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1.
Brain Nerve ; 73(2): 179-182, 2021 Feb.
Artigo em Japonês | MEDLINE | ID: mdl-33561832

RESUMO

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 farmacológico
2.
BMJ Case Rep ; 14(2)2021 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-33542005

RESUMO

Acute cerebellar ataxia is a rare primary manifestation of neuropsychiatric systemic lupus erythematosus (NPSLE). We report a case of a 22-year-old woman who presented with gait instability, behavioural changes and new-onset seizures. The tempo of disease progression was explained by an autoimmune cause, eventually fulfilling the criteria for systemic lupus erythematosus. The patient's neurological symptoms improved markedly following administration of steroids and immunomodulators. A review of literature on cerebellar ataxia in NPSLE and a summary of all reported cases to date are also presented.


Assuntos
Anti-Inflamatórios/uso terapêutico , Ataxia Cerebelar/etiologia , Vasculite Associada ao Lúpus do Sistema Nervoso Central/diagnóstico , Vasculite Associada ao Lúpus do Sistema Nervoso Central/tratamento farmacológico , Prednisona/uso terapêutico , Adulto , Antimaláricos/uso terapêutico , Feminino , Análise da Marcha , Cefaleia/etiologia , Humanos , Hidroxicloroquina/uso terapêutico , Vasculite Associada ao Lúpus do Sistema Nervoso Central/complicações , Convulsões/etiologia
3.
Am J Hum Genet ; 108(1): 186-193, 2021 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-33417887

RESUMO

POLR3B encodes the second-largest catalytic subunit of RNA polymerase III, an enzyme involved in transcription. Bi-allelic pathogenic variants in POLR3B are a well-established cause of hypomyelinating leukodystrophy. We describe six unrelated individuals with de novo missense variants in POLR3B and a clinical presentation substantially different from POLR3-related leukodystrophy. These individuals had afferent ataxia, spasticity, variable intellectual disability and epilepsy, and predominantly demyelinating sensory motor peripheral neuropathy. Protein modeling and proteomic analysis revealed a distinct mechanism of pathogenicity; the de novo POLR3B variants caused aberrant association of individual enzyme subunits rather than affecting overall enzyme assembly or stability. We expand the spectrum of disorders associated with pathogenic variants in POLR3B to include a de novo heterozygous POLR3B-related disorder.


Assuntos
Ataxia/genética , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/genética , RNA Polimerase III/genética , Adolescente , Adulto , Ataxia Cerebelar/genética , Criança , Pré-Escolar , Feminino , Genes Recessivos/genética , Heterozigoto , Humanos , Masculino , Mutação de Sentido Incorreto/genética , Proteômica/métodos , Adulto Jovem
4.
BMJ Case Rep ; 13(12)2020 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-33334756

RESUMO

Acquired cerebellar ataxia is a rare, in many cases immune-modulated and paraneoplastic illness. Acute and slowly progredient processes are possible. An early treatment is important for a good clinical outcome. Here we present the case of female patient in her 60s with an antirecoverin associated cerebellitis without retinopathia and neoplasia. After an immunosuppressive therapy with steroids and rituximab the symptoms improved, and the progression could be stopped.


Assuntos
Autoanticorpos/sangue , Ataxia Cerebelar/diagnóstico , Marcha Atáxica/diagnóstico , Imunossupressores/uso terapêutico , Recoverina/imunologia , Idade de Início , Autoanticorpos/imunologia , Ataxia Cerebelar/sangue , Ataxia Cerebelar/tratamento farmacológico , Ataxia Cerebelar/imunologia , Cerebelo/diagnóstico por imagem , Cerebelo/imunologia , Feminino , Marcha Atáxica/sangue , Marcha Atáxica/tratamento farmacológico , Marcha Atáxica/imunologia , Glucocorticoides/uso terapêutico , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Imagem por Ressonância Magnética , Pessoa de Meia-Idade , Rituximab/uso terapêutico
5.
BMJ Open ; 10(12): e040230, 2020 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-33334834

