RESUMO
OBJECTIVE: The aims of this study were to (i) explore psychotic experiences across the entire amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) spectrum from a clinical and genetic perspective, (ii) determine the rate of abnormal perceptual experiences across the five sensory modalities and (iii) explore the neurobiological factors that lead to psychosis vulnerability in ALS-FTD. METHODS: In a prospective case-controlled study design, 100 participants were enrolled including ALS (n = 37, 24% satisfied criteria for ALS-Plus), ALS-FTD (n = 11), bvFTD (n = 27) and healthy controls (n = 25). Psychotic experiences, perceptual abnormalities and psychosocial factors were determined by means of the clinical interview and carer and patient reports. Voxel-based morphometry analyses determined atrophy patterns in patients experiencing psychosis-like experiences and other perceptual abnormalities. RESULTS: The rates of psychotic experiences and abnormalities of perception in each sensory modality were high across the entire ALS-FTD continuum. The rate was highest in those with C9orf72 expansions. Rates were also high in patients with pure ALS including psychosis measured by carer-based reports (18%) and self-report measures of psychotic-like experiences (21%). In an ENTER regression model, social anxiety and ACE-III scores were the best predictors of psychosis proneness, accounting for 44% of the score variance. Psychosis-like experiences and perceptual abnormalities were associated with a predominantly frontal and temporal pattern of atrophy that extended to the cerebellum and centred on the anterior thalamus. INTERPRETATION: The model for psychosis proneness in ALS-FTD likely includes complex interactions between cognitive, social and neurobiological factors that determine vulnerability to psychosis and that may have relevance for individualised patient management.
Assuntos
Esclerose Lateral Amiotrófica/complicações , Demência Frontotemporal/complicações , Transtornos da Percepção/etiologia , Transtornos Psicóticos/etiologia , Idoso , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/patologia , Esclerose Lateral Amiotrófica/fisiopatologia , Proteína C9orf72 , Estudos de Casos e Controles , Feminino , Demência Frontotemporal/genética , Demência Frontotemporal/patologia , Demência Frontotemporal/fisiopatologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Transtornos da Percepção/genética , Transtornos da Percepção/patologia , Transtornos da Percepção/fisiopatologia , Estudos Prospectivos , Transtornos Psicóticos/genética , Transtornos Psicóticos/patologia , Transtornos Psicóticos/fisiopatologiaRESUMO
OBJECTIVE: Frontotemporal dementia (FTD) is typically associated with changes in behaviour, language and movement. However, recent studies have shown that patients can also develop an abnormal response to pain, either heightened or diminished. We aimed to investigate this symptom in mutation carriers within the Genetic FTD Initiative (GENFI). METHODS: Abnormal responsiveness to pain was measured in 462 GENFI participants: 281 mutation carriers and 181 mutation-negative controls. Changes in responsiveness to pain were scored as absent (0), questionable or very mild (0.5), mild (1), moderate (2) or severe (3). Mutation carriers were classified into C9orf72 (104), GRN (128) and MAPT (49) groups, and into presymptomatic and symptomatic stages. An ordinal logistic regression model was used to compare groups, adjusting for age and sex. Voxel-based morphometry was performed to identify neuroanatomical correlates of abnormal pain perception. RESULTS: Altered responsiveness to pain was present to a significantly greater extent in symptomatic C9orf72 expansion carriers than in controls: mean score 0.40 (SD 0.71) vs 0.00 (0.04), reported in 29% vs 1%. No significant differences were seen between the other symptomatic groups and controls, or any of the presymptomatic mutation carriers and controls. Neural correlates of altered pain perception in C9orf72 expansion carriers were the bilateral thalamus and striatum as well as a predominantly right-sided network of regions involving the orbitofrontal cortex, inferomedial temporal lobe and cerebellum. CONCLUSION: Changes in pain perception are a feature of C9orf72 expansion carriers, likely representing a disruption in somatosensory, homeostatic and semantic processing, underpinned by atrophy in a thalamo-cortico-striatal network.
