RESUMO
BACKGROUND: Anti-IgLON5 disease is a rare neurodegenerative tauopathy that displays heterogeneity in clinical spectrum, disease course, cerebrospinal fluid (CSF) findings, and variable response to immunotherapy. Sleep disorders, bulbar dysfunction, and gait abnormalities are common presenting symptoms, and conventional brain MRI scanning is often unrevealing. OBJECTIVE: To provide a comprehensive overview of the literature and to assess the frequency of symptoms, MRI findings, and treatment response in patients with IgLON5 autoimmunity in the serum and CSF or restricted to serum. METHODS: We examined a 65-year-old woman with bulbar-onset IgLON5 disease with serum-restricted antibodies, and we also performed a systematic review of all confirmed cases reported in the English literature. RESULTS: We identified 93 patients, included our case. Clinical data were obtained in 58 subjects, in whom the most frequent symptoms were sleep-disordered breathing, dysphagia, parasomnias, dysarthria, limb or gait ataxia, stridor or vocal cord paresis, movement disorders, and postural instability. Distinct MRI alterations were identified in 12.5% of cases, as opposed to unspecific or unremarkable changes in the remaining patients. T2-hyperintense non-enhancing signal alterations involving the hypothalamus and the brainstem tegmentum were observed only in the present case. Inflammatory CSF was found in half of the cases and serum-restricted antibodies in 4 patients. Treatment with immunosuppressant or immunomodulatory drugs led to sustained clinical response in 19/52 patients. CONCLUSION: Anti-IgLON5 autoimmunity should be considered in patients with sleep disorders, bulbar syndrome, autonomic involvement, and movement disorders, and high-field brain MRI can be of diagnostic help.
Assuntos
Doenças Autoimunes/imunologia , Paralisia Bulbar Progressiva/imunologia , Moléculas de Adesão Celular Neuronais/imunologia , Doenças Hipotalâmicas/imunologia , Doenças Neurodegenerativas/imunologia , Tauopatias/imunologia , Idoso , Doenças Autoimunes/diagnóstico por imagem , Doenças Autoimunes/patologia , Paralisia Bulbar Progressiva/diagnóstico por imagem , Paralisia Bulbar Progressiva/patologia , Feminino , Humanos , Doenças Hipotalâmicas/diagnóstico por imagem , Doenças Hipotalâmicas/patologia , Doenças Neurodegenerativas/diagnóstico por imagem , Doenças Neurodegenerativas/patologia , Tauopatias/diagnóstico por imagem , Tauopatias/patologiaRESUMO
Brown-Vialetto-Van Laere (BVVL) and Fazio-Londe are disorders with amyotrophic lateral sclerosis-like features, usually with recessive inheritance. We aimed to identify causative mutations in 10 probands. Neurological examinations, genetic analysis, audiometry, magnetic resonance imaging, biochemical and immunological testings, and/or muscle histopathology were performed. Mutations in known causative gene SLC52A3 were found in 7 probands. More importantly, only 1 mutated allele was observed in several patients, and variable expressivity and incomplete penetrance were clearly noted. Environmental insults may contribute to variable presentations. Putative causative mutations in other genes were identified in 3 probands. Two of the genes, WDFY4 and TNFSF13B, have immune-related functions. Inflammatory responses were implicated in the patient with the WDFY4 mutation. Malfunction of the immune system and mitochondrial anomalies were shown in the patient with the TNFSF13B mutation. Prevalence of heterozygous SLC52A3 BVVL causative mutations and notable variability in expressivity of homozygous and heterozygous genotypes are being reported for the first time. Identification of WDFY4 and TNFSF13B as candidate causative genes supports conjectures on involvement of the immune system in BVVL and amyotrophic lateral sclerosis.
