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BACKGROUND: Primary lateral sclerosis (PLS) is an extremely rare condition; therefore, to date no clinical studies have been conducted. The Primary Lateral Sclerosis Functional Rating Scale (PLSFRS) was developed in the United States of America. The PLSFRS is a crucial assessment scale for international collaborative research and future clinical trials for PLS. It is useful for evaluating medical conditions through face-to-face assessments and telephone interviews such as when a face-to-face assessment is not possible due to disasters or the burden of hospital visits. This study assessed the reliability and consistency of in-person and telephone interviews using the Japanese version of the PLSFRS. METHODS: We enrolled 19 Japanese patients who met the specific criteria for inclusion at the six collaborating institutions. The PLSFRS assessments were performed by two evaluators at defined time points and analyzed for intra-rater and inter-rater reliability and consistency between the in-person and telephone interviews. RESULTS: The Japanese version of the PLSFRS was developed by a specialized company and translator, and modified to consider the Japanese lifestyle through a consensus among motor neuron specialists. The quadratic-weighted kappa coefficients for the intra-rater and the inter-rater agreement were substantial (intra-rater: 0.691-1.000, inter-rater: 0.634-1.000). Moreover, the intraclass correlation coefficient for the PLSFRS total score was 0.997 (95% confidence interval, 0.992-0.999). CONCLUSIONS: This study provides results regarding the Japanese version of the PLSFRS intra-rater and inter-rater reliability and consistency between in-person and telephone interviews.
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Índice de Gravidade de Doença , Humanos , Reprodutibilidade dos Testes , Feminino , Masculino , Pessoa de Meia-Idade , Japão , Adulto , Idoso , Avaliação da Deficiência , População do Leste AsiáticoRESUMO
Fused in sarcoma (FUS) is a pathogenic RNA-binding protein in amyotrophic lateral sclerosis (ALS). We previously reported that FUS stabilizes Synaptic Ras-GTPase activating protein 1 (Syngap1) mRNA at its 3' untranslated region (UTR) and maintains spine maturation. To elucidate the pathologic roles of this mechanism in ALS patients, we identified the SYNGAP1 3'UTR variant rs149438267 in seven (four males and three females) out of 807 ALS patients at the FUS binding site from a multicenter cohort in Japan. Human-induced pluripotent stem cell (hiPSC)-derived motor neurons with the SYNGAP1 variant showed aberrant splicing, increased isoform α1 levels, and decreased isoform γ levels, which caused dendritic spine loss. Moreover, the SYNGAP1 variant excessively recruited FUS and heterogeneous nuclear ribonucleoprotein K (HNRNPK), and antisense oligonucleotides (ASOs) blocking HNRNPK altered aberrant splicing and ameliorated dendritic spine loss. These data suggest that excessive recruitment of RNA-binding proteins, especially HNRNPK, as well as changes in SYNGAP1 isoforms, are crucial for spine formation in motor neurons.SIGNIFICANCE STATEMENT It is not yet known which RNAs cause the pathogenesis of amyotrophic lateral sclerosis (ALS). We previously reported that Fused in sarcoma (FUS), a pathogenic RNA-binding protein in ALS, stabilizes synaptic Ras-GTPase activating protein 1 (Syngap1) mRNA at its 3' untranslated region (UTR) and maintains dendritic spine maturation. To elucidate whether this mechanism is crucial for ALS, we identified the SYNGAP1 3'UTR variant rs149438267 at the FUS binding site. Human-induced pluripotent stem cell (hiPSC)-derived motor neurons with the SYNGAP1 variant showed aberrant splicing, which caused dendritic spine loss along with excessive recruitment of FUS and heterogeneous nuclear ribonucleoprotein K (HNRNPK). Our findings that dendritic spine loss is because of excess recruitment of RNA-binding proteins provide a basis for the future exploration of ALS-related RNA-binding proteins.
