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1.
Neuropathology ; 44(2): 135-146, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37559506

RESUMO

Intravascular large B-cell lymphoma can induce central nervous system manifestations, including strokes, due to small-vessel occlusion caused by lymphoma cells. However, involvement in large-sized vessels is rare. Here, we present an unusual autopsy case of an 88-year-old man showing a rapid transition from multiple strokes due to small vessel occlusion, typical of intravascular lymphoma, to progressive embolic strokes caused by the occlusion of major cerebral arteries. Magnetic resonance angiography demonstrated the major cerebral arteries associated with those multiple progressive strokes, including the right posterior cerebral artery, left anterior cerebral artery, and right middle cerebral artery, but the detectability was poor. A random skin biopsy at the abdomen confirmed the diagnosis of intravascular large B-cell lymphoma. The patient died 106 days after hospitalization despite intensive treatment. An autopsy revealed broad liquefactive necrosis in the area governed by the major cerebral arteries and multiple small infarctions caused by intravascular lymphoma cells in the small-sized vessels. In addition, the major cerebral arteries showed multiple thromboembolism with partial organization and clusters of intravascular lymphoma cells. Notably, those cells were shown aggregated and attached along the vascular wall of the basilar artery, which might have caused focal hypercoagulation in the near vessels. This aggregation might have disseminated widely in the other major cerebral arteries. Moreover, the cluster of intravascular lymphoma cells in the basilar artery was positive for tumor necrosis factor α, and similar histopathology findings were observed in the splenic veins. However, the pathogenesis of this rare phenomenon involving these cells remains unknown. From a clinical perspective, we should consider the possibility that intravascular lymphoma cells may provoke similar progressive embolic strokes.


Assuntos
AVC Embólico , Linfoma Difuso de Grandes Células B , Acidente Vascular Cerebral , Masculino , Humanos , Idoso de 80 Anos ou mais , Linfoma Difuso de Grandes Células B/complicações , Artérias Cerebrais/patologia , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/patologia , Autopsia
2.
Eur J Neurol ; 28(11): 3760-3767, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34245630

RESUMO

BACKGROUND: Alexander disease (ALXDRD) affects a wide range of ages from infancy to adulthood. However, only a few cases involving patients with older-adult onset over 65 years of age have been reported. In contrast, regarding in-house data, 10.6% of 85 cases with the identification of GFAP mutations demonstrated older-adult onset. This discrepancy may be due to poor awareness of such cases. METHODS: The subjects included 9 older-adult-onset cases, with an onset age of 65 years or older. We characterized older-adult-onset ALXDRD by assessing neurological findings and several magnetic resonance imaging (MRI) parameters. RESULTS: The age at onset, mean age at diagnosis, and mean period from onset to diagnosis were 68.2 years, 70.4 years, and 2.2 years, respectively. The main neurological features at diagnosis included pyramidal signs with muscle weakness and/or cerebellar ataxia. Two-thirds of cases were dependent, and the dependence was significantly correlated with a longer period from onset to diagnosis. Quantitative MRI evaluation for brainstem atrophy demonstrated distinctive morphological features of bulbospinal ALXDRD. The corpus callosum index tended to be negatively correlated with the period from onset to diagnosis. CONCLUSIONS: Although neurological and MRI findings of older-adult-onset ALXDRD patients showed typical features of bulbospinal ALXDRD, their disease progression was more severe than that in younger-adult-onset ALXDRD, and patients developed dependence within 2 years from onset. Cerebral white matter damage tended to progress in proportion to the duration of illness. Our case study may help to advance understanding of the clinical spectrum of ALXDRD.


