森田 光哉

症例は73歳である。男性。長年の飲酒歴、53歳頃より糖尿病あり。64歳頃より両下肢つっぱり感と歩行困難・残尿感が出現し、70歳頃に杖歩行。その後、両足の異常感覚と頻尿・尿失禁を生じた。同症状の家族歴はなかった。両下肢の痙縮と軽度脱力、腱反射亢進・病的反射陽性、両足の感覚障害、頻尿・排尿困難、高度の痙性歩行がみられた。本邦では新規のSpastin遺伝子1726T>C(Leu534Pro)変異をみとめ、SPG4と診断した。多発ニューロパチーを合併した高齢孤発例であり、診断に苦慮した1例だった。(著者抄録)

We report an adult case of acute cerebellitis associated with influenza A. A 25-year-old woman with fever and headache was diagnosed as having influenza A infection, because nasal swab extract was found positive in the influenza assay. She was treated with oseltamivir. After the treatment, she gradually developed gait and speech disturbance. Neurological examination revealed dysarthria with scanning slurred speech, and limb and truncal ataxia. Cerebrospinal fluid showed pleocytosis and a four-fold or greater change in the antibody titer to influenza virus A (H3N2) detected by HI. T2-weighted brain MRI demonstrated a high signal lesion in the cerebellar cortex. 123I-IMP-SPECT showed hypoperfusion in the cerebellum. Thus, acute cerebellitis associated with influenza A infection was diagnosed. Her symptoms partially improved after steroid pulse therapy, whereas the cerebellar cortical lesion observed on MRI, truncal ataxia and cerebrospinal fluid pleocytosis remained. The cerebellar cortical lesion observed on MRI disappeared 80 days after hospitalization, and the truncal ataxia and cerebrospinal fluid pleocytosis had normalized about three months later.

Objective: To perform genetic linkage analysis in a family affected with ALS and frontotemporal dementia (FTD). Methods: The authors performed a genome-wide linkage analysis of a four-generation, 50-member Scandinavian family in which five individuals were diagnosed with ALS and nine with FTD. Linkage calculations assuming autosomal dominant inheritance of a single neurodegenerative disease manifesting as either ALS or FTD with age-dependent penetrance were performed. Further analyses for ALS alone and FTD alone were performed. A parametric logarithm of odds (lod) score of 2.0 or greater was required for further study of a potential locus and crossover (haplotype) analysis. Results: A new ALS-FTD locus was identified between markers D9s1870 and D9s1791 on human chromosome 9p21.3-p13.3. A maximum multipoint lod score of 3.00 was obtained between markers D9s1121 and D9s2154. Crossover analysis indicates this region covers approximately 21.8 cM, or 14Mb. Conclusions: A locus on chromosome 9p21.3-p13.3 is linked to ALS-FTD.

Progressive myoclonus epilepsy of the Unverricht-Lundborg type is an autosomal recessive disorder that is characterized clinically by myoclonic seizures and ataxia. The majority of affected individuals carry repeat expansions of a dodecamer in the promoter region of the cystatin B gene. The unusually high GC content of this tract is refractory to conventional polymerase chain reaction (PCR), and, as a result, a circumventive procedure involving the deamination of DNA with sodium bisulfite has been proposed. This study evaluates the effectiveness of this deamination modification for the detection of dodecamer repeat variants. An analysis of 258 healthy Japanese individuals revealed an allele with four copies of the dodecamer repeat with a frequency of 0.01, in addition to the more commonly observed two and three copy repeat alleles. Homozygous repeat expansions 600 and 680 base pairs in length were detected in the analyses of two affected individuals. For these cases, sequencing, along with an alternative PCR- stutter formation, revealed 41 and 48 copies, respectively, of the dodecamer repeat. The complete conversion of C to T was observed in the expanded tracts, indicating that no methylation occurred at the CpG sites. Based on these results, it was concluded that the use of deaminated DNA allows for a precise analysis of consecutive GC tracts.

