RESUMO
Three electrophysiological endophenotypes are routinely studied in schizophrenia (SCZ): smooth pursuit eye movement (SPEM) dysfunction, deficits in P50 auditory-evoked potential inhibition, and saccadic inhibition deficits. The current study aimed to investigate the relationship between the COMT val158met polymorphism and these three endophenotypes. One hundred four SCZ patients (DSM-IV-R criteria) and 89 healthy controls were included in this study. P50 auditory-evoked potential inhibition, antisaccade paradigm and SPEM were analyzed. All individuals were genotyped for the COMT val158met. SCZ patients showed a higher rate of deficits measured by the SPEM, antisaccade and P50 inhibition paradigms without association with COMT val158met. However, in our control group, we have found an association between the Val polymorphism and the smoking status. More importantly, we have found a higher accuracy of saccades during the predictive pursuit task associated to the Met polymorphism in controls but not in SCZ patients who were receiving antidopaminergic medications. This result is in line with the hypothesis of the relationship between the Met polymorphism of the COMT gene, a higher level of dopamine in the prefrontal cortex and the role of the fronto-cerebellar loop in smooth predictive pursuit.
Assuntos
Catecol O-Metiltransferase/genética , Potenciais Evocados Auditivos/fisiologia , Movimentos Oculares/fisiologia , Inibição Psicológica , Esquizofrenia/genética , Esquizofrenia/fisiopatologia , Filtro Sensorial/fisiologia , Adulto , Endofenótipos , Movimentos Oculares/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Filtro Sensorial/genética , Adulto JovemRESUMO
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder affecting carriers of the fragile X-premutation, who have an expanded CGG repeat in the 5'-UTR of the FMR1 gene. FXTAS is characterized by progressive development of intention tremor, ataxia, parkinsonism and neuropsychological problems. The disease is thought to be caused by a toxic RNA gain-of-function mechanism, and the major hallmark of the disease is ubiquitin-positive intranuclear inclusions in neurons and astrocytes. We have developed a new transgenic mouse model in which we can induce expression of an expanded repeat in the brain upon doxycycline (dox) exposure (i.e. Tet-On mice). This Tet-On model makes use of the PrP-rtTA driver and allows us to study disease progression and possibilities of reversibility. In these mice, 8 weeks of dox exposure was sufficient to induce the formation of ubiquitin-positive intranuclear inclusions, which also stain positive for the RAN translation product FMRpolyG. Formation of these inclusions is reversible after stopping expression of the expanded CGG RNA at an early developmental stage. Furthermore, we observed a deficit in the compensatory eye movements of mice with inclusions, a functional phenotype that could be reduced by stopping expression of the expanded CGG RNA early in the disease development. Taken together, this study shows, for the first time, the potential of disease reversibility and suggests that early intervention might be beneficial for FXTAS patients.
Assuntos
Ataxia/genética , Ataxia/fisiopatologia , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/fisiopatologia , Tremor/genética , Tremor/fisiopatologia , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Modelos Animais de Doenças , Movimentos Oculares/genética , Expressão Gênica , Genes Reporter , Humanos , Corpos de Inclusão Intranuclear/patologia , Camundongos , Camundongos Transgênicos , Peptídeos/metabolismo , Ligação Proteica , Transporte Proteico , Expansão das Repetições de Trinucleotídeos , Ubiquitina/metabolismoRESUMO
The neuroactive peptide calcitonin-gene related peptide (CGRP) is known to act at efferent synapses and their targets in hair cell organs, including the cochlea and lateral line. CGRP is also expressed in vestibular efferent neurons as well as a number of central vestibular neurons. Although CGRP-null (-/-) mice demonstrate a significant reduction in cochlear nerve sound-evoked activity compared with wild-type mice, it is unknown whether and how the loss of CGRP influence vestibular system function. Vestibular function was assessed by quantifying the vestibulo-ocular reflex (VOR) in alert mice. The loss of CGRP in (-/-) mice was associated with a reduction of the VOR gain of ≈50% without a concomitant change in phase. Using immunohistochemistry, we confirmed that, although CGRP staining was absent in the vestibular end-organs of null (-/-) mice, cholinergic staining appeared normal, suggesting that the overall gross development of vestibular efferent innervation was unaltered. We further confirmed that the observed deficit in vestibular function of null (-/-) mice was not the result of nontargeted effects at the level of the extraocular motor neurons and/or their innervation of extraocular muscles. Analysis of the relationship between vestibular quick phase amplitude and peak velocity revealed that extraocular motor function was unchanged, and immunohistochemistry revealed no abnormalities in motor endplates. Together, our findings show that the neurotransmitter CGRP plays a key role in ensuring VOR efficacy.