Assuntos
Proteína C9orf72/genética , Córtex Cerebral/diagnóstico por imagem , Corpo Estriado/diagnóstico por imagem , Demência Frontotemporal/fisiopatologia , Percepção da Dor , Transtornos da Percepção/fisiopatologia , Tálamo/diagnóstico por imagem , Adulto , Idoso , Doenças Assintomáticas , Atrofia/diagnóstico por imagem , Atrofia/genética , Atrofia/fisiopatologia , Cerebelo/diagnóstico por imagem , Cerebelo/patologia , Córtex Cerebral/patologia , Estudos de Coortes , Corpo Estriado/patologia , Expansão das Repetições de DNA , Feminino , Demência Frontotemporal/diagnóstico por imagem , Demência Frontotemporal/genética , Humanos , Modelos Logísticos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Mutação , Transtornos da Percepção/diagnóstico por imagem , Transtornos da Percepção/genética , Córtex Pré-Frontal/diagnóstico por imagem , Córtex Pré-Frontal/patologia , Progranulinas/genética , Lobo Temporal/diagnóstico por imagem , Lobo Temporal/patologia , Tálamo/patologia , Proteínas tau/genéticaRESUMO
Handedness and language lateralization are the most investigated phenotypes among functional hemispheric asymmetries, i.e. differences in function between the left and the right half of the human brain. Both phenotypes are left hemisphere-dominant, while investigations of the molecular factors underlying right hemisphere-dominant phenotypes are less prominent. In the classical line bisection task, healthy subjects typically show a leftward attentional bias due to a relative dominance of the right hemisphere for visuospatial attention. Based on findings of variations in dopamine-related genes affecting performance in the line bisection task, we first tested whether DNA methylation in non-neuronal tissue in the promoter regions of DBH, SLC6A3, and DRD2 are associated with line bisection deviation. We replicated the typical behavioral pattern and found an effect of DNA methylation in the DBH promoter region on line bisection deviation in right-aligned trials. A second exploratory analysis indicated that an overall DNA methylation profile of genes involved in dopamine function predicts line bisection performance in right-aligned trials. Genetic variation in dopamine-related genes has been linked to attention deficit hyperactivity disorder (ADHD), a neurodevelopmental trait associated with rightward attentional bias. Overall, our findings point towards epigenetic markers for functional hemispheric asymmetries in non-neuronal tissue not only for left hemisphere-dominant, but also for right hemisphere-dominant phenotypes.
Assuntos
Atenção , Metilação de DNA , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Lateralidade Funcional/genética , Idioma , Transtornos da Percepção/genética , Regiões Promotoras Genéticas , Adulto , Encéfalo/fisiopatologia , Mapeamento Encefálico , Feminino , Humanos , Masculino , Desempenho Psicomotor , Percepção Espacial , Adulto JovemRESUMO
PURPOSE OF REVIEW: There is a clear unmet need for either the development of new drugs for the treatment of painful pathologies or the better use of the existing agents denoted by the lack of efficacy of many existing drugs in a number of patients, limitations of their use due to severity of side effects, and by the high number of drugs that fail to reach clinical efficacy from preclinical development. This account considers the efforts being made to better validate new analgesic components and to improve translational efficacy of existing drugs. RECENT FINDINGS: A better use of the available models and tools can improve the predictive validity of new analgesic drugs, as well as using intermediate steps when translating drugs to clinical context such as characterizing drugs using stem cell-sensory derived neurones. Profiling patient sensory phenotypes can decrease the number of failed clinical trials and improve patient outcome. SUMMARY: An integrative approach, comprising the use of complementary techniques to fully characterize drug profiles, is necessary to improve translational success of new analgesics.
