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We report a 47-year-old woman who presented with progressive myalgia, weakness in the proximal limbs, and dysphagia for a month and a half. No skin rash was observed on admission. Examination of MRI data suggested inflammatory changes in the proximal limbs and trunk muscles. Biopsy specimens from the left biceps muscle showed no perifascicular atrophy, but immunohistochemical staining revealed the presence of myxovirus resistance protein A (MxA) in myofibers, strongly suggesting dermatomyositis (DM). In addition, her serum was positive for anti-nuclear matrix protein 2 (anti-NXP-2) antibody, which is reportedly useful as a marker of DM without skin lesions. Her symptoms gradually improved upon intravenous methylprednisolone pulse therapy in conjunction with oral prednisolone, oral tacrolimus, and intravenous immunoglobulin therapy. Our findings suggest that in cases where inflammatory muscle disease is suspected, anti-NXP-2 antibody analyses should be considered for precise diagnosis, even if there are no dermatological symptoms.
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Adenosina Trifosfatasas/inmunología , Anticuerpos Antinucleares/metabolismo , Proteínas de Unión al ADN/inmunología , Dermatomiositis/diagnóstico , Dermatomiositis/inmunología , Enfermedades Asintomáticas , Biomarcadores/metabolismo , Femenino , Humanos , Persona de Mediana Edad , Músculo Esquelético/metabolismo , Proteínas de Resistencia a Mixovirus/metabolismoRESUMEN
INTRODUCTION: Central nervous system demyelination caused by immune checkpoint inhibitors is a very rare condition. CASE PRESENTATION: A 65-year-old man who received nivolumab for renal cell carcinoma developed abnormal behavior, such as disagreeable speech and sudden anger. Brain-enhanced magnetic resonance imaging revealed multiple lesions with partial contrast effects in the cerebral white matter. We tentatively diagnosed demyelination caused by nivolumab, and performed steroid pulse therapy twice. After that, his symptoms improved. For the next 2 years, his symptoms did not recur, nor did his cancer progress. CONCLUSION: Demyelination caused by immune checkpoint inhibitors can be fatal and requires early diagnosis and treatment.
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Importance: Reports on dermatomyositis (DM) sine dermatitis (DMSD) are scarce, and the concept of the disease has not been widely accepted. Objective: To confirm the existence of DMSD, determine its prevalence, and characterize its serologic features. Design, Setting, and Participants: This is a cohort study that reviewed clinical information, laboratory data, and muscle pathology slides from January 2009 to August 2019. We further assessed the follow-up data of 14 patients with DMSD. The median (interquartile range) follow-up period was 34 (16-64) months. Muscle biopsy samples, along with clinical information and laboratory data, were sent to a referral center for muscle diseases in Japan for diagnosis. Of patients whose myopathologic diagnosis was made at the National Center of Neurology and Psychiatry between January 2009 and August 2019, 199 patients were eligible for inclusion. These patients underwent full investigation for DM-specific autoantibodies (against transcriptional intermediary factor γ, Mi-2, melanoma differentiation-associated gene 5, nuclear matrix protein 2 [NXP-2], and small ubiquitin-like modifier activating enzyme ); however, 17 patients were excluded because their muscle fibers did not express myxovirus resistance protein A, a sensitive and specific marker of DM muscle pathology. Main Outcomes and Measures: Diagnosis of DMSD was based on the absence of a skin rash at the time of muscle biopsy. Results: Of the 182 patients, 93 were women (51%) and 46 were children (25%) (<18 years). Fourteen patients (8%) had DMSD and none were clinically diagnosed with DM. Among the 14 patients with DMSD, 12 (86%) were positive for anti-NXP-2 autoantibodies, while the remaining 2 were positive for anti-transcriptional intermediary factor γ and anti-Mi-2 autoantibodies, respectively. Only 28% of patients (47 of 168) with a skin rash were positive for anti-NXP-2 autoantibodies, indicating a significant association between anti-NXP-2 autoantibodies and DMSD (86% [12 of 14] vs 28% [47 of 168]; P < .001). This association was also supported by multivariable models adjusted for disease duration (odds ratio, 126.47; 95% CI, 11.42-1400.64; P < .001). Conclusions and Relevance: Dermatomyositis sine dermatitis does exist and accounts for 8% of patients with DM confirmed with muscle biopsy. Dermatomyositis sine dermatitis is significantly associated with anti-NXP-2 autoantibodies, which contrasts with anti-MDA5 DM, which is typically clinically amyopathic in presentation. It is essential to distinguish DMSD from other types of myositis because DM-specific therapies that are currently under development, including Janus kinase inhibitors, may be effective for DMSD.