Assuntos
Peptídeo Relacionado com Gene de Calcitonina/deficiência , Reflexo Vestíbulo-Ocular/genética , Análise de Variância , Animais , Toxinas Botulínicas Tipo A/metabolismo , Calbindina 2/metabolismo , Peptídeo Relacionado com Gene de Calcitonina/genética , Colina O-Acetiltransferase/metabolismo , Movimentos Oculares/genética , Feminino , Regulação da Expressão Gênica/genética , Masculino , Camundongos , Camundongos Knockout , Miosina VIIa , Miosinas/metabolismo , Vestíbulo do Labirinto/metabolismoRESUMO
Neurofibromatosis type 1 (NF1) is an autosomal dominantly inherited disease, characterized by various neurocutaneous symptoms, cognitive impairments and problems in fine and gross motor performance. Although cognitive deficits in NF1 have been attributed to increased release of the inhibitory neurotransmitter γ-amino butyric acid (GABA) in the hippocampus, the origin of the motor deficits is unknown. Cerebellar Purkinje cells, the sole output neurons of the cerebellar cortex, are GABAergic neurons and express neurofibromin at high levels, suggesting an important role for the cerebellum in the observed motor deficits in NF1. To test this, we determined the cerebellar contribution to motor problems in Nf1(+/-) mice, a validated mouse model for NF1. Using the Rotarod, a non-specific motor performance test, we confirmed that, like NF1 patients, Nf1(+/-) mice have motor deficits. Next, to evaluate the role of the cerebellum in these deficits, mice were subjected to cerebellum-specific motor performance and learning tests. Nf1(+/-) mice showed no impairment on the Erasmus ladder, as step time and number of missteps were not different. Furthermore, when compensatory eye movements were tested, no performance deficits were found in the optokinetic reflex and vestibulo-ocular reflex in the dark (VOR) or in the light (VVOR). Finally, Nf1(+/-) mice successfully completed short- and long-term VOR adaptation paradigms, tests that both depend on cerebellar function. Thus, despite the confirmed presence of motor performance problems in Nf1(+/-) mice, we found no indication of a cerebellar component. These results, combined with recent clinical data, suggest that cerebellar function is not overtly affected in NF1 patients.
Assuntos
Cerebelo/fisiopatologia , Atividade Motora/genética , Transtornos das Habilidades Motoras/etiologia , Neurofibromatose 1/genética , Células de Purkinje/fisiologia , Animais , Movimentos Oculares/genética , Genes da Neurofibromatose 1 , Força da Mão/fisiologia , Heterozigoto , Aprendizagem/fisiologia , Camundongos , Camundongos Mutantes Neurológicos , Transtornos das Habilidades Motoras/genética , Transtornos das Habilidades Motoras/fisiopatologia , Neurofibromina 1/genética , Teste de Desempenho do Rota-RodRESUMO
PURPOSE: Two Chinese families (XT and YT) with congenital fibrosis of the extraocular muscles (CFEOM) were identified. The purpose of this study was to determine if previously described Homo sapiens kinesin family member 21A (KIF21A) mutations were responsible for CFEOM in these two Chinese pedigrees. METHODS: Clinical characterization and genetic studies were performed. Microsatellite genotyping for linkage to the CFEOM1 and CFEOM3 loci was performed. The probands were screened for KIF21A mutations by bidirectional direct sequencing. Once a mutation was detected in the proband, all other participating family members and 100 unrelated control normal individuals were screened for the mutation. RESULTS: All affected individuals in family XT shared the common manifestations of CFEOM1. Family YT had two affected individuals, a mother and a daughter. The daughter had CFEOM1, while her mother never had congential ptosis but did have limited extraocular movements status post strabismus surgery. Haplotype analysis revealed that pedigree XT was linked to the 12q CFEOM1 locus and the affected memberes harbored the second most common missense mutation in KIF21A (2,861G>A, R954Q). Family YT harbored the most common missense de novo mutation in KIF21A (2,860C>T, R954W). Both of these mutations have been previously described. CONCLUSIONS: The observation of these two KIF21A mutations in a Chinese pedigree underscores the homogeneity of these mutations as a cause of CFEOM1 and CFEOM3 across ethnic divisions.