A 54-year-old man with a history of partially dissected epidermoid cyst in the left cerebellopontine angle suffered from a slowly progressive dysesthesia and weakness in the lower extremities and trunk. Neurological examination revealed segmental muscular weakness and sensory disturbance in those regions, giving rise to the possibility of monoradiculopathy multiplex, as well as loss of tendon reflexes, dysuria and right facial nerve palsy. Electrophysiological studies indicated irregular motor axonopathy or neuronopathy and interruption of more central sensory pathways than the lumbosacral spinal nerve roots with spared peripheral sensory nerves. Although MRI demonstrated enhanced lesions in the cauda equina and lumbosacral leptomeninges, CSF cytology or a cauda equina biopsy showed no malignancy. His symptoms gradually progressed and he died 15 months after the onset. The autopsy failed to reveal any tumors in the general systemic internal organs. Histopathology demonstrated meningeal carcinomatosis with squamous-type carcinoma cells scattered in the cerebrospinal leptomeninges, and perineurium in almost all the spinal and cranial nerve roots, causing severe axonal degeneration. The dorsal root ganglions escaped tumor cell invasion. Absence of the malignant tumors in the systemic organs and the history of the operated epidermoid cyst indicate that the tumor may be the cause of the meningeal carcinomatosis in this case. Meningeal carcinomatosis almost always shows rapid progression and extremely poor prognosis with several month survival in general, and little attention has been paid that it can exhibit symptoms and signs of segmental involvement in the lumbosacral regions. Our present case prompts us to bear in mind that patients with this condition can survive fairly long, and raises the possibility that a careful neurological examination with segmental involvement will reveal such a feature more frequently than considered so far in this condition.

Hereditary spastic paraplegia (HSP) is a degenerative neuromuscular disease characterized by progressive lower extremity weakness, spasticity and hyperreflexia. Inheritance of HSP is commonly autosomal dominant, spastin was identified as the defective gene in chromosome 2p-linked autosomal dominant hereditary spastic paraplegia (AD-HSP). In a large American family with AD-HSP, we have identified a novel spastin mutation at a splice-acceptor site in intron 6 (1130-1 g --> a) and detected a corresponding aberrant transcript generated from a cryptic splice site. This is predicted to cause a frameshift and premature truncation of the abnormal spastin protein. Our data are the first to confirm that a mutation in an acceptor site in the spastin gene results in activation of a cryptic acceptor site and a translational frameshift. The clinical phenotype of this pedigree is also discussed. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.

症例は38歳,男性.右下肢筋力低下を主訴に受診し,口腔内アフタ,陰部潰瘍,両側足関節炎,意識障害や右上下肢不全麻痺などの神経症状より不全型のBehçet病と診断した.ステロイドパルスと内服治療にて症状は軽快した. Behçet病の脳病変は頭部MRIにて脳幹の小病変が特徴であるが,本例は大脳半球の巨大病変を呈し,稀なため報告した.脳梗塞との鑑別にはMRI拡散強調画像が有用であると考えられた.

Objective: To examine the possibility that CAG/CTG expansions are implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Methods: We have used the repeat expansion detection (RED) method to screen for CAG/CTG expansions in fifty-six cases of familial ALS (FALS), fifty-one cases of sporadic ALS (SALS) and fifty-one controls, We then tested the possibility that any detected expanded alleles originated from two specific loci, ERDA1/Dir1 or CTG18.1 using either the polymerase chain reaction (PCR) or Southern blotting. Results: CAG/CTG alleles with expansions of 144 bp or more base pairs were detected in 28.6% of FALS, 33.3% of SALS and 21.6% of controls. These alleles originated from either ERDA1/Dir1 or CTG18.1. Conclusion: The pathogenesis of familial and sporadic ALS does not commonly involve CAG/CTG expansions.

We have identified a novel mutation in exon 4 of the Cu/Zn superoxide dismutase (superoxide dismutase 1: SOD1) gene (GAC to GTC), which resulted in an Asp(90) to Val substitution in a Japanese family with amyotrophic lateral sclerosis (ALS) inherited as an autosomal dominant trait. The patients in this family usually died in 2-3 years without sensory or urinary impairment. The SOD1 activity was lower in the proband as compared to the normal controls. The clinical characteristics of this family resemble those of some patients heterozygous for the Asp90Ala mutation, but both the clinical features and SOD1 activity of this family differ from those of patients homozygous for the ASP90Ala mutation, Eur J Neurol 5:389-392 (C) 1998 Lippincott-Raven Publishers.

We studied the relationship between the number of CAG repeat units in the MJD1 gene and clinical features of Machado-Joseph disease (MJD) in eight patients from two generations of a Japanese MJD family. Because of lack of characteristic clinical signs of MJD such as dystonia, bulging eyes or facial myokymia, clinical diagnosis of MJD in this family was difficult to make prior to molecular testing for the CAG repeat expansion in the MJD1 gene. All the patients exhibited maternal transmission of MJD, and the intergenerational change in the number of CAG repeat units in the MJD1 gene was very small (+0.5+/-0.3, mean+/-S.E.M., n=4) in spite of marked genetic anticipation (-17.0 years/generation). In the present family, the degree of anticipation per repeat unit in maternal transmissions was much larger than that in maternal transmissions in the other six MJD families. This indicates that some maternal factors other than the increase of the number of CAG repeat units, which is known to be the basis of anticipation, may play a role in genetic anticipation in this MJD family. (C) 1998 Elsevier Science B.V.

