Novel mutation in EIF2B gene in a case of adult-onset leukoencephalopathy with vanishing white matter.
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Adult↗
Biomedical subjects
Masatoyo Nishizawa
Publications and source records attributed to Masatoyo Nishizawa.
Multiple system atrophy with progressive nocturnal hypoxemia: case report with polysomnography and continuous positive airway pressure treatment.
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Continuous Positive Airway Pressure↗
Familial amyotrophic lateral sclerosis: a SOD1-unrelated Japanese family of bulbar type with Bunina bodies and ubiquitin-positive skein-like inclusions in lower motor neurons.
We describe a new family with adult onset amyotrophic lateral sclerosis (FALS), in which the disease was characterized clinically by relatively rapid progression of bulbar symptoms. Gene analysis of Cu/Zn superoxide dismutase (SOD1) performed in one patient showed no mutations. Autopsy of another patient demonstrated degenerative changes restricted to the upper and lower motor neuron systems; no evident changes were observed in the posterior column, Clarke's column or spinocerebellar tracts. The presence of Bunina bodies and ubiquitin-positive skein-like inclusions in the lower motor neuron was of considerable interest. Cases of FALS with such pathological features are quite rare in the literature. Identification of the gene responsible for the disease is desirable in order to shed further light on the molecular pathology of not only familial, but also sporadic, ALS.
Aged↗
A possible variant of neuro-Behçet disease presenting chronic progressive ataxia without mucocutaneo-ocular symptoms.
Behçet disease (BD) is a chronic relapsing multisystem disorder of unknown etiology, which preferentially affects the oral and genital mucous membranes, skin, and eyes. Neurological involvement is one of the most serious manifestations of BD, known as neuro-Behçet disease (NBD). We here describe clinical, radiological, and neuropathological findings for two patients with a possible variant of NBD, who manifested progressive ataxia in the absence of mucocutaneo-ocular signs characteristic for BD. Both patients presented a slowly progressive cerebellar phenotype, accompanied by behavioral changes and sphincter disturbance. Brain MRI scan revealed mild atrophy in pons and cerebellum. Both patients showed a mild CSF pleocytosis, and were positive for HLA-B51. The post-mortem examination performed in one patient, showed widespread foci of chronic encephalitis, consistent with the diagnosis of NBD. Steroid pulse therapy was effective in one patient. Identifying the progressive ataxia phenotype of NBD without mucocutaneo-ocular symptoms is important, because these patients may benefit from early steroid therapy.
Adult↗
[Encephalitis and encephalopathy of unknown etiology: discussion].
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Brain Diseases↗
Corticobasal degeneration with focal, massive tau accumulation in the subcortical white matter astrocytes.
We report two sporadic cases of tauopathy with unusual neuropathological features. The ages of the patients at death were 86 and 74 years, and the disease durations were 4 and 3 years, respectively. The former patient showed progressive dementia and amyotrophy (autopsy revealed that severe cervical spondylosis was responsible for the amyotrophy), and the latter showed progressive parkinsonism and dementia. The essential brain pathologies were similar to each other; although ballooned neurons and astrocytic tau lesions (astrocytic plaques) were present in the affected cerebral cortex, the most striking finding was focal, much heavier accumulation of tau in the subcortical white matter. Moreover, double-labeling immunostaining, as well as Gallyas-Braak electron and AT8 immunoelectron microscopic studies strongly suggested that in the affected subcortical white matter, the accumulation of tau occurred mainly in the astrocytic processes. In the latter patient, for whom frozen brain tissue was available, immunoblotting of insoluble tau revealed a pattern compatible with that obtained from brain affected by typical corticobasal degeneration (CBD), and gene analysis of tau revealed no mutations, with a H1 haplotype. Finally, in both cases, the pathological diagnosis of CBD was considered to be appropriate. However, the tau pathology affecting the subcortical white matter astrocytes was very unusual for the disease.
Aged↗
Long-term therapeutic efficacy and safety of low-dose tacrolimus (FK506) for myasthenia gravis.