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Autoanticuerpos/inmunología , Enfermedades Autoinmunes/inmunología , Proteínas de Unión al ADN/inmunología , Dermatomiositis/inmunología , Factores de Transcripción/inmunología , Adolescente , Adulto , Anciano , Autoantígenos/inmunología , Enfermedades Autoinmunes/patología , Niño , Estudios de Cohortes , Dermatitis , Dermatomiositis/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
A 70-year-old woman who have achieved complete remission (CR) of acute promyelocytic leukemia (APL) with all-trans retinoic acid and chemotherapy presented with abnormal sensation in the right lateral thigh and the bilateral legs. In addition, neurological examination revealed weakness of the left shoulder abduction, the right hand, and the bilateral lower limbs. Atypical promyelocytes were detected in the cerebrospinal fluid, in spite of normal finding in the peripheral blood smear. Magnetic resonance imaging showed gadolinium-enhanced multiple intradural/extramedullary lesions in the whole spine. Nerve conduction studies of the right limbs revealed sensorimotor conduction abnormalities, conspicuously in the posterior tibial and sural nerves. As a result, she was diagnosed as having intrathecal relapse of APL, associated with multiple mononeuropathy. The neurological symptoms were completely disappeared by intrathecal chemotherapy and whole-spine radiotherapy, suggesting that the neuropathy was possibly caused by meningeal infiltration affecting multiple spinal nerve roots. Since extramedullary or intrathecal relapse is extremely rare in APL compared with other types of leukemia, precise neurological evaluations and suitable treatment should be performed immediately, when APL patients with CR manifest some neurological symptoms.
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Sistema Nervioso Central/patología , Leucemia Promielocítica Aguda/patología , Anciano , Sistema Nervioso Central/diagnóstico por imagen , Femenino , Humanos , Leucemia Promielocítica Aguda/diagnóstico , Leucemia Promielocítica Aguda/tratamiento farmacológico , Imagen por Resonancia Magnética , Invasividad Neoplásica , Recurrencia Local de Neoplasia , Conducción Nerviosa , Inducción de Remisión , Raíces Nerviosas Espinales/patología , Tretinoina/uso terapéuticoRESUMEN
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting motor neurons. The majority of patients are sporadic cases, while 5-10% of the patients have a family history of ALS (fALS). Mutations in the gene that encodes cytoplasmic Cu/Zn superoxide dismutase (SOD1) have been identified in about 25% of fALS cases. Although the precise pathogenesis of ALS is still unknown, experimental studies including animal models suggest that fALS is caused by the toxic gain-of-function of the SOD1 mutant. We have analyzed not only SOD1 gene mutation by genomic sequencing, but also SOD1 mutant protein by liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS). We analyzed 33 fALS patients and found 10 mutations in SOD1 gene, in which two were novel: Asp101His substitution in exon 4 and Gly141Glu substitution in exon 5. Here, we present their mass spectrometric protein analyses and clinical features.