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Esclerose Lateral Amiotrófica , Sarcoma , Masculino , Feminino , Humanos , Esclerose Lateral Amiotrófica/metabolismo , Regiões 3' não Traduzidas/genética , Proteína FUS de Ligação a RNA/genética , Proteína FUS de Ligação a RNA/metabolismo , Ribonucleoproteínas Nucleares Heterogêneas Grupo K/genética , Espinhas Dendríticas/metabolismo , Mutação , Proteínas de Ligação a RNA/genética , RNA Mensageiro/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteínas Ativadoras de GTPase/genética , Proteínas Ativadoras de GTPase/metabolismo , Sarcoma/genética , Proteínas Ativadoras de ras GTPase/genéticaRESUMO
BACKGROUND: Several genetic factors are associated with the pathogenesis of sporadic amyotrophic lateral sclerosis (ALS) and its phenotypes, such as disease progression. Here, in this study, we aimed to identify the genes that affect the survival of patients with sporadic ALS. METHODS: We enrolled 1076 Japanese patients with sporadic ALS with imputed genotype data of 7 908 526 variants. We used Cox proportional hazards regression analysis with an additive model adjusted for sex, age at onset and the first two principal components calculated from genotyped data to conduct a genome-wide association study. We further analysed messenger RNA (mRNA) and phenotype expression in motor neurons derived from induced pluripotent stem cells (iPSC-MNs) of patients with ALS. RESULTS: Three novel loci were significantly associated with the survival of patients with sporadic ALS-FGF1 at 5q31.3 (rs11738209, HR=2.36 (95% CI, 1.77 to 3.15), p=4.85×10-9), THSD7A at 7p21.3 (rs2354952, 1.38 (95% CI, 1.24 to 1.55), p=1.61×10-8) and LRP1 at 12q13.3 (rs60565245, 2.18 (95% CI, 1.66 to 2.86), p=2.35×10-8). FGF1 and THSD7A variants were associated with decreased mRNA expression of each gene in iPSC-MNs and reduced in vitro survival of iPSC-MNs obtained from patients with ALS. The iPSC-MN in vitro survival was reduced when the expression of FGF1 and THSD7A was partially disrupted. The rs60565245 was not associated with LRP1 mRNA expression. CONCLUSIONS: We identified three loci associated with the survival of patients with sporadic ALS, decreased mRNA expression of FGF1 and THSD7A and the viability of iPSC-MNs from patients. The iPSC-MN model reflects the association between patient prognosis and genotype and can contribute to target screening and validation for therapeutic intervention.
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Esclerose Lateral Amiotrófica , Células-Tronco Pluripotentes Induzidas , Humanos , Esclerose Lateral Amiotrófica/patologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Estudo de Associação Genômica Ampla , População do Leste Asiático , Fator 1 de Crescimento de Fibroblastos/genética , Fator 1 de Crescimento de Fibroblastos/metabolismo , Neurônios Motores/patologiaRESUMO
In amyotrophic lateral sclerosis (ALS), early diagnosis is essential for both current and potential treatments. To find a supportive approach for the diagnosis, we constructed an artificial intelligence-based prediction model of ALS using induced pluripotent stem cells (iPSCs). Images of spinal motor neurons derived from healthy control subject and ALS patient iPSCs were analyzed by a convolutional neural network, and the algorithm achieved an area under the curve of 0.97 for classifying healthy control and ALS. This prediction model by deep learning algorithm with iPSC technology could support the diagnosis and may provide proactive treatment of ALS through future prospective research. ANN NEUROL 2021;89:1226-1233.
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Esclerose Lateral Amiotrófica/diagnóstico , Aprendizado Profundo , Diagnóstico Precoce , Células-Tronco Pluripotentes Induzidas , Neurônios Motores , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: The aim of this study is to describe and clarify the factors affecting the prognosis of Japanese patients with amyotrophic lateral sclerosis (ALS) undergoing tracheostomy invasive ventilation (TIV) therapy. METHODS: We conducted a prospective longitudinal observational case-control study using a multicentre registry. ALS patients who started TIV therapy after registration (TIV group) and those who did not receive TIV (non-TIV group) were included. We compared the survival time between the TIV group and the non-TIV group using a propensity score matching analysis and evaluated the prognostic factors in the TIV group. RESULTS: From February 2006 to January 2018, 190 patients in the TIV group and 1093 patients in the non-TIV group were included in this study. The mean age of disease onset and usage rate of gastrostomy and non-invasive ventilation therapy differed between the groups. In the propensity score matching analysis using known prognostic factors, the median overall survival time of the TIV group was significantly greater than that of the non-TIV group (11.33 years vs 4.61 years; p<0.001). Analysis using the Cox proportional hazard model suggested that older age of onset and respiratory onset was an independent factor for poor prognosis after starting TIV therapy. CONCLUSION: We showed that there was a significant difference of approximately 7 years in life expectancy between Japanese ALS patients who did and did not receive TIV therapy.
