Assuntos
Encefalite , Encefalite Límbica , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Autoanticorpos , Encefalite/complicações , Encefalite/diagnóstico por imagem , Humanos , Encefalite Límbica/complicações , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/diagnóstico por imagem , Proteínas de Membrana , Carcinoma de Pequenas Células do Pulmão/complicações , Carcinoma de Pequenas Células do Pulmão/diagnóstico por imagemRESUMO
Corticobasal syndrome is generally considered to be a sporadic condition. There are familial and isolated genetic cases, associated with GRN, MAPT, c9orf72 or PNRP variants. Some reports implicate other genes: LRRK2, CHMP2B, GBA, CYP27A1, PSEN1, APP, TARDBP and TBK1. Here, we report a case of a patient carrying a SQSTM1 Pro392Leu variant. We report a 57-year-old right-handed-woman with a history of progressive speech impairment, marked right side rigidity and bradykinesia, with rest tremor and stimulus sensitive myoclonus. She had predominantly right-sided apraxia. She had right side agraphestesia and astereognosis. MRI showed asymmetrical left frontotemporoparietal atrophy. DaTSCAN showed predominantly left involvement, PiB-PET was negative. CSF NfL was of 9356.5pg/mL. She carried a heterozygous variant P392L in SQSTM1. This case report expands the spectrum of phenotypes associated with SQSTM1 pathogenic variants. It also expands the list of genes associated with corticobasal syndrome, supporting the involvement of the ubiquitin-proteasome system in this condition.
Assuntos
Afasia Primária Progressiva não Fluente , Proteína Sequestossoma-1 , Humanos , Feminino , Pessoa de Meia-Idade , Proteína Sequestossoma-1/genética , Afasia Primária Progressiva não Fluente/genética , Degeneração Corticobasal/genética , Degeneração Corticobasal/complicaçõesRESUMO
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and retinal vasculopathy with cerebral leukodystrophy and systemic manifestations (RVCL-S) are the most common forms of rare monogenic early-onset cerebral small vessel disease and share clinical, and, to different extents, neuroradiological and neuropathological features. However, whether CADASIL and RVCL-S overlapping phenotype may be explained by shared genetic risk or causative factors such as TREX1 coding variants remains poorly understood. To investigate this intriguing hypothesis, we used exome sequencing to screen TREX1 protein-coding variability in a large multi-ethnic cohort of 180 early-onset independent familial and apparently sporadic CADASIL-like Caucasian patients from the USA, Portugal, Finland, Serbia and Turkey. We report 2 very rare and likely pathogenic TREX1 mutations: a loss of function mutation (p.Ala129fs) clustering in the catalytic domain, in an apparently sporadic 46-year-old patient from the USA and a missense mutation (p.Tyr305Cys) in the well conserved C-terminal region, in a 57-year-old patient with positive family history from Serbia. In concert with recent findings, our study expands the clinical spectrum of diseases associated with TREX1 mutations.
Assuntos
CADASIL , Doenças de Pequenos Vasos Cerebrais , Leucoencefalopatias , Humanos , CADASIL/genética , Infarto Cerebral , Doenças de Pequenos Vasos Cerebrais/complicações , Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/genética , Mutação/genética , Receptor Notch3/genéticaRESUMO
PURPOSE: Patients with Parkinson's and Huntington's Disease (PD and HD) present impairments in cognitively challenging everyday activities. This study contrasts these two basal ganglia disorders on the ability to perform daily life- like tasks and their level of awareness regarding the disease impact on function. METHODS: 19 controls, 10 early-onset PD, 20 early stage PD, and 15 early manifest HD patients were compared in the "EcoKitchen," a virtual reality task with increasing executive load, the "Behavioural Assessment of Dysexecutive Syndrome battery - BADS," and "The Adults and Older Adults Functional Assessment Inventory - IAFAI," a self-report functional questionnaire. The EcoKitchen clinical correlates were investigated. RESULTS: All clinical groups presented slower EcoKitchen performance than controls, however, only HD patients showed decreased accuracy. HD and PD patients exhibited reduced BADS scores compared to the other study participants. Importantly, on the IAFAI, PD patients signalled more physically related incapacities and HD patients indicated more cognitively related incapacities. Accordingly, the EcoKitchen performance was significantly associated with PD motor symptom severity. CONCLUSIONS: Our findings suggest differential disease impact on cognition and function across PD and HD patients, with preserved awareness regarding disease- related functional sequelae. These observations have important implications for clinical management, research and rehabilitation.Implications for rehabilitationPatients with early stage Parkinson's and Huntington's disease have diagnosis-specific impairments in the performance of executively demanding everyday activities and, yet, show preserved awareness about the disease impact on their daily life.An active involvement of patients in the rehabilitation process should be encouraged, as their appraisal of the disease effects can help on practical decisions about meaningful targets for intervention, vocational choices, quality-of-life issues and/or specific everyday skills to boost.The EcoKitchen, a non-immersive virtual reality task, can detect and quantify early deficits in everyday-like tasks and is therefore a valuable tool for assessing the effects of rehabilitation strategies on the functional cognition of these patients.Rehabilitation efforts in the mild stages of Parkinson's and Huntington's disease should be aware of greater time needs from the patients in the performance of daily life tasks, target executive skills, and give a more prominent role to patients in symptoms report and management.