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Esclerosis Amiotrófica Lateral/genética , Mutación , Espectrometría de Masa por Ionización de Electrospray/métodos , Superóxido Dismutasa/genética , Edad de Inicio , Esclerosis Amiotrófica Lateral/etiología , Ácido Aspártico/genética , Cromatografía Liquida/métodos , Análisis Mutacional de ADN , Eritrocitos/metabolismo , Exones , Salud de la Familia , Femenino , Ácido Glutámico/genética , Glicina/genética , Histidina/genética , Humanos , Masculino , Biología Molecular/métodos , Datos de Secuencia Molecular , Pruebas de Precipitina/métodosAsunto(s)
Trastorno Bipolar/genética , Aberraciones Cromosómicas , Esquizofrenia/genética , Ataxias Espinocerebelosas/genética , Trastorno Bipolar/diagnóstico , Trastorno Bipolar/psicología , Comorbilidad , Diagnóstico Diferencial , Genes Dominantes , Humanos , Persona de Mediana Edad , Examen Neurológico , Fenotipo , Esquizofrenia/diagnóstico , Ataxias Espinocerebelosas/diagnóstico , Ataxias Espinocerebelosas/psicologíaRESUMEN
We report a case of a 37 year-old male with multiple acyl-CoA dehydrogenation deficiency (MADD). The patient had suffered from exercise intolerance in his hip and thigh muscles for one year. Then, restriction of carbohydrates for a diet made his symptoms rapidly deteriorate. Blood test revealed compound heterozygosity for two novel missense mutations in the electron transfer flavoprotein dehydrogenase gene (ETFDH), and an abnormal LDH isoenzyme pattern: LDH-1 (60.0%) and LDH-2 (26.0%) predominated with abnormally elevated LDH-1/LDH-2 ratio (2.3), compared with muscle-derived LDH-5 (4.0%). Oral riboflavin treatment significantly improved his exercise intolerance and the LDH profile: LDH-1 (34.4%), LDH-2 (34.9%), LDH-5 (6.9%) and LDH-1/LDH-2 ratio (1.0). The abnormal LDH isoenzyme pattern may be one feature of adult-onset MADD selectively affecting type I muscle fibers with relatively high LDH-1 content.
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L-Lactato Deshidrogenasa/sangre , Deficiencia Múltiple de Acil Coenzima A Deshidrogenasa/diagnóstico , Deficiencia Múltiple de Acil Coenzima A Deshidrogenasa/enzimología , Adulto , Humanos , Isoenzimas/sangre , Lactato Deshidrogenasa 5 , Masculino , Deficiencia Múltiple de Acil Coenzima A Deshidrogenasa/genética , Riboflavina/uso terapéuticoRESUMEN
The muscle volume analyzer (MVA) can predict limb muscle weight based on bioelectric impedance analysis, whereas the conventional handheld dynamometer (HHD) measures muscle strength. In this study, a 26-year-old female on invasive ventilation due to late-onset Pompe disease was treated with enzyme replacement therapy (ERT) for 12 months. MVA measurements demonstrated time-dependent improvement from the baseline compared to HHD measurements, showing remarkably fluctuating muscle strength. Thus, the MVA can be used as an alternative, particularly for patients suffering from severe limb muscle weakness.
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Electrodiagnóstico/métodos , Terapia de Reemplazo Enzimático/métodos , Enfermedad del Almacenamiento de Glucógeno Tipo II/diagnóstico , Enfermedad del Almacenamiento de Glucógeno Tipo II/tratamiento farmacológico , Músculo Esquelético/efectos de los fármacos , Evaluación de Resultado en la Atención de Salud/métodos , Adulto , Edad de Inicio , Impedancia Eléctrica , Electrodiagnóstico/instrumentación , Femenino , Enfermedad del Almacenamiento de Glucógeno Tipo II/fisiopatología , Humanos , Pierna/patología , Pierna/fisiopatología , Debilidad Muscular/diagnóstico , Debilidad Muscular/tratamiento farmacológico , Debilidad Muscular/fisiopatología , Músculo Esquelético/enzimología , Músculo Esquelético/fisiopatología , Atrofia Muscular/diagnóstico , Atrofia Muscular/tratamiento farmacológico , Atrofia Muscular/fisiopatología , Proteínas Recombinantes/farmacología , Proteínas Recombinantes/uso terapéutico , Recuperación de la Función/efectos de los fármacos , Recuperación de la Función/fisiología , Respiración Artificial , Parálisis Respiratoria/diagnóstico , Parálisis Respiratoria/tratamiento farmacológico , Parálisis Respiratoria/fisiopatología , Resultado del Tratamiento , alfa-Glucosidasas/deficiencia , alfa-Glucosidasas/farmacología , alfa-Glucosidasas/uso terapéuticoRESUMEN
Amyotrophic lateral scleorsis (ALS) is a progressive neurodegenerative disease, which predominantly affects both upper and lower motor neurons. ALS is usually fatal within a few years after clinical onset. An organotypic slice culture of rat spinal cord, in which glutamate toxicity induces slow loss of spinal motoneurons, has been used for preclinical drug screening for ALS. In this report, we modified the conventional slice culture to put mouse spinal cords to use, as an alternative in vitro model of ALS. L-trans pyrrolidine 2, 4-dicarboxylic acid (PDC), an inhibitor of glutamate uptake, induced slow loss of spinal motoneurons in anterior horns, whereas small neurons in posterior horns were relatively preserved. This technique using mouse allows us to use transgenic and knockout mice. In addition to glutamate toxicity, many other mechanisms including oxidative stress and neurofilamentous disorganization are also considered to be involved in development of this devastating disease. Thus, a better in vitro model of ALS is strongly anticipated. At present, we are making efforts to apply this technique to establish a better in vitro model using spinal cord from transgenic ALS model mice, where spontaneous loss of spinal motoneurons will be observed.