RESUMO

INTRODUCTION: Emerging evidence indicates that rehabilitation can improve ataxia, mobility and independence in everyday activities in individuals with hereditary cerebellar ataxia. However, with the rarity of the genetic ataxias and known recruitment challenges in rehabilitation trials, most studies have been underpowered, non-randomised or non-controlled. This study will be the first, appropriately powered randomised controlled trial to examine the efficacy of an outpatient and home-based rehabilitation programme on improving motor function for individuals with hereditary cerebellar ataxia. METHODS AND ANALYSIS: This randomised, single-blind, parallel group trial will compare a 30-week rehabilitation programme to standard care in individuals with hereditary cerebellar ataxia. Eighty individuals with a hereditary cerebellar ataxia, aged 15 years and above, will be recruited. The rehabilitation programme will include 6 weeks of outpatient land and aquatic physiotherapy followed immediately by a 24- week home exercise programme supported with fortnightly physiotherapy sessions. Participants in the standard care group will be asked to continue their usual physical activity. The primary outcome will be the motor domain of the Functional Independence Measure. Secondary outcomes will measure the motor impairment related to ataxia, balance, quality of life and cost-effectiveness. Outcomes will be administered at baseline, 7 weeks, 18 weeks and 30 weeks by a physiotherapist blinded to group allocation. A repeated measures mixed-effects linear regression model will be used to analyse the effect of the treatment group for each of the dependent continuous variables. The primary efficacy analysis will follow the intention-to-treat principle. ETHICS AND DISSEMINATION: The study has been approved by the Monash Health Human Research Ethics Committee (HREC/18/MonH/418) and the Human Research Ethics Committee of the Northern Territory Department of Health and Menzies School of Health Research (2019/3503). Results will be published in peer-reviewed journals, presented at national and/or international conferences and disseminated to Australian ataxia support groups. TRIAL REGISTRATION NUMBER: ACTRN12618000908235.


Assuntos
Ataxia Cerebelar , Pacientes Ambulatoriais , Modalidades de Fisioterapia , Qualidade de Vida , Adolescente , Ataxia , Austrália , Ataxia Cerebelar/reabilitação , Terapia por Exercício , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Método Simples-Cego
6.
Annu Int Conf IEEE Eng Med Biol Soc ; 2020: 3642-3648, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-33018791

RESUMO

In this study we evaluate the application of video-based markerless motion tracking based on deep neural networks for the analysis of ataxia-specific movement abnormalities in rodent models of cerebellar ataxia. Based on a small amount (<100) of manually labeled video frames, markerless motion tracking enabled the extraction of movement trajectories and parameters characterizing ataxia-specific movement abnormalities. In the first experiment, we analyzed videos of 6 shaker and 4 wildtype rats and were able to reproduce thê5 Hz tremor frequency in the shaker rat without the usage of a force plate. In the second experiment, we investigated a spinocerebellar ataxia type 3 (SCA3) mouse model (6 mice aged 3 months and 3 mice aged 9 months) in a beam-balancing task. By establishing a parameter for the assessment of rhythmicity of gait (RoG), we not only found a significantly higher RoG in wildtype mice compared to affected SCA3 mice aged 9 months, but were also able to reveal a significantly lower than typical RoG in SCA3 mice aged 3 months which exhibit no abnormalities in visual inspection. These prototypical results suggest the capability of the presented methods for the application in upcoming therapeutic intervention trials to identify subtle changes in movement behavior.


Assuntos
Ataxia Cerebelar , Transtornos Motores , Animais , Ataxia , Camundongos , Redes Neurais de Computação , Ratos , Roedores
7.
Annu Int Conf IEEE Eng Med Biol Soc ; 2020: 4571-4574, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-33019011

RESUMO

Cerebellar ataxia (CA) refers to the impaired balance and coordination resulting from injury or degeneration of the cerebellum. Testing balance is one of the simplest means of assessing CA. This study compares instrumented assessment and clinical assessment scales of the balance test called Romberg's test. Inertial Measurement Unit (IMU) data were collected from a sensor attached to their chest of 53 subjects while they performed the test. The corresponding clinical scores were also tabulated. Using this data, 99 features were extracted to quantify acceleration, tremor and displacement of body sway. These features were filtered to identify the subset that better characterize the distinctive behavior of CA subjects. Elastic Net Regression model resulted a greater agreement (0.70 Pearson coefficient) with the clinical SARA scores. The overall results indicated that data from a single IMU sensor is sufficient to accurately assess balance in CA. The significance of this study is that evaluation of balance using Recurrence Quantification Analysis produces a comprehensive framework for the assessment of CA.


