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1.
BMC Infect Dis ; 20(1): 535, 2020 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-32703183

RESUMO

BACKGROUND: Breakthrough invasive fungal infections (bIFIs) are an area of concern in the scarcity of new antifungals. The mixed form of bIFIs is a rare phenomenon but could be potentially a troublesome challenge when caused by azole-resistant strains or non-Aspergillus fumigatus. To raise awareness and emphasize diagnostic challenges, we present a case of mixed bIFIs in a child with acute lymphoblastic leukemia. CASE PRESENTATION: A newly diagnosed 18-month-old boy with acute lymphoblastic leukemia was complicated with prolonged severe neutropenia after induction chemotherapy. He experienced repeated episodes of fever due to extended-spectrum beta-lactamase-producing Escherichia coli bloodstream infection and pulmonary invasive fungal infection with Aspergillus fumigatus (early-type bIFIs) while receiving antifungal prophylaxis. Shortly after pulmonary involvement, his condition aggravated by abnormal focal movement, loss of consciousness and seizure. Cerebral aspergillosis with Aspergillus niger diagnosed after brain tissue biopsy. The patient finally died despite 108-day antifungal therapy. CONCLUSIONS: Mixed bIFIs is a rare condition with high morbidity and mortality in the patients receiving immunosuppressants for hematological malignancies. This case highlights the clinical importance of Aspergillus identification at the species level in invasive fungal infections with multiple site involvement in the patients on antifungal prophylaxis.


Assuntos
Antifúngicos/uso terapêutico , Aspergillus fumigatus/imunologia , Aspergillus niger/genética , Coinfecção/diagnóstico , Aspergilose Pulmonar Invasiva/diagnóstico , Aspergilose Pulmonar Invasiva/tratamento farmacológico , Neuroaspergilose/diagnóstico , Antígenos de Fungos/análise , Aspergillus fumigatus/isolamento & purificação , Aspergillus niger/isolamento & purificação , Cerebelo/microbiologia , Cerebelo/patologia , Criança , Coinfecção/microbiologia , Evolução Fatal , Humanos , Quimioterapia de Indução/efeitos adversos , Lactente , Aspergilose Pulmonar Invasiva/sangue , Aspergilose Pulmonar Invasiva/microbiologia , Masculino , Neuroaspergilose/microbiologia , Neutropenia/induzido quimicamente , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico
2.
Rinsho Shinkeigaku ; 60(8): 520-526, 2020 Aug 07.
Artigo em Japonês | MEDLINE | ID: mdl-32641633

RESUMO

A 46 year-old man with schizophrenia had taken several anti-psychotic drugs since 25 years of age. From ~35 years of age, he noticed occasional neck torsion to the left, and later an ataxic gait; both symptoms gradually worsened. On admission, the patient was taking olanzapine (5 mg/day) and biperiden hydrochloride (1 mg/day) because his schizophrenia was well controlled. His parents were not consanguineous, and there was no family history of neuropsychiatric diseases. On neurological examination, he showed mild cognitive impairment, saccadic eye pursuit with horizontal gaze nystagmus, mild dysarthria, dystonic posture and movement of the neck, incoordination of both hands, and an ataxic gait. Deep tendon reflexes were normal except for the patellar tendon reflex, which was exaggerated bilaterally. Pathological reflexes were negative and there was no sign of rigidity, sensory disturbance or autonomic dysfunction. Ophthalmological examinations detected thinning of the outer macula lutea in both eyes, indicative of macular dystrophy. After admission, all anti-psychotic drugs were ceased, but his dystonia was unchanged. Levodopa and trihexyphenidyl hydrochloride were not effective. General blood, urine and cerebrospinal fluid examinations showed no abnormalities. Brain MRI showed cerebellar atrophy and bilateral symmetrical thalamic lesions without brainstem atrophy or abnormal signals in the basal ganglia. I123-IMP SPECT also revealed a decreased blood flow in the cerebellum. Genetic screening, including whole exome sequencing conducted by the Initiative on Rare and Undiagnosed Disease identified no possible disease-causing variants. The patient's dystonia worsened and choreic movements manifested on his right hand and foot. We suspected dystonia with marked cerebellar atrophy (DYTCA), but could not exclude drug-induced dystonia. Macular dystrophy and bilateral thalamic lesions on brain MRI have not been previously described in DYTCA. Whether these features might be primarily associated with dystonia or cerebellar ataxia now remains to be determined.