We have identified a novel two-base mutation in exon 1 of the Cu/Zn superoxide dismutase (SOD1) gene (TGC to TTT), which resulted in Cys(6) to Phe substitution in a Japanese family with amyotrophic lateral sclerosis (ALS). This is the first case of familial ALS-associated two-base change of the SOD1 gene. Similar to several mutations in exon 1 of the SOD1 gene such as Ala(4) to Val, Ala(4) to Thr and Val(14) to Met, affected members of the present family showed a rapid progression of motor dysfunction. Although Ala(4), Cys(6) and Val(7) reside in the middle of the first beta-strand of the SOD1, a family with a mutation of Va1(7) to Glu associates with slow progression of the disease. These findings suggest that clinical courses are variable with each mutation, even in the same exon.

Cytotoxic action of leukocytes may be involved in the pathogenesis of inflammatory heart muscle disorders. We investigated the expression of rat leukocyte chemotactic cytokines-cytokine induced neutrophil chemoattractant (CINC) and JE-in cultured neonatal rat cardiac myocytes; CINC belongs to the interleukin 8 (IL-8) family and JE is a homologue of human monocyte chemoattractant protein 1 (MCP-1), In Northern blot analysis, CINC and JE transcripts were not clearly observed in unstimulated rat cardiac myocytes, However, their expression was clearly observed after exposure to tumour necrosis factor-alpha (TNF-alpha; 100 U/ml) for 26 h, We then evaluated IL-8 and MCP-I mRNA expression in human endomyocardial biopsy specimens from seven patients with idiopathic dilated cardiomyopathy by polymerase chain reaction analysis, Both IL-8 and MCP-1 mRNA transcripts were recognized in all patients studied, These results show for the first time that leukocyte chemotactic cytokines, IL-8 and MCP-1, are expressed in myocardial tissue, which might contribute to the pathogenesis of inflammatory heart muscle disorders.

A glucocorticoid, dexamethasone, inhibited the production of a leukocyte chemotactic cytokine, interleukin 8 (IL-8), as well as mRNA expression by a glioblastoma cell line, T98G, stimulated with interleukin 1 (IL-1). Dexamethasone also inhibited IL-8 promoter-driven chloramphenicol acetyltransferase (CAT) activities induced by IL-1, suggesting that dexamethasone inhibited IL-8 production mainly at the transcriptional level. Moreover, CAT assay revealed that the nuclear factor-kappa B (NF-kappa B) binding site was the crucial cis-element required for conferring IL-1 responsiveness in conjunction with the CCAAT enhancer binding protein/nuclear factor-IL-6 (NF-IL6) and/or the AP-1 binding site(s). Mutation of either the AP-1 or NF-IL6 binding site did not abolish IL-8 gene repression by dexamethasone, suggesting that these sites were not targets for dexamethasone. Trimerized kappa B sequence in the IL-8 gene was enough for conferring the induction by IL-1 and inhibition by dexamethasone of CAT activity. Finally, dexamethasone diminished the IL-l-induced formation of NF-kappa B complexes, which were identified immunochemically to consist of p50 and p65, without reducing the amount of translocated factors. Collectively, dexamethasone interfered with the binding of the most essential transcription factor, NF-kappa B, to its cognate cis-element, thereby suppressing the transcription of IL-8 gene.

In order to elucidate the role of inflammatory cytokines in the central nervous system, we examined the production of two leukocyte chemoattractants, IL-8 and monocyte chemotactic and activating factor (MCAF) in brain tumor cell lines. The glioma cell lines tested exhibited high levels of IL-g and MCAF mRNA expression upon stimulation with IL-1 or TNF-alpha, while none of the neuroblastoma cell lines expressed these cytokine mRNA. Both IL-8 and MCAF mRNA expression depended on the dose of IL-la and TNF-a and appeared very rapidly, reaching maximal levels at 3-6 hr, with substantial production of these cytokines in the culture supernatants. When various immunosuppressive drugs were tested, glucocorticoids but not other immunosuppressive drugs markedly inhibited the IL-1 or TNF-a-induced IL-8 and MCAF mRNA accumulation, suggesting that glucocorticoid is a potent regulator of these inflammatory cytokine production in the neural tissues. In addition, reverse transcription-polymerase chain reaction (RT-PCR) revealed the expression of IL-8 and MCAF mRNA expression in resected brain tumor tissues including glioblastoma, astrocytoma grade 2, ependymoma and medulloblastoma, indicating that these inflammatory cytokines are expressed in vivo.