Assuntos
Analgésicos/uso terapêutico , Desenvolvimento de Medicamentos/organização & administração , Dor/tratamento farmacológico , Analgésicos/administração & dosagem , Analgésicos/efeitos adversos , Animais , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Transtornos da Percepção/genética , Transtornos da Percepção/fisiopatologiaRESUMO
BACKGROUND: Visual-spatial neglect (VSN) is a neuropsychological syndrome, and right-hemisphere stroke is the most common cause. The pathogenetic mechanism of VSN remains unclear. This study aimed to investigate the behavioral and event-related potential (ERP) changes in patients with or without VSN after right-hemisphere stroke. METHODS: Eleven patients with VSN with right-hemisphere stroke (VSN group) and 11 patients with non-VSN with right-hemisphere stroke (non-VSN group) were recruited along with one control group of 11 age- and gender-matched healthy participants. The visual-spatial function was evaluated using behavioral tests, and ERP examinations were performed. RESULTS: The response times in the VSN and non-VSN groups were both prolonged compared with those of normal controls (Pâ<â0.001). In response to either valid or invalid cues in the left side, the accuracy in the VSN group was lower than that in the non-VSN group (Pâ<â0.001), and the accuracy in the non-VSN group was lower than that in controls (Pâ<â0.05). The P1 latency in the VSN group was significantly longer than that in the control group (F[2, 30]â=â5.494, Pâ=â0.009), and the N1 amplitude in the VSN group was significantly lower than that in the control group (F[2, 30]â=â4.343, Pâ=â0.022). When responding to right targets, the left-hemisphere P300 amplitude in the VSN group was significantly lower than that in the control group (F[2, 30]â=â4.255, Pâ=â0.025). With either left or right stimuli, the bilateral-hemisphere P300 latencies in the VSN and non-VSN groups were both significantly prolonged (all Pâ<â0.05), while the P300 latency did not differ significantly between the VSN and non-VSN groups (all Pâ>â0.05). CONCLUSIONS: Visual-spatial attention function is impaired after right-hemisphere stroke, and clinicians should be aware of the subclinical VSN. Our findings provide neuroelectrophysiological evidence for the lateralization of VSN.
Assuntos
Infarto Cerebral/fisiopatologia , Transtornos da Percepção/fisiopatologia , Acidente Vascular Cerebral/fisiopatologia , Adulto , Idoso , Eletrofisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Óxido Nítrico Sintase Tipo III/genética , PPAR gama/genética , Transtornos da Percepção/genética , Transtornos da Percepção/metabolismo , Polimorfismo Genético/genética , Tempo de Reação/genética , Tempo de Reação/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/metabolismo , Superóxido Dismutase/genéticaRESUMO
The occipital lobe contains a substantial part of the neural machinery involved in visual perception. Mutations in the LAMC3 gene have recently been shown to cause complex bilateral occipital cortical gyration abnormalities. However, to what extent these structural changes impact visual behavior is not known. We recorded responses for two screening test batteries targeting visual function (Leuven - Perceptual Organization Screening Test, Cortical Vision Screening Test) and measured eye fixation performance in a visual attention experiment from a patient with homozygous LAMC3 gene mutation. Using voxel-based morphometry (VBM) we quantitatively assessed the extent of structural changes brought on by the genetic mutation by comparing mean cortical curvature, cortical thickness, and gray matter volume in 34 cortical areas between patient and an age-, sex-, and education-matched control group. Anatomical connectivity between these cortical areas was investigated by a structural covariance analysis. Visual screening-, and behavioral results revealed that the patient's impairments were predominantly in visuo-spatial attention. Consistent with this, VBM and structural connectivity results revealed significant structural changes in cortical regions subserving attentional functions. We conclude that the LAMC3 gene mutation affects cortical areas beyond the occipital lobe and primarily those visual functions that involve heavily distributed networks - such as visuo-spatial attention.