Assuntos
Antipsicóticos/efeitos adversos , Ataxia Cerebelar/etiologia , Cerebelo/patologia , Distonia Muscular Deformante/etiologia , Distonia/etiologia , Esquizofrenia/complicações , Esquizofrenia/tratamento farmacológico , Atrofia/diagnóstico por imagem , Atrofia/etiologia , Biperideno/efeitos adversos , Ataxia Cerebelar/diagnóstico por imagem , Cerebelo/diagnóstico por imagem , Distonia/diagnóstico por imagem , Distonia Muscular Deformante/diagnóstico por imagem , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Pescoço , Olanzapina/efeitos adversos
3.
PLoS Genet ; 16(7): e1008901, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32645003

RESUMO

The RNA exosome is an evolutionarily-conserved ribonuclease complex critically important for precise processing and/or complete degradation of a variety of cellular RNAs. The recent discovery that mutations in genes encoding structural RNA exosome subunits cause tissue-specific diseases makes defining the role of this complex within specific tissues critically important. Mutations in the RNA exosome component 3 (EXOSC3) gene cause Pontocerebellar Hypoplasia Type 1b (PCH1b), an autosomal recessive neurologic disorder. The majority of disease-linked mutations are missense mutations that alter evolutionarily-conserved regions of EXOSC3. The tissue-specific defects caused by these amino acid changes in EXOSC3 are challenging to understand based on current models of RNA exosome function with only limited analysis of the complex in any multicellular model in vivo. The goal of this study is to provide insight into how mutations in EXOSC3 impact the function of the RNA exosome. To assess the tissue-specific roles and requirements for the Drosophila ortholog of EXOSC3 termed Rrp40, we utilized tissue-specific RNAi drivers. Depletion of Rrp40 in different tissues reveals a general requirement for Rrp40 in the development of many tissues including the brain, but also highlight an age-dependent requirement for Rrp40 in neurons. To assess the functional consequences of the specific amino acid substitutions in EXOSC3 that cause PCH1b, we used CRISPR/Cas9 gene editing technology to generate flies that model this RNA exosome-linked disease. These flies show reduced viability; however, the surviving animals exhibit a spectrum of behavioral and morphological phenotypes. RNA-seq analysis of these Drosophila Rrp40 mutants reveals increases in the steady-state levels of specific mRNAs and ncRNAs, some of which are central to neuronal function. In particular, Arc1 mRNA, which encodes a key regulator of synaptic plasticity, is increased in the Drosophila Rrp40 mutants. Taken together, this study defines a requirement for the RNA exosome in specific tissues/cell types and provides insight into how defects in RNA exosome function caused by specific amino acid substitutions that occur in PCH1b can contribute to neuronal dysfunction.


Assuntos
Doenças Cerebelares/genética , Proteínas do Citoesqueleto/genética , Drosophila melanogaster/genética , Complexo Multienzimático de Ribonucleases do Exossomo/genética , Proteínas do Tecido Nervoso/genética , Neurônios/metabolismo , Proteínas de Ligação a RNA/genética , Substituição de Aminoácidos/genética , Animais , Sistemas CRISPR-Cas/genética , Doenças Cerebelares/patologia , Cerebelo/metabolismo , Cerebelo/patologia , Modelos Animais de Doenças , Exossomos/genética , Humanos , Mutação/genética , Neurônios/patologia , RNA/genética
4.
PLoS One ; 15(7): e0236005, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32649711

RESUMO

The cerebellum (CB) has extensive connections with both cortical and subcortical areas of the brain, and is known to strongly influence function in areas it projects to. In particular, research using non-invasive brain stimulation (NIBS) has shown that CB projections to primary motor cortex (M1) are likely important for facilitating the learning of new motor skills, and that this process may involve modulation of late indirect (I) wave inputs in M1. However, the nature of this relationship remains unclear, particularly in regards to how CB influences the contribution of the I-wave circuits to neuroplastic changes in M1. Within the proposed research, we will therefore investigate how CB effects neuroplasticity of the I-wave generating circuits. This will be achieved by downregulating CB excitability while concurrently applying a neuroplastic intervention that specifically targets the I-wave circuitry. The outcomes of this study will provide valuable neurophysiological insight into key aspects of the motor network, and may inform the development of optimized interventions for modifying motor learning in a targeted way.


