RESUMO
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder caused by a limited expansion of CGG repeats in the FMR1 gene. Degeneration of neurons in FXTAS cell models can be triggered by accumulation of polyglycine protein (FMRpolyG), a by-product of translation initiated upstream to the repeats. Specific aims of our work included testing if naphthyridine-based molecules could (i) block FMRpolyG synthesis by binding to CGG repeats in RNA, (ii) reverse pathological alterations in affected cells and (iii) preserve the content of FMRP, translated from the same FMR1 mRNA. We demonstrate that cyclic mismatch binding ligand CMBL4c binds to RNA structure formed by CGG repeats and attenuates translation of FMRpolyG and formation of nuclear inclusions in cells transfected with vectors expressing RNA with expanded CGG repeats. Moreover, our results indicate that CMBL4c delivery can reduce FMRpolyG-mediated cytotoxicity and apoptosis. Importantly, its therapeutic potential is also observed once the inclusions are already formed. We also show that CMBL4c-driven FMRpolyG loss is accompanied by partial FMRP reduction. As complete loss of FMRP induces FXS in children, future experiments should aim at evaluation of CMBL4c therapeutic intervention in differentiated tissues, in which FMRpolyG translation inhibition might outweigh adverse effects related to FMRP depletion.
Assuntos
Ataxia/genética , Proteína do X Frágil da Deficiência Intelectual/genética , Síndrome do Cromossomo X Frágil/genética , Naftiridinas/farmacologia , Tremor/genética , Expansão das Repetições de Trinucleotídeos/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Ataxia/tratamento farmacológico , Ataxia/patologia , Proliferação de Células/efeitos dos fármacos , Proteína do X Frágil da Deficiência Intelectual/antagonistas & inibidores , Síndrome do Cromossomo X Frágil/tratamento farmacológico , Síndrome do Cromossomo X Frágil/patologia , Células HeLa , Humanos , Ligantes , Neurônios/efeitos dos fármacos , Neurônios/patologia , Peptídeos/genética , Biossíntese de Proteínas/efeitos dos fármacos , Ressonância de Plasmônio de Superfície , Tremor/tratamento farmacológico , Tremor/patologia , Expansão das Repetições de Trinucleotídeos/genética , Repetições de Trinucleotídeos/efeitos dos fármacos , Repetições de Trinucleotídeos/genéticaRESUMO
Children with neuroblastoma (NB) and opsoclonus-myoclonus-ataxia syndrome (OMAS) have a favorable oncologic outcome and overall survival. In contrast, despite intensive multidrug immunomodulation, the neurologic outcome is complicated by the relapsing nature of the neurologic symptoms and long-term neurobehavioral sequelae. Being associated with low-risk NB, there exists an ambiguity in the current literature regarding the administration of chemotherapy in these children. We reviewed our archives for children with NB-OMAS over a 22-year (January 1996 to January 2018) period. Eighteen children (10 female) with a median age at diagnosis of 23 months had NB-OMAS and were included. They had stage 1 (9/18; 50%), 2 (1/18; 5.5%), 3 (7/18; 39%), and 4 (1/18; 5.5%) disease according to the International Neuroblastoma Staging System. Multimodality therapy included surgery (16/18; 89%), chemotherapy (11/18; 61%), and immunomodulatory therapy (10/18; 55%). Complete oncologic remission was achieved in all children. Relapse of OMAS and presence of neurologic sequelae were observed in 1 (5.5%) and 5 (28%) cases, respectively. Presence of neurologic sequelae was significantly associated with low-tumor stage (P=0.036) and treatment without chemotherapy (P=0.003). Chemotherapy administration was the only variable significantly predicting a favorable neurologic outcome (95% confidence interval: 0.26-1.40, P=0.01). To conclude, our study including a limited cohort of patients highlights a favorable neurologic outcome associated with chemotherapy administration in children with NB-OMAS. However, further studies with larger sample size need to be conducted before drawing any definite conclusions.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ataxia/tratamento farmacológico , Neuroblastoma/tratamento farmacológico , Síndrome de Opsoclonia-Mioclonia/tratamento farmacológico , Centros de Atenção Terciária/estatística & dados numéricos , Adolescente , Adulto , Ataxia/complicações , Ataxia/patologia , Criança , Terapia Combinada , Gerenciamento Clínico , Progressão da Doença , Feminino , Seguimentos , Humanos , Masculino , Neuroblastoma/complicações , Neuroblastoma/patologia , Síndrome de Opsoclonia-Mioclonia/complicações , Síndrome de Opsoclonia-Mioclonia/patologia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Adulto JovemRESUMO
An 80-year-old man was diagnosed with prostate cancer in April 2014 and underwent anticancer treatment. His serum prostate-specific antigen (PSA) level was abruptly increased on December 26, 2014. He was admitted to the neurological department of our hospital on January 14, 2015, because of the appearance of staggering gait and diplopia. Neurological examination revealed marked opsoclonus, limb ataxia and ataxic gait. The patient was diagnosed with paraneoplastic opsoclonus and ataxia caused by prostate cancer relapse. Steroid pulse therapy was initiated and his symptoms, including opsoclonus and ataxia, markedly improved. Although most cases of paraneoplastic opsoclonus precede the discovery of cancer, our case developed symptoms simultaneously with relapse and acute progression of prostate cancer. Paraneoplastic opsoclonus with prostate cancer is rare. Additionally, our case showed excellent response of opsoclonus to steroid therapy without treatment of the underlying disease. (Received June 1, 2020; Accepted September 18, 2020; Published February 1, 2021).
