RESUMO
The TDP-43 type C pathological form of frontotemporal lobar degeneration is characterized by the presence of immunoreactive TDP-43 short and long dystrophic neurites, neuronal cytoplasmic inclusions, neuronal loss and gliosis and the absence of neuronal intranuclear inclusions. Frontotemporal lobar degeneration-TDP-type C cases are commonly associated with the semantic variant of primary progressive aphasia or behavioural variant frontotemporal dementia. Here, we provide detailed characterization of regional distributions of pathological TDP-43 and neuronal loss and gliosis in cortical and subcortical regions in 10 TDP-type C cases and investigate the relationship between inclusions and neuronal loss and gliosis. Specimens were obtained from the first 10 TDP-type C cases accessioned from the Northwestern Alzheimer's Disease Research Center (semantic variant of primary progressive aphasia, n = 7; behavioural variant frontotemporal dementia, n = 3). A total of 42 cortical (majority bilateral) and subcortical regions were immunostained with a phosphorylated TDP-43 antibody and/or stained with haematoxylin-eosin. Regions were evaluated for atrophy, and for long dystrophic neurites, short dystrophic neurites, neuronal cytoplasmic inclusions, and neuronal loss and gliosis using a semiquantitative 5-point scale. We calculated a 'neuron-to-inclusion' score (TDP-type C mean score - neuronal loss and gliosis mean score) for each region per case to assess the relationship between TDP-type C inclusions and neuronal loss and gliosis. Primary progressive aphasia cases demonstrated leftward asymmetry of cortical atrophy consistent with the aphasic phenotype. We also observed abundant inclusions and neurodegeneration in both cortical and subcortical regions, with certain subcortical regions emerging as particularly vulnerable to dystrophic neurites (e.g. amygdala, caudate and putamen). Interestingly, linear mixed models showed that regions with lowest TDP-type C pathology had high neuronal dropout, and conversely, regions with abundant pathology displayed relatively preserved neuronal densities (P < 0.05). This inverse relationship between the extent of TDP-positive inclusions and neuronal loss may reflect a process whereby inclusions disappear as their associated neurons are lost. Together, these findings offer insight into the putative substrates of neurodegeneration in unique dementia syndromes.
Assuntos
Afasia Primária Progressiva , Demência Frontotemporal , Degeneração Lobar Frontotemporal , Malformações do Sistema Nervoso , Afasia Primária Progressiva/patologia , Atrofia , Autopsia , Proteínas de Ligação a DNA/genética , Demência Frontotemporal/patologia , Degeneração Lobar Frontotemporal/patologia , Gliose , HumanosRESUMO
A 28-year-old man presented with osteosarcoma of the occipital bone 16 years after 24 Gy of craniospinal irradiation for acute lymphocytic leukemia. The tumor had both intra- and extra-cranial components. However, the affected skull appeared to be normal on imaging because of permeative infiltration by the tumor. Subtotal resection was achieved and the tumor was verified histologically as an osteosarcoma. The residual tumor soon showed remarkable enlargement and disseminated to the spinal cord. Both of the enlarged and disseminated tumor masses were treated by surgical intervention and chemotherapy. However, the patient deteriorated due to the tumor regrowth and died 11 months after the initial diagnosis. This patient had previously developed a leukemia, a colon cancer, a rectal cancer and a hepatocellular carcinoma. His brother also died of leukemia. The patient had a heterozygous TP53 germ-line mutation of codon 248 in the exon 7. In conclusion, we consider the present tumor to be a rare example of radiation-induced skull osteosarcoma in a member of the cancer-prone family with TP53 germ-line mutation which is associated with Li-Fraumeni syndrome.