Assuntos
Transtornos Cognitivos , Doença de Huntington , Doença de Parkinson , Idoso , Cognição , Transtornos Cognitivos/complicações , Humanos , Doença de Huntington/complicações , Doença de Huntington/diagnóstico , Testes NeuropsicológicosRESUMO
Mutations in GIGYF2 have recently been described as causative of Parkinson's disease in Europeans. In an attempt to replicate these results in independent populations, we sequenced the entire coding region of GIGYF2 in a large series of Portuguese and North American samples. We report the finding of two of the previously published mutations in neurologically normal Control individuals. This suggests that mutations in GIGYF2 are not strongly related to the development of the disease in either of these populations.
Assuntos
Proteínas de Transporte/genética , Doença de Parkinson/genética , Idoso , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Doença de Parkinson/epidemiologia , Polimorfismo de Nucleotídeo Único , Portugal/epidemiologia , Reprodutibilidade dos Testes , Estados Unidos/epidemiologiaRESUMO
Recently, several genome-wide association studies identified PHACTR1 as key locus for five diverse vascular disorders: coronary artery disease, migraine, fibromuscular dysplasia, cervical artery dissection and hypertension. Although these represent significant risk factors or comorbidities for ischemic stroke, PHACTR1 role in brain small vessel ischemic disease and ischemic stroke most important survival mechanism, such as the recruitment of brain collateral arteries like posterior communicating arteries (PcomAs), remains unknown. Therefore, we applied exome and genome sequencing in a multi-ethnic cohort of 180 early-onset independent familial and apparently sporadic brain small vessel ischemic disease and CADASIL-like Caucasian patients from US, Portugal, Finland, Serbia and Turkey and in 2 C57BL/6J stroke mouse models (bilateral common carotid artery stenosis [BCCAS] and middle cerebral artery occlusion [MCAO]), characterized by different degrees of PcomAs patency. We report 3 very rare coding variants in the small vessel ischemic disease-CADASIL-like cohort (p.Glu198Gln, p.Arg204Gly, p.Val251Leu) and a stop-gain mutation (p.Gln273*) in one MCAO mouse. These coding variants do not cluster in PHACTR1 known pathogenic domains and are not likely to play a critical role in small vessel ischemic disease or brain collateral circulation. We also exclude the possibility that copy number variants (CNVs) or a variant enrichment in Phactr1 may be associated with PcomA recruitment in BCCAS mice or linked to diverse vascular traits (cerebral blood flow pre-surgery, PcomA size, leptomeningeal microcollateral length and junction density during brain hypoperfusion) in C57BL/6J mice, respectively. Genetic variability in PHACTR1 is not likely to be a common susceptibility factor influencing small vessel ischemic disease in patients and PcomA recruitment in C57BL/6J mice. Nonetheless, rare variants in PHACTR1 RPEL domains may influence the stroke outcome and are worth investigating in a larger cohort of small vessel ischemic disease patients, different ischemic stroke subtypes and with functional studies.