Assuntos
Fator Ativador de Células B/genética , Paralisia Bulbar Progressiva/genética , Estudos de Associação Genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas de Membrana Transportadoras/genética , Mutação , Esclerose Lateral Amiotrófica/genética , Audiometria , Paralisia Bulbar Progressiva/diagnóstico , Paralisia Bulbar Progressiva/patologia , Feminino , Testes Genéticos , Humanos , Testes Imunológicos , Imageamento por Ressonância Magnética , Masculino , Músculos/patologia , Exame NeurológicoRESUMO
Riboflavin transporter deficiency (RTD) (MIM #614707) is a neurogenetic disorder with its most common manifestations including sensorineural hearing loss, peripheral neuropathy, respiratory insufficiency, and bulbar palsy. Here, we present a 2-year-old boy whose initial presentation was severe macrocytic anemia necessitating multiple blood transfusions and intermittent neutropenia; he subsequently developed ataxia and dysarthria. Trio-exome sequencing detected compound heterozygous variants in SLC52A2 that were classified as pathogenic and a variant of uncertain significance. Bone marrow evaluation demonstrated megaloblastic changes. Notably, his anemia and neutropenia resolved after treatment with oral riboflavin, thus expanding the clinical phenotype of this disorder. We reiterate the importance of starting riboflavin supplementation in a young child who presents with macrocytic anemia and neurological features while awaiting biochemical and genetic work up. We detected multiple biochemical abnormalities with the help of untargeted metabolomics analysis associated with abnormal flavin adenine nucleotide function which normalized after treatment, emphasizing the reversible pathomechanisms involved in this disorder. The utility of untargeted metabolomics analysis to monitor the effects of riboflavin supplementation in RTD has not been previously reported.
Assuntos
Anemia Macrocítica/patologia , Paralisia Bulbar Progressiva/patologia , Perda Auditiva Neurossensorial/patologia , Metaboloma , Deficiência de Riboflavina/patologia , Riboflavina/metabolismo , Adulto , Anemia Macrocítica/genética , Anemia Macrocítica/metabolismo , Paralisia Bulbar Progressiva/genética , Paralisia Bulbar Progressiva/metabolismo , Feminino , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/metabolismo , Humanos , Lactente , Masculino , Mutação , Receptores Acoplados a Proteínas G/genética , Deficiência de Riboflavina/genética , Deficiência de Riboflavina/metabolismoAssuntos
Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/patologia , Mutação de Sentido Incorreto , Transativadores/genética , Idoso , Esclerose Lateral Amiotrófica/diagnóstico , Brasil , Paralisia Bulbar Progressiva/diagnóstico , Paralisia Bulbar Progressiva/etiologia , Paralisia Bulbar Progressiva/genética , Paralisia Bulbar Progressiva/patologia , Progressão da Doença , Humanos , Masculino , Fatores de TempoRESUMO
BACKGROUND: There is an ongoing debate about the concept of restricted phenotypes of amyotrophic lateral sclerosis (ALS), including progressive bulbar palsy (PBP). OBJECTIVE: The study was designed to investigate specific white matter alterations in diffusion tensor imaging (DTI) data from PBP patients using a hypothesis-guided tract-of-interest-based approach (compared with 'classical' ALS patients and controls) to identify in vivo microstructural changes according to the neuropathologically defined ALS-related corticoefferent tract pathology. METHODS: DTI-based white matter mapping was performed both by an unbiased voxel-wise statistical comparison and by a hypothesis-guided tract-wise analysis of fractional anisotropy (FA) maps according to the ALS-staging pattern for 23 PBP and 23 ALS patients vs 23 matched controls. RESULTS: The analysis of white matter integrity demonstrated regional FA reductions along the CST and also in frontal and prefrontal brain areas both in PBP patients and ALS patients with additional regional FA reduction in the pons of the PBP group. In the tract-specific analysis according to the neuropathological ALS-staging pattern, PBP and ALS patients showed identical significant alterations of ALS-related tract systems when compared with controls. CONCLUSIONS: The DTI study including the tract-of-interest-based analysis showed the same microstructural corticoefferent involvement patterns in PBP patients as in ALS, which supports the hypothesis that PBP is a phenotypical variant of ALS.
Assuntos
Esclerose Lateral Amiotrófica/diagnóstico por imagem , Esclerose Lateral Amiotrófica/patologia , Paralisia Bulbar Progressiva/diagnóstico por imagem , Paralisia Bulbar Progressiva/patologia , Imagem de Tensor de Difusão/métodos , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
INTRODUCTION: The autoimmune disease myasthenia gravis can mimic a variety of neurological disorders leading to a delay in diagnosis and treatment. In the older population, due to confusion with signs of the ageing process or comorbidities due to ageing, there are many underdiagnosed or misdiagnosed cases of myasthenia gravis. A majority of myasthenia gravis symptoms appear as ocular or motor symptoms and there are very few cases of bulbar symptoms. We present a case of myasthenia gravis with only hypophonia as a clinical feature. CASE PRESENTATION: We present a case of a 51-year-old Madheshi woman whose only complaint was sudden onset of hypophonia which later showed a fluctuating nature throughout the daytime. There was only reduced pitch in her voice with no nasal tone or dysarthria (so-called dysphonia), which created a diagnostic dilemma. Later, a neurological examination and other relevant investigations suggested myasthenia gravis. CONCLUSIONS: Sudden onset and focal neurological deficit can raise the diagnostic dilemma of myasthenia gravis. Relevant laboratory tests and clinical examinations are important to diagnose this disease properly. In resources-deprived nations like Nepal, where several investigations are expensive and access to them is difficult, it becomes very difficult to achieve a solid diagnosis for rare presentations of diseases.