Assuntos
Genes p53 , Mutação em Linhagem Germinativa/genética , Síndrome de Li-Fraumeni/genética , Neoplasias Induzidas por Radiação/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adulto , Evolução Fatal , Genes p53/genética , Humanos , Síndrome de Li-Fraumeni/complicações , Síndrome de Li-Fraumeni/diagnóstico , Masculino , Osteossarcoma/etiologia , Osteossarcoma/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/radioterapia , Radioterapia/efeitos adversosRESUMO
BACKGROUND: Hereditary short stature syndromes are clinically and genetically heterogeneous disorders and the cause have not been fully identified. Yakuts are a population isolated in Asia; they live in the far east of the Russian Federation and have a high prevalence of hereditary short stature syndrome including 3-M syndrome. A novel short stature syndrome in Yakuts is reported here, which is characterised by autosomal recessive inheritance, severe postnatal growth retardation, facial dysmorphism with senile face, small hands and feet, normal intelligence, Pelger-Huët anomaly of leucocytes, and optic atrophy with loss of visual acuity and colour vision. This new syndrome is designated as short stature with optic atrophy and Pelger-Huët anomaly (SOPH) syndrome. AIMS: To identify a causative gene for SOPH syndrome. METHODS: Genomewide homozygosity mapping was conducted in 33 patients in 30 families. RESULTS: The disease locus was mapped to the 1.1 Mb region on chromosome 2p24.3, including the neuroblastoma amplified sequence (NBAS) gene. Subsequently, 33 of 34 patients were identified with SOPH syndrome and had a 5741G/A nucleotide substitution (resulting in the amino acid substitution R1914H) in the NBAS gene in the homozygous state. None of the 203 normal Yakuts individuals had this substitution in the homozygous state. Immunohistochemical analysis revealed that the NBAS protein is well expressed in retinal ganglion cells, epidermal skin cells, and leucocyte cytoplasm in controls as well as a patient with SOPH syndrome. CONCLUSION: These findings suggest that function of NBAS may associate with the pathogenesis of short stature syndrome as well as optic atrophy and Pelger-Huët anomaly.
Assuntos
Nanismo/complicações , Nanismo/genética , Proteínas de Neoplasias/genética , Atrofia Óptica/complicações , Atrofia Óptica/genética , Anomalia de Pelger-Huët/complicações , Anomalia de Pelger-Huët/genética , Adolescente , Adulto , Sequência de Aminoácidos , Substituição de Aminoácidos/genética , Sequência de Bases , Estatura/genética , Criança , Pré-Escolar , Cromossomos Humanos Par 2/genética , Nanismo/diagnóstico , Nanismo/diagnóstico por imagem , Feminino , Loci Gênicos/genética , Humanos , Imuno-Histoquímica , Lactente , Recém-Nascido , Masculino , Dados de Sequência Molecular , Proteínas de Neoplasias/química , Atrofia Óptica/diagnóstico por imagem , Atrofia Óptica/patologia , Anomalia de Pelger-Huët/diagnóstico por imagem , Anomalia de Pelger-Huët/patologia , Radiografia , Síndrome , Adulto JovemRESUMO
Tau is the pathological protein in several neurodegenerative disorders classified as frontotemporal lobar degeneration (FTLD), including corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP). We report an unusual tauopathy in three Japanese patients presenting with Parkinsonism and motor neuron disease (neuroimaging revealed frontotemporal cerebral atrophy in two patients who were examined). At autopsy, all cases showed FTLD with the most severe neuronal loss and gliosis evident in the premotor and precentral gyri. Although less severe, such changes were also observed in other brain regions, including the basal ganglia and substantia nigra. In the spinal cord, loss of anterior horn cells and degeneration of the corticospinal tract were evident. In addition, the affected regions exhibited neuronal cytoplasmic inclusions resembling neurofibrillary tangles. Immunostaining using antibodies against hyperphosphorylated tau and 4-repeat tau revealed widespread occurrence of neuronal and glial cytoplasmic inclusions in the central nervous system; the astrocytic tau lesions were unique, and different in morphology from astrocytic plaques in CBD, or tufted astrocytes in PSP. However, immunoblotting of frozen brain samples available in two cases revealed predominantly 4R tau, with the approximately 37-kDa and 33-kDa low-molecular mass tau fragments characteristic of CBD and PSP, respectively. No mutations were found in the tau gene in either of the two cases. Based on these clinicopathological, biochemical, and genetic findings, we consider that the present three patients form a distinct 4R tauopathy associated with sporadic FTLD.