Assuntos
Ataxia Cerebelar , Transtornos da Motilidade Ocular , Neoplasias da Próstata , Idoso de 80 Anos ou mais , Ataxia/tratamento farmacológico , Ataxia/etiologia , Humanos , Masculino , Recidiva Local de Neoplasia , Neoplasias da Próstata/complicações , Neoplasias da Próstata/tratamento farmacológicoRESUMO
Mutations affecting mitochondrial coenzyme Q (CoQ) biosynthesis lead to kidney failure due to selective loss of podocytes, essential cells of the kidney filter. Curiously, neighboring tubular epithelial cells are spared early in disease despite higher mitochondrial content. We sought to illuminate noncanonical, cell-specific roles for CoQ, independently of the electron transport chain (ETC). Here, we demonstrate that CoQ depletion caused by Pdss2 enzyme deficiency in podocytes results in perturbations in polyunsaturated fatty acid (PUFA) metabolism and the Braf/Mapk pathway rather than ETC dysfunction. Single-nucleus RNA-Seq from kidneys of Pdss2kd/kd mice with nephrotic syndrome and global CoQ deficiency identified a podocyte-specific perturbation of the Braf/Mapk pathway. Treatment with GDC-0879, a Braf/Mapk-targeting compound, ameliorated kidney disease in Pdss2kd/kd mice. Mechanistic studies in Pdss2-depleted podocytes revealed a previously unknown perturbation in PUFA metabolism that was confirmed in vivo. Gpx4, an enzyme that protects against PUFA-mediated lipid peroxidation, was elevated in disease and restored after GDC-0879 treatment. We demonstrate broader human disease relevance by uncovering patterns of GPX4 and Braf/Mapk pathway gene expression in tissue from patients with kidney diseases. Our studies reveal ETC-independent roles for CoQ in podocytes and point to Braf/Mapk as a candidate pathway for the treatment of kidney diseases.
Assuntos
Ataxia/metabolismo , Indenos/farmacologia , Nefropatias/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Doenças Mitocondriais/metabolismo , Debilidade Muscular/metabolismo , Podócitos/metabolismo , Proteínas Proto-Oncogênicas B-raf/metabolismo , Pirazóis/farmacologia , Ubiquinona/deficiência , Alquil e Aril Transferases/genética , Alquil e Aril Transferases/metabolismo , Animais , Ataxia/tratamento farmacológico , Ataxia/genética , Ataxia/patologia , Sistemas de Liberação de Medicamentos , Células HEK293 , Humanos , Nefropatias/tratamento farmacológico , Nefropatias/genética , Nefropatias/patologia , Peroxidação de Lipídeos/genética , Sistema de Sinalização das MAP Quinases/genética , Camundongos , Doenças Mitocondriais/tratamento farmacológico , Doenças Mitocondriais/genética , Doenças Mitocondriais/patologia , Debilidade Muscular/tratamento farmacológico , Debilidade Muscular/genética , Debilidade Muscular/patologia , Podócitos/patologia , Proteínas Proto-Oncogênicas B-raf/genética , RNA-Seq , Ubiquinona/genética , Ubiquinona/metabolismoRESUMO
Opsoclonus-myoclonus-ataxia syndrome is a heterogeneous constellation of symptoms ranging from full combination of these three neurological findings to varying degrees of isolated individual sign. Since the emergence of coronavirus disease 2019 (COVID-19), neurological symptoms, syndromes, and complications associated with this multi-organ viral infection have been reported and the various aspects of neurological involvement are increasingly uncovered. As a neuro-inflammatory disorder, one would expect to observe opsoclonus-myoclonus syndrome after a prevalent viral infection in a pandemic scale, as it has been the case for many other neuro-inflammatory syndromes. We report seven cases of opsoclonus-myoclonus syndrome presumably parainfectious in nature and discuss their phenomenology, their possible pathophysiological relationship to COVID-19, and diagnostic and treatment strategy in each case. Finally, we review the relevant data in the literature regarding the opsoclonus-myoclonus syndrome and possible similar cases associated with COVID-19 and its diagnostic importance for clinicians in various fields of medicine encountering COVID-19 patients and its complications.
