CANVAS-related RFC1 mutations in patients with immune-mediated neuropathy.

Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) has recently been attributed to biallelic repeat expansions in RFC1. More recently, the disease entity has expanded to atypical phenotypes, including chronic neuropathy without cerebellar ataxia or vestibular areflexia. Very recently, RFC1 expansions were found in patients with Sjögren syndrome who had neuropathy that did not respond to immunotherapy. In this study RFC1 was examined in 240 patients with acute or chronic neuropathies, including 105 with Guillain-Barré syndrome or Miller Fisher syndrome, 76 with chronic inflammatory demyelinating polyneuropathy, and 59 with other types of chronic neuropathy. Biallelic RFC1 mutations were found in three patients with immune-mediated neuropathies, including Guillain-Barré syndrome, idiopathic sensory ataxic neuropathy, or anti-myelin-associated glycoprotein (MAG) neuropathy, who responded to immunotherapies. In addition, a patient with chronic sensory autonomic neuropathy had biallelic mutations, and subclinical changes in Schwann cells on nerve biopsy. In summary, we found CANVAS-related RFC1 mutations in patients with treatable immune-mediated neuropathy or demyelinating neuropathy.

Memantine administration prevented chorea movement in Huntington's disease: a case report.

BACKGROUND: Huntington's disease is an autosomal dominant inherited disorder characterized by personality changes (such as irritability and restlessness) and psychotic symptoms (such as hallucinations and delusions). When the personality changes become noticeable, involuntary movements (chorea) also develop. The disease is caused by the CAG repeat expansion in the coding region of the HTT gene, and the diagnosis is based on the presence of this expansion. However, there is currently no effective treatment for the progression of Huntington's disease and its involuntary motor symptoms. Herein, we present a case in which memantine was effective in treating the chorea movements of Huntington's disease. CASE PRESENTATION: A 75-year-old Japanese woman presented to the hospital with involuntary movements of Huntington's disease that began when she was 73 years old. In a cerebral blood flow test (N-isopropyl-p-iodoamphetamine-single-photon emission computed tomography), decreased blood flow was observed in the precuneus (anterior wedge) and posterior cingulate gyrus. Usually, such areas of decreased blood flow are observed in patients with Alzheimer's-type dementia. So, we administered memantine for Alzheimer's-type dementia, and this treatment suppressed the involuntary movements of Huntington's disease, and the symptoms progressed slowly for 7 years after the onset of senility. In contrast, her brother died of complications of pneumonia during the course of Huntington's disease. CONCLUSIONS: We recorded changes in parameters such as the results of the N-isopropyl-p-iodoamphetamine-single-photon emission computed tomography and gait videos over 7 years. Treatment with memantine prevented the chorea movement and the progression of Huntington's disease. We believe this record will provide clinicians with valuable information in diagnosing and treating Huntington's disease.

Fremanezumab for Episodic Migraine Prevention in Japanese Patients: Subgroup Analysis from Two International Trials.

Purpose: The monoclonal antibody fremanezumab has been shown effective and well tolerated in numerous Phase 2 and Phase 3 trials. This subgroup analysis of the international HALO episodic migraine (EM; [NCT02629861]) trial and a similarly designed phase 2b/3 trial in Japanese and Korean patients (NCT03303092) sought to evaluate the efficacy and safety of fremanezumab in Japanese patients with EM. Patients and Methods: In both trials, eligible patients were randomly assigned at baseline to receive subcutaneous monthly fremanezumab, quarterly fremanezumab, or placebo in a 1:1:1 ratio. The primary endpoint was the mean change from baseline in the monthly (28-day) average number of migraine days during the 12-week period after the first dose of fremanezumab or placebo. Secondary endpoints assessed other aspects of efficacy, including disability and medication use. Results: A total of 301 patients in the Japanese and Korean phase 2b/3 trial and 75 patients in the HALO EM trial were Japanese with baseline and treatment characteristics similar between treatment groups. According to ANCOVA analysis of the primary endpoint, both fremanezumab quarterly and monthly led to greater reductions in the monthly (28-day) average number of migraine days than placebo. This was supported by MMRM analysis of the primary endpoint over the initial 4 weeks, highlighting the rapid onset of action of fremanezumab. Results of secondary endpoint analysis supported the primary endpoint analyses. Fremanezumab was well tolerated with no new safety signals seen in this population of Japanese patients. Conclusion: Fremanezumab appears to be an effective and well-tolerated preventive medication for Japanese patients with EM.