Assuntos
Cerebelo/patologia , Plasticidade Neuronal , Potencial Evocado Motor , Humanos , Córtex Motor/fisiologia , Estimulação Magnética Transcraniana
5.
Proc Natl Acad Sci U S A ; 117(27): 15702-15711, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32576691

RESUMO

Mammalian cells contain two isoforms of RNA polymerase III (Pol III) that differ in only a single subunit, with POLR3G in one form (Pol IIIα) and the related POLR3GL in the other form (Pol IIIß). Previous research indicates that POLR3G and POLR3GL are differentially expressed, with POLR3G expression being highly enriched in embryonic stem cells (ESCs) and tumor cells relative to the ubiquitously expressed POLR3GL. To date, the functional differences between these two subunits remain largely unexplored, especially in vivo. Here, we show that POLR3G and POLR3GL containing Pol III complexes bind the same target genes and assume the same functions both in vitro and in vivo and, to a significant degree, can compensate for each other in vivo. Notably, an observed defect in the differentiation ability of POLR3G knockout ESCs can be rescued by exogenous expression of POLR3GL. Moreover, whereas POLR3G knockout mice die at a very early embryonic stage, POLR3GL knockout mice complete embryonic development without noticeable defects but die at about 3 wk after birth with signs of both general growth defects and potential cerebellum-related neuronal defects. The different phenotypes of the knockout mice likely reflect differential expression levels of POLR3G and POLR3GL across developmental stages and between tissues and insufficient amounts of total Pol III in vivo.


Assuntos
Cerebelo/crescimento & desenvolvimento , Desenvolvimento Embrionário/genética , Neurônios/metabolismo , RNA Polimerase III/genética , Animais , Sítios de Ligação/genética , Diferenciação Celular/genética , Cerebelo/patologia , Células-Tronco Embrionárias/citologia , Células-Tronco Embrionárias/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/genética , Humanos , Camundongos , Camundongos Knockout , Neurônios/patologia , Ligação Proteica/genética , Isoformas de Proteínas/genética , Subunidades Proteicas/genética
6.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 36(1): 77-81, 2020 Jan 28.
Artigo em Chinês | MEDLINE | ID: mdl-32476377

RESUMO

OBJECTIVE: To evaluate the effects of prenatal radiation of 850~1 900 MHz mobile phone on white matter in cerebellum of adult rat offspring. METHODS: Pregnant rats were randomly divided into short term maternal radiation group, long term maternal radiation group and control group. Rats in short term and long term maternal radiation group were exposed to 6 h/d and 24 h/d mobile phone radiation during 1-17 days of pregnancy, respectively. The cerebellums of offspring rats at the age of 3 month(n=8)were taken. Cell morphology in cerebellum was studied by hematoxylin-eosin (HE) staining. The expressions of myelin basic protein (MBP), neurofilament-L (NF-L) and glial fibrillary acidic protein (GFAP) in cerebellum of rat offspring were detected by immunohistochemistry and Western blot. RESULTS: Compared to control group, the morphological changes of purkinje cells in cerebellum were obvious in rat offspring of short term and long term maternal radiation group. Compared to control group, decreased MBP and NF-L expressions and increased GFAP expression were observed in long term maternal radiation group(all P<0.05). Compared to short term radiation group, the expressions of MBP and NF-L were down-regulated (all P<0.05) and the expression of GFAP was up- regulated(P<0.05) in long term radiation group. CONCLUSION: Prenatal mobile phone radiation might lead to the damage of myelin and axon with activity of astrocytes in cerebellum of male rat offspring, which is related to the extent of radiation.


Assuntos
Telefone Celular , Cerebelo/efeitos da radiação , Radiação Eletromagnética , Efeitos Tardios da Exposição Pré-Natal , Substância Branca/efeitos da radiação , Animais , Cerebelo/patologia , Feminino , Proteína Glial Fibrilar Ácida/metabolismo , Masculino , Proteína Básica da Mielina/metabolismo , Proteínas de Neurofilamentos/metabolismo , Gravidez , Distribuição Aleatória , Ratos , Substância Branca/patologia
7.
BMC Neurol ; 20(1): 230, 2020 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-32503453

RESUMO

BACKGROUND: Intracranial necrotizing granulomatous space-occupying lesions are sparsely reported in literature. Variability in presenting symptomatology and radiographic features makes diagnostic work-up difficult. CASE PRESENTATION: This report presents the case of a 77-year-old female with sinusitis and fatigue who underwent an MRI revealing a posterior fossa lesion compressing the fourth ventricle. Subsequent contrast CT of the chest, abdomen, and pelvis was negative for primary malignancy. Histopathologic examination of the lesion following biopsy showed it to be a necrotizing granuloma in an antineutrophil cytoplasmic antibody (ANCA) negative patient. The most likely diagnosis was determined to be spontaneous necrotizing granuloma, a rare entity with only one previous report noted. CONCLUSIONS: Spontaneous necrotizing granuloma of the CNS is a rare entity that represents an important differential consideration in the work-up of space occupying lesions of the CNS.