Assuntos
Degeneração Lobar Frontotemporal/complicações , Doença dos Neurônios Motores/complicações , Transtornos Parkinsonianos/complicações , Tauopatias/complicações , Adulto , Idoso , Astrócitos/metabolismo , Astrócitos/patologia , Astrócitos/ultraestrutura , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/ultraestrutura , Citoplasma/metabolismo , Citoplasma/patologia , Citoplasma/ultraestrutura , Degeneração Lobar Frontotemporal/metabolismo , Degeneração Lobar Frontotemporal/patologia , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Doença dos Neurônios Motores/metabolismo , Doença dos Neurônios Motores/patologia , Emaranhados Neurofibrilares/metabolismo , Emaranhados Neurofibrilares/patologia , Emaranhados Neurofibrilares/ultraestrutura , Neuroglia/metabolismo , Neuroglia/patologia , Neuroglia/ultraestrutura , Neurônios/metabolismo , Neurônios/patologia , Neurônios/ultraestrutura , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/patologia , Medula Espinal/metabolismo , Medula Espinal/patologia , Medula Espinal/ultraestrutura , Tauopatias/metabolismo , Tauopatias/patologia , Proteínas tau/genética , Proteínas tau/metabolismoRESUMO
Alzheimer's disease (AD) is the most common cause of dementia in the elderly. Corticobasal degeneration (CBD) is a rare neurodegenerative disease affecting adults, being characterized clinically by a combination of extrapyramidal signs and focal cortical syndromes. In both diseases, tau deposits are a characteristic neuropathological feature. We report two new patients with autopsy-proven AD, in whom clinical diagnoses of CBD were made during life. The ages of the patients at onset were 52 and 67 years, and the disease durations were 9 and 15 years, respectively. At autopsy, both cases exhibited marked cortical atrophy with evident neuronal loss in the convex areas of the frontal and parietal lobes. Immunohistochemically, AT8-positive neurofibrillary tangles (NFTs) and Abeta-positive senile plaques (SPs) were widespread and abundant in the cerebral cortex (Alzheimer pathology stage VI/C of Braak and Braak), leading us to the final pathological diagnosis of AD. No tau lesions suggestive of CBD were observed, and the deep gray matter areas, including the substantia nigra, were unremarkable (exceptionally, only mild neuronal loss was noted in the putamen in case 2). These findings further strengthen the idea that in AD, neurodegeneration with tau and Abeta deposits may begin in the fronto-parietal neocortical areas, which are often preferentially affected in CBD, earlier than, or as early as the medial temporal lobe, and that extrapyramidal signs, such as rigidity and tremor, can occur in the absence of neuronal loss in the basal ganglia and substantia nigra.
Assuntos
Doença de Alzheimer/patologia , Encéfalo/patologia , Doenças Neurodegenerativas/diagnóstico , Emaranhados Neurofibrilares/patologia , Placa Amiloide/patologia , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Atrofia/metabolismo , Atrofia/patologia , Encéfalo/metabolismo , Diagnóstico Diferencial , Progressão da Doença , Feminino , Humanos , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Doenças Neurodegenerativas/metabolismo , Emaranhados Neurofibrilares/metabolismo , Placa Amiloide/metabolismoRESUMO
Recently, sporadic amyotrophic lateral sclerosis (SALS), a fatal neurological disease, has been shown to be a multisystem proteinopathy of TDP-43 in which both neurons and glial cells in the central nervous system are widely affected. In general, the natural history of SALS is short (<5 years). However, it is also known that a few patients may survive for 10 years or more, even without artificial respiratory support (ARS). In the present study using TDP-43 immunohistochemistry, we examined various regions of the nervous system in six patients with SALS of long duration (10-20 years) without ARS, in whom lower motor-predominant disease with Bunina bodies and ubiquitinated inclusions (UIs) in the affected lower motor neurons was confirmed. One case also showed UIs in the hippocampal dentate granule cells (UDG). In all cases, except one with UDG, the occurrence of TDP-43-immunoreactive (ir) neuronal cytoplasmic inclusions (NCIs) was confined to a few regions in the spinal cord and brainstem, including the anterior horns. In one case with UDG, TDP-43-ir NCIs were also detected in the substantia nigra, and some regions of the cerebrum, including the hippocampal dentate gyrus (granule cells). The number of neurons displaying NCIs in each region was very small (1-3 per region, except the dentate gyrus). On the other hand, the occurrence of TDP-43-ir glial cytoplasmic inclusions (GCIs) was more widespread in the central nervous system, including the cerebral white matter. Again, however, the number of glial cells displaying GCIs in each region was very small (1-3 per region). In conclusion, compared to the usual form of SALS, TDP-43 pathology shown in SALS of long duration was apparently mild in degree and limited in distribution, corresponding to the relatively benign clinical courses observed. It is now apparent that SALS of long duration is actually part of a TDP-43 proteinopathy spectrum.