Fremanezumab for Chronic Migraine Prevention in Japanese Patients: Subgroup Analysis from Two International Trials.

Purpose: Fremanezumab monoclonal antibody therapy has demonstrated efficacy for chronic migraine (CM) with rapid onset and good tolerability. This subgroup analysis of two clinical trials (Japanese and Korean CM Phase 2b/3 [NCT03303079] and HALO CM Phase 3 [NCT02621931]) aimed to evaluate the efficacy and safety of fremanezumab in Japanese patients. Patients and Methods: Both trials randomly assigned eligible patients at baseline (1:1:1 ratio) to subcutaneous monthly fremanezumab, quarterly fremanezumab, or placebo at 4-week intervals. The primary endpoint was the mean change from baseline in the monthly (28-day) average number of headache days of at least moderate severity during the 12-week period after the first dose of study medication (analyzed by ANCOVA over 12 weeks and MMRM over initial 4 weeks). Secondary endpoints examined other aspects of efficacy, including medication use and disability. Results: A total of 479 and 109 patients were Japanese in the Japanese and Korean CM Phase 2b/3 and HALO CM trials, respectively. Baseline and treatment characteristics were generally similar between treatment groups for both trials. Results of subgroup analyses for the primary endpoint according to ANCOVA demonstrated the superiority of fremanezumab over placebo in Japanese patients (quarterly fremanezumab, p=0.0005; monthly fremanezumab, p=0.0002 in both trials). Results using the MMRM analysis confirmed the rapid onset of action in this population. Results of the secondary endpoints further supported the efficacy of fremanezumab in Japanese patients. Fremanezumab was well tolerated with nasopharyngitis and injection-site reactions representing the most common adverse events in all treatment groups. Conclusion: Despite the limitations of subgroup analyses, these consistent results confirm the efficacy and tolerability of fremanezumab in Japanese patients with CM.

Hemiplegic migraine type 2 with new mutation of the ATP1A2 gene in Japanese cases.

We analyzed the clinical symptoms of hemiplegic migraine (HM) and their relevance in four Japanese patients considered to have ATP1A2 mutations as a cause. Sequencing of ATP1A2 was performed using the Sanger method in 43 blood samples from clinically suspected patients with familial HM. Subsequently, algorithm analysis, allele frequency determination, and three-dimensional structure analysis of the recognized variants were performed, and the recognized variants were evaluated. We found four heterozygous missense mutations in ATP1A2 (Case 1: p.R51C; Case 2: p.R65L; Case 3: p.A269P; Case 4: p.D999H), three of which had not been reported to date. These four mutations may also affect the structure of the protein products, as assessed using a three-dimensional structural analysis. In all four cases, the clinical symptoms included visual, sensory, motor, and verbal symptoms and the frequency and duration of headache attacks varied. Additionally, oral administration of a combination of lomerizine hydrochloride and topiramate had a partial effect in three cases. We report four missense mutations in ATP1A2. This report will be useful for the future analysis of mutations and clinical types in Asians, as well as Westerners, with migraine.

Lung carcinoma-associated cognitive impairment in a patient with Alzheimer's disease pathology: A case report.

A patient with Alzheimer's disease (AD) pathology when cognitive impairment is detected tends to be diagnosed with AD. However, before diagnosing, we make an effort to exclude other diseases, for example, carcinoma.

Longitudinal study of primary progressive aphasia in a patient with pathologically diagnosed Alzheimer's disease: a case report.