Assuntos
Ataxia Cerebelar , Aceleração , Ataxia Cerebelar/diagnóstico , Humanos , Equilíbrio Postural , Tórax , Tremor
8.
Annu Int Conf IEEE Eng Med Biol Soc ; 2020: 5640-5643, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-33019256

RESUMO

Cerebellar Ataxia is a neurological disorder without an approved treatment. Patients will have impaired and uncoordinated motor functionality making them unable to complete their day-to-day activities. Ataxia clinics are established around the world to facilitate research and rehabilitate patients. However, the patients are generally evaluated by human - observation. Therefore, machine learning based data analysis is popular on motion captured via sensors. There are many neurological tests designed to analyse the motor impairments in different domains (such as upper limb, lower limb, gait, balance and speech). Clinicians follow scoring protocols to record the severity of patients for each domain test. This paper delivers a clinical assessment platform combining 12 neurological tests in 5 domains. It captures motion (from BioKin sensors), haptic and audio data (from the tablet or laptop screen). A data analysis system is hosted in a remote server which evaluates data to produce a severity score via different models built for each neurological test. The assessment platform clients and server communicate via a cloud buffer system. The scores input by the clinicians and predicted by the machine learning models are logged in the cloud database. This enables clinicians and doctors to view and compare the history of patient diagnosis. The server system is structured for automated score model upgrades via prompted approval. Thus, the most viable scoring model could be accommodated for each test based on longitudinal studies.


Assuntos
Ataxia Cerebelar , Ataxia , Ataxia Cerebelar/diagnóstico , Marcha , Humanos , Fala , Extremidade Superior
9.
Annu Int Conf IEEE Eng Med Biol Soc ; 2020: 816-819, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-33018110

RESUMO

Human observer-based assessments of Cerebellar Ataxia (CA) are subjective and are often inadequate to track mild motor symptoms. This study examines the potential use of a comprehensive sensor-based approach for objective evaluation of CA in five domains (speech, upper limb, lower limb, gait and balance) through the instrumented versions of nine bedside neurological tests. A total of twenty-three participants diagnosed with CA to varying degrees and eleven healthy controls were recruited. Data was collected using wearable inertial sensors and Kinect camera. In our study, an optimal feature subset based on feature importance in the Random Forest classifier model demonstrated an impressive performance accuracy of 97% (F1 score = 95.2%) for CA-control discrimination. Our experimental findings also indicate that the Romberg test contributed most, followed by the peripheral tests, while the Gait test contributed least to the classification. Sensor-based approaches, therefore, have the potential to complement existing clinical assessment techniques, offering advantages in terms of consistency, objectivity and informed clinical decision-making.


Assuntos
Ataxia Cerebelar , Ataxia Cerebelar/diagnóstico , Marcha , Humanos , Reprodutibilidade dos Testes , Fala , Extremidade Superior
10.
Annu Int Conf IEEE Eng Med Biol Soc ; 2020: 820-823, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-33018111

RESUMO

The progression of neurodegenerative conditions can be effectively monitored and improved by using objective assessments. The conditions such as Friedreich Ataxia (FA) are clinically assessed by means of subjective measures commonly practised in clinics. Here, we propose a device capable of measuring ataxia, in the form of a `cup' capable of sensing certain kinematic parameters of interest while engaging in an activity that is closely related to daily living. In this study, the functional task of 'drinking' was utilised to diagnose participants with FA and capture features in terms of diagnosis (separation) and correlation with the clinical scales. Frequency domain analysis was incorporated enabling the classification of control subjects and FA patients to an accuracy of 88% with a correlation of 90% with the clinical scores.


Assuntos
Ataxia Cerebelar , Ataxia de Friedreich , Ataxia , Fenômenos Biomecânicos , Progressão da Doença , Ataxia de Friedreich/diagnóstico , Humanos
11.
Annu Int Conf IEEE Eng Med Biol Soc ; 2020: 859-862, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-33018120

RESUMO

Cerebellar ataxia (CA) results from injury to or disease of the cerebellum. It describes the resulting motor dysfunction, characterised by inaccuracy, incoordination and delay in initiation of movement, tremor, and imbalance. Assessment of ataxia to diagnose and monitor progress is by clinical observance of the performance of standard motor tasks. An accurate instrumented measurement of CA would therefore be of great interest. This study was aimed at assessing upper-limb ataxia during ballistic tracking of a computer-generated target in individuals with CA and controls using motion measures obtained from a Kinect camera and a wearable motioncaptured device. A set of features derived from these motion measurements were used to develop a method for objective quantification of CA. Difference between ataxic and non-ataxic movements can be readily be observed in features from both devices (p= 0.008) and their values associated with a standard clinical scale (rho = 0.80, p < 0.001). The combination of multimodal features improved the ability to distinguish between CA subjects and controls and to measure the severity of upper limb ataxia.