Assuntos
Paralisia Bulbar Progressiva/patologia , Inibidores da Colinesterase/uso terapêutico , Disfonia/patologia , Miastenia Gravis/diagnóstico , Neostigmina/administração & dosagem , Brometo de Piridostigmina/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Paralisia Bulbar Progressiva/etiologia , Paralisia Bulbar Progressiva/terapia , Disfonia/etiologia , Feminino , Humanos , Pessoa de Meia-Idade , Miastenia Gravis/complicações , Miastenia Gravis/terapia , Exame Neurológico , Procedimentos Cirúrgicos Otorrinolaringológicos , Prednisolona/uso terapêutico , Recuperação de Função Fisiológica , Resultado do TratamentoRESUMO
OBJECTIVE: To describe the histopathologic features of a case of facial-onset sensory and motor neuronopathy (FOSMN). METHODS: We describe a postmortem examination performed on a 54-year-old man with FOSMN associated with personality change. RESULTS: Postmortem examination revealed TAR DNA-binding protein (TDP) 43 proteinopathy with widespread distribution. TDP43 pathology was seen in the neurons and glial cells and was most pronounced in the subthalamic nucleus followed by the spinal cord, including dorsal root ganglia, brainstem, and other deep cerebral nuclei. In the medial temporal lobe, neocortex and subcortical hemispheric white matter TDP43 pathologic inclusions were very rare. In contrast to TDP43 pathologies associated with typical amyotrophic lateral sclerosis (ALS) or frontotemporal dementia (FTD)-TDP, in this case, there were more frequent TDP43-positive oligodendroglial, coiled body-like cytoplasmic inclusions than neuronal inclusions. Neuronal cytoplasmic TDP43 inclusions with globular and skein-like morphology were seen in both anterior horn cells and dorsal root ganglia. No ß-amyloid, α-synuclein, or significant hyperphosphorylated tau pathology was seen. CONCLUSION: This case provides further evidence that FOSMN is a neurodegenerative disease characterized by TDP43 pathology. Despite minimal cortical TDP43 pathology, the clinical features of the behavioral variant of FTD in this patient suggest that FOSMN may fall within or overlap with the FTD-ALS spectrum.
Assuntos
Encéfalo/patologia , Paralisia Bulbar Progressiva/patologia , Proteínas de Ligação a DNA/metabolismo , Paralisia Facial/patologia , Gânglios Espinais/patologia , Medula Espinal/patologia , Proteinopatias TDP-43/patologia , Autopsia , Humanos , Corpos de Inclusão/patologia , Masculino , Pessoa de Meia-Idade , Oligodendroglia/patologia , Parestesia , Personalidade , Síndrome , Proteinopatias TDP-43/psicologiaRESUMO
This report describes the first case of a child with genetically confirmed Brown-Vialetto-van Laere syndrome in sub-Saharan Africa. This is an extremely rare clinical condition that presents with an auditory neuropathy, bulbar palsy, stridor, muscle weakness, and respiratory compromise that manifests with diaphragmatic and vocal cord paralysis. It is an autosomal recessive condition for which the genetic mutation has only recently been linked to a riboflavin transporter deficiency. We describe an 11-month-old affected male infant. He has required long-term respiratory support and a gastrostomy tube to support feeding. With high-dose riboflavin supplementation, he had limited recovery of motor function. His respiratory chain enzyme studies were abnormal suggestive of mitochondrial (mt) dysfunction. In the setting of limited resources, recognition of this striking clinical phenotype is important to highlight, specifically regarding the genetic implications of the condition and the potentially remedial response to vitamin supplementation.