Assuntos
Ataxia/fisiopatologia , COVID-19/fisiopatologia , Tosse/fisiopatologia , Febre/fisiopatologia , Mialgia/fisiopatologia , Síndrome de Opsoclonia-Mioclonia/fisiopatologia , SARS-CoV-2/patogenicidade , Adulto , Anticonvulsivantes/uso terapêutico , Ataxia/diagnóstico por imagem , Ataxia/tratamento farmacológico , Ataxia/etiologia , Azitromicina/uso terapêutico , COVID-19/complicações , COVID-19/diagnóstico por imagem , Clonazepam/uso terapêutico , Tosse/diagnóstico por imagem , Tosse/tratamento farmacológico , Tosse/etiologia , Dispneia/diagnóstico por imagem , Dispneia/tratamento farmacológico , Dispneia/etiologia , Dispneia/fisiopatologia , Feminino , Febre/diagnóstico por imagem , Febre/tratamento farmacológico , Febre/etiologia , Humanos , Hidroxicloroquina/uso terapêutico , Levetiracetam/uso terapêutico , Masculino , Pessoa de Meia-Idade , Mialgia/diagnóstico por imagem , Mialgia/tratamento farmacológico , Mialgia/etiologia , Síndrome de Opsoclonia-Mioclonia/diagnóstico por imagem , Síndrome de Opsoclonia-Mioclonia/tratamento farmacológico , Síndrome de Opsoclonia-Mioclonia/etiologia , Oseltamivir/uso terapêutico , SARS-CoV-2/efeitos dos fármacos , Ácido Valproico/uso terapêutico , Tratamento Farmacológico da COVID-19RESUMO
Erdheim-Chester disease (ECD) is a rare disorder characterized by accumulation of non-Langerhans cell histiocytes in multiple organs. The clinical manifestations are protean and vary from asymptomatic focal disease to potentially fatal multisystem disorder. The commonest presentation is symmetric osterosclerotic lesions of lower extremity long bones; other organs, including cardiovascular, nervous, and endocrine system may be affected. Central nervous system involvement can occur in up to 50% cases and is associated with poor prognosis. The disease pathogenesis involves organ involvement secondary to histiocytic infiltration and systemic inflammation driven by Th1 cytokine activation. The recent discovery of activating mutations in proto-oncogene B-rapidly accelerated fibrosarcoma (BRAF) V600E and other genes involved in mitogen-activated protein kinase (MAPK) pathways has led to redefinition of ECD as a myeloid neoplastic disorder. The diagnosis requires histochemical and molecular analysis of histiocytes in tissue biopsies in patients with compatible clinical and imaging features. The treatment options include interferon-alpha, anakinra, and immunosuppressive therapies. Better understanding of disease pathogenesis has led to development of novel targeted and effective therapies including BRAF and MEK inhibitors. The rarity of the disease and variable clinical features and course often results in diagnostic errors and delays. Rare primary neurological presentation can occur mimicking CNS inflammatory, neoplastic, or demyelinating disorders. We report an unusual case of ECD presenting with progressive encephalopathy and ataxia along with multifocal brainstem and cerebellar lesions. A comprehensive review of clinical and neuroimaging features and immunohistochemical and molecular characteristic of ECD are presented along with review of neuroimaging findings in two previously reported cases.
Assuntos
Ataxia/diagnóstico por imagem , Encefalopatias/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Doença de Erdheim-Chester/diagnóstico por imagem , Adulto , Ataxia/tratamento farmacológico , Ataxia/etiologia , Encefalopatias/tratamento farmacológico , Encefalopatias/etiologia , Doença de Erdheim-Chester/complicações , Doença de Erdheim-Chester/tratamento farmacológico , Feminino , Humanos , Interferon-alfa/uso terapêutico , Imageamento por Ressonância Magnética , Neuroimagem , Inibidores de Proteínas Quinases/uso terapêutico , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/uso terapêuticoRESUMO
We present the case of a 29-year-old south Asian man born of consanguineous marriage, presenting with ataxia, peripheral neuropathy and cognitive impairment. An initial diagnosis of coeliac disease was thought to explain the pertinent clinical features; however, further investigation led to an additional diagnosis of the rare yet treatable autosomal recessive condition, cerebrotendinous xanthomatosis. With both conditions employing highly diverse and overlapping clinical phenotypes, this contributed to a delay in diagnosis. Our report highlights the importance of paying close attention to both the clinical phenotype and family history.