Assuntos
Doenças Cerebelares , Cerebelo , Granuloma , Necrose , Idoso , Biópsia , Cerebelo/diagnóstico por imagem , Cerebelo/patologia , Feminino , Humanos , Imagem por Ressonância Magnética
8.
J Vet Sci ; 21(3): e44, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32476318

RESUMO

BACKGROUND: Congenital portosystemic shunt (cPSS) is one of the most common congenital disorders diagnosed in dogs. Hepatic encephalopathy (HE) is a frequent complication in dogs with a cPSS and is a major cause of morbidity and mortality. Despite HE been a major cause of morbidity in dogs with a cPSS, little is known about the cellular changes that occur in the central nervous system of dogs with a cPSS. OBJECTIVES: The objective of this study was to characterise the histological changes in the cerebral cortex and cerebellum of dogs with cPSS with particular emphasis on astrocyte morphology. METHODS: Eight dogs with a confirmed cPSS were included in the study. RESULTS: Six dogs had substantial numbers of Alzheimer type II astrocytes and all cases had increased immunoreactivity for glial fibrillary acidic protein in the cerebral cortex, even if there were minimal other morphological changes. CONCLUSIONS: This study demonstrates that dogs with a cPSS have marked cellular changes in the cerebral cortex and cerebellum. The cellular changes that occur in the cerebral cortex and cerebellum of dogs with spontaneously arising HE are similar to changes which occur in humans with HE, further validating dogs with a cPSS as a good model for human HE.


Assuntos
Astrócitos/patologia , Cerebelo/patologia , Córtex Cerebral/patologia , Doenças do Cão/patologia , Encefalopatia Hepática/veterinária , Animais , Doenças do Cão/congênito , Doenças do Cão/etiologia , Cães , Feminino , Encefalopatia Hepática/congênito , Encefalopatia Hepática/etiologia , Encefalopatia Hepática/patologia , Masculino
9.
BMC Neurol ; 20(1): 222, 2020 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-32493244

RESUMO

BACKGROUND: Palato-pharyngo-laryngeal myoclonus, a variant of palatal myoclonus, is characterized by involuntary rhythmic movements of palatal, pharyngeal, and laryngeal muscles. Symptomatic palatal myoclonus is classically associated with hypertrophic olivary degeneration on MRI imaging due to a lesion in the triangle of Guillain-Mollaret. CASE PRESENTATION: We report a case of palato-pharyngo-laryngeal myoclonus in a patient post-cerebellar hemorrhagic stroke who presented with recurrent retrograde migration of his gastrojejunostomy feeding tubes. Treatment with either divalproex sodium or gabapentin resulted in a significant decrease in his gastrointestinal symptoms and no further episodes of gastrojejunostomy tube migration. CONCLUSIONS: This case study indicates that the movement disorder associated with hypertrophic olivary degeneration may involve the gastrointestinal system. Anticonvulsants, such as gabapentin and divalproex sodium, may reduce the severity of gastrointestinal symptoms in cases associated with hypertrophic olivary degeneration. The anatomy of the Guillain-Mollaret triangle and the pathophysiology of hypertrophic olivary degeneration are reviewed.


Assuntos
Hemorragias Intracranianas/complicações , Mioclonia/etiologia , Acidente Vascular Cerebral/complicações , Cerebelo/patologia , Nutrição Enteral , Humanos , Hipertrofia , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Núcleo Olivar/fisiopatologia
10.
BMC Neurol ; 20(1): 167, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32357846

RESUMO

BACKGROUND: Stroke-like episodes (SLEs) in mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) with m.3243A > G mutation usually develop in the cerebral cortex. Few reports have documented SLEs in the cerebellum. The clinical neuroimaging features of cerebellar SLEs have not been fully investigated. We report distinctive features of cerebellar stroke-like lesions (SLLs) in a case of MELAS with m.3243A > G mutation. CASE PRESENTATION: A 47-year-old Japanese man with type-2 diabetes presented to our hospital with acute onset of aphasia. A brain MRI obtained on admission (day 1) showed increased diffusion-weighted imaging (DWI)/fluid-attenuated inversion recovery (FLAIR) signal in the left anterolateral temporal lobe, which subsequently spread along the cortex posteriorly accompanied by a new lesion in the right anterior temporal lobe. The patient was initially treated with acyclovir and subsequently with immunotherapy. However, on day 45, cerebellar ataxia developed. The brain MRI showed extensive increased DWI/FLAIR signals in the cerebellum along the folia without involvement of deep cerebellar nucleus or cerebellar peduncle; SLLs were incongruent with a vascular territory, similarly to classic cerebral SLLs. Apparent diffusion coefficient (ADC) map did not show reduction in ADC values in the affected folia. Genomic analysis revealed m.3243A > G mutation (heteroplasmy in leukocytes, 17%), confirming the diagnosis of MELAS. After the treatment with taurine (12,000 mg/day), L-arginine (12,000 mg/day), vitamin B1 (100 mg/day), and carnitine (3000 mg/day), the patient became able to follow simple commands, and he was transferred to a rehabilitation center on day 146. The follow-up MRI showed diffuse brain atrophy, including the cerebellum. CONCLUSIONS: SLLs develop in the cerebellum in MELAS with m.3243A > G mutation. The neuroimaging similarities to cerebral SLLs suggest the presence of the common pathophysiological mechanisms underlying both SLEs, which include microangiopathy and increased susceptibility of the cortex to metabolic derangements.