BACKGROUND: Alzheimer's disease is a neurodegenerative disease involving the deposition of pathologic amyloid-ß and tau protein in the cerebral cortex. Alzheimer's disease is commonly characterized by progressive impairment of recent memory. Primary progressive aphasia is also often observed in patients with Alzheimer's disease. Moreover, language-associated symptoms, such as primary progressive aphasia, are diverse and varied in Alzheimer's disease. However, nonfluent/agrammatic variant primary progressive aphasia is not generally considered a symptom of Alzheimer's disease. To date, there has been no longitudinal study of primary progressive aphasia in Japanese-speaking patients or in patients speaking other languages with pathologically diagnosed Alzheimer's disease. Here we present a longitudinal study of primary progressive aphasia in a Japanese patient pathologically diagnosed with Alzheimer's disease. CASE PRESENTATION: A 75-year-old Japanese man, whose wife reported that his memory was impaired, also suffered from suspected aphasia. He was pathologically diagnosed with Alzheimer's disease using 11C-Pittsburgh compound-B positron emission tomography and 18F-THK5351 positron emission tomography. Based on clinical observation and the results of the Japanese standard language test of aphasia, he was also diagnosed with nonfluent/agrammatic variant primary progressive aphasia. During the subsequent 2 years, his cognitive impairment, aphasia, and behavioral and psychological symptoms of dementia progressed. Furthermore, progression of pathologic amyloid-ß and tau protein deposition was revealed through 11C-Pittsburgh compound-B positron emission tomography and 18F-THK5351 positron emission tomography. Although the results of [123I] iodoamphetamine single-photon emission computed tomography suggested corticobasal degeneration, this was not observed on the [123I] FP-CIT single-photon emission computed tomography (SPECT) (DaTscan). A previous study had reported that Alzheimer's disease with a nonfluent/agrammatic variant primary progressive aphasia was accompanied by corticobasal degeneration; however, this was not true in our case. CONCLUSIONS: This is possibly the first longitudinal study of nonfluent/agrammatic variant primary progressive aphasia in a Japanese-speaking patient with pathologically diagnosed Alzheimer's disease, but without corticobasal degeneration.

Phenotypic and molecular diversities of spinocerebellar ataxia type 2 in Japan.

BACKGROUND: We intended to clarify the phenotypic and molecular diversities of spinocerebellar ataxia type 2 (SCA2) in Japan. METHODS: DNA was extracted from the peripheral blood of 436 patients, including 126 patients with chronic neuropathy, 108 with amyotrophic lateral sclerosis, and 202 with cerebellar ataxia. We then PCR-amplified and sequenced the ATXN2 gene. The biopsied sural nerves of mutation-positive patients were subjected to light-microscopic and electron-microscopic analyses. Transfection analyses were performed using a Schwann cell line, IMS32. RESULTS: We found PCR-amplified products potentially corresponding to expanded CAG repeats in four patients. Two patients in the chronic neuropathy group had a full repeat expansion or an intermediate expansion (39 or 32 repeats), without limb ataxia. The sural nerve biopsy findings of the two patients included axonal neuropathy and mixed neuropathy (axonal changes with demyelination). Schwann cells harbored either cytoplasmic or nuclear inclusions on electron microscopic examination. Both patients recently exhibited pyramidal signs. In the third patient in the cerebellar ataxia group, we identified a novel 21-base duplication mutation near 22 CAG repeats (c.432_452dup). The transfection study revealed that the 21-base-duplication mutant Ataxin-2 proteins aggregated in IMS32 and rendered cells susceptible to oxidative stress, similar to a CAG-expanded mutant. The fourth patient, with 41 repeats, had ataxia and spasticity. The two patients with cerebellar ataxia also had peripheral neuropathy. CONCLUSIONS: Patients with expanded CAG repeats can exhibit a neuropathy-dominant phenotype not described previously. The novel 21-base-duplication mutant seems to share the aggregation properties of polyglutamine-expanded mutants.

