Microbleed clustering in thalamus sign in CADASIL patients with NOTCH3 R75P mutation.

Background and objective: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebral microvascular disease characterized by the development of vascular dementia and lacunar infarctions. This study aimed to identify the genetic and clinical features of CADASIL in Japan. Methods: We conducted genetic analysis on a case series of patients clinically diagnosed with CADASIL. Clinical and imaging analyses were performed on 32 patients with pathogenic mutations in the NOTCH3 gene. To assess the presence of cerebral microbleeds (CMBs), we utilized several established rating scales including the Fazekas scale, Scheltens rating scale, and Microbleed Anatomical Rating Scale, based on brain MRI images. Results: Among the 32 CADASIL patients, 24 cases were found carrying the R75P mutation in NOTCH3, whereas the remaining eight cases had other NOTCH3 mutations (R75Q, R110C, C134F, C144F, R169C, and R607C). The haplotype analysis of the R75P mutation uncovered the presence of a founder effect. A brain MRI analysis revealed that cases with the R75P mutation had a significantly higher total number of CMBs, particularly in the thalamus when compared to patients with other NOTCH3 mutations. Among 15 out of 24 cases with the R75P mutation, we observed a notable clustering of CMBs in the thalamus, termed microbleed clustering in thalamus sign (MCT sign). Conclusion: We propose that the MCT sign observed in NOTCH3 R75P-related CADASIL patients may serve as a potentially characteristic imaging feature. This finding offers further insights into the interactions between genotypes and phenotypes between NOTCH3 and CADASIL.

Correlation between clinical and radiologic features of patients with Gerstmann-Sträussler-Scheinker syndrome (Pro102Leu).

BACKGROUND AND PURPOSE: Gerstmann-Sträussler-Scheinker syndrome is a rare hereditary neurodegenerative disorder with clinical heterogeneity. This study is aim to demonstrate the clinical spectrum and radiologic characteristics of patients caused by Pro102Leu mutation in PRNP. MATERIALS AND METHODS: We retrospect clinical manifestations of five patients from four Japanese families, and comprehensively analyzed their brain MRI, SPECT (N-isopropyl-p-[123I] iodoamphetamine), and PET (18F-2-fluoro-2-deoxy-d-glucose) images. RESULTS: All patients developed ataxia of lower limbs and trunk, gait disturbance, dysesthesia in legs, and lower limb hyporeflexia. In the early clinical stage before dementia began, no noticeable abnormalities could be observed from brain MRI, but SPECT and PET revealed mosaic-like pattern of blood flow and glucose metabolism of the brain. Predominant abnormalities were found in the occipital and frontal lobes on SPECT and PET analysis, respectively. In SPECT analysis, blood flow of the anterior cerebellar lobes was lower than that of the posterior cerebellar lobes. CONCLUSIONS: Clinical symptoms resulting from failure of dorsal horn of spinal cord and spinocerebellar tracts were observed in all cases. Radiologic findings revealed individual differences of involved region in their brain, which could produce clinical diversity. We identified a downtrend of blood flow in the anterior cerebellar lobes, a projection field of the spinocerebellar tracts, which is an important feature of Gerstmann-Sträussler-Scheinker syndrome.

New type of encephalomyelitis responsive to trimethoprim/sulfamethoxazole treatment in Japan.

OBJECTIVE: To determine the causative pathogen and investigate the effective treatment of a new type of encephalomyelitis with an unknown pathogen in Japan and report the preliminary ultrastructural and genomic characterization of the causative agent. METHODS: From 2005 to 2012, we treated 4 Japanese patients with geographic clustering and comparable clinical features, serum/CSF cytology, and radiologic findings. Brain biopsy was conducted in all patients to analyze neuropathologic changes by histology, and electron microscopy was applied to reveal the features of the putative pathogen. Genomic DNA was obtained from the affected brain tissues and CSF, and an unbiased high-throughput sequencing approach was used to screen for specific genomic sequences indicative of the pathogen origin. RESULTS: All patients exhibited progressive dementia with involuntary tongue movements. Cytologic examination of CSF revealed elevated mononuclear cells. Abnormal MRI signals were observed in temporal lobes, subcortical white matter, and spinal cord. Biopsied brain tissue exhibited aggregated periodic acid-Schiff-positive macrophages and 2-7 µm diameter round/oval bodies without nuclei or cell walls scattered around the vessels. Unbiased high-throughput sequencing identified more than 100 archaea-specific DNA fragments. All patients were responsive to trimethoprim/sulfamethoxazole (TMP-SMX) plus corticosteroid therapy. CONCLUSIONS: We report 4 cases of encephalomyelitis due to an unknown pathogen. On the basis of ultrastructural and genomic studies, we propose a new disease entity resulting from a causative pathogen having archaeal features. TMP-SMX therapy was effective against this new type of encephalomyelitis.

Inclusion body myositis coexisting with hypertrophic cardiomyopathy: an autopsy study.