Assuntos
Ataxia Cerebelar , Dispositivos Eletrônicos Vestíveis , Ataxia Cerebelar/diagnóstico , Cerebelo , Humanos , Movimento , Tremor
12.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 45(4): 469-475, 2020 Apr 28.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-32879074

RESUMO

Wernekink commissure syndrome (WCS) is very rare. Four patients with WCS, admitted to our hospital from April to May 2018, were chosen for this study, and their clinical manifestations, imaging features, and etiology were retrospectively analyzed based on the literatures. All patients with WCS manifested as bilateral cerebellar ataxia such as symmetrical limb and trunk ataxia, but the degree of ataxia was asymmetrical distribution based on the anatomy. Dysarthria was the main and constant clinical manifestation of the syndrome. Ophthalmoplegia had great variability, and WCS with oculomotor nerve palsy may be considered as atypical WCS. The incidence of olivary degeneration and palatine myoclonus is relatively low, which may be related to the difference in the reported time intervals of cases. Changes in consciousness and emotion may be the characteristic of neglected WCS, which should be paid more attention. Cerebral infarction is the main etiology of WCS. We reported that cerebral infarction and WCS was the first symptom in a patient with systemic lupus erythematosus (SLE). We should pay more attention to special etiology in diagnosis and treatment of WCS.


Assuntos
Ataxia Cerebelar , Lúpus Eritematoso Sistêmico , Infarto Cerebral , Humanos , Estudos Retrospectivos , Síndrome
13.
Acta Neurol Taiwan ; 29(3): 86-89, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32996116

RESUMO

PURPOSE: Focal signs are a big deal in neurology and are among the most important clues leading to diagnosis and localization. Wernekink commissure syndrome is due to lesions in the caudal paramedian midbrain involving the entire decussation of the superior cerebellar peduncles, resulting in the clinical hallmark of a bilateral cerebellar syndrome. CASE REPORT: A 79-year-old man presented with sudden, severe unsteadiness associated with slurring of speech, binocular double vision, and bilateral hand tremor. Examination showed right INO, moderately severe dysarthria, bilateral dysmetria and dysdiadochokinesia, with severe truncal ataxia and bilateral upper and lower limb ataxia. Also, bilateral coarse tremor was noted in both hands which was present at rest, action and on reaching for objects. Brain MRI revealed an acute infarction involving the Wernekinck decussation in the right caudal midbrain and mesencephalo-pontine junction. CONCLUSION: The differential of Wernekink Commissure Syndrome is complex, and localization and lateralization are extremely difficult owing to prominent bilateral cerebellar symptoms. The finding of an associated unilateral INO in some cases makes it possible to confidently narrow the list of differentials and localize the lesion to the paramedian tegmentum ipsilateral to the non-adducting eye.


Assuntos
Ataxia Cerebelar/etiologia , Doenças Cerebelares , Infarto Cerebral/complicações , Mesencéfalo/diagnóstico por imagem , Tegmento Mesencefálico/irrigação sanguínea , Idoso , Doenças Cerebelares/diagnóstico por imagem , Doenças Cerebelares/etiologia , Infarto Cerebral/diagnóstico por imagem , Humanos , Imagem por Ressonância Magnética , Masculino , Transtornos da Motilidade Ocular/etiologia , Formação Reticular/patologia , Síndrome
14.
Brain Nerve ; 72(9): 923-930, 2020 Sep.
Artigo em Japonês | MEDLINE | ID: mdl-32934181