Clinical Application of the FoundationOne CDx Assay to Therapeutic Decision-Making for Patients with Advanced Solid Tumors.

BACKGROUND: Implementation of personalized medicine requires the accessibility of tumor molecular profiling in order to allow prioritization of appropriate targeted therapies for individual patients. Our aim was to study the role of comprehensive genomic profiling assays that may inform treatment recommendations for patients with solid tumors. MATERIALS AND METHODS: We performed a prospective study to evaluate the feasibility of application of the FoundationOne CDx panel-which detects substitutions, insertions and deletions, and copy number alterations in 324 genes, select gene rearrangements, and genomic signatures including microsatellite instability and tumor mutation burden (TMB)-to patients with advanced or recurrent solid tumors before its approval in Japan. RESULTS: A total of 181 samples were processed for genomic testing between September 2018 and June 2019, with data being successfully obtained for 175 of these samples, yielding a success rate of 96.7%. The median turnaround time was 41 days (range, 21-126 days). The most common known or likely pathogenic variants were TP53 mutations (n = 113), PIK3CA mutations (n = 33), APC mutations (n = 32), and KRAS mutations (n = 29). Among the 153 patients assessed for TMB, the median TMB was 4 mutations/Mb, and tumors with a high TMB (≥10 mutations/Mb) were more prevalent for lung cancer (11/32) than for other solid tumor types (9/121, Fisher's exact test p < .01). No clear trend toward increased efficacy for immune checkpoint inhibitor (ICI) monotherapy or ICI combination chemotherapy in patients with a high programmed cell death-ligand 1 tumor proportion score or a high TMB was apparent. Among the 174 patients found to harbor known or likely pathogenic actionable alterations, 24 individuals (14%) received matched targeted therapy. CONCLUSION: The FoundationOne CDx assay was performed with formalin-fixed, paraffin-embedded tumor specimens with a success rate of >95%. Such testing may inform the matching of patients with cancer with investigational or approved targeted drugs. IMPLICATIONS FOR PRACTICE: This prospective cohort study was initiated to investigate the feasibility and utility of clinical application of FoundationOne CDx. A total of 181 samples were processed for genomic testing between September 2018 and June 2019, with data being successfully obtained for 175 of these samples, yielding a success rate of 96.7%, and 24 individuals (14%) received matched targeted therapy.

A Guillain-Barré syndrome-associated SIGLEC10 rare variant impairs its recognition of gangliosides.

Guillain-Barré syndrome (GBS), including its variant Miller Fisher syndrome (MFS), is an acute peripheral neuropathy that involves autoimmune mechanisms leading to the production of autoantibodies to gangliosides; sialic acid-containing glycosphingolipids. Although association with various genetic polymorphisms in the major histocompatibility complex (MHC) is shown in other autoimmune diseases, GBS is an exception, showing no such link. No significant association was found by genome wide association studies, suggesting that GBS is not associated with common variants. To address the involvement of rare variants in GBS, we analyzed Siglec-10, a sialic acid-recognizing inhibitory receptor expressed on B cells. Here we demonstrate that two rare variants encoding R47Q and A108V substitutions in the ligand-binding domain are significantly accumulated in patients with GBS. Because of strong linkage disequilibrium, there was no patient carrying only one of them. Recombinant Siglec-10 protein containing R47Q but not A108V shows impaired binding to gangliosides. Homology modeling revealed that the R47Q substitution causes marked alteration in the ligand-binding site. Thus, GBS is associated with a rare variant of the SIGLEC10 gene that impairs ligand binding of Siglec-10. Because Siglec-10 regulates antibody production to sialylated antigens, our finding suggests that Siglec-10 regulates development of GBS by suppressing antibody production to gangliosides, with defects in its function predisposing to disease.

Progressive amnestic cognitive impairment in a middle-aged patient with developmental language disorder: a case report.