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Esclerose Lateral Amiotrófica/mortalidade , Esclerose Lateral Amiotrófica/terapia , Respiração Artificial , Traqueostomia , Idoso , Esclerose Lateral Amiotrófica/complicações , Estudos de Casos e Controles , Feminino , Humanos , Japão , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Taxa de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: In patients with lower lateral medullary infarction (LMI) located under the vestibular nucleus, proprioceptive impairment due to dorsal spinocerebellar tract (DSCT) is considered a pathological condition for body lateropulsion. In patients with brainstem infarction located at or above the level of the vestibular nucleus, other pathways, such as the crossed vestibulothalamic tract (CVTT), are considered responsible. RESEARCH QUESTION: The clinical course of body lateropulsion between each anatomical level of infarction remains unclear. Further, whether body lateropulsion refers to a static or a dynamic symptom also remains unclear. METHODS: We examined 47 patients who exhibited body lateropulsion and categorized them into four groups: lower LMI under the vestibular nucleus, LMI at the level of the vestibular nucleus, pontine infarction, and midbrain infarction. The patients' time to acquire static upright standing position and gait in a straight line were statistically analyzed by a log-rank test using the Kaplan-Meier method. RESULTS: Body lateropulsion in the static upright position was less frequent in the lower LMI group than in the other groups. SIGNIFICANCE: Lower LMI primarily affected body lateropulsion in gait. DSCT damage could affect ipsilateral hip joint or leg coordination, causing body lateropulsion in dynamic situation.
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Infartos do Tronco Encefálico/fisiopatologia , Marcha , Extremidade Inferior/irrigação sanguínea , Mesencéfalo/irrigação sanguínea , Atividade Motora , Ponte/irrigação sanguínea , Postura , Propriocepção , Núcleos Vestibulares/irrigação sanguínea , Adulto , Idoso , Idoso de 80 Anos ou mais , Infartos do Tronco Encefálico/diagnóstico por imagem , Infartos do Tronco Encefálico/psicologia , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-IdadeRESUMO
Mutations in small heat shock protein beta-1 (HspB1) have been linked to Charcot-Marie-Tooth (CMT) disease type 2F and distal hereditary motor neuropathy type 2B. Only four cases with HSPB1 mutations have been reported to date in Japan. In this study between April 2007 and October 2014, we conducted gene panel sequencing in a case series of 1,030 patients with inherited peripheral neuropathies (IPNs) using DNA microarray, targeted resequencing, and whole-exome sequencing. We identified HSPB1 variants in 1.3% (13 of 1,030) of the patients with IPNs, who exhibited a male predominance. Based on neurological and electrophysiological findings, seven patients were diagnosed with CMT disease type 2F, whereas the remaining six patients were diagnosed with distal hereditary motor neuropathy type 2B. P39L, R127W, S135C, R140G, K141Q, T151I, and P182A mutations identified in 12 patients were described previously, whereas a novel K123* variant with unknown significance was found in 1 patient. Diabetes and impaired glucose tolerance were detected in 6 of the 13 patients. Our findings suggest that HSPB1 mutations result in two phenotypes of inherited neuropathies and extend the phenotypic spectrum of HSPB1-related disorders.