Assuntos
Atenção/fisiologia , Córtex Cerebral/anormalidades , Movimentos Oculares/fisiologia , Laminina/genética , Rede Nervosa/anormalidades , Transtornos da Percepção/patologia , Transtornos da Percepção/fisiopatologia , Percepção Visual/fisiologia , Adulto , Córtex Cerebral/diagnóstico por imagem , Feminino , Humanos , Imageamento por Ressonância Magnética , Mutação , Rede Nervosa/diagnóstico por imagem , Neuroimagem , Lobo Occipital/anormalidades , Lobo Occipital/diagnóstico por imagem , Transtornos da Percepção/diagnóstico por imagem , Transtornos da Percepção/genéticaRESUMO
Synesthesia is a rare nonpathological phenomenon where stimulation of one sense automatically provokes a secondary perception in another. Hypothesized to result from differences in cortical wiring during development, synesthetes show atypical structural and functional neural connectivity, but the underlying molecular mechanisms are unknown. The trait also appears to be more common among people with autism spectrum disorder and savant abilities. Previous linkage studies searching for shared loci of large effect size across multiple families have had limited success. To address the critical lack of candidate genes, we applied whole-exome sequencing to three families with sound-color (auditory-visual) synesthesia affecting multiple relatives across three or more generations. We identified rare genetic variants that fully cosegregate with synesthesia in each family, uncovering 37 genes of interest. Consistent with reports indicating genetic heterogeneity, no variants were shared across families. Gene ontology analyses highlighted six genes-COL4A1, ITGA2, MYO10, ROBO3, SLC9A6, and SLIT2-associated with axonogenesis and expressed during early childhood when synesthetic associations are formed. These results are consistent with neuroimaging-based hypotheses about the role of hyperconnectivity in the etiology of synesthesia and offer a potential entry point into the neurobiology that organizes our sensory experiences.
Assuntos
Percepção Auditiva/genética , Axônios/fisiologia , Percepção de Cores/genética , Transtornos da Percepção/genética , Percepção Auditiva/fisiologia , Colágeno Tipo IV/genética , Percepção de Cores/fisiologia , Feminino , Expressão Gênica , Variação Genética , Humanos , Integrina alfa2/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Masculino , Miosinas/genética , Proteínas do Tecido Nervoso/genética , Linhagem , Transtornos da Percepção/etiologia , Proteínas RGS/genética , Receptores de Superfície Celular , Receptores Imunológicos/genética , Trocadores de Sódio-Hidrogênio/genética , SinestesiaRESUMO
Posterior cortical atrophy (PCA) is a rare neurodegenerative syndrome characterized by initial predominant visuoperceptual deficits followed by a progressive decline in other cognitive functions. This syndrome has not been as thoroughly described as other dementias, particularly from a neuropsychological evolution perspective with only a few studies describing the evolution of its cognitive progression. In this investigation we review the literature on this rare condition and we perform a 7-year neuropsychological and neuroradiological follow-up of a 64-year-old man with PCA. The subject's deficits initially appeared in his visuoperceptual skills with later affectation appearing in language and other cognitive functions, this being coherent with the patient's parieto-temporal atrophy evolution.
Assuntos
Encefalopatias/complicações , Córtex Cerebral/diagnóstico por imagem , Transtornos Cognitivos/etiologia , Transtornos da Percepção/etiologia , Atrofia/complicações , Atrofia/diagnóstico por imagem , Encefalopatias/genética , Transtornos Cognitivos/diagnóstico por imagem , Transtornos Cognitivos/genética , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Neuroimagem , Testes Neuropsicológicos , Transtornos da Percepção/genética , Percepção Visual/fisiologiaRESUMO
Endocannabinoids (ECBs) depress transmitter release at sites throughout the brain. Here, we describe another form of ECB signaling that triggers a novel form of long-term potentiation (LTP) localized to the lateral perforant path (LPP) which conveys semantic information from cortex to hippocampus. Two cannabinoid CB1 receptor (CB1R) signaling cascades were identified in hippocampus. The first is pregnenolone sensitive, targets vesicular protein Munc18-1 and depresses transmitter release; this cascade is engaged by CB1Rs in Schaffer-Commissural afferents to CA1 but not in the LPP, and it does not contribute to LTP. The second cascade is pregnenolone insensitive and LPP specific; it entails co-operative CB1R/ß1-integrin signaling to effect synaptic potentiation via stable enhancement of transmitter release. The latter cascade is engaged during LPP-dependent learning. These results link atypical ECB signaling to the encoding of a fundamental component of episodic memory and suggest a novel route whereby endogenous and exogenous cannabinoids affect cognition.