BACKGROUND: Developmental disorder and dementia in older adults have been considered unrelated clinical entities because their timing of diagnosis differs greatly; however, recent studies have suggested an association between them. This case describes a middle-aged patient with language disorder exhibiting progressive amnestic cognitive impairment. CASE PRESENTATION: A 44-year-old Japanese man with long-term language dysfunction presented for his first-ever medical evaluation at age 36 years. Although his conversational ability had been impaired since childhood, he was able to graduate from secondary school and gain unskilled employment. At age 36 years, however, his workplace environment became more stressful, which led to behavioral problems that necessitated medical consultation. He consulted two psychiatrists in vain. At age 44 years, the third attending psychiatrist examined him in detail. The major component of his language disorder was amnestic cognitive impairment in the language domain as shown by logical memory subtests of the Wechsler Memory Scale-Revised. Magnetic resonance imaging showed normal findings for his age and no small vessel disease. Global cerebral hypoperfusion versus cerebellar blood flow was shown on (123I) iodoamphetamine single-photon emission computed tomography, and amyloid-ß deposition was negative on positron emission tomography with 11C-Pittsburgh compound B. Pathologic tau accumulation was negative on 18F-THK5351 positron emission tomography imaging. Laboratory tests show no infections, no vitamin deficiencies, and no other diseases that may cause dementia. Clinical features, results of neurocognitive tests and neuroimaging studies showed no well-known neurodegenerative diseases. Collectively, he was diagnosed with language disorder based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria. Over a 2-year follow-up period, amnestic cognitive impairment in visual and language domains progressed in parallel with global cerebral hypoperfusion. CONCLUSION: This case suggests a possible link between language disorder as defined by Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria and progressive amnestic cognitive impairment in middle age, which may ultimately lead to dementia, derived from a neurodegenerative disease.

Regional gray matter-dedicated SUVR with 3D-MRI detects positive amyloid deposits in equivocal amyloid PET images.

PURPOSE: It is usually easy to judge whether amyloid PET images should be interpreted as positive or negative for amyloid deposits by visual inspection or quantitative measurement standard uptake value ratio (SUVR), but the findings are equivocal in some cases. As conventional mean cortical SUVR (mcSUVR) measures accumulation in both gray matter (GM) and white matter, it may mis-estimate amyloid deposits. The purpose of the study was to develop a regional GM-dedicated SUVR measuring (GMSUVR) system for amyloid PET images with 3D-MRI, and evaluate its utility for detecting amyloid deposits in equivocal cases. METHODS: Of 126 subjects who underwent amyloid PET with 11C-PiB and 3D-MRI, the area of amyloid-positive regions and the critical regional GMSUVR thresholds were first determined in 15 amyloid-positive and 15 amyloid-negative patients, using the automatic volumetric measurement of segmented brain images system. We then tested 36 amyloid-negative, 60 amyloid-positive, and 13 equivocal subjects with this GMSUVR system and with conventional mcSUVR. RESULTS: Sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) were 100%, 92%, 97%, 95%, and 100% for the GMSUVR system; and 97%, 86%, 93%, 92% and 94%, respectively, for mcSUVR. In 24 cases in which the findings were equivocal or discordant, the sensitivity, specificity, accuracy, PPV, and NPV were all 100% for the GMSUVR system; and were 90%, 33%, 83%, 90%, and 33%, respectively, for mcSUVR. CONCLUSION: The regional GMSUVR measurement method was well able to discriminate between amyloid-positive and -negative subjects, even in cases where amyloid deposition was equivocal.

Neutral Lipid Storage Disease Associated with the PNPLA2 Gene: Case Report and Literature Review.

Mutations in the PNPLA2 gene cause neutral lipid storage disease with myopathy (NLSDM) or triglyceride deposit cardiomyovasculopathy. We report a detailed case study of a 53-year-old man with NLSDM. The PNPLA2 gene was analyzed according to the reported method. We summarized the clinical, laboratory, and genetic information of 56 patients, including our patient and 55 other reported patients with homozygous or compound heterozygous mutations in the PNPLA2 gene. We found a novel homozygous mutation (c.194delC) in the PNPLA2 gene that resulted in frameshift. The patient suffered from normal-tension glaucoma and pulmonary cysts, symptoms that are relatively common in the elderly but were not previously reported for this disease. Our summary confirmed that Jordan's anomaly, polymorphonuclear leukocytes with lipid accumulation, was the most consistent finding of this disease. Because this disease is potentially treatable, our results may help rapid and correct diagnosis.