Assuntos
Isquemia Encefálica , Proteínas dos Microfilamentos , Mutação de Sentido Incorreto , Acidente Vascular Cerebral , Idoso , Substituição de Aminoácidos , Animais , Isquemia Encefálica/genética , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Pessoa de Meia-Idade , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologiaRESUMO
Pathological basal ganglia calcification, or Fahr's Syndrome, can be secondary to a variety of diseases, namely parathyroid disturbances. Movement disorders are common clinical features, in which chorea is seen in less than 20% of cases and dystonia just in 8%. We report the clinical case of a 49-year-old male with a history of thyroidectomy, who was admitted in Emergency Service with acute generalized chorea and focal painful feet dystonia. Laboratory analysis showed hypocalcemia and rhabdomyolysis, and computed tomography scan revealed parenchymal calcification with basal ganglia involvement. After complementary studies we established a Fahr's Syndrome diagnosis secondary to an iatrogenic hypoparathyroidism. Clinical management has been successful with stabilized calcium levels, with no more neurologic symptoms. Hypocalcemia should be readily investigated and treated after a thyroidectomy, given the irreversibility of intracerebral calcifications and potential neurological or systemic consequences.
A calcificação dos núcleos da base, ou síndrome de Fahr, pode ser secundária a variadas doenças, nomeadamente as que cursam com envolvimento da paratiróide. Distúrbios do movimento são achados clínicos comuns, mas a coreia é observada em menos de 20% dos casos e a distonia apenas em 8%. Apresentamos o caso de um homem de 49 anos com antecedentes de tiroidectomia, admitido no serviço de urgência com coreia aguda generalizada e distonia focal dolorosa dos pés, cujo estudo laboratorial revelava hipocalcémia e rabdomiólise e a tomografia computorizada crânio-encefálica mostrava calcificações parenquimatosas extensas com envolvimento dos núcleos da base. A alargada investigação complementar permitiu fazer o diagnóstico de síndrome de Fahr secundária a hipoparatiroidismo iatrogénico. Após estabilização da calcémia, a evolução clínica foi favorável com resolução dos sintomasneurológicos. A hipocalcémia deve ser investigada e corrigida depois de tiroidectomias, dada a irreversibilidade das calcificações intracerebrais e as potenciais consequências neurológicas e sistémicas.
Assuntos
Doenças dos Gânglios da Base/etiologia , Calcinose/etiologia , Coreia/etiologia , Distonia/etiologia , Hipoparatireoidismo/complicações , Doenças Neurodegenerativas/etiologia , Doenças dos Gânglios da Base/diagnóstico , Calcinose/diagnóstico , Humanos , Hipocalcemia/diagnóstico , Hipocalcemia/etiologia , Doença Iatrogênica , Masculino , Pessoa de Meia-Idade , Doenças Neurodegenerativas/diagnóstico , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/etiologia , Tireoidectomia/efeitos adversos , Tomografia Computadorizada por Raios XRESUMO
Dopamine dysregulation syndrome is a rare complication of Parkinson's disease (PD) treatment. We present a 70-year-old woman with a long-standing PD and a clinical picture compatible with dopaminergic dysregulation, which was ultimately revealed to be induced by her companion. Patient's exuberant choreiform dyskinesia led to a potential financial advantage when performed outside the hospital but excessive dopamine intake also occurred during hospital admission, without any obvious reward for the abuser. Even in cases where there is no place for a definitive diagnosis, deceptive behaviours must be identified as their management is based on psychological and social support in parallel to the adjustment of PD therapy.
Assuntos
Carbidopa/efeitos adversos , Transtornos Disruptivos, de Controle do Impulso e da Conduta/induzido quimicamente , Levodopa/efeitos adversos , Doença de Parkinson/tratamento farmacológico , Idoso , Carbidopa/administração & dosagem , Transtornos Disruptivos, de Controle do Impulso e da Conduta/diagnóstico , Combinação de Medicamentos , Feminino , Humanos , Levodopa/administração & dosagem , Transtornos Relacionados ao Uso de Substâncias/complicações , SíndromeRESUMO
BACKGROUND: Mutations in the genes PRKN and LRRK2 are the most frequent known genetic lesions among Parkinson's disease patients. We have previously reported that in the Portuguese population the LRRK2 c.6055G > A; p.G2019S mutation has one of the highest frequencies in Europe. METHODS: Here, we follow up on those results, screening not only LRRK2, but also PRKN, SNCA and PINK1 in a cohort of early-onset and late-onset familial Portuguese Parkinson disease patients. This series comprises 66 patients selected from a consecutive series of 132 patients. This selection was made in order to include only early onset patients (age at onset below 50 years) or late-onset patients with a positive family history (at least one affected relative). All genes were sequenced bi-directionally, and, additionally, SNCA, PRKN and PINK1 were subjected to gene dosage analysis. RESULTS: We found mutations both in LRRK2 and PRKN, while the remaining genes yielded no mutations. Seven of the studied patients showed pathogenic mutations, in homozygosity or compound heterozygosity for PRKN, and heterozygosity for LRRK2. CONCLUSION: Mutations are common in Portuguese patients with Parkinson's disease, and these results clearly have implications not only for the genetic diagnosis, but also for the genetic counseling of these patients.