Assuntos
Povo Asiático/genética , Cinesinas/genética , Mutação/genética , Transtornos da Motilidade Ocular/congênito , Transtornos da Motilidade Ocular/genética , Músculos Oculomotores/patologia , Adolescente , Sequência de Bases , China , Análise Mutacional de DNA , Movimentos Oculares/genética , Família , Feminino , Fibrose , Haplótipos/genética , Humanos , Escore Lod , Masculino , Repetições de Microssatélites/genética , Dados de Sequência Molecular , Transtornos da Motilidade Ocular/fisiopatologia , Músculos Oculomotores/fisiopatologia , LinhagemRESUMO
Tay-Sachs disease is a genetically determined neurodegenerative disorder, resulting from mutations of the hexosaminidase (Hex) A gene coding for the alpha-subunit of beta-D-N-acetyl-hexosaminidase. Clinically, there is severe encephalomyelopathy leading to death within the first few years of life. Hex A activity is usually absent in tissue and body fluids of these patients. Juvenile and adult Hex A deficiencies are less severe but rare variants with some residual Hex A activity. All these variants are most prevalent among Ashkenazi Jews. We describe a non-Jewish family in which four adult brothers and sisters had markedly reduced Hex A activities and onset of symptoms in the second decade of life. The phenotypical expression was remarkably homogeneous, consisting in a combination of slowly progressive motor neuron disease, ataxia and ocular motor disturbances. None of the patients were demented at this stage of their illness. Magnetic resonance studies showed severe cerebellar atrophy, but were otherwise normal. Hex A deficiency was established by biochemical measurements in the serum and skin fibroblasts using the fluorogenic substrates 4-MUG and 4-MUGS as well as by gel electrophoresis. Molecular genetic studies revealed that the patients are compound heterozygotes for the 'adult' mutation Gly269 --> Ser and the 'infantile' 4-base insertion in exon 11 of the Hex A gene.
Assuntos
Ataxia Cerebelar/diagnóstico , Músculos Oculomotores/fisiopatologia , beta-N-Acetil-Hexosaminidases/deficiência , Adulto , Idade de Início , Biópsia , Ataxia Cerebelar/complicações , Ataxia Cerebelar/genética , DNA/análise , Éxons/genética , Movimentos Oculares/genética , Feminino , Hexosaminidase A , Humanos , Imageamento por Ressonância Magnética , Masculino , Doença dos Neurônios Motores/complicações , Doença dos Neurônios Motores/diagnóstico , Doença dos Neurônios Motores/genética , Debilidade Muscular/etiologia , Debilidade Muscular/fisiopatologia , Condução Nervosa , Núcleo Familiar , Músculos Oculomotores/enzimologia , Linhagem , Fenótipo , Pele/inervação , Pele/patologia , Doença de Tay-Sachs/diagnóstico , Doença de Tay-Sachs/genética , beta-N-Acetil-Hexosaminidases/genéticaRESUMO
The success of the neurosciences in opening pathways to the understanding of psychotic disorders has led to enormous optimism about solutions to the mysteries of these illnesses. Yet the Holy Grail for this field--the discovery linkage between a chromosomal locus that is linked to a diseased gene--has thus far eluded us, whereas it has been grasped in such disorders as cystic fibrosis, Huntington's disease, and neurofibromatosis. This paper argues that those biological studies that bypass the psychological domain, and have directly attempted to find biochemical measures associated with schizophrenia, probably will not succeed. Seeking direct links from such molar behaviors as psychotic symptoms to molecular events has not worked in the past, and is not likely to work in the future. The approach recommended here focuses on working one's way from the behavioral through the psychological and psychophysiological levels toward the neural, biochemical and molecular levels. Psychology has much strength to contribute in the search for traits that broaden the phenotype of schizophrenia. Examples are given in the study of eye movement abnormalities as aids in the genetic exploration of schizophrenia.