RESUMO
Primary dystonia is thought to emerge through abnormal functional relationships between basal ganglia and cerebellar motor circuits. These interactions may differ across disease subtypes and provide a novel biomarker for diagnosis and treatment. Using a network mapping algorithm based on resting-state functional MRI (rs-fMRI), a method that is readily implemented on conventional MRI scanners, we identified similar disease topographies in hereditary dystonia associated with the DYT1 or DYT6 mutations and in sporadic patients lacking these mutations. Both networks were characterized by contributions from the basal ganglia, cerebellum, thalamus, sensorimotor areas, as well as cortical association regions. Expression levels for the two networks were elevated in hereditary and sporadic dystonia, and in non-manifesting carriers of dystonia mutations. Nonetheless, the distribution of abnormal functional connections differed across groups, as did metrics of network organization and efficiency in key modules. Despite these differences, network expression correlated with dystonia motor ratings, significantly improving the accuracy of predictions based on thalamocortical tract integrity obtained with diffusion tensor MRI (DTI). Thus, in addition to providing unique information regarding the anatomy of abnormal brain circuits, rs-fMRI functional networks may provide a widely accessible method to help in the objective evaluation of new treatments for this disorder.
Assuntos
Distonia , Distúrbios Distônicos , Humanos , Distonia/diagnóstico por imagem , Distonia/genética , Distonia/patologia , Vias Neurais , Distúrbios Distônicos/diagnóstico por imagem , Distúrbios Distônicos/genética , Distúrbios Distônicos/patologia , Cerebelo , Gânglios da Base , Imageamento por Ressonância MagnéticaRESUMO
BACKGROUND: Although men and women with the LRRK2 G2019S variant appear to be equally likely to have Parkinson's disease (PD), the sex-distribution among glucocerebrosidase (GBA) variant carriers with PD, including limited to specific variant severities of GBA, is not well understood. Further, the sex-specific genetic contribution to PD without a known genetic variant is controversial. OBJECTIVES: To better understand sex differences in genetic contribution to PD, especially sex-specific frequencies among GBA variant carriers with PD (GBA PD) and LRRK2-G2019S variant carriers with PD (LRRK2 PD). METHODS: We assess differences in the sex-specific frequency in GBA PD, including in subsets of GBA variant severity, LRRK2 PD, and idiopathic PD in an Ashkenazi Jewish cohort with PD. Further, we expand prior work evaluating differences in family history of parkinsonism. RESULTS: Both idiopathic PD (267/420 men, 63.6%) (P < 0.001) and GBA PD overall (64/107, 59.8%) (P = 0.042) were more likely to be men, whereas no difference was seen in LRRK2 PD (50/99, 50.5%) and LRRK2/GBA PD (5/10, 50%). However, among GBA PD probands, severe variant carriers were more likely to be women (15/19 women, 79.0%) (P = 0.005), whereas mild variant carriers (44/70 men, 62.9%) (P = 0.039) and risk-variant carriers (15/17 men, 88.2%) (P = 0.001) were more likely to be men. CONCLUSIONS: Our study demonstrates that the male-sex predominance present in GBA PD overall was not consistent across GBA variant severities, and a female-sex predominance was present among severe GBA variant carriers. Therefore, research and trial designs for PD should consider sex-specific differences, including across GBA variant severities. © 2022 International Parkinson and Movement Disorder Society.
Assuntos
Glucosilceramidase , Doença de Parkinson , Feminino , Masculino , Humanos , Glucosilceramidase/genética , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Mutação , Heterozigoto , Doença de Parkinson/genéticaRESUMO
The natural history of idiopathic Parkinson's disease (PD) varies considerably across patients. While PD is generally sporadic, there are known genetic influences: the two most common, mutations in the LRRK2 or GBA1 gene, are associated with slower and more aggressive progression, respectively. Here, we applied graph theory to metabolic brain imaging to understand the effects of genotype on the organization of previously established PD-specific networks. We found that closely matched PD patient groups with the LRRK2-G2019S mutation (PD-LRRK2) or GBA1 variants (PD-GBA) expressed the same disease networks as sporadic disease (sPD), but PD-LRRK2 and PD-GBA patients exhibited abnormal increases in network connectivity that were not present in sPD. Using a community detection strategy, we found that the location and modular distribution of these connections differed strikingly across genotypes. In PD-LRRK2, connections were gained within the network core, with the formation of distinct functional pathways linking the cerebellum and putamen. In PD-GBA, by contrast, the majority of functional connections were formed outside the core, involving corticocortical pathways at the network periphery. Strategically localized connections within the core in PD-LRRK2 may maintain PD network activity at lower levels than in PD-GBA, resulting in a less aggressive clinical course.