Effect of expression alteration in flanking genes on phenotypes of St8sia2-deficient mice.

ST8 alpha-N-acetyl-neuraminide alpha-2,8-sialyltransferase 2 (ST8SIA2) synthesizes polysialic acid (PSA), which is essential for brain development. Although previous studies reported that St8sia2-deficient mice that have a mixed 129 and C57BL/6 (B6) genetic background showed mild and variable phenotypes, the reasons for this remain unknown. We hypothesized that this phenotypic difference is caused by diversity in the expression or function of flanking genes of St8sia2. A genomic polymorphism and gene expression analysis in the flanking region revealed reduced expression of insulin-like growth factor 1 receptor (Igf1r) on the B6 background than on that of the 129 strain. This observation, along with the finding that administration of an IGF1R agonist during pregnancy increased litter size, suggests that the decreased expression of Igf1r associated with ST8SIA2 deficiency caused lethality. This study demonstrates the importance of gene expression level in the flanking regions of a targeted null allele having an effect on phenotype.

A comparative study of curated contents by knowledge-based curation system in cancer clinical sequencing.

Medical oncologists are challenged to personalize medicine with scientific evidence, drug approvals, and treatment guidelines based on sequencing of clinical samples using next generation sequencer (NGS). Knowledge-based curation systems have the potential to help address this challenge. We report here the results of examining the level of evidence regarding treatment approval and clinical trials between recommendations made by Watson for Genomics (WfG), QIAGEN Clinical Insight Interpret (QCII), and Oncomine knowledge-based reporter (OKR). The tumor samples obtained from the solid cancer patients between May to June 2018 at Kindai University Hospital. The formalin-fixed paraffin-embedded tumor samples (n = 31) were sequenced using Oncomine Comprehensive Assay v3. Variants including copy number alteration and gene fusions identified by the Ion reporter software were used commonly on three curation systems. Curation process of data were provided for 25 solid cancers using three curation systems independently. Concordance and distribution of curated evidence levels of variants were analyzed. As a result of sequencing analysis, nonsynonymous mutation (n = 58), gene fusion (n = 2) or copy number variants (n = 12) were detected in 25 cases, and subsequently subjected to knowledge-based curation systems (WfG, OKR, and QCII). The number of curated information in any systems was 51/72 variants. Concordance of evidence levels was 65.3% between WfG and OKR, 56.9% between WfG and QCII, and 66.7% between OKR and QCII. WfG provided great number of clinical trials for the variants. The annotation of resistance information was also observed. Larger differences were observed in clinical trial matching which could be due to differences in the filtering process among three curation systems. This study demonstrates knowledge-based curation systems (WfG, OKR, and QCII) could be helpful tool for solid cancer treatment decision making. Difference in non-concordant evidence levels was observed between three curation systems, especially in the information of clinical trials. This point will be improved by standardized filtering procedure and enriched database of clinical trials in Japan.

PSP-Phenotype in SCA8: Case Report and Systemic Review.

Spinocerebellar ataxia type 8 (SCA8) is a rare autosomal dominant neurodegenerative disease caused by expanded CTA/CTG repeats in the ATXN8OS gene. Many patients had pure cerebellar ataxia, while some had parkinsonism, both without causal explanation. We analyzed the ATXN8OS gene in 150 Japanese patients with ataxia and 76 patients with Parkinson's disease or related disorders. We systematically reassessed 123 patients with SCA8, both our patients and those reported in other studies. Two patients with progressive supranuclear palsy (PSP) had mutations in the ATXN8OS gene. Systematic analyses revealed that patients with parkinsonism had significantly shorter CTA/CTG repeat expansions and older age at onset than those with predominant ataxia. We show the imaging results of patients with and without parkinsonism. We also found a significant inverse relationship between repeat sizes and age at onset in all patients, which has not been detected previously. Our results may be useful to genetic counseling, improve understanding of the pathomechanism, and extend the clinical phenotype of SCA8.