Assuntos
Cerebelo , Síndrome MELAS , Acidente Vascular Cerebral , Cerebelo/diagnóstico por imagem , Cerebelo/patologia , Cerebelo/fisiopatologia , Humanos , Síndrome MELAS/complicações , Síndrome MELAS/diagnóstico por imagem , Síndrome MELAS/genética , Síndrome MELAS/fisiopatologia , Masculino , Pessoa de Meia-Idade , Mutação/genética , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/fisiopatologia
11.
BMC Med Genet ; 21(1): 96, 2020 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-32381069

RESUMO

BACKGROUND: Joubert syndrome (JBTS) is a genetically heterogeneous group of neurodevelopmental syndromes caused by primary cilia dysfunction. Usually the neurological presentation starts with abnormal neonatal breathing followed by muscular hypotonia, psychomotor delay, and cerebellar ataxia. Cerebral MRI shows mid- and hindbrain anomalies including the molar tooth sign. We report a male patient with atypical presentation of Joubert syndrome type 23, thus expanding the phenotype. CASE PRESENTATION: Clinical features were consistent with JBTS already from infancy, yet the syndrome was not suspected before cerebral MRI later in childhood showed the characteristic molar tooth sign and ectopic neurohypophysis. From age 11 years seizures developed and after few years became increasingly difficult to treat, also related to inadequate compliance to therapy. He died at 23 years of sudden unexpected death in epilepsy (SUDEP). The genetic diagnosis remained elusive for many years, despite extensive genetic testing. We reached the genetic diagnosis by performing whole genome sequencing of the family trio and analyzing the data with the combination of one analysis pipeline for single nucleotide variants (SNVs)/indels and one for structural variants (SVs). This lead to the identification of the most common variant detected in patients with JBTS23 (OMIM# 616490), rs534542684, in compound heterozygosity with a 8.3 kb deletion in KIAA0586, not previously reported. CONCLUSIONS: We describe for the first time ectopic neurohypophysis and SUDEP in JBTS23, expanding the phenotype of this condition and raising the attention on the possible severity of the epilepsy in this disease. We also highlight the diagnostic power of WGS, which efficiently detects SNVs/indels and in addition allows the identification of SVs.


Assuntos
Anormalidades Múltiplas/genética , Proteínas de Ciclo Celular/genética , Cerebelo/anormalidades , Morte Súbita/patologia , Epilepsia/genética , Anormalidades do Olho/genética , Doenças Renais Císticas/genética , Retina/anormalidades , Anormalidades Múltiplas/mortalidade , Anormalidades Múltiplas/patologia , Adulto , Cerebelo/patologia , Criança , Morte Súbita/epidemiologia , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/mortalidade , Deficiências do Desenvolvimento/patologia , Epilepsia/mortalidade , Epilepsia/patologia , Anormalidades do Olho/mortalidade , Anormalidades do Olho/patologia , Feminino , Heterozigoto , Humanos , Mutação INDEL , Doenças Renais Císticas/mortalidade , Doenças Renais Císticas/patologia , Masculino , Neuro-Hipófise/metabolismo , Neuro-Hipófise/patologia , Retina/patologia , Sequenciamento Completo do Genoma , Adulto Jovem
13.
J Vet Diagn Invest ; 32(3): 463-466, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32404029

RESUMO

A juvenile raccoon (Procyon lotor) was submitted dead to the Minnesota Veterinary Diagnostic Laboratory for rabies testing without history. The animal had marked hypoplasia of the cerebellum. Histology demonstrated that most folia lacked granule cells and had randomly misplaced Purkinje cells. Immunohistochemistry revealed the presence of parvoviral antigen in a few neurons and cell processes. PCR targeting feline and canine parvovirus yielded a positive signal. Sequencing analyses from a fragment of the nonstructural protein 1 (NS1) gene and a portion of the viral capsid protein 2 (VP2) gene confirmed the presence of DNA of a recent canine parvovirus variant (CPV-2a-like virus) in the cerebellum. Our study provides evidence that (canine) parvovirus may be associated with cerebellar hypoplasia and dysplasia in raccoons, similar to the disease that occurs naturally and has been reproduced experimentally by feline parvoviral infection of pregnant cats, with subsequent intrauterine or neonatal infections of the offspring.