Assuntos
Esclerose Lateral Amiotrófica/metabolismo , Proteínas de Ligação a DNA/metabolismo , Corpos de Inclusão/metabolismo , Neuroglia/metabolismo , Neurônios/metabolismo , Idoso , Esclerose Lateral Amiotrófica/patologia , Células do Corno Anterior/metabolismo , Células do Corno Anterior/patologia , Células do Corno Anterior/ultraestrutura , Autopsia , Encéfalo/metabolismo , Encéfalo/patologia , Tronco Encefálico/metabolismo , Tronco Encefálico/patologia , Cérebro/metabolismo , Cérebro/patologia , Giro Denteado/metabolismo , Giro Denteado/patologia , Feminino , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Imuno-Histoquímica , Corpos de Inclusão/patologia , Masculino , Microscopia Imunoeletrônica , Pessoa de Meia-Idade , Neuroglia/patologia , Neurônios/patologia , Medula Espinal/metabolismo , Medula Espinal/patologia , Substância Negra/metabolismo , Substância Negra/patologia , Fatores de Tempo , Ubiquitina/metabolismoRESUMO
It has been reported that widespread multisystem degeneration can occur in patients with sporadic amyotrophic lateral sclerosis (SALS) who have survived for long periods with artificial respiratory support (ARS). We report a case of SALS of 8 years and 8 months duration in a 71-year-old woman, who received ARS for 7 years and 8 months. In this patient, the symptoms at the early stage were those of typical ALS, and a totally locked-in state with frontal lobe atrophy appeared a few years after the start of ARS. At autopsy, marked atrophy of the frontal lobe and brainstem tegmentum was evident. Microscopically, widespread multisystem degeneration with obvious neuronal loss was a feature. Bunina bodies and ubiquitinated inclusions were observed in the remaining lower motor neurons. Of interest was that Lewy body-like hyaline inclusions (LBHIs), which were later shown to be immunnoreactive (ir) for 43-kDa TAR DNA-binding protein (TDP-43) and ubiquitin, were also detected in neurons in various regions of the nervous system, including the lower and upper motor neuron nuclei. The distributions of neurons with TDP-43-ir and ubiquitin-ir cytoplasmic inclusions were also widespread in the nervous system, and in each region, the numbers of these neurons were apparently larger than those of neurons with LBHIs. Importantly, double-labeling immunofluorescence revealed that the widespread TDP-43-ir inclusions were often ubiqutinated. In conclusion, the entire pathological picture appeared to correspond well to the patient's long-standing, progressive disease, including the TDP-43 pathology with ubiquitination. These findings further strengthen the idea that TDP-43 abnormality is closely associated with the pathogenesis of SALS.