Assuntos
Mutação/genética , Doença de Parkinson/genética , Proteínas Quinases/genética , Proteínas Serina-Treonina Quinases/genética , Ubiquitina-Proteína Ligases/genética , alfa-Sinucleína/genética , Idoso , Análise Mutacional de DNA , Éxons/genética , Saúde da Família , Feminino , Predisposição Genética para Doença , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Masculino , Metionina/genética , Pessoa de Meia-Idade , Doença de Parkinson/epidemiologia , Portugal/epidemiologia , Portugal/etnologia , Treonina/genéticaRESUMO
BACKGROUND: Pathological brain iron deposition has been implicated as a source of neurotoxic reactive oxygen species in Alzheimer (AD) and Parkinson diseases (PD). Iron metabolism is associated with the gene hemochromatosis (HFE Human genome nomenclature committee ID:4886), and mutations in HFE are a cause of the iron mismetabolism disease, hemochromatosis. Several reports have tested the association of HFE variants with neurodegenerative diseases, such as AD and PD with conflicting results. METHODS: Genotypes were analysed for the two most common variants of HFE in a series of 130 AD, 55 Mild Cognitive Impairment (MCI) and 132 PD patients. Additionally, a series of 115 healthy age-matched controls was also screened. RESULTS: A statistically significant association was found in the PD group when compared to controls, showing that the presence of the C282Y variant allele may confer higher risk for developing the disease. CONCLUSION: Taken together these results suggest that the common variants in HFE may be a risk factor for PD, but not for AD in the Portuguese population.
Assuntos
Doença de Alzheimer/genética , Transtornos Cognitivos/genética , Predisposição Genética para Doença/genética , Antígenos de Histocompatibilidade Classe I/genética , Distúrbios do Metabolismo do Ferro/genética , Proteínas de Membrana/genética , Doença de Parkinson/genética , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/fisiopatologia , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Transtornos Cognitivos/epidemiologia , Transtornos Cognitivos/fisiopatologia , Estudos de Coortes , Comorbidade , Análise Mutacional de DNA , Feminino , Frequência do Gene/genética , Testes Genéticos , Variação Genética/genética , Genótipo , Proteína da Hemocromatose , Humanos , Ferro/metabolismo , Distúrbios do Metabolismo do Ferro/epidemiologia , Distúrbios do Metabolismo do Ferro/fisiopatologia , Masculino , Pessoa de Meia-Idade , Mutação/genética , Doença de Parkinson/epidemiologia , Doença de Parkinson/fisiopatologia , Portugal/epidemiologia , Tamanho da Amostra , Distribuição por SexoRESUMO
Tremor frequency analysis is usually performed by EMG studies but accelerometers are progressively being more used. The iPhone® contains an accelerometer and many applications claim to be capable of measuring tremor frequency. We tested three applications in twenty-two patients with a diagnosis of PD, ET and Holmes' tremor. EMG needle assessment as well as accelerometry was performed at the same time. There was very strong correlation (Pearson >0.8, pâ<â0.001) between the three applications, the EMG needle and the accelerometry. Our data suggests the apps LiftPulse®, iSeismometer® and Studymytremor® are a reliable alternative to the EMG for tremor frequency assessment.
Assuntos
Acelerometria/normas , Eletromiografia/normas , Tremor Essencial/diagnóstico , Aplicações da Informática Médica , Monitorização Ambulatorial/normas , Doença de Parkinson/diagnóstico , Smartphone , Tremor/diagnóstico , Acelerometria/instrumentação , Idoso , Humanos , Pessoa de Meia-Idade , Monitorização Ambulatorial/instrumentação , Doença de Parkinson/complicações , Reprodutibilidade dos Testes , Tremor/etiologiaRESUMO
Sneddon syndrome is a rare clinical entity characterized by the association of ischemic cerebrovascular disease and livedo reticularis. The authors report a case of stroke and myocardial infarction in a 39-year-old man with Sneddon syndrome and antiphospholipid syndrome who subsequently met some criteria for systemic lupus erythematosus, highlighting the complexity of cardiovascular involvement in systemic diseases.