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Doença de Charcot-Marie-Tooth/genética , Proteínas de Choque Térmico HSP27/genética , Atrofia Muscular Espinal/genética , Idoso , Feminino , Proteínas de Choque Térmico , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Chaperonas Moleculares , Mutação , LinhagemRESUMO
OBJECTIVE: To classify the patterns of functional decline in patients with sporadic amyotrophic lateral sclerosis (ALS) and explore the genetic backgrounds that modified these patterns. METHODS: We included 465 patients with sporadic ALS in the analysis and clustered the longitudinal functional scores in the registered patients, using a mixture approach of a non-linear mixed-effects model. We conducted a genome-wide analysis of 572â 983 single nucleotide polymorphisms (SNPs). We then assessed the association between the clusters of longitudinal functional scores and SNPs. RESULTS: We identified the following four clusters of longitudinal functional decline in the cases: a rapid decline cluster, an intermediate decline cluster, a sigmoidal decline cluster and a moderate decline cluster. We identified seven SNPs associated with the rapid decline cluster, using a recessive model (p=3.47-8.34×10(-8)). The OR for the probabilities of the rapid decline cluster ranged from 5.5 to 5.84. Homozygosity for the minor alleles in the seven SNPs, which constituted a linkage disequilibrium (LD) block, was associated with decreased expression of TTN (encoding Titin, a large sarcomere protein) in the expression quantitative trait loci database of a large-scale Japanese genetic variation database (p=8.6×10(-10)-1.1×10(-7)). TTN expression in immortalised lymphocyte lines was decreased in patients who were homozygous for the minor alleles compared with those who were homozygous for the major alleles (n=19 in each group, p=0.002). CONCLUSIONS: We detected an LD block associated with a rapid functional decline in patients with sporadic ALS, which is linked to decreased expression of TTN.
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Esclerose Lateral Amiotrófica/diagnóstico , Esclerose Lateral Amiotrófica/genética , Conectina/genética , Predisposição Genética para Doença/genética , Alelos , Feminino , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação , Masculino , Polimorfismo de Nucleotídeo Único/genética , PrognósticoRESUMO
We report the case of a 5-year-old Japanese girl who initially had acute disseminated encephalomyelitis (ADEM) and was positive for the myelin oligodendrocyte glycoprotein (MOG) antibodies and developed unilateral optic neuritis (ON) 71 days after ADEM onset. The patient's serum was positive for the anti-MOG antibodies from the onset of ADEM to the development of ON. This phenotype has been reported in only two previous articles, and the specific mechanism of action of the anti-MOG antibodies is not yet understood. Our case suggests that the anti-MOG antibody can be associated with the pathogenesis of ADEM followed by ON. Thus, patients with ADEM who test positive for the anti-MOG antibody may be at risk of developing subsequent ON.
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Autoanticorpos/sangue , Encefalomielite Aguda Disseminada/sangue , Encefalomielite Aguda Disseminada/etiologia , Glicoproteína Mielina-Oligodendrócito/imunologia , Neurite Óptica/complicações , Encéfalo/patologia , Pré-Escolar , Feminino , Humanos , Imageamento por Ressonância MagnéticaRESUMO
BACKGROUND: Previous studies have reported a high incidence of amyotrophic lateral sclerosis (ALS) in endemic foci in the Kii Peninsula, Japan. However, little is known about the ALS frequency in the whole country. Furthermore, the presence of ethnic variation in the incidence of ALS remains unknown. METHODS: We conducted a nationwide survey of ALS frequency in 2013 to estimate its annual prevalence and incidence. ALS was diagnosed based on the El Escorial Criteria. The study period was the 2009 fiscal year, from April 2009 to March 2010. To compare the incidence of ALS among prefectures, standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) were calculated under the assumption of Poisson distribution. RESULTS: The annual crude prevalence and incidence rates per 100 000 people per year were 9.9 (95% CI 9.7-10.1) and 2.2 (95% CI 2.1-2.3), respectively. The age group with the highest prevalence as well as incidence was 70-79 years, and the male-female ratio was approximately 1.5. The annual incidence rate adjusted for age and sex using the 2000 U.S. standard population was 2.3 (95% CI 2.2-2.4) per 100 000 people. Some prefectures had significantly high SIRs: Okinawa, Nara and Wakayama in the Kii Peninsula, and Niigata for males; Kumamoto for females. CONCLUSIONS: This is the first report on the annual prevalence and incidence of ALS in the representative population of Japan. We identified some prefectures with a high incidence of ALS. However, the incidence of ALS in the Japanese population was much lower than in the Caucasian populations of Europe and North America.