Assuntos
Esclerose Lateral Amiotrófica/patologia , Encéfalo/patologia , Proteínas de Ligação a DNA/metabolismo , Idoso , Esclerose Lateral Amiotrófica/metabolismo , Atrofia/metabolismo , Atrofia/patologia , Encéfalo/metabolismo , Feminino , Imunofluorescência , Humanos , Corpos de Inclusão/metabolismo , Corpos de Inclusão/patologia , Neurônios Motores/metabolismo , Neurônios Motores/patologia , Respiração ArtificialRESUMO
We report a case of solitary fibrous tumor (SFT) in the cerebral convexity, and present characteristic radiological and surgical findings to determine its origin. The patient was a 59-year-old man with mental dullness and mild gait disturbance. CT scan and MR images showed a highly enhanced large mass lesion mimicking a meningioma in the left parietal convexity. However, neither dural enhancement nor tail sign indicative of meningioma was observed. Angiography showed prominent feedings from branches of the internal carotid and basilar arteries rather than the external carotid artery. For this reason, presurgically, we suggested hemangiopericytoma or other specific meningiomas as a differential diagnoses. Surgery confirmed that the tumor had no attachment to the dura mater and was covered by the arachnoid membrane. The bottom of the tumor adhered tightly to brain tissue. The origin was considered to be the brain surface, pia mater or a part of the arachnoid membrane. Histopathologically, the tumor was diagnosed as a SFT with findings of "attemless pattern" and diffuse CD34 staining. The radiological and surgical findings of the present case indicated in the cerebral convexity as a unique site of origin of SFT.
Assuntos
Neoplasias Meníngeas/cirurgia , Neoplasias de Tecido Fibroso/cirurgia , Diagnóstico Diferencial , Gadolínio DTPA , Hemangiopericitoma/diagnóstico , Humanos , Imageamento por Ressonância Magnética , Masculino , Neoplasias Meníngeas/diagnóstico , Meningioma/diagnóstico , Pessoa de Meia-Idade , Neoplasias de Tecido Fibroso/diagnóstico , Procedimentos Neurocirúrgicos/métodos , Tomografia Computadorizada por Raios XRESUMO
We report an autopsy case of a 74-year-old man with late onset Charcot-Marie-Tooth disease type 1A (CMT1A) diagnosed by genetic screening, later associated with amyotrophic lateral sclerosis (ALS). At the age of 70 years, the patient was admitted to our hospital because of progressive weakness and dysesthesia in the right upper limb. In the early stages of the illness, he was diagnosed with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and transient improvement was achieved with intravenous immunoglobulin. However, the symptoms progressively worsened and became refractory. Gene analysis revealed PMP22 gene duplication, which confirmed CMT1A. On sural nerve biopsy, severe demyelinating neuropathy and abundant onion-bulb formations with endoneurial infiltration of inflammatory cells were observed. Thereafter, pseudo-bulbar palsy and respiratory muscle weakness developed insidiously and progressed rapidly along with muscle weakness in the limbs and trunk. The patient died about four years after the onset of this disease. Postmortem examination showed moderate neuronal cell loss, Bunina bodies, and TDP-43-positive inclusions in the anterior horn cells. The spinal cord revealed axonal loss and extensive macrophage permeation in the corticospinal tracts. On the basis of these findings, the final neuropathological diagnosis was ALS. This is the first report of an autopsy case of CMT1A complicated with ALS. We here discuss the significant clinical and neuropathological findings of this case.
Assuntos
Esclerose Lateral Amiotrófica/complicações , Esclerose Lateral Amiotrófica/diagnóstico , Doença de Charcot-Marie-Tooth/complicações , Doença de Charcot-Marie-Tooth/diagnóstico , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/complicações , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/diagnóstico , Idoso , Esclerose Lateral Amiotrófica/patologia , Autopsia , Doença de Charcot-Marie-Tooth/genética , Doença de Charcot-Marie-Tooth/patologia , Diagnóstico Diferencial , Progressão da Doença , Evolução Fatal , Duplicação Gênica , Humanos , Masculino , Proteínas da Mielina , Patologia Molecular , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/patologiaRESUMO
To elucidate the maturation process of TDP-43-positive neuronal inclusions, we immunohistochemically and immunoelectron-microscopically examined multiple areas from the brain and spinal cord from ten patients with amyotrophic lateral sclerosis (ALS) and 25 control subjects. TDP-43 immunohistochemistry demonstrated three types of inclusions in ALS: skein-like, round, and dot-like inclusions. Skein-like inclusions were found in all cases of ALS. Dot-like inclusions were found in the anterior horn in seven cases of ALS, all of whom had round inclusions, but not in cases without round inclusions. In addition, careful examination revealed two types of diffuse punctate cytoplasmic staining: linear wisps and punctate granules. Linear wisps were present in all cases of ALS but in none of 25 controls. In contrast, punctate granules were detected in all cases of ALS as well as in five of 13 normal and in seven of 12 diseased controls. Immunoelectron-microscopy revealed that skein-like inclusions consisted of granule-associated parallel filaments. Round and dot-like inclusions were composed of granulo-filamentous structures. However, punctate granules corresponded to the mitochondria and were not immunostained with anti-ubiquitin, indicating that punctate granules represent cross-reaction. We assumed that linear wisps ("fine skein") aggregate as thicker and longer threads ("coarse skein"), whereas round inclusions arise from dot-like inclusions. These findings suggest that there are differences in the formation process between skein-like and round inclusions, despite the antigenic and ultrastructural similarities.