RESUMO

Marie et al. (1922) first proposed a disease entity "late cortical cerebellar atrophy (LCCA)", which is characterized neuropathologically by pure cerebello-olivary degeneration. LCCA was originally described as sporadic, late-onset, pure cerebellar ataxia of unknown etiology; however, it has occasionally been used to denote familial or secondary ataxias, particularly alcoholic cerebellar degeneration. Sporadic ataxia is classified mainly into LCCA or CCA and olivo-ponto-cerebellar atrophy (OPCA) in Japan. OPCA, now multiple system atrophy with predominant cerebellar ataxia, has characteristic brain imaging features and is clearly diagnosed based on the consensus criteria. On the other hand, there is no specific biomarker for LCCA/CCA, and neuropathological examination is required for a definitive diagnosis. Therefore, the clinical diagnosis of LCCA/CCA depends on the exclusion of other diseases manifesting as cerebellar ataxia. However the differential diagnosis for LCCA/CCA is not necessarily made carefully. As a result, the LCCA/CCA category in Japan is a "waste basket," including OPCA, hereditary ataxias, and secondary ataxias, which are unidentified yet. To refine the LCCA/CCA category, we proposed the clinically-defined term "idiopathic cerebellar ataxia (IDCA)" and established its diagnostic criteria. By nationwide screening, we have identified 51 patients with probable IDCA according to the criteria so far. Here we review the clinical characteristics of IDCA patients.


Assuntos
Ataxia Cerebelar , Degenerações Espinocerebelares , Atrofia/patologia , Ataxia Cerebelar/diagnóstico , Cerebelo , Humanos , Japão , Degenerações Espinocerebelares/diagnóstico , Degenerações Espinocerebelares/patologia
15.
Brain Nerve ; 72(9): 931-937, 2020 Sep.
Artigo em Japonês | MEDLINE | ID: mdl-32934182

RESUMO

Cerebellar ataxia-predominant multiple system atrophy (MSA-C) and cortical cerebellar atrophy are representative diseases of adult-onset sporadic degenerative ataxia. Both diseases are distinctly different because of α-synuclein pathology. However, it takes approximately 2 years for cerebellar ataxia to progress to concomitant severe autonomic dysfunction in patients with MSA-C. The period of only cerebellar ataxia (mono system atrophy) may extend to more than 10 years. Understanding mono system atrophy is vital for the early diagnosis and drug development for MSA. In this review, we discuss mono system atrophy focusing on the concept and natural history and the possibility of the of early diagnosis and disease-modifying therapy for MSA.


Assuntos
Ataxia Cerebelar , Atrofia de Múltiplos Sistemas , Adulto , Ataxia , Atrofia/patologia , Ataxia Cerebelar/diagnóstico , Ataxia Cerebelar/tratamento farmacológico , Cerebelo , Humanos , Atrofia de Múltiplos Sistemas/diagnóstico , Atrofia de Múltiplos Sistemas/tratamento farmacológico , Atrofia de Múltiplos Sistemas/patologia
16.
Brain Nerve ; 72(9): 961-967, 2020 Sep.
Artigo em Japonês | MEDLINE | ID: mdl-32934185

RESUMO

Recently, the diagnostic criteria for idiopathic cerebellar ataxia (IDCA) have been proposed in Japan as a diagnosis to replace the clinical concept of cortical cerebellar atrophy, which was originally described as a neuropathological disorder. However, IDCA proposed in Japan may include various diseases such as multiple system atrophy with early stage, rare hereditary ataxias, and autoimmune-mediated cerebellar ataxia. We tackled this significant clinical challenge by detecting anti-cerebellar autoantibodies in patients' sera and identifying their target antigens. We detected anti-cerebellar autoantibodies in the sera of some patients diagnosed with IDCA in Japan. In the future, it will be necessary to confirm the efficacy of immunotherapy for anti-cerebellar autoantibody-positive cases among patients who were thought to be difficult to treat.


Assuntos
Ataxia Cerebelar , Atrofia , Autoanticorpos , Ataxia Cerebelar/diagnóstico , Ataxia Cerebelar/terapia , Cerebelo , Humanos , Japão
17.
Brain Nerve ; 72(9): 969-972, 2020 Sep.
Artigo em Japonês | MEDLINE | ID: mdl-32934186

RESUMO

Cortical cerebellar atrophy has been defined as a sporadic degenerative cerebellar disorder other than multiple system atrophy, whereas the term "idiopathic cerebellar ataxia (IDCA)" has been recently proposed by a Japanese expert group. There is no diagnostic biomarker for IDCA; therefore, the diagnosis largely depends on exclusion of other cerebellar diseases, such as multiple system atrophy and hereditary spinocerebellar ataxia. Other important differential diagnoses include immune-mediated cerebellar ataxia, such as Hashimoto's encephalopathy, gluten ataxia, anti-glutamic acid decarboxylase-positive cerebellar ataxia, alcoholic cerebellar degeneration, and drug-induced ataxia. Secondary cerebellar disorders are treatable and should be recognized and screened.