Assuntos
Paralisia Bulbar Progressiva/terapia , Perda Auditiva Neurossensorial/terapia , Proteínas de Membrana Transportadoras/deficiência , Proteínas de Membrana Transportadoras/genética , África Subsaariana , Paralisia Bulbar Progressiva/genética , Paralisia Bulbar Progressiva/patologia , Paralisia Bulbar Progressiva/fisiopatologia , Suplementos Nutricionais , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/patologia , Perda Auditiva Neurossensorial/fisiopatologia , Humanos , Lactente , Masculino , Fenótipo , Riboflavina/administração & dosagemAssuntos
Paralisia Bulbar Progressiva/diagnóstico , Perda Auditiva Neurossensorial/diagnóstico , Hipotonia Muscular/diagnóstico , Debilidade Muscular/diagnóstico , Nistagmo Patológico/diagnóstico , Paralisia Bulbar Progressiva/genética , Paralisia Bulbar Progressiva/patologia , Paralisia Bulbar Progressiva/fisiopatologia , Pré-Escolar , Diagnóstico Diferencial , Progressão da Doença , Feminino , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/patologia , Perda Auditiva Neurossensorial/fisiopatologia , Humanos , Masculino , Hipotonia Muscular/genética , Hipotonia Muscular/patologia , Hipotonia Muscular/fisiopatologia , Debilidade Muscular/genética , Debilidade Muscular/patologia , Debilidade Muscular/fisiopatologia , Músculo Esquelético/patologia , Nistagmo Patológico/genética , Nistagmo Patológico/patologia , Nistagmo Patológico/fisiopatologia , IrmãosRESUMO
Brown-Vialetto-Van Laere syndrome represents a phenotypic spectrum of motor, sensory, and cranial nerve neuropathy, often with ataxia, optic atrophy and respiratory problems leading to ventilator-dependence. Loss-of-function mutations in two riboflavin transporter genes, SLC52A2 and SLC52A3, have recently been linked to Brown-Vialetto-Van Laere syndrome. However, the genetic frequency, neuropathology and downstream consequences of riboflavin transporter mutations are unclear. By screening a large cohort of 132 patients with early-onset severe sensory, motor and cranial nerve neuropathy we confirmed the strong genetic link between riboflavin transporter mutations and Brown-Vialetto-Van Laere syndrome, identifying 22 pathogenic mutations in SLC52A2 and SLC52A3, 14 of which were novel. Brain and spinal cord neuropathological examination of two cases with SLC52A3 mutations showed classical symmetrical brainstem lesions resembling pathology seen in mitochondrial disease, including severe neuronal loss in the lower cranial nerve nuclei, anterior horns and corresponding nerves, atrophy of the spinothalamic and spinocerebellar tracts and posterior column-medial lemniscus pathways. Mitochondrial dysfunction has previously been implicated in an array of neurodegenerative disorders. Since riboflavin metabolites are critical components of the mitochondrial electron transport chain, we hypothesized that reduced riboflavin transport would result in impaired mitochondrial activity, and confirmed this using in vitro and in vivo models. Electron transport chain complex I and complex II activity were decreased in SLC52A2 patient fibroblasts, while global knockdown of the single Drosophila melanogaster riboflavin transporter homologue revealed reduced levels of riboflavin, downstream metabolites, and electron transport chain complex I activity. This in turn led to abnormal mitochondrial membrane potential, respiratory chain activity and morphology. Riboflavin transporter knockdown in Drosophila also resulted in severely impaired locomotor activity and reduced lifespan, mirroring patient pathology, and these phenotypes could be partially rescued using a novel esterified derivative of riboflavin. Our findings expand the genetic, clinical and neuropathological features of Brown-Vialetto-Van Laere syndrome, implicate mitochondrial dysfunction as a downstream consequence of riboflavin transporter gene defects, and validate riboflavin esters as a potential therapeutic strategy.