Assuntos
Cerebelo/anormalidades , Malformações do Sistema Nervoso/veterinária , Infecções por Parvoviridae/veterinária , Parvovirus Canino/isolamento & purificação , Guaxinins/virologia , Animais , Cerebelo/patologia , Cerebelo/virologia , Deficiências do Desenvolvimento/patologia , Deficiências do Desenvolvimento/virologia , Feminino , Imuno-Histoquímica , Malformações do Sistema Nervoso/patologia , Malformações do Sistema Nervoso/virologia , Infecções por Parvoviridae/virologia , Parvovirus Canino/genética , Reação em Cadeia da Polimerase/veterinária
14.
Nat Commun ; 11(1): 1982, 2020 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-32341345

RESUMO

Whole-organ/body three-dimensional (3D) staining and imaging have been enduring challenges in histology. By dissecting the complex physicochemical environment of the staining system, we developed a highly optimized 3D staining imaging pipeline based on CUBIC. Based on our precise characterization of biological tissues as an electrolyte gel, we experimentally evaluated broad 3D staining conditions by using an artificial tissue-mimicking material. The combination of optimized conditions allows a bottom-up design of a superior 3D staining protocol that can uniformly label whole adult mouse brains, an adult marmoset brain hemisphere, an ~1 cm3 tissue block of a postmortem adult human cerebellum, and an entire infant marmoset body with dozens of antibodies and cell-impermeant nuclear stains. The whole-organ 3D images collected by light-sheet microscopy are used for computational analyses and whole-organ comparison analysis between species. This pipeline, named CUBIC-HistoVIsion, thus offers advanced opportunities for organ- and organism-scale histological analysis of multicellular systems.


Assuntos
Encéfalo/patologia , Cerebelo/patologia , Eletrólitos , Imageamento Tridimensional , Microscopia de Fluorescência , Adulto , Animais , Animais Recém-Nascidos , Callithrix , Feminino , Corantes Fluorescentes , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Imagem Óptica
15.
BMC Neurol ; 20(1): 156, 2020 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-32340607

RESUMO

BACKGROUND: Genetic familiar causes of oro-facial dyskinesia are usually restricted to Huntington's disease, whereas other causes are often missed or underestimated. Here, we report the case of late-onset oro-facial dyskinesia in an elderly patient with a genetic diagnosis of Spinocerebellar Ataxia type 2 (SCA2). CASE PRESENTATION: A 75-year-old man complained of progressive balance difficulty since the age of 60 years, associated with involuntary movements of the mouth and tongue over the last 3 months. No exposure to anti-dopaminergic agents, other neuroleptics, antidepressants, or other drugs was reported. Family history was positive for SCA2 (brother and the son of the brother). At rest, involuntary movements of the mouth and tongue were noted; they appeared partially suppressible and became more evident during stress and voluntary movements. Cognitive examination revealed frontal-executive dysfunction, memory impairment, and attention deficit. Brain magnetic resonance imaging (MRI) disclosed signs of posterior periventricular chronic cerebrovascular disease and a marked ponto-cerebellar atrophy, as confirmed by volumetric MRI analysis. A dopamine transporter imaging scan demonstrated a bilaterally reduced putamen and caudate nucleus uptake. Ataxin-2 (ATXN2) gene analysis revealed a 36 cytosine-adenine-guanine (CAG) repeat expansion, confirming the diagnosis of SCA2. CONCLUSIONS: SCA2 should be considered among the possible causes of adult-onset oro-facial dyskinesia, especially when the family history suggests an inherited cerebellar disorder. Additional clinical features, including parkinsonism and motor neuron disease, may represent relevant cues for an early diagnosis and adequate management.