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Esclerose Lateral Amiotrófica/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Inquéritos Epidemiológicos , Humanos , Incidência , Lactente , Recém-Nascido , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Prevalência , Adulto JovemRESUMO
Background: Previous studies have reported a high incidence of amyotrophic lateral sclerosis (ALS) in endemic foci in the Kii Peninsula, Japan. However, little is known about the ALS frequency in the whole country. Furthermore, the presence of ethnic variation in the incidence of ALS remains unknown.Methods: We conducted a nationwide survey of ALS frequency in 2013 to estimate its annual prevalence and incidence. ALS was diagnosed based on the El Escorial Criteria. The study period was the 2009 fiscal year, from April 2009 to March 2010. To compare the incidence of ALS among prefectures, standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) were calculated under the assumption of Poisson distribution.Results: The annual crude prevalence and incidence rates per 100 000 people per year were 9.9 (95% CI 9.7-10.1) and 2.2 (95% CI 2.1-2.3), respectively. The age group with the highest prevalence as well as incidence was 70-79 years, and the male-female ratio was approximately 1.5. The annual incidence rate adjusted for age and sex using the 2000 U.S. standard population was 2.3 (95% CI 2.2-2.4) per 100 000 people. Some prefectures had significantly high SIRs: Okinawa, Nara and Wakayama in the Kii Peninsula, and Niigata for males; Kumamoto for females.Conclusions: This is the first report on the annual prevalence and incidence of ALS in the representative population of Japan. We identified some prefectures with a high incidence of ALS. However, the incidence of ALS in the Japanese population was much lower than in the Caucasian populations of Europe and North America.
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Amyotrophic lateral sclerosis (ALS) is an adult-onset intractable motor neuron disease characterized by selective degeneration of cortical neurons in the frontotemporal lobe and motor neurons in the brainstem and spinal cord. Impairment of these neural networks causes progressive muscle atrophy and weakness that spreads throughout the body, resulting in life-threatening bulbar palsy and respiratory muscle paralysis. However, no therapeutic strategy has yet been established to halt ALS progression. Although evidence for clinical practice in ALS remains insufficient, novel research findings have steadily accumulated in recent years. To provide updated evidence-based or expert consensus recommendations for the diagnosis and management of ALS, the ALS Clinical Practice Guideline Development Committee, approved by the Japanese Society of Neurology, revised and published the Japanese clinical practice guidelines for the management of ALS in 2023. In this guideline, disease-modifying therapies that have accumulated evidence from randomized controlled trials were defined as "Clinical Questions," in which the level of evidence was determined by systematic reviews. In contrast, "Questions and Answers" were defined as issues of clinically important but insufficient evidence, according to reports of a small number of cases, observational studies, and expert opinions. Based on a literature search performed in February 2022, recommendations were reached by consensus, determined by an independent panel, reviewed by external reviewers, and submitted for public comments by Japanese Society of Neurology members before publication. In this article, we summarize the revised Japanese guidelines for ALS, highlighting the regional and cultural diversity of care processes and decision-making. The guidelines cover a broad range of essential topics such as etiology, diagnostic criteria, disease monitoring and treatments, management of symptoms, respiration, rehabilitation, nutrition, metabolism, patient instructions, and various types of care support. We believe that this summary will help improve the daily clinical practice for individuals living with ALS and their caregivers.