Assuntos
Encéfalo/patologia , Paralisia Bulbar Progressiva/genética , Perda Auditiva Neurossensorial/genética , Proteínas de Membrana Transportadoras/genética , Receptores Acoplados a Proteínas G/genética , Medula Espinal/patologia , Adolescente , Animais , Atrofia , Encéfalo/ultraestrutura , Paralisia Bulbar Progressiva/metabolismo , Paralisia Bulbar Progressiva/patologia , Criança , Pré-Escolar , Citrato (si)-Sintase/metabolismo , Drosophila melanogaster , Complexo I de Transporte de Elétrons/metabolismo , Complexo II de Transporte de Elétrons/metabolismo , Complexo III da Cadeia de Transporte de Elétrons/metabolismo , Feminino , Fibroblastos/metabolismo , Técnicas de Silenciamento de Genes , Perda Auditiva Neurossensorial/metabolismo , Perda Auditiva Neurossensorial/patologia , Humanos , Técnicas In Vitro , Lactente , Locomoção/genética , Longevidade/genética , Masculino , Microscopia Eletrônica , Vias Neurais , Riboflavina , Tratos Espinocerebelares/patologia , Tratos Espinotalâmicos/patologia , Adulto JovemRESUMO
BACKGROUND: Progressive bulbar palsy (PBP) is a classic phenotype of bulbar onset amyotrophic lateral sclerosis (ALS) with more rapid progression and worse prognosis. However, as an often under-understood variant of ALS, isolated bulbar palsy (IBP) appears to progress more slowly and has a relatively benign prognosis. This study aimed to investigate the natural course and clinical features of IBP in Chinese population and to compare them with those of PBP. METHODS: The clinical data of patients with bulbar onset ALS were collected from January 2009 to December 2013. Revised ALS Functional Rating Scale (ALSFRS-R), forced vital capacity (FVC), and follow-up evaluation were performed, and the differences in basic clinical features, ALSFRS-R, FVC, and primary outcome measures between IBP and PBP were analyzed. The independent t-test, Chi-square test, Mann-Whitney U-test, and Kaplan-Meier analysis were used. RESULTS: Totally 154 patients with bulbar onset ALS were categorized into two groups, 33 with IBP and 121 with PBP. In the IBP group, the male to female ratio was 0.7 to 1.0, and the mean onset age was 58.5 years. The mean duration from the onset was 16.0 months, and the mean ALSFRS-R score was 43.4 at patients' first visit to our hospital. In 14 IBP patients performing FVC examination, the mean FVC value was 90.5% and there were only two cases with abnormal FVC. In 26 IBP patients completing follow-up, 15 (58%) suffered death or tracheotomy and the mean survival time was 40.5 months. Significant differences were noted in sex ratio, onset age, ALSFRS-R score, upper motor neuron limb signs, pure lower motor neuron (LMN) bulbar signs, FVC, and survival time between IBP and PBP. CONCLUSIONS: IBP was evidently different from PBP, which was characterized with the predominance of female, pure LMN bulbar signs, an older onset age, a relative preservation of respiratory function, and a better prognosis.
Assuntos
Esclerose Lateral Amiotrófica/patologia , Paralisia Bulbar Progressiva/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Esclerose Lateral Amiotrófica/mortalidade , Paralisia Bulbar Progressiva/mortalidade , China , Progressão da Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Capacidade Vital/fisiologia , Adulto JovemRESUMO
Riboflavin, also known as vitamin B2, is essential for cellular reduction-oxidation reactions, but is not readily synthesized by mammalian cells. It has been proposed that riboflavin absorption occurs through solute carrier family 52 members (SLC52) A1, A2 and A3. These transporters are also candidate genes for the childhood onset-neural degenerative syndrome Brown-Vialetto-Van Laere (BVVL). Although riboflavin is an essential nutrient, why mutations in its transporters result in a neural cell-specific disorder remains unclear. Here, we provide evidence that Slc52a3 is the mouse ortholog of SLC52A3 and show that Slc52a3 deficiency results in early embryonic lethality. Loss of mutant embryos was associated with both defects in placental formation and increased rates of apoptosis in embryonic cells. In contrast, Slc52a3 -/- embryonic stem cell lines could be readily established and differentiated into motor neurons, suggesting that this transporter is dispensable for neural differentiation and short-term maintenance. Consistent with this finding, examination of Slc52a3 gene products in adult tissues revealed expression in the testis and intestine but little or none in the brain and spinal cord. Our results suggest that BVVL patients with SCL52A3 mutations may be good candidates for riboflavin replacement therapy and suggests that either the mutations these individuals carry are hypomorphic, or that in these cases alternative transporters act during human embryogenesis to allow full-term development.