Assuntos
Córtex Cerebral/fisiologia , Endocanabinoides/metabolismo , Hipocampo/fisiologia , Memória/fisiologia , Vias Neurais/fisiologia , Transdução de Sinais/fisiologia , Animais , Inibidores Enzimáticos/farmacologia , GABAérgicos/farmacologia , Hipocampo/citologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Munc18/deficiência , Proteínas Munc18/genética , Vias Neurais/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Transtornos da Percepção/genética , Transtornos da Percepção/patologia , Piperidinas/farmacologia , Pirazóis/farmacologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacosRESUMO
Early detection may be the key to developing therapies that will combat Alzheimer's disease (AD). It has been consistently demonstrated that one of the main pathologies of AD, tau, is present in the brain decades before a clinical diagnosis. Tau pathology follows a stereotypical route through the medial temporal lobe beginning in the entorhinal and perirhinal cortices. If early pathology leads to very subtle changes in behavior, it may be possible to detect these changes in subjects years before a clinical diagnosis can currently be made. We aimed to discover if cognitively normal middle-aged adults (40-60 years old) at increased risk for AD due to family history would have impaired performance on a cognitive task known to challenge the perirhinal cortex. Using an oddity detection task, we found that subjects with a family history of AD had lowered accuracy without demonstrating differences in rate of acquisition. There were no differences between subjects' medial temporal lobe volume or cortical thickness, indicating that the changes in behavior were not due to significant atrophy. These results demonstrate that subtle changes in perceptual processing are detectable years before a typical diagnosis even when there are no differences detectable in structural imaging data. Anatomically-targeted cognitive testing may be useful in identifying subjects in the earliest stages of AD.
Assuntos
Doença de Alzheimer/complicações , Discriminação Psicológica/fisiologia , Saúde da Família , Transtornos da Percepção/etiologia , Reconhecimento Psicológico/fisiologia , Adulto , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/genética , Córtex Cerebral/diagnóstico por imagem , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Transtornos da Percepção/diagnóstico por imagem , Transtornos da Percepção/genética , Estimulação Luminosa , Detecção de Sinal PsicológicoRESUMO
Recent research into synaesthesia has highlighted the role of learning, yet synaesthesia is clearly a genetic condition. Here we ask how can the idea that synaesthesia reflects innate, genetic differences be reconciled with models that suggest it is driven by learning. A number of lines of evidence suggest that synaesthesia relies on, or at least interacts with, processes of multisensory integration that are common across all people. These include multisensory activations that arise in early regions of the brain as well as feedback from longer-term cross-modal associations generated in memory. These cognitive processes may interact independently to influence the phenomenology of the synaesthetic experience, as well as the individual differences within particular types of synaesthesia. The theoretical framework presented here is consistent with both an innate difference as the fundamental driver of the condition of synaesthesia, and with experiential and semantic influences on the eventual phenotype that emerges. In particular, it proposes that the internally generated synaesthetic percepts are treated similarly to other sensory information as the brain is learning the multisensory attributes of objects and developing cross-modal associations that merge in the concept of the object.