Assuntos
Ataxia/genética , Doença Celíaca/diagnóstico , Disfunção Cognitiva/genética , Doenças do Sistema Nervoso Periférico/genética , Xantomatose Cerebrotendinosa/diagnóstico , Administração Oral , Adulto , Ataxia/tratamento farmacológico , Doença Celíaca/complicações , Doença Celíaca/dietoterapia , Ácido Quenodesoxicólico/administração & dosagem , Colestanotriol 26-Mono-Oxigenase/genética , Consanguinidade , Análise Mutacional de DNA , Diagnóstico Tardio , Dieta Livre de Glúten , Humanos , Masculino , Anamnese , Mutação de Sentido Incorreto , Linhagem , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Resultado do Tratamento , Xantomatose Cerebrotendinosa/complicações , Xantomatose Cerebrotendinosa/tratamento farmacológico , Xantomatose Cerebrotendinosa/genéticaRESUMO
CANOMAD (chronic ataxic neuropathy, ophthalmoplegia, immunoglobulin M [IgM] paraprotein, cold agglutinins, and disialosyl antibodies) is a rare syndrome characterized by chronic neuropathy with sensory ataxia, ocular, and/or bulbar motor weakness in the presence of a monoclonal IgM reacting against gangliosides containing disialosyl epitopes. Data regarding associated hematologic malignancies and effective therapies in CANOMAD are scarce. We conducted a French multicenter retrospective study that included 45 patients with serum IgM antibodies reacting against disialosyl epitopes in the context of evocating neurologic symptoms. The main clinical features were sensitive symptoms (ataxia, paresthesia, hypoesthesia; n = 45, 100%), motor weakness (n = 18, 40%), ophthalmoplegia (n = 20, 45%), and bulbar symptoms (n = 6, 13%). Forty-five percent of the cohort had moderate to severe disability (modified Rankin score, 3-5). Cold agglutinins were identified in 15 (34%) patients. Electrophysiologic studies showed a demyelinating or axonal pattern in, respectively, 60% and 27% of cases. All patients had serum monoclonal IgM gammopathy (median, 2.6 g/L; range, 0.1-40 g/L). Overt hematologic malignancies were diagnosed in 16 patients (36%), with the most frequent being Waldenström macroglobulinemia (n = 9, 20%). Forty-one patients (91%) required treatment of CANOMAD. Intravenous immunoglobulins (IVIg) and rituximab-based regimens were the most effective therapies with, respectively, 53% and 52% of partial or better clinical responses. Corticosteroids and immunosuppressive drugs were largely ineffective. Although more studies are warranted to better define the optimal therapeutic sequence, IVIg should be proposed as the standard of care for first-line treatment and rituximab-based regimens for second-line treatment. These compiled data argue for CANOMAD to be included in neurologic monoclonal gammopathy of clinical significance.
Assuntos
Linfócitos B/efeitos dos fármacos , Paraproteinemias/tratamento farmacológico , Rituximab/uso terapêutico , Corticosteroides/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ataxia/tratamento farmacológico , Ataxia/etiologia , Autoanticorpos/sangue , Autoanticorpos/imunologia , Linfócitos B/patologia , Crioglobulinas/análise , Feminino , França/epidemiologia , Neoplasias Hematológicas/sangue , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/imunologia , Humanos , Imunoglobulina M/sangue , Imunoglobulina M/imunologia , Imunoglobulinas Intravenosas/uso terapêutico , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Oftalmoplegia/tratamento farmacológico , Oftalmoplegia/etiologia , Paraproteinemias/sangue , Paraproteinemias/imunologia , Paraproteinemias/terapia , Parestesia/tratamento farmacológico , Parestesia/etiologia , Estudos Retrospectivos , Síndrome , Macroglobulinemia de Waldenstrom/sangue , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Macroglobulinemia de Waldenstrom/imunologiaRESUMO
Immune-mediated ataxias account for a substantial number of sporadic otherwise idiopathic ataxias. Despite some well-characterised entities such as paraneoplastic cerebellar degeneration where diagnostic markers exist, the majority of immune ataxias remained undiagnosed and untreated. We present here our experience in the treatment of suspected primary autoimmune cerebellar ataxia (PACA) using mycophenolate. All patients reported attend the Sheffield Ataxia Centre on a regular basis and had undergone extensive investigations, including genetic testing using next-generation sequencing, with other causes of ataxia excluded. The diagnosis of PACA was strongly suspected based on investigations, pattern of disease progression, and cerebellar involvement. Patients were treated with mycophenolate and monitored using MR spectroscopy of the cerebellar vermis. Thirty patients with PACA are reported here. Of these, 22 received mycophenolate (group 1). The remaining 8 were not on treatment (group 2-control group). Out of the 22 treated patients, 4 underwent serial MR spectroscopy prior to starting treatment and thus were used as controls making the total number of patients in the control group 12. The mean change of the MRS within the vermis (NAA/Cr area ratio) in the treatment group was + 0.144 ± 0.09 (improved) and in the untreated group - 0.155 ± 0.06 (deteriorated). The difference was significant. We also demonstrated a strong correlation between the spectroscopy and the SARA score. We have demonstrated the effectiveness of mycophenolate in the treatment of PACA. The results suggest that immune-mediated ataxias are potentially treatable, and that there is a need for early diagnosis to prevent permanent neurological deficit. The recently published diagnostic criteria for PACA would hopefully aid the diagnosis and treatment of this entity.
