. The submission below represents an exception because it addresses a genetic sequencing error published in Neurology in 2003. In addition, these Writ e Click submissions will be available as open access to all readers in an effort to further publicize the Correction. In 2003, Saiki et al.1 reported an autosomal dominant transmission of chorea-acanthocytosis (ChAc) that constituted a significant challenge to the generally …

Binding of neuronal ELAV‐like proteins to the uridine‐rich sequence in the 3′‐untranslated region of tumor necrosis factor‐α messenger RNA

Tumor necrosis factor‐α (TNF‐α) is a proinflammatory cytokine that is involved in the pathogenesis of several human CNS disorders. The AU‐rich element (ARE) in the 3′‐untranslated region (UTR) of TNF‐α mRNA is implicated in post‐transcriptional control of TNF‐α. In this study, we showed that a human neuronal ELAV‐like protein binds to the ARE in the 3′‐UTR of TNF‐α mRNA. The protein binds to the uridine stretch in AUUUA pentanucleotides inside the ARE in the 3′‐UTR of TNF‐α mRNA. The TNF‐α mRNA‐binding region in the protein appears to be identical to the c‐myc and IL‐3 mRNA‐binding regions. Moreover, this study showed that in vitro treatment of neuroblastoma cells with interleukin‐4 (IL‐4), which inhibits TNF‐α production, reduced the expression of the neuronal ELAV‐like proteins. These results suggest that the expression of neuronal ELAV‐like proteins may be closely associated with the expression of TNF‐α in neuronal cells.

Varicose veins associated with CADASIL result from a novel mutation in the Notch3 gene.

No genetically diagnosed cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) pedigrees with venous insufficiency have been described. In a CADASIL pedigree with varicose veins, the authors have identified a novel heterozygous mutation in the 3′ splice acceptor site of intron 15 of the Notch3 gene. This, based on mRNA analysis, resulted in skipping of exon 16 including eight cysteine residues of EGF-like repeats.

Induction of anti-Purkinje cell antibodies in vivo by immunizing with a recombinant 52-kDa paraneoplastic cerebellar degeneration-associated protein

We immunized five different strains of mice with the recombinant human PCD17 protein, which is recognized by anti-Purkinje cell antibodies in the sera of patients with paraneoplastic cerebellar degeneration, and explored whether or not antibodies against cerebellar Purkinje cells could be induced in vivo. Autoantibodies against the cytoplasmic protein of Purkinje cells and other neurons were raised in all the strains of mice. These antisera stained the cytoplasm of cytoplasm of the Purkinje cell in a coarse, granular pattern, but spared the nucleus. The antisera did not stain cerebellar granular cells. This pattern of immunostaining seen with the mouse antisera is similar to that seen with the human PCD sera, but more widespread cells in the central nervous system were stained with these antisera. The titers of the induced antibodies were comparable to or even higher than those of humans. The deposition of IgG was also demonstrated in the cytoplasm of Purkinje cells in the immunized mice. In spite of the generation of anti-Purkinje cell antibodies in vivo, neither clinical nor pathological changes consistent with cerebellar degeneration were detected 1 year following the first immunization.

Primary skeletal muscle involvement in chorea-acanthocytosis.

Chorea‐acanthocytosis (ChAc) is a hereditary disease characterized by involuntary movements and amyotrophy with elevation of serum creatine kinase. Although skeletal muscle involvement in ChAc has been suggested, the mechanism remains unclear. To investigate chorein abnormalities of the skeletal muscles of ChAc patients with an apparently heterozygous VPS13A mutation compared with those of other hereditary choreic diseases, we performed histological and immunohistochemical studies of the skeletal muscles from 3 ChAc, 1 Huntingtons disease (HD), 1 McLeod syndrome (MLS), and 1 normal control (NC) with 2 originally generated anti‐chorein antibodies. Chorein immunoreactivities in HD, MLS, and NC were found linearly along the sarcolemma and appeared as speckles in the sarcoplasma, but those in ChAc were uneven and discontinuous along the sarcolemmas and increased in the sarcoplasma especially in type I fibers. This histological observation suggests chorein abnormalities of skeletal muscles might be associated with primary involvement of skeletal muscles in this disorder.