Assuntos
Encéfalo/fisiopatologia , Aprendizagem , Modelos Psicológicos , Transtornos da Percepção/fisiopatologia , Transtornos da Percepção/psicologia , Percepção Auditiva , Humanos , Individualidade , Memória , Transtornos da Percepção/genética , Fenótipo , Semântica , Sinestesia , Percepção VisualRESUMO
Erroneous activation of the pain-sensing system, as in chronic or neuropathic pain, represents a major health burden with insufficient treatment options. However, the study of genetic disorders rendering individuals completely unable to feel pain offers hope. All causes of congenital painlessness affect nociceptors, evolutionarily conserved specialist neurons able to sense all type of tissue damage. The discovery of new genes essential for sensing pain (SCN11A, PRDM12, and CLTCL1) has provided unexpected insights into the biological mechanisms that drive distinct stages of nociception. Drugs targeting two previously discovered painlessness genes, NGF and SCN9A, are currently in late-stage clinical trials; thus, characterization of these new painlessness genes has significant potential for the generation of new classes of analgesics.
Assuntos
Nociceptores/fisiologia , Percepção da Dor/fisiologia , Transtornos da Percepção/genética , Proteínas de Transporte/genética , Cadeias Pesadas de Clatrina/genética , Humanos , Canal de Sódio Disparado por Voltagem NAV1.9/genética , Proteínas do Tecido Nervoso/genética , Neurônios/fisiologia , Transtornos da Percepção/fisiopatologiaRESUMO
There are a number of cognitive models of autism that aim to explain how mental processes are handled differently in the condition. These models make claims about the nature of cognitive function in people with autism, and suggest that these differences applied in social contexts lead to the characteristic behavioural patterns. However, it is difficult to study these cognitive differences directly because of the complexity of social situations. Studies of perceptual function are tempting as an alternative way to study cognition because it is far easier to control the conditions and the stimuli that participants are exposed to. This makes hypothesis generation and interpretation of results more objective and more convincing. However, the study of perception in autism hasn't been very productive in contributing towards a model of cognition in autism. In many areas there are studies reporting contradictory results, preventing arrival at a consensus about the largest unresolved issues in the area. These studies tend to be repeated multiple times, but continue to provide contradictory evidence that doesn't allow us to place confidence in any of the cognitive models. An approach to these issues is proposed, focusing on critical analysis of contradictory studies rather than the endless process of repetition. This allows previous studies to be interpreted more objectively and resolve conflicts, and guides the design of future studies in ways that avoid the pitfalls that have been identified. Both of these outcomes result in more productive work being done. The first example is in the study of motion perception in autism, where the use of non-identical stimuli has been problematic. On closer critical analysis, a fundamental aspect of the motion stimuli demonstrates that the contradictions might be expected based on the differences in stimuli used. Addressing this issue can move the field towards resolution. A second example is in the study of spatial frequency sensitivity. Here, poor study design has created results leading to an "eagle-eyed visual acuity" hypothesis of autism. Errors in the initial study are revealed, suggesting that the model should be abandoned. Finally, a general issue is the assumption of homogeneity of perceptual ability and genetics in autism, where the reality is that subgroups exist within the population of people with autism, and significant variation exists between them. The evidence for this is summarised and the issues that it creates explored.
Assuntos
Transtorno do Espectro Autista/psicologia , Cognição , Modelos Psicológicos , Transtornos da Percepção/psicologia , Transtorno do Espectro Autista/diagnóstico , Transtorno do Espectro Autista/genética , Emoções , Humanos , Percepção de Movimento , Reconhecimento Visual de Modelos , Transtornos da Percepção/diagnóstico , Transtornos da Percepção/genética , Fenótipo , Meio Social , Aprendizagem EspacialRESUMO
Dyslexia is a specific impairment in reading that affects 1 in 10 people. Previous studies have failed to isolate a single cause of the disorder, but several candidate genes have been reported. We measured motion perception in two groups of dyslexics, with and without a deletion within the DCDC2 gene, a risk gene for dyslexia. We found impairment for motion particularly strong at high spatial frequencies in the population carrying the deletion. The data suggest that deficits in motion processing occur in a specific genotype, rather than the entire dyslexia population, contributing to the large variability in impairment of motion thresholds in dyslexia reported in the literature.