Assuntos
Ataxia/tratamento farmacológico , Ataxia Cerebelar/tratamento farmacológico , Cerebelo/efeitos dos fármacos , Ácido Micofenólico/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Ataxia/complicações , Ataxia Cerebelar/genética , Progressão da Doença , Feminino , Humanos , Espectroscopia de Ressonância Magnética/efeitos adversos , Masculino , Pessoa de Meia-Idade , Ataxias Espinocerebelares/diagnóstico , Ataxias Espinocerebelares/tratamento farmacológico , Adulto JovemAssuntos
Ataxia , Transtornos Neurológicos da Marcha , Imunoglobulinas Intravenosas/farmacologia , Fatores Imunológicos/farmacologia , Neoplasias do Mediastino/diagnóstico , Neoplasias Embrionárias de Células Germinativas/diagnóstico , Polineuropatia Paraneoplásica , Transtornos de Sensação , Adulto , Ataxia/diagnóstico , Ataxia/tratamento farmacológico , Ataxia/etiologia , Transtornos Neurológicos da Marcha/diagnóstico , Transtornos Neurológicos da Marcha/tratamento farmacológico , Transtornos Neurológicos da Marcha/etiologia , Humanos , Imunoglobulinas Intravenosas/administração & dosagem , Fatores Imunológicos/administração & dosagem , Masculino , Neoplasias do Mediastino/complicações , Neoplasias Embrionárias de Células Germinativas/complicações , Polineuropatia Paraneoplásica/diagnóstico , Polineuropatia Paraneoplásica/tratamento farmacológico , Polineuropatia Paraneoplásica/etiologia , Transtornos de Sensação/diagnóstico , Transtornos de Sensação/tratamento farmacológico , Transtornos de Sensação/etiologiaRESUMO
BACKGROUND: To describe a patient with sleep alleviated episodic ataxia type 2 with a novel CACNA1A pathogenic variant and provide a possible link to sleep responsive migraine. CASE PRESENTATION: A 26-year-old woman with recurrent attacks of dizziness, nausea, vomiting, ataxia and dysarthria presented for a possible diagnosis of vestibular migraine. Unique to her attacks was if she could fall asleep for as little as 15 min the spells would subside. If however she remained awake the attacks would continue unabated. A presumed diagnosis of episodic ataxia type 2 was made and she became attack free on acetazolamide without recurrence. Genetic testing demonstrated a novel pathogenic variant in CACNA1A on chromosome 19. This pathogenic variant has not been previously reported in the literature and is suggested to truncate the CACNA1A polypeptide by introducing a premature stop codon. CONCLUSION: A case of episodic ataxia type 2 with a novel pathogenic variant in CACNA1A is described. Interestingly, the patient's symptoms would completely alleviate with sleep which suggests a sleep modulated channelopathy. The mechanisms by which sleep could potentially alter this pathogenic variant are hypothesized. A potential link to sleep alleviated migraine is suggested. Further study of this novel pathogenic variant may help us understand not only how sleep can modulate episodic ataxia type 2, but also migraine.
Assuntos
Ataxia/genética , Canais de Cálcio/genética , Sono , Acetazolamida/uso terapêutico , Adulto , Ataxia/complicações , Ataxia/tratamento farmacológico , Inibidores da Anidrase Carbônica/uso terapêutico , Canalopatias/genética , Códon sem Sentido , Feminino , Humanos , Transtornos de Enxaqueca/genética , LinhagemRESUMO
We herein report a 68-year-old man with neurologic immune-related adverse events (irAEs) who exhibited nivolumab-induced steroid-responsive progressive ataxia, tremor, and anti-thyroid antibodies. His symptoms matched abnormalities on N-isopropyl-p-(123I)-iodoamphetamine single-photon emission computed tomography (SPECT) and dopamine transporter SPECT. Based on these clinical findings, we diagnosed the patient with a condition similar to the cerebellar type of Hashimoto's encephalopathy with nivolumab-induced anti-thyroid antibodies. Neurologic irAEs can be difficult to diagnose due to their varied clinical courses and lack of specific examinations. Therefore, a comprehensive approach, including assessments of autoantibodies and functional imaging, might be important for the diagnosis of neurologic irAEs.
Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Ataxia/induzido quimicamente , Ataxia Cerebelar/induzido quimicamente , Encefalite/diagnóstico , Doença de Hashimoto/diagnóstico , Nivolumabe/efeitos adversos , Idoso , Ataxia/tratamento farmacológico , Autoanticorpos/análise , Encéfalo/diagnóstico por imagem , Diagnóstico Diferencial , Glucocorticoides/uso terapêutico , Humanos , Masculino , Prednisolona/uso terapêutico , Tomografia Computadorizada de Emissão de Fóton Único , Tremor/induzido quimicamente , Tremor/tratamento farmacológicoRESUMO
The case of a 17-year-old man with Hodgkin's lymphoma who presented with paraneoplastic sensory neuropathy is presented. The patient visited our hospital because of acute progression of dysesthesiae in the bilateral face and extremities. He also developed an ataxic gait due to decreased deep sensation. Post-contrast T1-weighted MRI showed enhancement of both trigeminal nerves and the cauda equina. Cerebrospinal fluid examination was unremarkable. Intravenous immunoglobulin therapy and subsequent steroid pulse therapy did not improve his symptoms. Laboratory data showed an elevated serum soluble interleukin-2 receptor level. His chest X-ray and CT showed enlarged lymph nodes in the mediastinum, and the histopathologic examination of a lymph node biopsy specimen showed classical Hodgkin's lymphoma. He was treated with chemotherapy. His symptoms of neuropathy improved promptly while the lymphoma was being successfully treated, and he was able to walk with a cane. The present case was characterized by paraneoplastic sensory neuropathy as the initial clinical feature in association with Hodgkin's lymphoma. It is necessary to consider a paraneoplastic neurological syndrome even in a young patient with acute/subacute sensory neuropathy. Paraneoplastic sensory neuropathy associated with Hodgkin's lymphoma could be expected to improve with oncotherapy, and examination of the malignancy and early treatment are important.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doença de Hodgkin/complicações , Doença de Hodgkin/tratamento farmacológico , Neoplasias do Mediastino/complicações , Neoplasias do Mediastino/tratamento farmacológico , Polineuropatia Paraneoplásica/tratamento farmacológico , Polineuropatia Paraneoplásica/etiologia , Parestesia/tratamento farmacológico , Parestesia/etiologia , Doença Aguda , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Ataxia/tratamento farmacológico , Ataxia/etiologia , Bleomicina/administração & dosagem , Dacarbazina/administração & dosagem , Doxorrubicina/administração & dosagem , Doença de Hodgkin/diagnóstico , Humanos , Imageamento por Ressonância Magnética , Masculino , Neoplasias do Mediastino/diagnóstico , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Vimblastina/administração & dosagemRESUMO
BACKGROUND: Acute ophthalmoparesis without ataxia was designated as 'atypical Miller Fisher syndrome' as it presents with progressive, relatively symmetrical ophthalmoplegia, but without ataxia nor limb weakness, in the presence of anti-GQ1b antibody. Idiopathic intracranial hypertension is characterized by signs of raised intracranial pressure occurring in the absence of cerebral pathology, with normal composition of cerebrospinal fluid and a raised opening pressure of more than 20 cmH2O during lumbar puncture. We aim to report a rare case of acute ophthalmoplegia with co-occurrence of raised intracranial pressure. CASE DESCRIPTION: A 28-year-old gentleman with body mass index of 34.3 was referred to us for management of double vision of 2 weeks duration. His symptom started after a brief episode of upper respiratory tract infection. His best corrected visual acuity was 6/6 OU. He had bilateral sixth nerve palsy worse on the left eye and bilateral hypometric saccade. His deep tendon reflexes were found to be hyporeflexic in all four limbs. No sensory or motor power deficit was detected, and his gait was normal. Plantar reflexes were downwards bilaterally and cerebellar examination was normal. Both optic discs developed hyperaemia and swelling. Magnetic resonance imaging of brain was normal and lumbar puncture revealed an opening pressure of 50 cmH2O. Anti-GQ1b IgG and anti-GT1a IgG antibody were tested positive. CONCLUSION: Acute ophthalmoparesis without ataxia can present with co-occurrence of raised intracranial pressure. It is important to have a full fundoscopic assessment to look for papilloedema in patients presenting with Miller Fisher syndrome or acute ophthalmoparesis without ataxia.
Assuntos
Oftalmoplegia/complicações , Pseudotumor Cerebral/complicações , Doenças do Nervo Abducente/diagnóstico , Acetazolamida/uso terapêutico , Doença Aguda , Administração Oral , Adulto , Ataxia/complicações , Ataxia/diagnóstico , Ataxia/tratamento farmacológico , Ataxia/imunologia , Autoanticorpos/sangue , Diplopia/diagnóstico , Diuréticos/uso terapêutico , Gangliosídeos/imunologia , Humanos , Imunoglobulina G/sangue , Imageamento por Ressonância Magnética , Masculino , Oftalmoplegia/diagnóstico , Oftalmoplegia/tratamento farmacológico , Oftalmoplegia/imunologia , Oftalmoscopia , Pseudotumor Cerebral/diagnóstico , Pseudotumor Cerebral/tratamento farmacológico , Pseudotumor Cerebral/imunologiaRESUMO
The identification of an increasing number of immune mediated ataxias suggests that the cerebellum is often a target organ for autoimmune insults. The diagnosis of immune mediated ataxias is challenging as there is significant clinical overlap between immune mediated and other forms of ataxia. Furthermore the classification of immune mediated ataxias requires further clarification particularly for those ataxias where no specific antigenic trigger and associated antibodies have been identified. Recognition of immune mediated ataxias remains imperative as therapeutic interventions can be effective, although given the relative rarity of this entity, large-scale treatment trials may not be feasible. This review will discuss advances in therapies for immune mediated ataxias based on what is currently available in the literature.
Assuntos
Anticorpos/uso terapêutico , Ataxia/tratamento farmacológico , Ataxia Cerebelar/tratamento farmacológico , Ataxia/imunologia , Ataxia Cerebelar/diagnóstico , Ataxia Cerebelar/imunologia , Doenças Cerebelares/tratamento farmacológico , Doenças Cerebelares/imunologia , Cerebelo/efeitos dos fármacos , Cerebelo/imunologia , Humanos , Reconhecimento Psicológico/efeitos dos fármacosRESUMO
Background: Cerebrotendinous xanthomatosis is a rare autosomal recessive neurometabolic disorder characterized by chronic diarrhea, tendon xanthomas, juvenile cataracts, and neurological symptoms. Case Report: An adult patient with cerebrotendinous xanthomatosis exhibited ataxia and palatal tremor in the absence of tendon xanthomas and cataracts. Discussion: The importance of this case resides on the fact that cerebrotendinous xanthomatosis should be considered as a possible etiology of the syndrome of progressive ataxia with palatal tremor, even in the absence of tendon xanthomas and cataracts. Early diagnosis is critical to the institution of specific treatment with chenodeoxycholic acid.