The novel de novo mutation of KIF1A gene as the cause for Spastic paraplegia 30 in a Japanese case.

Spastic paraplegia 30 is a recently established autosomal recessive disease characterized by a complex form of spastic paraplegia associated with neuropathy. Homozygous mutations of KIF1A reportedly lead to hereditary spastic paraplegia or hereditary sensory and autonomic neuropathy type 2 (HSAN2), whereas heterozygous mutations can cause nonsyndromic and syndromic intellectual disability (MRD9). Here we report the case of a 37-year-old female who presented with gait disturbance complicated with moyamoya disease. RESULTS: The patient exhibited hypotonia during infancy, after which intellectual disability, epileptic fits, spastic paraplegia, and cerebellar atrophy occurred. Genetic analysis revealed a novel de novo mutation (c.254C > A, p.A85D) in the motor domain of KIF1A.

Noncoding repeat expansions for ALS in Japan are associated with the ATXN8OS gene.

OBJECTIVE: To assess the contribution of noncoding repeat expansions in Japanese patients with amyotrophic lateral sclerosis (ALS). METHODS: Sporadic ALS in Western countries is frequently associated with noncoding repeat expansions in the C9ORF72 gene. Spinocerebellar ataxia type 8 (SCA8) is another noncoding repeat disease caused by expanded CTA/CTG repeats in the ATXN8OS gene. Although the involvement of upper and lower motor neurons in SCA8 has been reported, a positive association between SCA8 and ALS remains unestablished. Spinocerebellar ataxia type 36 is a recently identified disease caused by noncoding repeat expansions in the NOP56 gene and is characterized by motor neuron involvement. We collected blood samples from 102 Japanese patients with sporadic ALS and analyzed the ATXN8OS gene by the PCR-Sanger sequencing method and the C9ORF72 and NOP56 genes by repeat-primed PCR assay. RESULTS: Three patients with ALS (3%) had mutations in the ATXN8OS gene, whereas no patient had a mutation in the C9ORF72 or NOP56 gene. The mutation-positive patients were clinically characterized by neck weakness or bulbar-predominant symptoms. None of our patients had apparent cerebellar atrophy on MRI, but 2 had nonsymptomatic abnormalities in the white matter or putamen. CONCLUSIONS: Our finding reveals the importance of noncoding repeat expansions in Japanese patients with ALS and extends the clinical phenotype of SCA8. Three percent seems small but is still relatively large for Japan, considering that the most commonly mutated genes, including the SOD1 and SQSTM1 genes, only account for 2%-3% of sporadic patients each.

Diagnosis of Parkinson's disease and the level of oxidized DJ-1 protein.

Parkinson's disease (PD) is difficult to distinguish from progressive supranuclear palsy (PSP) and multiple system atrophy (MSA); in addition, biomarker studies in PD mostly focused on those found in the cerebrospinal fluid, and there are few reports of simple biomarkers identified by blood analysis. Previously, the DJ-1 gene was identified as a causative gene of familial PD. Oxidized DJ-1 protein (oxDJ-1) levels were reported to increase in the blood of patients with unmedicated PD. Therefore, we determined the levels of oxDJ-1 in the erythrocytes of patients with PD, PSP, and MSA using ELISA. The oxDJ-1 levels were 165±117, 96±78, and 69±40ng/mg protein in the PD, PSP, and MSA groups, respectively. The mean level in disease control group was 66±31, revealing significant differences between the PD and PSP groups, the PD and MSA groups, and the PD and disease control groups. Our results indicated that oxDJ-1 levels in erythrocytes can be used as a marker for the differential diagnosis of PD.