Inclusion body myositis is an inflammatory myopathy characterized pathologically by rimmed vacuoles and the accumulation of amyloid-related proteins. Autopsy studies in these patients, including histochemical examinations of multiple skeletal muscles, have not yet been published. In this paper, we describe the autopsy findings of a patient with inclusion body myositis and hypertrophic cardiomyopathy. A 69-year-old man, who was a human T lymphotropic virus type 1 carrier, exhibited slowly progressive muscle weakness and atrophy, predominantly affecting the scapular, quadriceps femoris, and forearm flexor muscles. His disease course was more rapidly progressive than that typically observed; the patient died suddenly of arrhythmia 5 years after diagnosis. Autopsy findings revealed that multiple muscles, including the respiratory muscles, were involved. Longitudinal studies revealed an increased frequency of rimmed vacuoles and p62/sequestosome 1- and/or TAR DNA-binding protein 43-positive deposits in autopsied muscles, although the amount of inflammatory infiltrate appeared to be decreased. We speculated that muscle degeneration may be more closely involved in disease progression compared with autoimmunity. Genetic analysis revealed a myosin binding protein C3 mutation, which is reportedly responsible for familial hypertrophic cardiomyopathy. This mutation and human T lymphotropic virus type 1 infection may have affected the skeletal muscles of this patient.

Clinical and genetic characterization of 16q-linked autosomal dominant spinocerebellar ataxia in South Kyushu, Japan.

16q-ADCA (OMIM no. 117210) is an autosomal dominant spinocerebellar ataxia (AD-SCA) characterized by late-onset pure cerebellar ataxia and -16C>T substitution of the puratrophin-1 gene. Recently, a series of single-nucleotide polymorphisms (haplotype block) were found to be specific to 16q-ADCA. We screened patients with ataxia and found 62 patients, including four homozygotes who carry the C-T substitution of the puratrophin-1 gene. By further analysis of the patients with the haplotype block, we observed a single-founder effect for 16q-ADCA, even in patients who are supposed to be sporadic late cortical cerebellar atrophy (LCCA). We also observed slippage mutations of microsatellite markers, GATA01 and 17 msm, in the pedigrees. We compared the clinical course of 16q-ADCA in heterozygotes and homozygotes with the haplotype block and observed no apparent gene dosage effect. 16q-ADCA accounts for 27% of AD-SCAs and is the most frequent AD-SCA in South Kyushu, Japan.

MRI studies of spinal visceral larva migrans syndrome.

We report serial MR findings in four patients with myelitis caused by visceral larva migrans syndrome due to Toxocara canis or Ascaris suum infection. MR imaging revealed spinal cord swelling with or without gadolinium enhancement in three patients. T2-weighted images showed high signal intensities preferentially located in both lateral and posterior columns. Antihelmintic and corticosteroid treatment yielded improvement in neurologic deficits and spinal lesions. However, one patient with T. canis infection relapsed associated with reappearance of MRI abnormalities.

Fine mapping of 16q-linked autosomal dominant cerebellar ataxia type III in Japanese families.

The autosomal dominant cerebellar ataxias (ADCAs) are a clinically and genetically heterogeneous group of disorders. To date, at least 11 genes and 13 additional loci have been identified in ADCAs. Despite phenotypic differences, spinocerebellar ataxia 4 (SCA4) and Japanese 16q-linked ADCA type III map to the same region of 16q22.1. We report four Japanese families with pure cerebellar ataxia and a disease locus at 16q22.1. Our families yielded a peak lod score of 6.01 at marker D16S3141. To refine the candidate region, we carried out genetic linkage studies in four pedigrees with a high density set of DNA markers from chromosome 16q22.1. Our linkage data suggest that the disease locus for 16q-ADCA type III is within the 1.25-Mb interval delineated by markers 17msm and CTTT01. We screened for mutations in 36 genes within the critical region. Our critical region lies within the linkage interval reported for SCA4 and for Japanese 16q-ADCA type III. These data suggest that the ADCA that we have characterized is allelic with SCA4 and Japanese 16q-linked ADCA type III.

Clinical and pathological studies of familial amyotrophic lateral sclerosis (FALS) with SOD1 H46R mutation in large Japanese families.

We clarified the clinical and pathological aspects of familial amyotrophic lateral sclerosis (FALS) with SOD1 H46R heterozygous mutation in the Miyakonojo Basin, a region in southern Japan where the prevalence of ALS is 11.4 per 10(5) of the population. We studied 17 patients, including one autopsy case, in three FALS families with the mutation. The average age at disease onset in the families was 44.3+/-8.7 years, and the mean disease duration was 12+/-7.6 years, with a range of 6 to 30 years. Ten of 17 patients were unable to walk by the mean age of 56.4+/-12.2 years. The initial symptom was muscle weakness in the distal leg muscle in all patients. The autopsy findings of one FALS patient showed atrophy of lateral and anterior funiculi, decreased numbers of anterior horn cells, preserved posterior funiculus and absence of neuronal inclusion bodies. Percentages of mutant SOD1 protein measured by mass spectrometry were 14% in erythrocytes, 43% in the spinal cord, 47% in the iliopsoas muscle and 60% in the diaphragm. In this study, we confirmed that FALS with SOD1 H46R mutation showed uniform initial symptoms and slow disease progression with intra-familial variation of disease severity and that inclusion body formation is not essential in FALS with this mutation.