Assuntos
Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Transtornos Parkinsonianos/fisiopatologia , Ataxias Espinocerebelares/genética , Idoso , Cerebelo/patologia , Humanos , Imagem por Ressonância Magnética , Masculino , Ponte/patologia
16.
BMC Neurol ; 20(1): 157, 2020 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-32340608

RESUMO

BACKGROUND: The "hot cross bun" (HCB) sign, a cruciform hyperintensity in the pons on magnetic resonance imaging (MRI), has gradually been identified as a typical finding in multiple system atrophy, cerebellar-type (MSA-C). Few reports have evaluated the sensitivity of an HCB, including a cruciform hyperintensity and vertical line in the pons, which precedes a cruciform hyperintensity, in the early stages of MSA-C. Moreover, the difference in frequency and timing of appearance of an HCB between MSA-C and spinocerebellar ataxia type 3 (SCA3) has not been fully investigated. METHODS: This study investigated the time at which an HCB and orthostatic hypotension (OH) appeared in 41 patients with MSA-C, based on brain MRI and head-up tilt test. The MRI findings were compared with those of 26 patients with SCA3. The pontine signal findings on T2-weighted MRI were graded as 0 (no change), 1 (a vertical T2 high-intensity line), or 2 (a cruciform T2 high-intensity line), with grades 1 or 2 considered as an HCB. OH 30/15 was defined as a decrease in systolic blood pressure of > 30 mmHg or diastolic blood pressure of > 15 mmHg. RESULTS: Among the 24 patients with MSA-C within 2 years from the onset of motor symptoms, an HCB was detected in 91.7%, whereas OH 30/15 was present in 60.0%. Among the 36 patients with MSA-C within 3 years from the onset of motor symptoms, a grade 2 HCB was detected in 66.7% of those with MSA-C but in none of those with SCA-3. CONCLUSIONS: HCB is a highly sensitive finding for MSA-C, even in the early stages of the disease. A grade 2 HCB in the early stage is an extremely specific finding for differentiating MSA-C from SCA-3.


Assuntos
Hipotensão Ortostática/etiologia , Doença de Machado-Joseph/diagnóstico , Atrofia de Múltiplos Sistemas/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Cerebelo/patologia , Feminino , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Ponte/patologia , Estudos Retrospectivos , Adulto Jovem
17.
Neurology ; 94(18): e1908-e1915, 2020 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-32265233

RESUMO

OBJECTIVE: To test the hypothesis that the trajectory of functional connections over time of the striatum and the cerebellum differs between presymptomatic patients with the Huntington disease (HD) gene expansion (GE) and patients with a family history of HD but without the GE (GNE), we evaluated functional MRI data from the Kids-HD study. METHODS: We utilized resting-state, functional MRI data from participants in the Kids-HD study between 6 and 18 years old. Participants were divided into GE (CAG 36-59) and GNE (CAG <36) groups. Seed-to-seed correlations were calculated among 4 regions that provide input signals to the anterior cerebellum: (1) dorsocaudal putamen, (2) globus pallidus externa, (3) subthalamic nucleus, and (4) pontine nuclei; and 2 regions that represented output from the cerebellum: the dentate nucleus to the (1) ventrolateral thalamus and (2) dorsocaudal putamen. Linear mixed effects regression models evaluated differences in developmental trajectories of these connections over time between groups. RESULTS: Four of the six striatal-cerebellum correlations showed significantly different trajectories between groups. All showed a pattern where in the early age ranges (6-12 years) there was hyperconnectivity in the GE compared to the GNE, with those trajectories showing linear decline in the latter half of the age range. CONCLUSION: These results parallel previous findings showing striatal hypertrophy in children with GE as early as age 6. These findings support the notion of developmentally higher connectivity between the striatum and cerebellum early in the life of the child with HD GE, possibly setting the stage for cerebellar compensatory mechanisms.


Assuntos
Cerebelo/patologia , Corpo Estriado/patologia , Doença de Huntington/patologia , Vias Neurais/patologia , Adolescente , Cerebelo/crescimento & desenvolvimento , Criança , Corpo Estriado/crescimento & desenvolvimento , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Vias Neurais/crescimento & desenvolvimento
18.
Cell Mol Life Sci ; 77(20): 4015-4029, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32306062

RESUMO

The family of hereditary cerebellar ataxias is a large group of disorders with heterogenous clinical manifestations and genetic etiologies. Among these, over 30 autosomal dominantly inherited subtypes have been identified, collectively referred to as the spinocerebellar ataxias (SCAs). Generally, the SCAs are characterized by a progressive gait impairment with classical cerebellar features, and in a subset of SCAs, accompanied by extra-cerebellar features. Beyond the common gait impairment and cerebellar atrophy, the wide range of additional clinical features observed across the SCAs is likely explained by the diverse set of mutated genes that encode proteins with seemingly disparate functional roles in nervous system biology. By synthesizing knowledge obtained from studies of the various SCAs over the past several decades, convergence onto a few key cellular changes, namely ion channel dysfunction and transcriptional dysregulation, has become apparent and may represent central mechanisms of cerebellar disease pathogenesis. This review will detail our current understanding of the molecular pathogenesis of the SCAs, focusing primarily on the first described autosomal dominant spinocerebellar ataxia, SCA1, as well as the emerging common core mechanisms across the various SCAs.