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Esclerose Lateral Amiotrófica , Humanos , Esclerose Lateral Amiotrófica/terapia , Esclerose Lateral Amiotrófica/diagnóstico , Progressão da Doença , Medicina Baseada em Evidências , JapãoRESUMO
CHCHD2 and CHCHD10, linked to Parkinson's disease and amyotrophic lateral sclerosis-frontotemporal dementia (ALS), respectively, are mitochondrial intermembrane proteins that form a heterodimer. This study aimed to investigate the impact of the CHCHD2 P14L variant, implicated in ALS, on mitochondrial function and its subsequent effects on cellular homeostasis. The missense variant of CHCHD2, P14L, found in a cohort of patients with ALS, mislocalized CHCHD2 to the cytoplasm, leaving CHCHD10 in the mitochondria. Drosophila lacking the CHCHD2 ortholog exhibited mitochondrial degeneration. In contrast, human CHCHD2 P14L, but not wild-type human CHCHD2, failed to suppress this degeneration, suggesting that P14L is a pathogenic variant. The mitochondrial Ca2+ buffering capacity was reduced in Drosophila neurons expressing human CHCHD2 P14L. The altered Ca2+-buffering phenotype was also observed in cultured human neuroblastoma SH-SY5Y cells expressing CHCHD2 P14L. In these cells, transient elevation of cytoplasmic Ca2+ facilitated the activation of calpain and caspase-3, accompanied by the processing and insolubilization of TDP-43. These observations suggest that CHCHD2 P14L causes abnormal Ca2+ dynamics and TDP-43 aggregation, reflecting the pathophysiology of ALS.
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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective loss of motor neurons. Several susceptibility genes for ALS have been reported; however, ALS etiology and pathogenesis remain largely unknown. To identify further ALS-susceptibility genes, we conducted a large-scale case-control association study using gene-based tag single-nucleotide polymorphisms (SNPs). A functional SNP (rs2275294) was found to be significantly associated with ALS through a stepwise screening approach (combined P= 9.3 × 10(-10), odds ratio = 1.32). The SNP was located in an enhancer region of ZNF512B, a transcription factor of unknown biological function, and the susceptibility allele showed decreased activity and decreased binding to nuclear proteins. ZNF512B over-expression increased transforming growth factor-ß (TGF-ß) signaling, while knockdown had the opposite effect. ZNF512B expression was increased in the anterior horn motor neurons of the spinal cord of ALS patients when compared with controls. Our results strongly suggest that ZNF512B is an important positive regulator of TGF-ß signaling and that decreased ZNF512B expression increases susceptibility to ALS.
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Esclerose Lateral Amiotrófica/genética , Povo Asiático/genética , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Predisposição Genética para Doença , Adulto , Idoso , Idoso de 80 Anos ou mais , Esclerose Lateral Amiotrófica/metabolismo , Estudos de Casos e Controles , Feminino , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Transdução de Sinais , Medula Espinal/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Adulto JovemRESUMO
OBJECTIVE: To clarify the emergence of muscle weakness in regions of the body that affect survival, and deterioration in activities of daily living (ADL) in amyotrophic lateral sclerosis (ALS) patients. METHODS: We conducted a multicentre-based prospective cohort study of patients with ALS. We enrolled 401 sporadic patients with ALS. Death or the introduction of invasive ventilation was defined as the primary endpoint, and the time to five clinical markers of ADL deterioration associated with bulbar paralysis or limb weakness were defined as ADL milestones. Muscle weakness was assessed in the neck flexor muscles; the bilateral abductors of the shoulders; the bilateral wrist extensor muscles; the bilateral flexor muscles of the hips; and the bilateral ankle dorsiflexion muscles. We performed Cox proportional hazards regression analyses for the primary endpoint and the five ADL milestones, adjusting for known covariate prognostic factors for ALS. RESULTS: The Medical Research Council (MRC) score for the neck flexors was the most significant prognostic factor for the primary endpoint (HR 0.74, p<0.001), loss of speech (HR 0.66, p<0.001), and loss of swallowing function (HR 0.73, p<0.001), and was one of the significant prognostic factors for loss of upper limb function, difficulty turning in bed, and loss of walking ability (p=0.001, 0.002, and 0.008, respectively). The MRC score for the neck flexors was also a significant prognostic factor for covariates of the previously reported prognostic factors. CONCLUSIONS: Neck weakness is an independent prognostic factor for survival and deterioration in ADL in Patients with ALS.