Assuntos
Esclerose Lateral Amiotrófica/patologia , Proteínas de Ligação a DNA/metabolismo , Corpos de Inclusão/patologia , Neurônios/patologia , Idoso , Esclerose Lateral Amiotrófica/complicações , Esclerose Lateral Amiotrófica/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Demência/complicações , Feminino , Humanos , Imuno-Histoquímica , Corpos de Inclusão/metabolismo , Masculino , Microscopia Imunoeletrônica , Pessoa de Meia-Idade , Neurônios/metabolismo , Medula Espinal/metabolismo , Medula Espinal/patologiaAssuntos
Esclerose Lateral Amiotrófica/fisiopatologia , Eletromiografia , Movimentos da Cabeça/fisiologia , Debilidade Muscular/fisiopatologia , Músculos do Pescoço/fisiopatologia , Esclerose Lateral Amiotrófica/diagnóstico , Esclerose Lateral Amiotrófica/epidemiologia , Eletromiografia/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Debilidade Muscular/diagnóstico , Debilidade Muscular/epidemiologia , Estudos RetrospectivosRESUMO
A nuclear protein, 43-kDa TAR DNA-binding protein (TDP-43), was recently identified as a component of the ubiquitinated inclusions (UIs) in frontotemporal lobar degeneration (FTLD-U) and sporadic amyotrophic lateral sclerosis (SALS). In the present study using immunohistochemistry, we examined various regions of the nervous system in a series of 35 SALS cases using a polyclonal antibody against TDP-43. Seven of the 35 cases had disease durations of more than 10 years with artificial respiratory support (ARS; duration: 69-156 months). In all cases, TDP-43-immunoreactive (ir) neuronal and glial cytoplasmic inclusions (NCIs and GCIs) were found together in many regions, including the histologically affected lower motor neuron nuclei. Cluster analysis of the distribution pattern of TDP-43-ir NCIs for cases without ARS (n = 28) identified two types (type 1, n = 16; type 2, n = 12). Type 2 was distinguished from type 1 by the presence of TDP-43-ir NCIs in the frontotemporal cortex, hippocampal formation, neostriatum and substantia nigra, and was significantly associated with dementia. Eleven of the 28 cases showed UIs in the hippocampal dentate granule cells, all of which had type-2 distribution pattern. Cases with ARS (n = 7) were also classified into the same types (type 1, n = 5; type 2, n = 2). Cases having type-1 distribution pattern (n = 21) showed no evident neuronal loss in most of the non-motor neuron nuclei where TDP-43-ir NCIs were present, whereas cases having type-2 distribution pattern (n = 14) often showed evident neuronal loss in the frontotemporal cortices, amygdaloid nuclei and substantia nigra. These findings indicate that SALS is a multisystem degenerative disease widely affecting both neurons and glial cells with a heterogeneous pattern of TDP-43-ir NCI distribution (SALS showing type-2 distribution pattern being closely linked to FTLD-U), and that long-term survival supported by a respirator has no apparent influence on the TDP-43 neuronal distribution pattern.