Assuntos
Dislexia/diagnóstico , Dislexia/genética , Deleção de Genes , Proteínas Associadas aos Microtúbulos/genética , Percepção de Movimento/fisiologia , Transtornos da Percepção/diagnóstico , Transtornos da Percepção/genética , Adolescente , Dislexia/epidemiologia , Feminino , Humanos , Masculino , Transtornos da Percepção/epidemiologia , Estimulação Luminosa/métodos , Adulto JovemRESUMO
Colored-sequence synesthesia (CSS) is a neurological condition in which sequential stimuli such as letters, numbers, or days of the week trigger simultaneous, involuntary color perception. Although the condition appears to run in families and several studies have sought a genetic link, the genetic contribution to synesthesia remains unclear. We conducted the first comparative twin study of CSS and found that CSS has a pairwise concordance of 73.9% in monozygotic twins, and a pairwise concordance of 36.4% in dizygotic twins. In line with previous studies, our results suggest a heritable element of synesthesia. However, consonant with the findings of previous single-pair case studies, our large sample size verifies that synesthesia is not completely conferred by genetics; if it were, monozygotic twins should have 100% concordance. These findings implicate a genetic mechanism of CSS that may work differently than previously thought: collectively, our data suggest that synesthesia is a heritable condition with incomplete penetrance that is substantially influenced by epigenetic and environmental factors.
Assuntos
Transtornos da Percepção/genética , Epigênese Genética , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Sinestesia , Gêmeos Dizigóticos , Gêmeos MonozigóticosRESUMO
Mitochondrial complex III (CIII) deficiency comprises a group of complex and heterogeneous genetic disorders. TTC19 mutations constitute a rare cause of CIII deficiency and are associated with neurological disorders in childhood and adulthood. Herein, we describe a 27-year-old Japanese man with cerebellar ataxia, spastic paraparesis, loss of deep sensation, mild frontal lobe dysfunction and transient psychiatric symptoms. Brain magnetic resonance imaging showed cerebellar atrophy and bilateral high-intensity signals in the inferior olives and regions adjacent to periaqueductal gray matter, on T2-weighted images. On whole-exome sequencing, we detected a novel homozygous frameshift mutation c.157_158dup [p.Pro54Alafs*48] in TTC19. Mitochondrial enzyme assays confirmed mild impairment of CIII enzymatic activity in lymphoblasts, which was consistent with TTC19-related CIII deficiency. His symptoms and radiological findings demonstrated an early stage or mild form of this disease, and further clarify the characteristics of patients with rare TTC19 mutations.
Assuntos
Povo Asiático/genética , Ataxia Cerebelar/genética , Homozigoto , Proteínas de Membrana/genética , Proteínas Mitocondriais/genética , Mutação , Paraparesia Espástica/genética , Transtornos da Percepção/genética , Adulto , Encéfalo/patologia , Ataxia Cerebelar/diagnóstico , Análise Mutacional de DNA , Complexo de Proteínas da Cadeia de Transporte de Elétrons/metabolismo , Complexo III da Cadeia de Transporte de Elétrons/deficiência , Complexo III da Cadeia de Transporte de Elétrons/genética , Humanos , Japão , Imageamento por Ressonância Magnética , Masculino , Proteínas de Membrana/metabolismo , Mitocôndrias/genética , Mitocôndrias/metabolismo , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Paraparesia Espástica/diagnóstico , Transtornos da Percepção/diagnósticoRESUMO
In our study we analysed clinical and neuropsychological data in a cohort of 57 Sardinian patients with FTD (55 apparently unrelated and two belonging to the same family), who underwent genetic screening for the C9orf72 mutation. Eight out of 56 patients were found positive for the C9orf72 mutation representing 14% of the entire cohort and 31.6% of the familial cases (6/19). C9orf72 mutated patients differed from the other FTD cases of the cohort for a younger age of onset, higher frequency of familial history for FTD and higher prevalence of delusional psychotic symptoms and hallucinations. In the neuropsychological assessment, C9orf72 mutated patients differed from non-mutated for the high frequency of visuospatial dysfunction regarding constructional apraxia (p = 0.02). In conclusion, our study confirms that Sardinian FTD patients have peculiar genetic characteristics and that C9orf72 mutated patients have a distinctive clinical and neuropsychological profile that could help differentiate them from other FTD patients. In our cohort we found that constructional apraxia, rarely reported in FTD, can properly discriminate between C9orf72 mutated and non-mutated patients and contribute to broaden the neuropsychological profile in frontotemporal dementia associated with this mutation.