Assuntos
Ataxia Cerebelar , Doença de Hashimoto , Degenerações Espinocerebelares , Ataxia , Ataxia Cerebelar/diagnóstico , Diagnóstico Diferencial , Humanos , Degenerações Espinocerebelares/diagnóstico
18.
PLoS One ; 15(8): e0236808, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32750061

RESUMO

BACKGROUND: Ataxia with oculomotor apraxia type 1 (AOA1) is a rare autosomal recessive cerebellar ataxia, caused by mutations in the APTX gene. The disease is characterized by early-onset cerebellar ataxia, oculomotor apraxia and severe axonal polyneuropathy. The aim of this study was to detect the disease-causing variants in two unrelated consanguineous Jordanian families with cerebellar ataxia using whole exome sequencing (WES), and to correlate the identified mutation(s) with the clinical and cellular phenotypes. METHODS: WES was performed in three affected individuals and segregation analysis of p.W279* APTX candidate variant was performed. Expression levels of APTX were measured in patients' skin fibroblasts and peripheral blood mononuclear cells, followed by western blot analysis in skin fibroblasts. Genotoxicity assay was performed to detect the sensitivity of APTX mutated cells to H2O2, MMC, MMS and etoposide. RESULTS: A recurrent homozygous nonsense variant in APTX gene (c.837G>A, p.W279*) was revealed in all affected individuals. qRT-PCR showed normal APTX levels in peripheral blood and lower levels in fibroblast cells. However, western blot showed the absence of APTX protein in patients' skin fibroblasts. Significant hypersensitivity to H2O2, MMC and etoposide and lack of sensitivity to MMS were noted. CONCLUSIONS: This is the first study to report the identification of a nonsense variant in the APTX gene (c.837G>A; p.W279*) in AOA1 patients within the Jordanian population. This study confirmed the need of WES to assist in the diagnosis of cerebellar ataxia and it emphasizes the importance of studying the pathophysiology of the APTX gene.


Assuntos
Ataxia Cerebelar/genética , Códon sem Sentido , Dano ao DNA , Proteínas de Ligação a DNA/genética , Proteínas Nucleares/genética , Criança , Pré-Escolar , Consanguinidade , DNA/efeitos dos fármacos , Feminino , Humanos , Masculino , Mutagênicos/farmacologia , Sequenciamento Completo do Exoma
20.
Science ; 369(6507)2020 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-32855309

RESUMO

Neuronal synapses undergo structural and functional changes throughout life, which are essential for nervous system physiology. However, these changes may also perturb the excitatory-inhibitory neurotransmission balance and trigger neuropsychiatric and neurological disorders. Molecular tools to restore this balance are highly desirable. Here, we designed and characterized CPTX, a synthetic synaptic organizer combining structural elements from cerebellin-1 and neuronal pentraxin-1. CPTX can interact with presynaptic neurexins and postsynaptic AMPA-type ionotropic glutamate receptors and induced the formation of excitatory synapses both in vitro and in vivo. CPTX restored synaptic functions, motor coordination, spatial and contextual memories, and locomotion in mouse models for cerebellar ataxia, Alzheimer's disease, and spinal cord injury, respectively. Thus, CPTX represents a prototype for structure-guided biologics that can efficiently repair or remodel neuronal circuits.


Assuntos
Proteína C-Reativa/farmacologia , Proteínas do Tecido Nervoso/farmacologia , Vias Neurais/efeitos dos fármacos , Precursores de Proteínas/farmacologia , Receptores de AMPA/metabolismo , Proteínas Recombinantes/farmacologia , Sinapses/efeitos dos fármacos , Doença de Alzheimer/terapia , Animais , Proteína C-Reativa/química , Proteína C-Reativa/uso terapêutico , Ataxia Cerebelar/terapia , Modelos Animais de Doenças , Células HEK293 , Hipocampo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/uso terapêutico , Domínios Proteicos , Precursores de Proteínas/química , Precursores de Proteínas/uso terapêutico , Receptores de Glutamato/genética , Proteínas Recombinantes/química , Proteínas Recombinantes/uso terapêutico , Coluna Vertebral/efeitos dos fármacos , Coluna Vertebral/fisiologia
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