Assuntos
Esclerose Lateral Amiotrófica/classificação , Esclerose Lateral Amiotrófica/patologia , Proteínas de Ligação a DNA/metabolismo , Corpos de Inclusão/metabolismo , Neuroglia/patologia , Neurônios/patologia , Esclerose Lateral Amiotrófica/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Análise por Conglomerados , Imunofluorescência , Humanos , Imuno-Histoquímica , Corpos de Inclusão/patologia , Microscopia Eletrônica de Transmissão , Neuroglia/metabolismo , Neurônios/metabolismo , Respiração Artificial , Medula Espinal/metabolismo , Medula Espinal/patologia , Ubiquitina/metabolismoRESUMO
Two embryonal CNS tumors, atypical teratoid/rabdoid tumor (AT/RT) and primitive neuroectodermal tumor (PNET), may be confused with each other and misdiagnosed. Here we report an infant with a congenital supratentorial tumor, which was detected by fetal MRI at 37 weeks gestation. On routine histological examination, the tumor was composed mainly of small undifferentiated cells, among which many rhabdoid cells and occasional sickle-shaped embracing cells were observed. No mesenchymal or epithelial areas were evident. Our impression was that the tumor was an atypical example of AT/RT. Immunohistochemically, almost all the tumor cells were strongly positive for vimentin. However, epithelial membrane antigen was notably negative, and most of the tumor cell nuclei were clearly positive for INI1. In addition, many tumor cells were positive for neurofilament protein. There were also occasional small areas containing many tumor cells positive for glial fibrillary acidic protein. Finally, a diagnosis of PNET, with a rhabdoid phenotype and expression of neuronal and glial markers, was made. In the present case, application of INI1 immunostaining was very helpful for distinguishing PNET from AT/RT.
Assuntos
Proteínas Cromossômicas não Histona/metabolismo , Proteínas de Ligação a DNA/metabolismo , Tumores Neuroectodérmicos Primitivos/patologia , Neoplasias Supratentoriais/congênito , Neoplasias Supratentoriais/patologia , Teratoma/patologia , Fatores de Transcrição/metabolismo , Biomarcadores Tumorais/análise , Diagnóstico Diferencial , Feminino , Humanos , Imuno-Histoquímica , Recém-Nascido , Tumores Neuroectodérmicos Primitivos/congênito , Tumores Neuroectodérmicos Primitivos/metabolismo , Gravidez , Diagnóstico Pré-Natal , Tumor Rabdoide/congênito , Tumor Rabdoide/metabolismo , Tumor Rabdoide/patologia , Proteína SMARCB1 , Neoplasias Supratentoriais/metabolismo , Teratoma/congênito , Teratoma/metabolismoRESUMO
Mutations of selenoprotein N, 1 gene (SEPN1) cause rigid spine with muscular dystrophy type 1 (RSMD1), multiminicore disease, and desmin-related myopathy. We found two novel SEPN1 mutations in two Japanese patients with RSMD1. To clarify the pathomechanism of RSMD1, we performed immunohistochemical studies using a newly developed antibody for selenoprotein N. Selenoprotein N was diffusely distributed in the cytoplasm of the control muscle, but was reduced and irregularly expressed in the cytoplasm of a patient with RSMD1. The expression pattern was very similar to that of calnexin, a transmembrane protein of the endoplasmic reticulum. Selenoprotein N seems to be an endoplasmic reticulum glycoprotein, and loss of this protein leads to disturbance of muscular function. One of the families had the SEPN1 homozygous mutation in the initiation codon 1_2 ins T in exon 1 and showed truncated protein expression. The other had a homozygous 20-base duplication mutation at 80 (80_99dup, frameshift at R27) which, in theory, should generate many nonsense mutations including TGA. These nonsense mutations are premature translation termination codons and they degrade immediately by the process of nonsense-mediated decay (NMD). However, truncated selenoprotein N was also expressed. A possible mechanism behind this observation is that SEPN1 mRNAs may be resistant to NMD. We report on the possible molecular mechanism behind these mutations in SEPN1. Our study clarifies molecular mechanisms of this muscular disorder.