Assuntos
Ataxias Espinocerebelares/patologia , Animais , Cerebelo/patologia , Humanos , Proteínas Nucleares/genética , Degenerações Espinocerebelares/patologia
19.
Proc Natl Acad Sci U S A ; 117(11): 6023-6034, 2020 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-32132200

RESUMO

Despite a growing number of ion channel genes implicated in hereditary ataxia, it remains unclear how ion channel mutations lead to loss-of-function or death of cerebellar neurons. Mutations in the gene KCNMA1, encoding the α-subunit of the BK channel have emerged as responsible for a variety of neurological phenotypes. We describe a mutation (BKG354S) in KCNMA1, in a child with congenital and progressive cerebellar ataxia with cognitive impairment. The mutation in the BK channel selectivity filter dramatically reduced single-channel conductance and ion selectivity. The BKG354S channel trafficked normally to plasma, nuclear, and mitochondrial membranes, but caused reduced neurite outgrowth, cell viability, and mitochondrial content. Small interfering RNA (siRNA) knockdown of endogenous BK channels had similar effects. The BK activator, NS1619, rescued BKG354S cells but not siRNA-treated cells, by selectively blocking the mutant channels. When expressed in cerebellum via adenoassociated virus (AAV) viral transfection in mice, the mutant BKG354S channel, but not the BKWT channel, caused progressive impairment of several gait parameters consistent with cerebellar dysfunction from 40- to 80-d-old mice. Finally, treatment of the patient with chlorzoxazone, a BK/SK channel activator, partially improved motor function, but ataxia continued to progress. These studies indicate that a loss-of-function BK channel mutation causes ataxia and acts by reducing mitochondrial and subsequently cellular viability.


Assuntos
Cerebelo/patologia , Clorzoxazona/administração & dosagem , Subunidades alfa do Canal de Potássio Ativado por Cálcio de Condutância Alta/genética , Mitocôndrias/patologia , Degenerações Espinocerebelares/genética , Adolescente , Animais , Animais Recém-Nascidos , Linhagem Celular , Cerebelo/citologia , Análise Mutacional de DNA , Dependovirus/genética , Modelos Animais de Doenças , Feminino , Técnicas de Silenciamento de Genes , Vetores Genéticos/genética , Humanos , Subunidades alfa do Canal de Potássio Ativado por Cálcio de Condutância Alta/antagonistas & inibidores , Subunidades alfa do Canal de Potássio Ativado por Cálcio de Condutância Alta/metabolismo , Mutação com Perda de Função , Camundongos , Oócitos , Ratos , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Degenerações Espinocerebelares/diagnóstico , Degenerações Espinocerebelares/tratamento farmacológico , Degenerações Espinocerebelares/patologia , Transfecção , Sequenciamento Completo do Exoma , Xenopus
20.
Nucleic Acids Res ; 48(7): 3678-3691, 2020 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-32123907

RESUMO

Genomic instability resulting from defective DNA damage responses or repair causes several abnormalities, including progressive cerebellar ataxia, for which the molecular mechanisms are not well understood. Here, we report a new murine model of cerebellar ataxia resulting from concomitant inactivation of POLB and ATM. POLB is one of key enzymes for the repair of damaged or chemically modified bases, including methylated cytosine, but selective inactivation of Polb during neurogenesis affects only a subpopulation of cortical interneurons despite the accumulation of DNA damage throughout the brain. However, dual inactivation of Polb and Atm resulted in ataxia without significant neuropathological defects in the cerebellum. ATM is a protein kinase that responds to DNA strand breaks, and mutations in ATM are responsible for Ataxia Telangiectasia, which is characterized by progressive cerebellar ataxia. In the cerebella of mice deficient for both Polb and Atm, the most downregulated gene was Itpr1, likely because of misregulated DNA methylation cycle. ITPR1 is known to mediate calcium homeostasis, and ITPR1 mutations result in genetic diseases with cerebellar ataxia. Our data suggest that dysregulation of ITPR1 in the cerebellum could be one of contributing factors to progressive ataxia observed in human genomic instability syndromes.


Assuntos
Ataxia Cerebelar/genética , Cerebelo/metabolismo , Metilação de DNA , DNA Polimerase beta/genética , Receptores de Inositol 1,4,5-Trifosfato/genética , Animais , Proteínas Mutadas de Ataxia Telangiectasia/genética , Encéfalo/embriologia , Encéfalo/patologia , Cerebelo/anormalidades , Cerebelo/patologia , Citosina/metabolismo , Dano ao DNA , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Camundongos , Camundongos Knockout , Neurogênese/genética
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