Assuntos
Doença de Alexander , Ataxia Cerebelar , Substância Branca , Adulto , Idoso , Doença de Alexander/diagnóstico por imagem , Doença de Alexander/genética , Humanos , Imageamento por Ressonância Magnética , Radiografia
3.
BMC Neurol ; 21(1): 265, 2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34225694

RESUMO

BACKGROUND: Oculopharyngeal muscular dystrophy (OPMD) is a late-onset muscular dystrophy characterised by slowly progressive ptosis, dysphagia, and proximal limb muscle weakness. A common cause of OPMD is the short expansion of a GCG or GCA trinucleotide repeat in PABPN1 gene. CASE PRESENTATION: A 78-year-old woman presented with ptosis and gradually progressive dysphagia. Her son had the same symptoms. A physical examination and muscle imaging (MRI and ultrasound) showed impairment of the tongue, proximal muscles of the upper limbs, and flexor muscles of the lower limbs. Needle-electromyography (EMG) of bulbar and facial muscles revealed a myopathic pattern. Based on the characteristic muscle involvement pattern and needle-EMG findings, we suspected that the patient had OPMD. Gene analysis revealed PABPN1 c.35G > C point mutation, which mimicked the effect of a common causative repeat expansion mutation of OPMD. CONCLUSION: We herein describe the first reported Japanese case of OPMD with PABPN1 point mutation, suggesting that this mutation is causative in Asians as well as in Europeans, in whom it was originally reported.


Assuntos
Distrofia Muscular Oculofaríngea , Proteína I de Ligação a Poli(A)/genética , Idoso , Feminino , Humanos , Masculino , Distrofia Muscular Oculofaríngea/diagnóstico , Distrofia Muscular Oculofaríngea/genética , Mutação Puntual
4.
Glia ; 66(5): 1053-1067, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29383757

RESUMO

Alexander disease (AxD) is a rare neurodegenerative disorder caused by gain of function mutations in the glial fibrillary acidic protein (GFAP) gene. Accumulation of GFAP proteins and formation of Rosenthal fibers (RFs) in astrocytes are hallmarks of AxD. However, malfunction of astrocytes in the AxD brain is poorly understood. Here, we show aberrant Ca2+ responses in astrocytes as playing a causative role in AxD. Transcriptome analysis of astrocytes from a model of AxD showed age-dependent upregulation of GFAP, several markers for neurotoxic reactive astrocytes, and downregulation of Ca2+ homeostasis molecules. In situ AxD model astrocytes produced aberrant extra-large Ca2+ signals "AxCa signals", which increased with age, correlated with GFAP upregulation, and were dependent on stored Ca2+ . Inhibition of AxCa signals by deletion of inositol 1,4,5-trisphosphate type 2 receptors (IP3R2) ameliorated AxD pathogenesis. Taken together, AxCa signals in the model astrocytes would contribute to AxD pathogenesis.


Assuntos
Doença de Alexander/metabolismo , Astrócitos/metabolismo , Sinalização do Cálcio/fisiologia , Cálcio/metabolismo , Envelhecimento/metabolismo , Envelhecimento/patologia , Doença de Alexander/patologia , Animais , Astrócitos/patologia , Cátions Bivalentes/metabolismo , Modelos Animais de Doenças , Proteína Glial Fibrilar Ácida/genética , Proteína Glial Fibrilar Ácida/metabolismo , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , RNA Mensageiro/metabolismo , Transcriptoma
5.
Eur Neurol ; 77(5-6): 296-302, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28448978

RESUMO

Brain MRI in adult patients with Alexander disease (AxD) mainly shows atrophy in the medulla oblongata. However, currently there is no quantitative standard for assessing this atrophy. In this study, we quantitatively evaluated the brain stem of AxD patients with glial fibrillary acidic protein (GFAP) mutation using conventional MRI to evaluate its usefulness as an aid to diagnosing AxD in daily clinical practice. Nineteen AxD patients with GFAP mutation were compared with 14 patients negative for GFAP mutation in whom AxD was suspected due to "atrophy of the medulla oblongata." In the GFAP mutation-positive group, the sagittal diameter of the medulla oblongata, the ratio of the diameter of the medulla oblongata to that of the midbrain (MO/MB), and the ratio of the sagittal diameter of the medulla oblongata to that of the pons (MO/Po) were significantly smaller compared to those of the GFAP mutation-negative group (p < 0.01). The sensitivity and specificity of each parameter were 87.5 and 92.3%, 91.7 and 81.3%, and 88.2 and 100% with a sagittal diameter of the medulla oblongata <9.0 mm, MO/MB <0.60, and sagittal MO/Po <0.46, respectively. These parameters can provide very useful information to differentially diagnose AxD from other disorders associated with brain stem atrophy in adult patients.