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Esclerosis Amiotrófica Lateral/patología , Neuronas Motoras/patología , Médula Espinal/patología , Animales , Células del Asta Anterior/patología , Muerte Celular , Técnicas de Cultivo , Ácidos Dicarboxílicos/farmacología , Ratones , Ratones Transgénicos , Pirrolidinas/farmacología , RatasRESUMEN
Hepatoma-derived growth factor (HDGF) is a heparin-binding proliferating factor originally isolated from conditioned medium of the hepatoma-derived cell line HuH-7. HDGF has greatest homology in an amino acid sequence with high mobility group 1 (HMG1), which has been characterized as a DNA-binding, inflammatory, and potent neurite outgrowth molecule. HDGF is reported to be widely expressed and act as a growth factor in many kinds of cells. However, it has not been investigated in the nervous system. Here, we show by Western blot analysis that HDGF is present in the mouse brain from the embryonic period until adulthood. In situ hybridization and immunohistochemical analyses revealed that HDGF was expressed mainly in neurons, and HDGF protein was localized to the nucleus. HDGF and high mobility group 1 were secreted under physiological conditions and released extracellularly in necrotic conditions. Furthermore, we showed that exogenously supplied HDGF had a neurotrophic effect and was able to partially prevent the cell death of neurons in which endogenous HDGF was suppressed. Therefore, we propose that HDGF is a novel type of neurotrophic factor, on account of its localization in the nucleus and its potential to function in an autocrine manner under both physiological and pathological conditions throughout life.
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Núcleo Celular/metabolismo , Péptidos y Proteínas de Señalización Intercelular/fisiología , Factores de Crecimiento Nervioso/fisiología , Animales , Apoptosis/fisiología , Comunicación Autocrina , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Proteína HMGA1a/metabolismo , Hipocampo/citología , Hipocampo/metabolismo , Hipocampo/ultraestructura , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Péptidos y Proteínas de Señalización Intercelular/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Factores de Crecimiento Nervioso/genética , Factores de Crecimiento Nervioso/metabolismo , Factores de Crecimiento Nervioso/farmacología , Neuronas/citología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , ARN Mensajero/biosíntesisRESUMEN
Valproic acid (VPA) has long been used as an antiepileptic drug and recently as a mood stabilizer, and evidence is increasing that VPA exerts neuroprotective effects through changes in a variety of intracellular signalling pathways including upregulation of Bcl-2 protein with an antiapoptotic property and inhibiting glycogen synthase kinase 3-beta, which is considered to promote cell survival. Although the neuroprotective effects of VPA have been demonstrated in a murine model of human immunodeficiency virus-1 encephalitis, there have been no reports on the effect of VPA in chronic progressing neurodegenerative disease models including amyotrophic lateral sclerosis (ALS). ALS is a devastating disease selectively affecting motoneurons, and its disease model mice bear a close resemblance to ALS symptomatically and pathologically. First, we used an organotypic slice culture using mouse spinal cord, and showed that VPA protected spinal motoneurons against death from glutamate toxicity in vitro. Then, we treated ALS model mice with VPA at the dose effective level for epileptic model mice after 45 days of age (pre-onset treatment) or the day of the disease onset (post-onset treatment). We found a significant prolongation of the disease duration in ALS model mice in both methods of treatment. Considering the long usage of VPA for epileptic patients with good tolerance and safety, these data strongly support the clinical application of VPA for ALS treatment.