Assuntos
Variação Genética/fisiologia , Glucosilceramidase/metabolismo , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/metabolismo , Redes e Vias Metabólicas/fisiologia , Doença de Parkinson/diagnóstico , Doença de Parkinson/metabolismo , Estudos Transversais , Feminino , Glucosilceramidase/genética , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/genética , Tomografia por Emissão de Pósitrons/métodosRESUMO
Dominant mutations of ATP1A3, a neuronal Na,K-ATPase α subunit isoform, cause neurological disorders with an exceptionally wide range of severity. Several new mutations and their phenotypes are reported here (p.Asp366His, p.Asp742Tyr, p.Asp743His, p.Leu924Pro, and a VUS, p.Arg463Cys). Mutations associated with mild or severe phenotypes [rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), or early infantile epileptic encephalopathy (EIEE)] were expressed in HEK-293 cells. Paradoxically, the severity of human symptoms did not correlate with whether there was enough residual activity to support cell survival. We hypothesized that distinct cellular consequences may result not only from pump inactivation but also from protein misfolding. Biosynthesis was investigated in four tetracycline-inducible isogenic cell lines representing different human phenotypes. Two cell biological complications were found. First, there was impaired trafficking of αß complex to Golgi apparatus and plasma membrane, as well as changes in cell morphology, for two mutations that produced microcephaly or regions of brain atrophy in patients. Second, there was competition between exogenous mutant ATP1A3 (α3) and endogenous ATP1A1 (α1) so that their sum was constant. This predicts that in patients, the ratio of normal to mutant ATP1A3 proteins will vary when misfolding occurs. At the two extremes, the results suggest that a heterozygous mutation that only impairs Na,K-ATPase activity will produce relatively mild disease, while one that activates the unfolded protein response could produce severe disease and may result in death of neurons independently of ion pump inactivation.
Assuntos
Distúrbios Distônicos/genética , Hemiplegia/genética , ATPase Trocadora de Sódio-Potássio/genética , ATPase Trocadora de Sódio-Potássio/metabolismo , Adulto , Alelos , Distúrbios Distônicos/metabolismo , Feminino , Células HEK293 , Hemiplegia/metabolismo , Humanos , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Mutação , Fenótipo , Transporte Proteico/genética , Deficiências na Proteostase/genética , Deficiências na Proteostase/metabolismo , Espasmos Infantis/genética , Espasmos Infantis/metabolismo , Resposta a Proteínas não Dobradas/genéticaRESUMO
In healthy subjects, brain activation in motor regions is greater during the visual perception of "natural" target motion, which complies with the two-thirds power law, than of "unnatural" motion, which does not. It is unknown whether motion perception is normally mediated by a specific network that can be altered in the setting of disease. We used block-design functional magnetic resonance imaging and covariance analysis to identify normal network topographies activated in response to "natural" versus "unnatural" motion. A visual motion perception-related pattern (VPRP) was identified in 12 healthy subjects, characterized by covarying activation responses in the inferior parietal lobule, frontal operculum, lateral occipitotemporal cortex, amygdala, and cerebellum (Crus I). Selective VPRP activation during "natural" motion was confirmed in 12 testing scans from healthy subjects. Consistent network activation was not seen, however, in 29 patients with dystonia, a neurodevelopmental disorder in which motion perception pathways may be involved. Using diffusion tractography, we evaluated the integrity of anatomical connections between the major VPRP nodes. Indeed, fiber counts in these pathways were substantially reduced in the dystonia subjects. In aggregate, the findings associate normal motion perception with a discrete brain network which can be disrupted under pathological conditions.