Assuntos
Síndrome Antifosfolipídica/complicações , Infarto do Miocárdio/etiologia , Síndrome de Sneddon/complicações , Acidente Vascular Cerebral/etiologia , Adulto , Humanos , MasculinoRESUMO
Mutations in the gene encoding beta-glucocerebrosidase, a lysosomal degrading enzyme, have recently been associated with the development of Parkinson disease. Here we report the results found in a cohort of Portuguese Parkinson disease patients and healthy age-matched controls for mutations in the aforementioned gene. This screening was accomplished by sequencing the complete open-reading frame, as well as intron/exon boundaries, of the glucocerebrosidase gene, in a total of 230 patients and 430 controls. We have found an increased number of Parkinson disease patients presenting mutations in GBA when compared to controls. These results, together with recent literature, clearly suggest a role of glucocerebrosidase in the development of Parkinson disease.
Assuntos
Encéfalo/enzimologia , Predisposição Genética para Doença/genética , Glucosilceramidase/genética , Mutação/genética , Doença de Parkinson/enzimologia , Doença de Parkinson/genética , Encéfalo/fisiopatologia , Estudos de Casos e Controles , Estudos de Coortes , Análise Mutacional de DNA , Regulação Enzimológica da Expressão Gênica/genética , Frequência do Gene/genética , Marcadores Genéticos/genética , Testes Genéticos , Genótipo , Humanos , Fases de Leitura Aberta , Doença de Parkinson/diagnóstico , Polimorfismo Genético/genética , PortugalRESUMO
OBJECTIVE: To investigate the effects of nebicapone, a new catechol-O-methyltransferase (COMT) inhibitor, on levodopa pharmacokinetics, COMT activity, and motor fluctuations in Parkinson disease in comparison to placebo and entacapone. METHODS: Randomized, double-blind, placebo-controlled, 4-way crossover study consisting of 4 treatment periods (6-9 days duration each) in 19 patients (65.3 +/- 8.5 years) treated with carbidopa/levodopa 3 to 7 times per day. Nebicapone/entacapone/placebo and carbidopa/levodopa doses were administered concomitantly. At the end of each period, a levodopa test was performed, and levodopa and 3-O-methyldopa levels and COMT activity were assayed. RESULTS: After 75 mg nebicapone, 150 mg nebicapone, and 200 mg entacapone, levodopa area under the plasma concentration time curve significantly increased 28.1, 48.4, and 33.3%, and 3-O-methyldopa area under the plasma concentration time curve significantly decreased 59.2, 70.8, and 59.1%, respectively. Peak COMT inhibition was similar between active treatments, but extent of COMT inhibition was more sustained with 75 and 150 mg nebicapone than with 200 mg entacapone. After the levodopa test doses, ON time significantly increased 29 minutes with 75 mg nebicapone, 45 minutes with 150 mg nebicapone, and 16 minutes with 200 mg entacapone. Patients' diaries showed a decrease in daily OFF time of 109 minutes with 75 mg nebicapone, 103 minutes with 150 mg nebicapone, and 71 minutes with 200 mg entacapone, and an increase in daily ON time of 74, 101, and 74 minutes, respectively. Treatments were generally well tolerated and safe; no relevant changes in liver function tests were reported. CONCLUSIONS: Nebicapone, a new COMT inhibitor, significantly decreased COMT activity, increased systemic exposure to levodopa, and improved motor response. Nebicapone deserves further evaluation in larger samples of patients.
Assuntos
Acetofenonas/farmacologia , Antiparkinsonianos/farmacocinética , Inibidores de Catecol O-Metiltransferase , Inibidores Enzimáticos/farmacologia , Levodopa/farmacocinética , Doença de Parkinson/tratamento farmacológico , Adulto , Idoso , Antiparkinsonianos/farmacologia , Carbidopa/farmacologia , Catecóis/farmacologia , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Interações Medicamentosas , Feminino , Humanos , Levodopa/sangue , Masculino , Pessoa de Meia-Idade , Atividade Motora/efeitos dos fármacos , Nitrilas/farmacologia , Doença de Parkinson/sangue , Doença de Parkinson/enzimologia , Doença de Parkinson/fisiopatologia , PlacebosRESUMO
LRRK2 mutations have recently been described in families with Parkinson's disease. Here we show that one of them (G2019S) is present in 6% (7 of 124) unrelated cases of disease in a clinic-based sample series from central Portugal, but not present in 126 controls from the same population. Thus, LRRK2 mutations appear to be a common cause of typical Parkinson's disease and as such will alter clinical practice.