Effect of a paraneoplastic cerebellar degeneration-associated neural protein on B-myb promoter activity.

In this study, we have shown that a paraneoplastic cerebellar degeneration (PCD)-associated antigen, pcd17, binds to a cell cycle-related protein, MRG15. MRG15 derepresses the E2F-responsive B-myb promoter. The pcd17 antigen inhibits the derepression of the B-myb transcriptional activity by MRG15, and, as a result, pcd17 represses the promoter. Delivery of anti-Purkinje cell antibodies (anti-Yo) into the cells inhibits the repression of B-myb promoter activity by pcd17. Because derepression of the B-myb promoter has been implicated in neuronal death, the results suggest the possible role of the antibodies in the pathogenesis of PCD.

Interaction of a Paraneoplastic Cerebellar Degeneration-Associated Neuronal Protein with the Nuclear Helix-Loop-Helix Leucine Zipper Protein MRG X

Paraneoplastic cerebellar degeneration-associated antigen PCD17/cdr2 is a neuronal protein expressed predominantly in the cytoplasm of cerebellar Purkinje cells. The biological activities of this protein are not known; however, the presence of a leucine zipper motif in its amino acid sequence suggests that this protein might interact with other proteins harboring a leucine zipper motif. In this study we found by means of a yeast two-hybrid system, ligand overlay assay, and co-immunoprecipitation assay that PCD17 interacts with a nuclear helix-loop-helix leucine zipper protein, MRG X. Overexpression of MRG X in T98G glioblastoma cells by transfection caused abnormal morphological changes in the nucleus and induced cell death. On the other hand, coexpression of PCD17 with MRG X prevented nuclear morphological changes and cell death in T98G cells. MRG X, which is thought to be functionally related to the cell cycle and cell growth, may be regulated by PCD17/cdr2 in Purkinje cells.

Induction of major histocompatibility complex class I molecules on human neuroblastoma line cells by a flavoid antioxidant

Human major histocompatibility complex (MHC) class I expression is usually suppressed in neuronal cells and neuroblastoma cells. In the present study, we analyzed the effect of a flavonoid antioxidant, silymarin, on the induction of MHC class I molecules in human neuroblastoma line cells. Treatment of neuroblastoma cells with silymarin resulted in the expression of MHC class I molecules. Silymarin treatment enhanced the transcriptional activity of the reporter construct containing MHC class I promoter truncated within -428 bp of transcription initiation, but not the construct containing the promoter truncated within -284 bp. Because an E-box element is located between -428 and -285 bp of the transcription initiation, results suggest that silymarin acts on the enhancer activity of the E-box in the MHC class I promoter. Our findings indicate that silymarin induces the transcriptional factors to enhance the MHC class I promoter through the class I E-box element.

Antibody recognition and RNA binding of a neuronal nuclear autoantigen associated with paraneoplastic neurological syndromes and small cell lung carcinoma

The PLE21/HuC neural protein is an autoantigen for anti-neuronal nuclear autoantibodies (ANNA-1/anti-Hu/Type IIa antibodies) from a patient with paraneoplastic limbic encephalomyelitis and small cell lung carcinoma. This antigen belongs to the Hu/ELAV-like protein family, contains three RNA recognition motifs (RRMs) and has RNA binding capacity. In many autoimmune diseases mediated by autoantibodies, antibodies often interfere with the biological functions of their target antigens. To investigate the influences of the autoantibodies on the biological function of the antigen, we mapped the regions which were required for the antibody recognition and for the RNA binding. Deletion analysis of the antigen revealed that the epitopes for the antibodies were localized in the regions of 12 residues, amino acids 161-172, and eight residues, amino acids 29-38, of the first and second RRMs. It was also shown that the eight residues, amino acids 29-38, and the 10 residues, amino acids 187-194, were required for the RNA binding. Although amino acids 29-38 were necessary for both the antibody recognition and the RNA bindings, pre-incubation of the PLE21 antigen with the antibodies did not inhibit the formation of the complex of PLE21, the antibodies and RNA. Thus, the regions required for the antibody recognition are not identical with those for the RNA binding, and it seems unlikely that the autoantibodies interfere with RNA binding of the antigen.