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Esclerose Lateral Amiotrófica/diagnóstico , Debilidade Muscular/fisiopatologia , Pescoço/fisiopatologia , Atividades Cotidianas , Idoso , Esclerose Lateral Amiotrófica/mortalidade , Esclerose Lateral Amiotrófica/fisiopatologia , Esclerose Lateral Amiotrófica/terapia , Biomarcadores , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Debilidade Muscular/complicações , Prognóstico , Estudos Prospectivos , Fatores de TempoRESUMO
OBJECTIVE AND METHODS: Dysferlin encoded by DYSF deficiency leads to two main phenotypes, limb girdle muscular dystrophy (LGMD) 2B and Miyoshi myopathy. To reveal in detail the mutational and clinical features of LGMD2B in Japan, we observed 40 Japanese patients in 36 families with LGMD2B in whom dysferlin mutations were confirmed. RESULTS AND CONCLUSIONS: Three mutations (c.1566C>G, c.2997G>T and c.4497delT) were relatively more prevalent. The c.2997G>T mutation was associated with late onset, proximal dominant forms of dysferlinopathy, a high probability that muscle weakness started in an upper limb and lower serum creatine kinase (CK) levels. The clinical features of LGMD2B are as follows: (1) onset in the late teens or early adulthood, except patients homozygous for the c.2997G>T mutation; (2) lower limb weakness at onset; (3) distal change of lower limbs on muscle CT at an early stage; (4) impairment of lumbar erector spinal muscles on muscle CT at an early stage; (5) predominant involvement of proximal upper limbs; (6) preservation of function of the hands at late stage; (7) preservation of strength in neck muscles at late stage; (8) lack of facial weakness or dysphagia; (9) avoidance of scoliosis; (10) hyper-Ckaemia; (11) preservation of cardiac function; and (12) a tendency for respiratory function to decline with disease duration. It is important that the late onset phenotype is found with prevalent mutations.
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Proteínas de Membrana/genética , Proteínas Musculares/genética , Distrofia Muscular do Cíngulo dos Membros/genética , Distrofia Muscular do Cíngulo dos Membros/fisiopatologia , Mutação/genética , Mutação/fisiologia , Adolescente , Adulto , Idade de Início , Povo Asiático , Creatina Quinase/sangue , Disferlina , Feminino , Testes de Função Cardíaca , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Debilidade Muscular/etiologia , Debilidade Muscular/fisiopatologia , Músculo Esquelético/diagnóstico por imagem , Músculo Esquelético/fisiopatologia , Distrofia Muscular do Cíngulo dos Membros/diagnóstico por imagem , Testes de Função Respiratória , Estudos Retrospectivos , Análise de Sobrevida , Tomografia Computadorizada por Raios X , Adulto JovemRESUMO
This study aimed to clarify whether short-term neurofeedback training during the acute stroke phase led to prefrontal activity self-regulation, providing positive efficacy to working memory. A total of 30 patients with acute stroke performed functional near-infrared spectroscopy-based neurofeedback training for a day to increase their prefrontal activity. A randomized, Sham-controlled, double-blind study protocol was used comparing working memory ability before and after neurofeedback training. Working memory was evaluated using a target-searching task requiring spatial information retention. A decline in spatial working memory performance post-intervention was prevented in patients who displayed a higher task-related right prefrontal activity during neurofeedback training compared with the baseline. Neurofeedback training efficacy was not associated with the patient's clinical background such as Fugl-Meyer Assessment score and time since stroke. These findings demonstrated that even short-term neurofeedback training can strengthen prefrontal activity and help maintain cognitive ability in acute stroke patients, at least immediately after training. However, further studies investigating the influence of individual patient clinical background, especially cognitive impairment, on neurofeedback training is needed. Current findings provide an encouraging option for clinicians to design neurorehabilitation programs, including neurofeedback protocols, for acute stroke patients.