OBJECTIVE: To elucidate the long-term therapeutic efficacy and safety of low-dose FK506 (tacrolimus) in patients with myasthenia gravis (MG). PATIENTS AND METHODS: We treated nine patients with MG (all women: age range: 35-83 years (mean: 51.1 years); MGFA classification: 4 type IIa, 4 type IIb, and 1 type IVb patients) with FK506 for more than 24 months (observation period: 24-46 months). All the patients had undergone extended thymectomy before FK506 treatment; two patients (22.2%) had noninvasive thymoma and six (66.7%) had thymic hyperplasia. We evaluated total Quantitative MG (Q-MG) score, anti-acetylcholine receptor (AChR) antibody titer in the blood, interleukin 2 (IL-2) production in peripheral blood mononuclear cells (PBMCs), administration dosage of prednisolone (PSL), and adverse effects of FK506. RESULTS: A reduction in steroid dosage of 50% without worsening of the symptoms was observed 1 year after FK506 administration in three out of six steroid-dependent MG patients (50.0%). The total Q-MG scores (range: 0-39 points) at 6 months and 1 year after FK506 administration improved by 3 points or more in six (66.7%) and seven (77.8%) out of nine patients, respectively. The efficacy of FK506 was maintained for more than 2 years. Although adverse effects were observed in three patients (33.3%), these were not serious. CONCLUSIONS: Our study indicates that low-dose FK506 treatment may be efficacious not only in controlling intractable myasthenic symptoms, but also in reducing steroid dosage, and that FK506 is safe as an adjunctive drug to PSL for MG treatment for a maximum of 3 years.
Adult↗
Three-dimensional anisotropy contrast periodically rotated overlapping parallel lines with enhanced reconstruction (3DAC PROPELLER) on a 3.0T system: a new modality for routine clinical neuroimaging.
BACKGROUND: Clinical magnetic resonance imaging (MRI) has recently entered the "high-field" era, and systems equipped with 3.0-4.0T superconductive magnets are becoming the gold standard for diagnostic imaging. While higher signal-to-noise ratio (S/N) is a definite advantage of higher field systems, higher susceptibility effect remains to be a significant trade-off. To take advantage of a higher field system in performing routine clinical images of higher anatomical resolution, we implemented a vector contrast image technique to 3.0T imaging, three-dimensional anisotropy contrast (3DAC), with a PROPELLER (Periodically Rotated Overlapping Parallel Lines with Enhanced Reconstruction) sequence, a method capable of effectively eliminating undesired artifacts on rapid diffusion imaging sequences. METHODS: One hundred subjects (20 normal volunteers and 80 volunteers with various central nervous system diseases) participated in the study. Anisotropic diffusion-weighted PROPELLER images were obtained on a General Electric (Waukesha, WI, USA) Signa 3.0T for each axis, with b-value of 1100 sec/mm(2). Subsequently, 3DAC images were constructed using in-house software written on MATLAB (MathWorks, Natick, MA, USA). RESULTS: The vector contrast allows for providing exquisite anatomical detail illustrated by clear identification of all major tracts through the entire brain. 3DAC images provide better anatomical resolution for brainstem glioma than higher-resolution T2 reversed images. Degenerative processes of disease-specific tracts were clearly identified as illustrated in cases of multiple system atrophy and Joseph-Machado disease. CONCLUSION: Anatomical images of significantly higher resolution than the best current standard, T2 reversed images, were successfully obtained. As a technique readily applicable under routine clinical setting, 3DAC PROPELLER on a 3.0T system will be a powerful addition to diagnostic imaging.
Anisotropy↗
[Reevaluation of validity of percent creatinuria for diagnosing steroid myopathy].
Steroid myopathy is usually a slowly progressive disease, which causes weakness primarily to the proximal muscles of the upper and lower extremities. The monitoring of this problem is difficult in situations in which the primary disease itself produces muscle weakness. The distinguishing feature in steroid myopathy is the occurrence of creatinuria in the presence of normal muscle enzymes including creatine kinase and aldolase. To evaluate the usefulness of percent creatinuria {urinary excretion of creatine/(urinary excretion of creatine + urinary excretion of creatinine)} in the diagnosis of steroid myopathy, we measured percent creatinuria in 26 patients (14 male and 12 female) without muscle diseases before the initiation of steroid treatment We found that the median values of percent creatinuria of the male and female patients were 2.5% and 17.1%, and that the ratios of the male and female patients presenting with an elevated percent creatinuria (more than 10%) were 3 out of 14 patients (21.4%) and 8 out of 12 patients (66.7%), respectively. We also found one patient with mild renal dysfunction presenting with an elevated percent creatinuria but without muscle weakness or myalgia. These findings suggest that the measurement of percent creatinuria is of little value in the diagnosis of steroid myopathy with a cutoff value of 10%. Furthermore, it is important to measure percent creatinuria before the steroid treatment, while paying close attention to the measurement method, sex, renal function and protein level of the diet.
Creatine↗
[Oral cyclophosphamide therapy for multifocal fibrosclerosis with hypertrophic intracranial pachymeningitis].