Assuntos
Ataxia/diagnóstico , Ataxia/etiologia , Tremor/diagnóstico , Tremor/etiologia , Xantomatose Cerebrotendinosa/complicações , Xantomatose Cerebrotendinosa/diagnóstico , Adulto , Ataxia/tratamento farmacológico , Diagnóstico Diferencial , Feminino , Humanos , Tremor/tratamento farmacológico , Xantomatose Cerebrotendinosa/tratamento farmacológicoRESUMO
Endosomes have emerged as a central hub and pathogenic driver of Alzheimer's disease (AD). The earliest brain cytopathology in neurodegeneration, occurring decades before amyloid plaques and cognitive decline, is an expansion in the size and number of endosomal compartments. The strongest genetic risk factor for sporadic AD is the ε4 allele of Apolipoprotein E (ApoE4). Previous studies have shown that ApoE4 potentiates presymptomatic endosomal dysfunction and defective endocytic clearance of amyloid beta (Aß), although how these two pathways are linked at a cellular and mechanistic level has been unclear. Here, we show that aberrant endosomal acidification in ApoE4 astrocytes traps the low-density lipoprotein receptor-related protein (LRP1) within intracellular compartments, leading to loss of surface expression and Aß clearance. Pathological endosome acidification is caused by ε4 risk allele-selective down-regulation of the Na+/H+ exchanger isoform NHE6, which functions as a critical leak pathway for endosomal protons. In vivo, the NHE6 knockout (NHE6KO) mouse model showed elevated Aß in the brain, consistent with a causal effect. Increased nuclear translocation of histone deacetylase 4 (HDAC4) in ApoE4 astrocytes, compared with the nonpathogenic ApoE3 allele, suggested a mechanistic basis for transcriptional down-regulation of NHE6. HDAC inhibitors that restored NHE6 expression normalized ApoE4-specific defects in endosomal pH, LRP1 trafficking, and amyloid clearance. Thus, NHE6 is a downstream effector of ApoE4 and emerges as a promising therapeutic target in AD. These observations have prognostic implications for patients who have Christianson syndrome with loss of function mutations in NHE6 and exhibit prominent glial pathology and progressive hallmarks of neurodegeneration.
Assuntos
Peptídeos beta-Amiloides/metabolismo , Apolipoproteína E4/metabolismo , Astrócitos/metabolismo , Endossomos/metabolismo , Epigênese Genética , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/genética , Animais , Apolipoproteína E4/genética , Astrócitos/patologia , Ataxia/tratamento farmacológico , Ataxia/genética , Ataxia/metabolismo , Ataxia/patologia , Endossomos/genética , Endossomos/patologia , Epilepsia/tratamento farmacológico , Epilepsia/genética , Epilepsia/metabolismo , Epilepsia/patologia , Doenças Genéticas Ligadas ao Cromossomo X/tratamento farmacológico , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/metabolismo , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Deficiência Intelectual/tratamento farmacológico , Deficiência Intelectual/genética , Deficiência Intelectual/metabolismo , Deficiência Intelectual/patologia , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade , Camundongos , Camundongos Knockout , Microcefalia/tratamento farmacológico , Microcefalia/genética , Microcefalia/metabolismo , Microcefalia/patologia , Transtornos da Motilidade Ocular/tratamento farmacológico , Transtornos da Motilidade Ocular/genética , Transtornos da Motilidade Ocular/metabolismo , Transtornos da Motilidade Ocular/patologia , Receptores de LDL/genética , Receptores de LDL/metabolismo , Trocadores de Sódio-Hidrogênio/genética , Trocadores de Sódio-Hidrogênio/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismoRESUMO
INTRODUCTION: Ipilimumab and nivolumab are immune-checkpoint inhibitors commonly used for melanoma. The combination is being investigated for its efficacy against several types of cancer, including malignant pleural mesothelioma. Although immune-related adverse events have been reported in patients receiving immune-checkpoint inhibitors, opsoclonus-myoclonus-ataxia syndrome has never been previously described. CASE PRESENTATION: We describe a 74-year-old male with malignant pleural mesothelioma who presented with opsoclonus and marked truncal ataxia â¼10 weeks following immunotherapy with ipilimumab and nivolumab. No myoclonus was present. Oligoclonal bands were detected in cerebrospinal fluid. Treatment with methylprednisolone and intravenous immunoglobulin along with clonazepam and valproic acid resulted in a rapid clinical improvement. A follow-up visit 2 months afterward showed a resolution of opsoclonus and he was able to walk with cane. CONCLUSIONS: A variant of opsoclonus-myoclonus-ataxia syndrome may occur following treatment with ipilimumab and nivolumab.
Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Ataxia/induzido quimicamente , Ipilimumab/efeitos adversos , Nivolumabe/efeitos adversos , Síndrome de Opsoclonia-Mioclonia/induzido quimicamente , Idoso , Ataxia/tratamento farmacológico , Clonazepam/uso terapêutico , Humanos , Imunoglobulinas/uso terapêutico , Imunossupressores/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Mesotelioma/tratamento farmacológico , Mesotelioma Maligno , Metilprednisolona/uso terapêutico , Síndrome de Opsoclonia-Mioclonia/tratamento farmacológico , Neoplasias Pleurais/tratamento farmacológico , Ácido Valproico/uso terapêuticoRESUMO
BACKGROUND: Nephrotic syndrome can be caused by a subgroup of mitochondrial diseases classified as primary coenzyme Q10 (CoQ10) deficiency. Pathogenic COQ2 variants are a cause of primary CoQ10 deficiency and present with phenotypes ranging from isolated nephrotic syndrome to fatal multisystem disease. CASE-DIAGNOSIS/TREATMENT: We report three pediatric patients with COQ2 variants presenting with nephrotic syndrome. Two of these patients had normal leukocyte CoQ10 levels prior to treatment. Pathologic findings varied from mesangial sclerosis to focal segmental glomerulosclerosis, with all patients having abnormal appearing mitochondria on kidney biopsy. In two of the three patients treated with CoQ10 supplementation, the nephrotic syndrome resolved; and at follow-up, both have normal renal function and stable proteinuria. CONCLUSIONS: COQ2 nephropathy should be suspected in patients presenting with nephrotic syndrome, although less common than disease due to mutations in NPHS1, NPHS2, and WT1. The index of suspicion should remain high, and we suggest that providers consider genetic evaluation even in patients with normal leukocyte CoQ10 levels, as levels may be within normal range even with significant clinical disease. Early molecular diagnosis and specific treatment are essential in the management of this severe yet treatable condition.
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Alquil e Aril Transferases/genética , Ataxia/tratamento farmacológico , Doenças Mitocondriais/tratamento farmacológico , Debilidade Muscular/tratamento farmacológico , Síndrome Nefrótica/terapia , Ubiquinona/análogos & derivados , Ubiquinona/deficiência , Ataxia/complicações , Ataxia/diagnóstico , Ataxia/genética , Biópsia , Criança , Pré-Escolar , Testes Genéticos , Humanos , Rim/patologia , Transplante de Rim , Masculino , Doenças Mitocondriais/complicações , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/genética , Debilidade Muscular/complicações , Debilidade Muscular/diagnóstico , Debilidade Muscular/genética , Síndrome Nefrótica/sangue , Síndrome Nefrótica/diagnóstico , Síndrome Nefrótica/etiologia , Resultado do Tratamento , Ubiquinona/administração & dosagem , Ubiquinona/genéticaRESUMO
Purpose: No previous clinical trial has been conducted for patients with neuroblastoma associated opsoclonus myoclonus ataxia syndrome (OMA), and current treatment is based on case reports. To evaluate the OMA response to prednisone and risk-adapted chemotherapy and determine if the addition of intravenous gammaglobulin (IVIG) further improves response, the Children's Oncology Group designed a randomized therapeutic trial. Patient and Methods: Eligible subjects were randomized to receive twelve cycles of IVIG (IVIG+) or no IVIG (NO-IVIG) in addition to prednisone and neuroblastoma risk-adapted chemotherapy. All low-risk patients were treated with cyclophosphamide. The severity of OMA symptoms was evaluated at 2, 6, and 12 months using a scale developed by Mitchell and Pike and baseline versus best response scores were compared. A single patient who did not undergo neurologic assessment was excluded from OMA response analysis. This study is registered with Clinical Trials.gov (identifier NCT00033293). Results: Of the 53 patients enrolled in the study, 62% (33/53) were female. There were 44 low-risk, 7 intermediate-risk, and 2 high-risk neuroblastoma patients. Twenty-six subjects were randomized to receive IVIG+ and 27 were randomized to NO-IVIG. The neuroblastoma 3-year event-free survival (95% confidence interval (CI)) was 94.1% (87.3%, 100%) and overall survival was 98.0% (94.1%, 100%). Significantly higher rates of OMA response were observed in patients randomized to IVIG+ compared to NO-IVIG [21/26=80.8% for IVIG+; 11/27=40.7% for NO-IVIG (odds ratio=6.1; 95% CI: (1.5, 25.9), p=0.0029)]. For the majority of patients, the IVIG+ OMA regimen combined with cytoxan or other risk-based chemotherapy was well tolerated, although there was one toxic death in a high-risk subject. Conclusion: This is the only randomized prospective therapeutic clinical trial in children with neuroblastoma-associated OMA. The addition of IVIG to prednisone and risk-adapted chemotherapy significantly improves OMA response rate. IVIG+ constitutes a back-bone upon which to build additional therapy.