Assuntos
Apraxias/etiologia , Apraxias/genética , Demência Frontotemporal/complicações , Demência Frontotemporal/genética , Mutação/genética , Proteínas/genética , Idoso , Encéfalo/diagnóstico por imagem , Proteína C9orf72 , Estudos de Coortes , Feminino , Demência Frontotemporal/diagnóstico por imagem , Estudos de Associação Genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Transtornos da Percepção/etiologia , Transtornos da Percepção/genética , Fenótipo , Estimulação Luminosa , Tomografia Computadorizada de Emissão de Fóton ÚnicoRESUMO
Developmental dyslexia (DD) is a heritable neurodevelopmental reading disorder that could arise from auditory, visual, and cross-modal integration deficits. A deletion in intron 2 of the DCDC2 gene (hereafter DCDC2d) increases the risk for DD and related phenotypes. In this study, first we report that illusory visual motion perception-specifically processed by the magnocellular-dorsal (M-D) stream-is impaired in children with DD compared with age-matched and reading-level controls. Second, we test for the specificity of the DCDC2d effects on the M-D stream. Children with DD and DCDC2d need significantly more contrast to process illusory motion relative to their counterpart without DCDC2d and to age-matched and reading-level controls. Irrespective of the genetic variant, children with DD perform normally in the parvocellular-ventral task. Finally, we find that DCDC2d is associated with the illusory motion perception also in adult normal readers, showing that the M-D deficit is a potential neurobiological risk factor of DD rather than a simple effect of reading disorder. Our findings demonstrate, for the first time, that a specific neurocognitive dysfunction tapping the M-D stream is linked with a well-defined genetic susceptibility.
Assuntos
Dislexia , Deleção de Genes , Ilusões/genética , Íntrons/genética , Proteínas Associadas aos Microtúbulos/deficiência , Percepção de Movimento/fisiologia , Transtornos da Percepção/etiologia , Estudos de Casos e Controles , Criança , Dislexia/complicações , Dislexia/genética , Dislexia/patologia , Feminino , Predisposição Genética para Doença/genética , Humanos , Masculino , Proteínas Associadas aos Microtúbulos/genética , Testes Neuropsicológicos , Transtornos da Percepção/genética , Estimulação LuminosaRESUMO
Angelman syndrome (AS) is a neurogenetic disorder characterized by intellectual disability, developmental delay, lack of speech, and epileptic seizures. Previous studies have indicated that children with AS due to 15q11.2-q13 deletions have a more severe developmental delay and present more often autistic features than those with AS caused by other genetic etiologies. The present study investigated the neurodevelopmental profiles of the different genetic etiologies of AS, and examined the evolution of mental development and autistic features over a 12-year period in children with a 15q11.2-q13 deletion. This study included 42 children with AS. Twelve had a Class I deletion, 18 had Class II deletions, three showed atypical large deletions, five had paternal uniparental disomy (pUPD) and four had UBE3A mutations. Children with a deletion (Class I and Class II) showed significantly reduced developmental age in terms of visual perception, receptive language, and expressive language when compared to those with a UBE3A mutation and pUPD. Within all subgroups, expressive language performance was significantly reduced when compared to the receptive performance. A follow-up study of seven AS cases with 15q11.2-q13 deletions revealed that over 12 years, the level of autistic features did not change, but both receptive and expressive language skills improved.