Assuntos
Paralisia Bulbar Progressiva/genética , Paralisia Bulbar Progressiva/patologia , Diferenciação Celular , Embrião de Mamíferos/citologia , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/patologia , Proteínas de Membrana Transportadoras/metabolismo , Neurônios Motores/citologia , Mutação/genética , Animais , Células Cultivadas , Embrião de Mamíferos/metabolismo , Feminino , Humanos , Masculino , Proteínas de Membrana Transportadoras/genética , Camundongos , Camundongos Knockout , Neurônios Motores/metabolismo , NeurogêneseRESUMO
Introducción. La parálisis supranuclear progresiva (PSP) es una enfermedad neurodegenerativa que se describió por primera vez en 1964 y en la que se produce una acumulación citoplasmática de proteína tau asociada a microtúbulos (MAPT) como consecuencia de su fosforilación anómala. Objetivo. El objetivo de este trabajo ha sido revisar los avances en el conocimiento de la PSP en los últimos años. Desarrollo. La PSP es la taupatía más frecuente, de aparición esporádica pero con algunos casos hereditarios por mutaciones en el gen MAPT. Las manifestaciones clínicas más características de esta enfermedad consisten en inestabilidad postural con caídas, deterioro cognitivo y parálisis supranuclear de la mirada. Se han descrito distintas variantes clínicas, entre las que destacan el Síndrome de Richardson, la PSP- Parkinsonismo, la acinesia pura con congelación de la marcha, la PSP-corticobasal y la afasia no fluente progresiva. Las diferentes características clínicas de estos subtipos vienen determinadas por la distinta densidad y localización de los agregados tau. El diagnóstico definitivo se realiza mediante confirmación anatomopatológica postmortem. Aunque se han producido algunos ensayos terapéuticos, en la actualidad no se dispone de tratamiento eficaz modificador de la enfermedad. Conclusiones. Los recientes avances han permitido un mejor conocimiento de la fisiopatología y genética de esta enfermedad. Existen distintas líneas de investigación abiertas en la actualidad siendo necesario que se profundice en estudios dirigidos a descubrir marcadores biológicos y agentes terapéuticos (AU)
Introduction. Progressive supranuclear palsy (PSP) is a neurodegenerative disease that was first reported in 1964 and which entails a cytoplasmic accumulation of microtubule-associated protein tau (MAPT) as a consequence of its abnormal phosphorylation. Aims. The objective of this research is to review the advances produced in the knowledge of PSP in recent years. Development. PSP is the most frequent tauopathy, which appears sporadically but with some hereditary cases due to mutations in the MAPT gene. The most characteristic clinical manifestations of this disease consist in postural instability with falls, cognitive impairment and supranuclear gaze palsy. Several different clinical variants have been described, including Richardsons syndrome, Parkinsonism-PSP, pure akinesia with freezing of gait, corticobasal-PSP and progressive non-fluent aphasia. The different clinical features of these subtypes are determined by the different density and location of the tau aggregates. The definitive diagnosis is reached by confirmation from post-mortem pathological analyses. Although some therapeutic trials have been conducted, today there is still no effective disease-modifying treatment available. Conclusions. Recent advances have made it possible to gain a better understanding of the pathophysiology and genetics of this disease. Different lines of research are currently open, but there is a need for further in-depth studies aimed at discovering biological markers and therapeutic agents (AU)
Assuntos
Humanos , Masculino , Feminino , Paralisia Bulbar Progressiva/genética , Fosforilação/genética , Afasia Primária Progressiva não Fluente/genética , Levodopa/administração & dosagem , Fotofobia/metabolismo , Blefarospasmo/diagnóstico , Tauopatias/genética , Paralisia Bulbar Progressiva/patologia , Fosforilação/fisiologia , Afasia Primária Progressiva não Fluente/metabolismo , Levodopa/genética , Fotofobia/complicações , Blefarospasmo/complicações , Tauopatias/metabolismoRESUMO
We evaluated the clinicopathological features of familial amyotrophic lateral sclerosis (ALS) with the fused in sarcoma (FUS) P525L mutation. Two sisters and their mother had a similar clinical course, which was characterized by the development of limb weakness at a young age with rapid disease progression. An elder sister, patient 1, progressed into a totally locked-in state requiring mechanical ventilation and died 26 years after the onset of the disease. In contrast, the younger sister, patient 2, died in the early stages of the disease. The patients had neuropathological findings that indicated a very active degeneration of motor neurons and multiple system degeneration, which led to marked brain and spinal cord atrophy in the long term clinical outcome. The multiple system degeneration included the frontal lobe, the basal ganglia and substantia nigra, cerebellum and related area. Compared with previously reported ALS cases, the severe degeneration of the frontal lobe and the striatum were the characteristic features in the patient 1 in this case study. The degeneration spread over multiple systems might be caused not only by the appearance of the FUS immunoreactive neuronal cytoplasmic inclusions but also by the degeneration of neuronal connections from the primary motor cortex and related areas.