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BACKGROUND AND OBJECTIVES: To assess the clinical and electrophysiologic features of female carriers and early-stage male patients with spinal and bulbar muscular atrophy (SBMA) to elucidate the early pathophysiologic changes of the disease. METHODS: Female carriers, early-stage male patients with SBMA, and age-matched male and female healthy controls were recruited. The results of motor functional scales, motor unit number estimation, dual-energy X-ray absorptiometry, and peripheral blood tests were compared between female carriers and healthy female controls and between patients with SBMA and healthy male controls. EMG was also investigated in female carriers. RESULTS: We enrolled 21 female carriers and 11 early-stage male patients. Seventeen female and 14 male age-matched healthy controls were also enrolled. Female carriers experienced early-stage symptoms such as muscle cramps more frequently than healthy female controls. Decreased motor unit number estimation and EMG abnormalities including high amplitude or polyphasic potentials were observed in female carriers together with mild muscle weakness in neck flexion and a slow walking speed. Changes of muscle-related markers, including serum creatine kinase and dual-energy X-ray absorptiometry, were clearly detected in early-stage male patients with SBMA, but not in female carriers. DISCUSSION: The present study revealed that female carriers of SBMA manifest mild muscular weakness associated with changes in neurogenic biomarkers. Conversely, male patients showed neurogenic and myopathic changes even at the early stage. These results suggest a testosterone-independent neurodegenerative pathophysiology in female SBMA carriers.
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Atrofia Bulboespinal Ligada ao X , Atrofia Muscular Espinal , Humanos , Masculino , Feminino , Atrofia Muscular Espinal/diagnóstico por imagem , HeterozigotoRESUMO
Objectives: This retrospective observational study investigated whether the degree of muscular echogenicity in patients admitted to the intensive care unit (ICU) could help with the early detection of ICU-acquired weakness (ICU-AW) and predict physical function at hospital discharge. Methods: Twenty-five patients who were mechanically ventilated for more than 48 h in the ICU were enrolled. We also enrolled 23 outpatients with nonmuscular diseases as the control group. The target sites for measuring muscular echogenicity were the upper arm and lower leg. First, the muscular echogenicity was compared between surviving nonsurgical patients admitted to the ICU and stable outpatients with nonmuscular diseases. Second, we investigated the relationship between muscular echogenicity and clinical features, e.g., the manual muscle test (MMT), Medical Research Council (MRC) sum score, and Functional Independence Measure (FIM). Results: Muscular echogenicity in the upper arm in the ICU group was significantly higher than that in the control group. In the ICU group, the degree of muscular echogenicity of the upper arm was inversely correlated with the MMT of elbow flexion (P=0.006; r=-0.532) and the MRC sum score (P=0.002; r=-0.591). However, muscular echogenicity of the upper arm did not correlate with functional FIM (P=0.100; r=-0.344) at hospital discharge. Conclusions: Critically ill patients can experience pathological muscle weakness associated with increased muscular echogenicity in the upper arm. Additionally, the degree of muscular echogenicity in the upper arm correlated with the MRC sum score and can facilitate early detection of ICU-AW. The relationship between echogenicity and functional outcome at discharge requires elucidation.
RESUMO
Mutations in superoxide dismutase 1 gene (SOD1) are linked to amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder predominantly affecting upper and lower motor neurons. The clinical phenotype of ALS shows inter- and intrafamilial heterogeneity. The aim of the study was to analyze the relations between individual SOD1 mutations and the clinical presentation using in silico methods to assess the SOD1 mutations severity. We identified SOD1 causative variants in a group of 915 prospectively tested consecutive Polish ALS patients from a neuromuscular clinical center, performed molecular modeling of mutated SOD1 proteins and in silico analysis of mutation impact on clinical phenotype and survival analysis of associations between mutations and hazard of clinical end-points. Fifteen SOD1 mutations were identified in 21.1% familial and 2.3% sporadic ALS cases. Their effects on SOD1 protein structure and functioning inferred from molecular modeling and in silico analyses correlate well with the clinical data. Molecular modeling results support the hypothesis that folding intermediates rather than mature SOD1 protein give rise to the source of cytotoxic conformations in ALS. Significant associations between type of mutation and clinical end-points were found.