Assuntos
Doença de Alexander/diagnóstico por imagem , Doença de Alexander/patologia , Tronco Encefálico/diagnóstico por imagem , Tronco Encefálico/patologia , Adulto , Atrofia/diagnóstico por imagem , Atrofia/patologia , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade
6.
J Neurol Neurosurg Psychiatry ; 86(5): 483-9, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25253871

RESUMO

BACKGROUND: In hereditary myopathy with early respiratory failure (HMERF), cytoplasmic bodies (CBs) are often localised in subsarcolemmal regions, with necklace-like alignment (necklace CBs), in muscle fibres although their sensitivity and specificity are unknown. OBJECTIVE: To elucidate the diagnostic value of the necklace CBs in the pathological diagnosis of HMERF among myofibrillar myopathies (MFMs). METHODS: We sequenced the exon 343 of TTN gene (based on ENST00000589042), which encodes the fibronectin-3 (FN3) 119 domain of the A-band and is a mutational hot spot for HMERF, in genomic DNA from 187 patients from 175 unrelated families who were pathologically diagnosed as MFM. We assessed the sensitivity and specificity of the necklace CBs for HMERF by re-evaluating the muscle pathology of our patients with MFM. RESULTS: TTN mutations were identified in 17 patients from 14 families, whose phenotypes were consistent with HMERF. Among them, 14 patients had necklace CBs. In contrast, none of other patients with MFM had necklace CBs except for one patient with reducing body myopathy. The sensitivity and specificity were 82% and 99%, respectively. Positive predictive value was 93% in the MFM cohort. CONCLUSIONS: The necklace CB is a useful diagnostic marker for HMERF. When muscle pathology shows necklace CBs, sequencing the FN3 119 domain of A-band in TTN should be considered.


Assuntos
Citoplasma/patologia , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/metabolismo , Proteínas Musculares/metabolismo , Doenças Musculares/diagnóstico , Doenças Musculares/metabolismo , Agregação Patológica de Proteínas/metabolismo , Insuficiência Respiratória/diagnóstico , Insuficiência Respiratória/metabolismo , Adulto , Idoso , Biomarcadores/metabolismo , Conectina/genética , Citoplasma/ultraestrutura , Feminino , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Musculares/genética , Músculo Esquelético/patologia , Músculo Esquelético/ultraestrutura , Doenças Musculares/genética , Doenças Musculares/patologia , Mutação , Insuficiência Respiratória/genética , Insuficiência Respiratória/patologia , Sensibilidade e Especificidade
8.
Intern Med ; 63(2): 309-313, 2024 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-37197954

RESUMO

A 57-year-old man whose mother had been pathologically diagnosed with Alexander disease (ALXDRD), presented with cerebellar ataxia, pyramidal signs, and mild dysarthria. Brain magnetic resonance imaging revealed typical ALXDRD alterations, such as atrophy of the medulla oblongata (MO) and cervical spinal cord, a reduced sagittal diameter of the MO, and garland-like hyperintensity signals along the lateral ventricular walls. A genetic analysis of GFAP by Sanger sequencing revealed a single heterozygous mutation of Glu to Lys at codon 332 (c.994G>A) in the GFAP gene. Our results newly confirmed that p.E332K alone is the pathogenic causative mutation for adult-onset ALXDRD.


Assuntos
Doença de Alexander , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Alexander/diagnóstico por imagem , Doença de Alexander/genética , Códon/genética , Proteína Glial Fibrilar Ácida/genética , Imageamento por Ressonância Magnética/métodos , Bulbo/diagnóstico por imagem , Bulbo/patologia , Mutação
9.
Sci Rep ; 9(1): 14763, 2019 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-31611638

RESUMO

Alexander disease (AxD) is an extremely rare neurodegenerative disorder caused by glial fibrillary acidic protein (GFAP) gene mutations. Compared with the cerebral type, which is characterized by infantile onset, the bulbospinal type and intermediate form are associated with a late onset, spanning from juveniles to the elderly, and more diverse clinical spectrum, suggesting the existence of factors contributing to phenotypic diversity. To build a foundation for future genetic studies of this rare disease, we obtained genomic data by whole exome-sequencing (WES) and DNA microarray derived from thirty-one AxD patients with the bulbospinal type and intermediate form. Using this data, we aimed to identify genetic variations determining the age at onset (AAO) of AxD. As a result, WES- or microarray-based association studies between younger (<45 years; n = 13)- and older (≥45 years; n = 18)-onset patients considering the predicted GFAP-mutation pathogenicity identified no genome-wide significant variant. The candidate gene approach identified several variants likely correlated with AAO (p < 0.05): GAN, SLC1A2, CASP3, HDACs, and PI3K. Although we need to replicate the results using an independent population, this is the first step towards constructing a database, which may serve as an important tool to advance our understanding of AxD.