Assuntos
Esclerose Lateral Amiotrófica/genética , Encéfalo/patologia , Mutação de Sentido Incorreto , Mutação Puntual , Proteína FUS de Ligação a RNA/genética , Medula Espinal/patologia , Adulto , Idade de Início , Esclerose Lateral Amiotrófica/classificação , Esclerose Lateral Amiotrófica/complicações , Esclerose Lateral Amiotrófica/patologia , Atrofia , Paralisia Bulbar Progressiva/etiologia , Paralisia Bulbar Progressiva/patologia , Corpo Estriado/patologia , Progressão da Doença , Feminino , Lobo Frontal/patologia , Gliose/etiologia , Gliose/patologia , Humanos , Corpos de Inclusão/ultraestrutura , Proteínas do Tecido Nervoso/análise , Quadriplegia/etiologia , Respiração Artificial , Insuficiência Respiratória/etiologia , Insuficiência Respiratória/terapia , Coloração e RotulagemRESUMO
Amyotrophic lateral sclerosis (ALS) is the most common adult-onset fatal motor neuron disease. In spinal motor neurons of patients with sporadic ALS, normal RNA editing of GluA2, a subunit of the L-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, is inefficient. Adenosine deaminase acting on RNA 2 (ADAR2) specifically mediates RNA editing at the glutamine/arginine (Q/R) site of GluA2 and motor neurons expressing Q/R site-unedited GluA2 undergo slow death in conditional ADAR2 knockout mice. Therefore, investigation into whether inefficient ADAR2-mediated GluA2 Q/R site-editing occurs universally in motor neurons of patients with ALS would provide insight into the pathogenesis of ALS. We analyzed the extents of GluA2 Q/R site-editing in an individual laser-captured motor neuron of 29 ALS patients compared with those of normal and disease control subjects. In addition, we analyzed the enzymatic activity of three members of the ADAR family (ADAR1, ADAR2 and ADAR3) in ALS motor neurons expressing unedited GluA2 mRNA and those expressing only edited GluA2 mRNA. Q/R site-unedited GluA2 mRNA was expressed in a significant proportion of motor neurons from all of the ALS cases examined. Conversely, motor neurons of the normal and disease control subjects expressed only edited GluA2 mRNA. ADAR2, but not ADAR1 or ADAR3, was significantly downregulated in all the motor neurons of ALS patients, more extensively in those expressing Q/R site-unedited GluA2 mRNA than those expressing only Q/R site-edited GluA2 mRNA. These results indicate that ADAR2 downregulation is a profound pathological change relevant to death of motor neurons in ALS.
Assuntos
Adenosina Desaminase/metabolismo , Esclerose Lateral Amiotrófica/patologia , Regulação para Baixo/fisiologia , Neurônios Motores/enzimologia , Proteínas de Ligação a RNA/metabolismo , Medula Espinal/patologia , Adenosina Desaminase/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Animais , Paralisia Bulbar Progressiva/patologia , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Ligação a RNA/genética , Receptores de AMPA/genética , Receptores de AMPA/metabolismo , Adulto JovemRESUMO
BACKGROUND: In order to clarify the laryngeal sensation of bulbar palsy patients, we studied the relationship between laryngopharyngeal sensation and brainstem lesion in patients with dysphagia caused by bulbar palsy. METHODS: Fifteen patients with lateral medullary infarction and dysphagia were included in this study. We performed laryngeal sensory test using the flexible laryngoscope and probes method previously developed by Yaguchi et al. The test sites included the right and left tip of the laryngeal surface of the epiglottis and bilateral arytenoid regions. Lesion sites were identified by magnetic resonance imaging and classified horizontally according to Kim's classification. We also used the anatomical atlas Cytoarchitecture of the Human Brain Stem to determine whether the lesions included the nucleus solitarius and nucleus ambiguus. RESULTS: Eight cases had normal sensation and 7 cases had decreased sensation of the affected side of the epiglottis and arytenoid region. The lesions of decreased laryngeal sensation group were classified horizontally as large type or dorsal type and included the nucleus solitarius. Decreased laryngeal sensation was significantly correlated with lesions that included the nucleus solitarius (Fisher exact test; P = .026). CONCLUSIONS: This study clarifies that patients with dysphagia caused by bulbar palsy may present with laryngeal sensory impairment of the affected side and laryngopharyngeal movement disorder. The important finding is that damage to both the nucleus solitarius and ambiguus cause dysphagia accompanied by decreased laryngeal sensation and that the lesions are relatively extensive and affect the middle level of the dorsal medulla.