A 54-year-old man was admitted to our hospital because of a headache, dry cough, low grade fever and hearing loss sustained for 6 months. Physical and neurological examinations revealed bilateral conjunctival hyperemia, fine crackles in the lower lungs, cutaneous scars, horizontal gaze evoked nystagmus, bilateral moderate sensorineural deafness and mild hyperreflexia. Hypertrophic intracranial pachymeningitis (HIP) accompanied by episcleritis, pulmonary fibrosis, subcutaneous fibrosis of the trunk and upper limbs, bilateral chronic otitis media and sinusitis of the paranasal cavities were observed. Histopathological investigation of biopsied tissues from the dura matter, lung, skin and nasal mucosa showed marked fibrosis with lymphocyte and plasma cell infiltrations. The diagnosis of multifocal fibrosclerosis (MF) was made; this is a rare syndrome of unknown etiology characterized by fibrosis involving multiple organ systems. Although steroid pulse therapy and cyclophosphamide (CP) pulse therapy was not effective in his illnesses, the combination therapy of corticosteroid and oral CP was dramatically effective. We concluded that HIP can be a manifestation of MF, and additional oral CP should be considered as a treatment for steroid-resistant MF with HIP.
Administration, Oral↗
[A patient with HIV encephalopathy presenting with parkinsonism during HAART therapy].
We report the case of a 32-year-old man presenting symptoms of parkinsonism. Neurological examination revealed parkinsonism symptoms such as akinesia and postural instability, dementia and frontal lobe signs. He was diagnosed as having human immunodeficiency virus (HIV) encephalopathy. Brain MRI, 99mTc ECD-SPECT and 1H-MR spectroscopy demonstrated symmetrical cerebral white matter lesions, predominantly in the bilateral frontal lobes. Frontal lobe dysfunction could be responsible for his parkinsonism associated with HIV encephalopathy. His neurological symptoms improved transiently after the initiation of HAART but fluctuated when antiretroviral drugs were changed because of their side effects. Although HAART effectively decreased plasma HIV-RNA load and increased peripheral blood CD4 cell count, his parkinsonism and dementia eventually exacerbated. Our results suggest that a combination of antiretroviral drugs affects the therapeutic efficacy against HIV encephalopathy, and that CNS symptoms could be aggravated during HAART, even when plasma HIV-RNA load and CD4 cell count are maintained under favorable conditions.
AIDS Dementia Complex↗
[Longitudinal analysis of age at onset and initial symptoms in patients with amyotrophic lateral sclerosis].
To investigate the longitudinal changes in age at onset and the initial symptom of patients with sporadic amyotrophic lateral sclerosis (ALS), we performed a single hospital-based retrospective study over the past 38 years. A total of 280 sporadic ALS patients (169 men and 111 women) hospitalized in our department between 1965 and 2003 were investigated in this study. The clinical features including age at onset and the initial symptom of these patients were obtained from medical records. All the patients underwent an intensive diagnostic evaluation including electrophysiological examination, laboratory examinations of blood and cerebrospinal fluid, and neuroimagings of the brain and spinal cord to exclude other conditions similar to ALS. The mean age at onset was 58.3 +/- 11.3 years and age at onset significantly increased at the rate of 0.459 years per year (r = 0.406, p< 0.001). The percentage of patients whose age at onset was > or = 70 years has increased from 3.0% (1980-1984) to 31.1% (2000-2003). To investigate the initial symptom of senile-onset ALS, patients whose age at onset was > or = 70 years were analyzed. The percentages of bulbar palsy-onset patients with onset in terms of age were 62.5% (30/48 patients; > or = 70 years) and 23.3% (54/232 patients; <70 years). The odd ratio for bulbar palsy was 5.40 (95% confidence interval, 2.79-10.44). Taken together, our study demonstrates that the ratio of senile-onset ALS has significantly increased, and that there were more bulbar palsy-onset patients among the patients.
Adult↗
[A case of primary central nervous system malignant lymphoma developing from the optic chiasma and hypothalamus].
A 63-year-old woman was admitted to our hospital with a 1-month history of visual field defect and reduced bilateral visual acuity. Neurological examination revealed enlargement of bilateral central scotoma and blurred vision, and brain MRI showed masses in the optic chiasma and right hypothalamus on Ti-weighted image with contrast enhancement. Although the patient was treated with high-doses of methylprednisolone four times, the masses spread to the right internal capsule and the vicinity of the right lateral ventricle. An open biopsy was performed and microscopic examination of the sample revealed lymphoplasmacytic lymphoma. Although primary central nervous system lymphoma (PCNSL) developing from the optic chiasma and hypothalamus is rare, PCNSL should be considered in patients with multiple lesions in the optic chiasma and hypothalamus.