Assuntos
Doença de Alexander/genética , Adolescente , Adulto , Idoso , Criança , Feminino , Variação Genética , Genômica , Proteína Glial Fibrilar Ácida/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Análise de Sequência com Séries de Oligonucleotídeos , Sequenciamento do Exoma , Adulto Jovem
11.
Hum Genome Var ; 4: 17028, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28690862

RESUMO

Alexander disease (AxD) is a rare hereditary neurodegenerative disorder caused by glial fibrillary acidic protein (GFAP) gene mutations, most of which are missense mutations. We present an AxD case with a novel de novo three-base duplication mutation in GFAP resulting in E243dup.

14.
Intern Med ; 53(11): 1187-90, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24881746

RESUMO

We herein report the case of a patient with hepatitis C virus (HCV)-associated neuropathy with atypical pathological findings of a biopsied sural nerve. A 48-year-old man was admitted for a gait disturbance. Purpura and edema on the legs and hyperalgesia on the distal extremities were noted. The plasma HCV viral load was high, and cryoglobulin was positive. In the biopsied sural nerve, perivascular eosinophilic infiltration was associated with extravascular granuloma formation in the epineurium. The patient's symptoms disappeared following treatment with interferon-α and ribavirin. The present case suggests that HCV infection can lead to peripheral neuropathy associated with eosinophilic infiltration and granuloma formation.


Assuntos
Hepatite C/complicações , Doenças do Sistema Nervoso Periférico/etiologia , Nervo Sural/patologia , Vasculite/etiologia , Antivirais/uso terapêutico , Eosinofilia/etiologia , Granuloma/complicações , Hepacivirus , Hepatite C/tratamento farmacológico , Humanos , Interferon-alfa/uso terapêutico , Masculino , Pessoa de Meia-Idade , Púrpura/etiologia , Ribavirina/uso terapêutico , Carga Viral
15.
Rinsho Shinkeigaku ; 54(8): 671-4, 2014.
Artigo em Japonês | MEDLINE | ID: mdl-25142542

RESUMO

A 79-year-old man was admitted due to progressive weakness of both hands for two and a half years. Neurologically, he presented with weakness of the upper limbs, predominantly in the left distal portion, and hypoactive deep tendon reflexes. Nerve conduction studies were consistent with a motor and sensory demyelinating neuropathy. Sural nerve biopsy revealed a decrease of myelinated fibers with a predominance of larger diameter fibers. Widening of myelin lamellae and uncompacted myelin were detected on electron microscopy. Laboratory examinations showed IgM-kappa-type M-protein and anti-myelin-associated glycoprotein (MAG) antibody. He was diagnosed as having anti-MAG-associated demyelinating neuropathy based on the laboratory, electrophysiological, and pathological findings. While no bulbar symptoms or upper motor neuron signs were shown, the patient developed quadriparesis and respiratory failure after three years. Although anti-MAG-associated demyelinating neuropathy is usually characterized by sensory symptoms, particularly sensory ataxia, the present case indicates that motor symptoms such as quadriparesis and respiratory failure can be among the clinical manifestations of antiMAG-associated demyelinating neuropathy.


Assuntos
Autoanticorpos/sangue , Glicoproteínas/imunologia , Bainha de Mielina/imunologia , Polineuropatias/complicações , Polirradiculoneuropatia/complicações , Quadriplegia/etiologia , Insuficiência Respiratória/etiologia , Idoso , Progressão da Doença , Humanos , Masculino , Neurônios Motores/patologia , Polineuropatias/patologia , Polirradiculoneuropatia/patologia , Células Receptoras Sensoriais/patologia , Fatores de Tempo
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