Assuntos
Paralisia Bulbar Progressiva/complicações , Mucosa Laríngea/fisiopatologia , Síndrome Medular Lateral/complicações , Transtornos de Sensação/etiologia , Núcleo Solitário/fisiopatologia , Doenças do Nervo Vago/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Paralisia Bulbar Progressiva/patologia , Paralisia Bulbar Progressiva/fisiopatologia , Feminino , Humanos , Mucosa Laríngea/inervação , Síndrome Medular Lateral/patologia , Síndrome Medular Lateral/fisiopatologia , Masculino , Pessoa de Meia-Idade , Transtornos de Sensação/patologia , Transtornos de Sensação/fisiopatologia , Núcleo Solitário/patologia , Doenças do Nervo Vago/patologia , Doenças do Nervo Vago/fisiopatologiaRESUMO
To describe a rare association between rheumatoid arthritis (RA) and amyotrophic lateral sclerosis (ALS). Two new cases of patients with RA who developed amyotrophic lateral sclerosis (ALS), one receiving anti-TNFα agents, were reported. Only other five cases of this rare association have been previously described in literature. The simultaneous presence of the two diseases represents a difficult diagnostic challenge because RA may mimic some musculoskeletal symptoms of ALS. There is no evidence in favor of a common pathophysiologic mechanism, and thus the possibility of a fortuitous association must be raised. A neurotoxic side effect of various drugs for RA treatment could be considered. Casual or causal association remains a difficult choice. The possibility of a coincidental association must be raised but neurologic side effects of TNFα blockers lead to discussion.
Assuntos
Esclerose Lateral Amiotrófica/patologia , Artrite Reumatoide/patologia , Idoso , Esclerose Lateral Amiotrófica/complicações , Anticorpos Monoclonais/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/complicações , Artrite Reumatoide/tratamento farmacológico , Paralisia Bulbar Progressiva/etiologia , Paralisia Bulbar Progressiva/patologia , Feminino , Humanos , Infliximab , Fator de Necrose Tumoral alfa/antagonistas & inibidoresRESUMO
OBJECTIVE: To report outcomes for the first known cochlear implantation procedures in two patients with Brown-Vialetto-Van-Laere syndrome. PATIENTS: Two adult patients (a brother and sister) with post-lingual sensorineural deafness associated with Brown-Vialetto-Van-Laere syndrome. The female patient presented with a milder form of the syndrome. INTERVENTION: Cochlear implantation. MAIN OUTCOME MEASURE: Post-implantation speech discrimination scores. RESULTS: Auditory evoked potential testing suggested pathological changes in both patients' cochleae, auditory nerves, brainstem and (probably) central auditory pathways. In the male patient, despite implantation of the better ear, the Bamford-Kowal-Bench sentence score was zero at 21 months post-implantation. In the female patient, Bamford-Kowal-Bench sentence scores at six months post-implantation were 25 per cent in quiet and 3 per cent in noise. CONCLUSION: These poor clinical outcomes appear to be related to retrocochlear and probable central auditory pathway degeneration.
Assuntos
Implante Coclear , Potenciais Evocados Auditivos , Perda Auditiva Neurossensorial/cirurgia , Percepção da Fala , Adulto , Limiar Auditivo/fisiologia , Paralisia Bulbar Progressiva/patologia , Paralisia Bulbar Progressiva/fisiopatologia , Paralisia Bulbar Progressiva/cirurgia , Implantes Cocleares , Progressão da Doença , Feminino , Auxiliares de Audição , Perda Auditiva Neurossensorial/patologia , Perda Auditiva Neurossensorial/fisiopatologia , Humanos , Masculino , Irmãos , Testes de Discriminação da Fala , Resultado do TratamentoRESUMO
Brown-Vialetto-Van Laere syndrome (BVVLS) is a rare neurological disease characterized by sensorineural hearing loss and multiple cranial nerve palsies, usually involving the VIIth and IXth to XIIth cranial nerves. We describe the clinical and pathological features of a 33-year-old woman with BVVLS. The patient developed progressive exertional dyspnea, with clinical and laboratory findings of right-sided heart failure and pulmonary hypertension. She developed status epilepticus in the setting of cardiac deterioration and respiratory infection, and died of cardiogenic and septic shock. Autopsy disclosed bilateral neuronal loss and gliosis in the inferior colliculi, locus coeruleus and facial and vestibular nuclei. Cor pulmonale is a complication of hypoventilation-induced hypoxia and hypercapnia and had not yet been reported in BVVLS.