Brain Neoplasms↗
Sporadic four-repeat tauopathy with frontotemporal degeneration, parkinsonism and motor neuron disease.
We report a sporadic tauopathy of 6-year duration in a 76-year-old woman. Her initial symptoms were asymmetrical parkinsonism and muscle weakness, with apraxia appearing 2 years later. The brain showed frontal and temporal cerebral atrophy; severe neuronal loss and gliosis were observed in the precentral cortex (loss of Betz cells was also evident) and premotor area, and in the medial temporal lobe, including the temporal tip, amygdala, and hippocampal CA1-subiculum border zone. The substantia nigra showed moderate neuronal loss and gliosis. In the spinal cord, loss of the anterior horn cells and degeneration of the corticospinal tracts were a characteristic feature. In addition, in the affected regions, the remaining neurons were often found to contain intracytoplasmic inclusions resembling neurofibrillary tangles. Tau immunostaining revealed widespread glial-predominant lesions in the cerebral gray and white matter. In contrast, predominance of neuronal lesions (pretangles/tangles) was a feature in the subcortical gray matter, including the spinal cord. The remaining upper and lower motor neurons were also affected by tau pathology. Accumulated tau in these glial cells and neurons was clearly recognized by a specific antibody against four-repeat (4R) tau. The ultrastructural presence of tau-positive tubular structures was confirmed in the glial cells and neurons (tangles). Immunoblotting of a frozen frontal lobe sample revealed accumulation of 4R-predominant tau isoforms. No mutations were found in the tau gene. These findings indicate that a sporadic 4R tauopathy can cause frontotemporal degeneration, parkinsonism, and motor neuron disease. The present case could represent a new clinicopathological phenotype of non-familial tauopathy.
Aged↗
Selective silencing of a mutant transthyretin allele by small interfering RNAs.
Familial amyloidotic polyneuropathy (FAP) is a hereditary systemic amyloidosis caused by dominantly acting missense mutations in the gene encoding transthyretin (TTR). The most common mutant TTR is of the Val30Met type, which results from a point mutation. Because the major constituent of amyloid fibrils is mutant TTR, agents that selectively suppress mutant TTR expression could be powerful therapeutic tools. This study has been performed to evaluate the use of small interfering RNAs (siRNAs) for the selective silencing of mutant Val30Met TTR in cell culture systems. We have identified an siRNA that specifically inhibits mutant, but not wild-type, TTR expression even in cells expressing both alleles. Thus, this siRNA-based approach may have potential for the gene therapy of FAP.
Amyloid Neuropathies, Familial↗
Polyglutamine represses cAMP-responsive-element-mediated transcription without aggregate formation.
Transcriptional dysregulation, particularly cAMP-responsive-element-mediated transcriptional repression, has been implicated in expanded polyglutamine diseases. However, it has not been clarified whether this transcriptional repression is a cause or result of neurodegeneration. Furthermore, the association between aggregates of expanded polyglutamine stretches and transcriptional repression is not clear. We established isogenic cell lines with polyglutamine stretches, which also expressed d2EGFP under the control of cAMP-responsive elements. In this system, the polyglutamine stretch repressed cAMP-responsive-element-mediated transcription without the formation of macroscopic expanded polyglutamine aggregates. Furthermore, aggregate formation did not have an adverse effect on the repression of transcriptional activity. The results demonstrated that the repression of cAMP-responsive-element-mediated transcription is an early event caused by a soluble form of polyglutamine stretch.
Cell Line↗
A mutant PSEN1 causes dementia with Lewy bodies and variant Alzheimer's disease.
We report early-onset parkinsonism and dementia of 18 years' duration in a 52-year-old man whose grandfather and father had suffered from a similar neurological disease. In this patient, we found neuronal loss in various brain regions including the substantia nigra and cerebral cortex, Lewy bodies, cotton wool plaques, corticospinal tract degeneration, cerebral amyloid angiopathy, and a novel three-base pair deletion in exon 12 of the presenilin-1 (PSEN1) gene. We considered that the mutant PSEN1 might play an important role in the pathogenetic process of both aggregation of alpha-synuclein into Lewy bodies and deposition of beta-amyloid into cotton wool plaques.
Alzheimer Disease↗
Sacsin-related autosomal recessive ataxia without prominent retinal myelinated fibers in Japan.
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) has been described in the Quebec region and in Tunisia. We report on two Japanese siblings with a new homozygous mutation (6543 del A) of the SACS gene. Compared with previously reported ARSACS patients, both of these patients had a unique phenotype characterized by dementia, ophthalmoplegia, and the absence of prominent retinal myelinated fibers.
Ataxia↗