Assuntos
Encéfalo/fisiopatologia , Distúrbios Distônicos/fisiopatologia , Percepção de Movimento/fisiologia , Adulto , Encéfalo/diagnóstico por imagem , Mapeamento Encefálico , Imagem de Tensor de Difusão , Distúrbios Distônicos/diagnóstico por imagem , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Vias Neurais/diagnóstico por imagem , Vias Neurais/fisiopatologiaRESUMO
BACKGROUND: In 2015, the International Parkinson and Movement Disorder Society Task Force recommended research criteria for the estimation of prodromal PD. OBJECTIVES: We aimed to evaluate, for the first time, the criteria in first-degree relatives of Ashkenazi Jewish G2019S-LRRK2 PD patients, who are considered a population at risk for developing PD, and assess the sensitivity and specificity of the criteria in identifying phenoconverters. METHODS: Participants were evaluated longitudinally over a period of 5 years (average follow-up: 49.2 ± 12.3 months). Likelihood ratios and probability estimations were calculated based on the International Parkinson and Movement Disorder Society Research Criteria for Prodromal Parkinson's Disease markers and examined for each assessment point. RESULTS: One hundred twenty healthy carriers (49.53 ± 13.4 years; 54% female) and 111 healthy noncarriers (48.43 ± 15.79 years; 49% female) participated in this study. Probability scores were significantly higher in healthy carriers than healthy noncarriers (P < 0.0001). Of the 20 participants (8.6%) who met criteria for probable prodromal PD at baseline, 17 were healthy carriers. Participants who reached the threshold were older (P < 0.0001), had higher UPDRS-III (P < 0.001), lower cognitive function (P = 0.001), and more nonmotor symptoms (P < 0.0001), compared to those who did not. Ten participants were diagnosed with incident PD within 5 years from baseline resulting in a specificity of 91.82% (95% confidence interval: 86.69-96.94), sensitivity of 80% (95% confidence interval: 55.21-100), positive predictive value of 47.06% (95% confidence interval: 23.33-70.79), and negative predictive value of 98.06% (95% confidence interval: 95.39-100). All 10 phenoconvertors were G2019S-LRRK2 carriers. CONCLUSIONS: The results showed the utility of using the criteria and high sensitivity and specificity in identifying prodromal PD in this high-risk unique cohort. These results may be valuable for future disease modification clinical trials. © 2018 International Parkinson and Movement Disorder Society.
Assuntos
Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Transtornos dos Movimentos/diagnóstico , Transtornos dos Movimentos/genética , Mutação/genética , Sintomas Prodrômicos , Sociedades Médicas/normas , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Glicina/genética , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Serina/genética , Adulto JovemRESUMO
The recent series of large genome-wide association studies in European and Japanese cohorts established that Parkinson disease (PD) has a substantial genetic component. To further investigate the genetic landscape of PD, we performed a genome-wide scan in the largest to date Ashkenazi Jewish cohort of 1130 Parkinson patients and 2611 pooled controls. Motivated by the reduced disease allele heterogeneity and a high degree of identical-by-descent (IBD) haplotype sharing in this founder population, we conducted a haplotype association study based on mapping of shared IBD segments. We observed significant haplotype association signals at three previously implicated Parkinson loci: LRRK2 (OR = 12.05, P = 1.23 × 10(-56)), MAPT (OR = 0.62, P = 1.78 × 10(-11)) and GBA (multiple distinct haplotypes, OR > 8.28, P = 1.13 × 10(-11) and OR = 2.50, P = 1.22 × 10(-9)). In addition, we identified a novel association signal on chr2q14.3 coming from a rare haplotype (OR = 22.58, P = 1.21 × 10(-10)) and replicated it in a secondary cohort of 306 Ashkenazi PD cases and 2583 controls. Our results highlight the power of our haplotype association method, particularly useful in studies of founder populations, and reaffirm the benefits of studying complex diseases in Ashkenazi Jewish cohorts.
Assuntos
Mapeamento Cromossômico , Etnicidade/genética , Genealogia e Heráldica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Doença de Parkinson/genética , Idoso , Estudos de Coortes , Demografia , Feminino , Loci Gênicos/genética , Haplótipos/genética , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Reprodutibilidade dos TestesRESUMO
BACKGROUND: Reduced arm swing is a well-known clinical feature of Parkinson's disease (PD), often observed early in the course of the disease. We hypothesized that subtle changes in arm swing and axial rotation may also be detectable in the prodromal phase. OBJECTIVE: The purpose of this study was to evaluate the relationship between the LRRK2-G2019S mutation, arm swing, and axial rotation in healthy nonmanifesting carriers and noncarriers of the G2019S mutation and in patients with PD. METHODS: A total of 380 participants (186 healthy nonmanifesting controls and 194 PD patients) from 6 clinical sites underwent gait analysis while wearing synchronized 3-axis body-fixed sensors on the lower back and bilateral wrists. Participants walked for 1 minute under the following 2 conditions: (1) usual walking and (2) dual-task walking. Arm swing amplitudes, asymmetry, variability, and smoothness were calculated for both arms along with measures of axial rotation. RESULTS: A total of 122 nonmanifesting participants and 67 PD patients were carriers of the G2019S mutation. Nonmanifesting mutation carriers walked with greater arm swing asymmetry and variability and lower axial rotation smoothness under the dual task condition when compared with noncarriers (P < .04). In the nonmanifesting mutation carriers, arm swing asymmetry was associated with gait variability under dual task (P = .003). PD carriers showed greater asymmetry and variability of movement than PD noncarriers, even after controlling for disease severity (P < .009). CONCLUSIONS: The G2019S mutation is associated with increased asymmetry and variability among nonmanifesting participants and patients with PD. Prospective studies should determine if arm swing asymmetry and axial rotation smoothness may be used as motor markers of prodromal PD. © 2016 International Parkinson and Movement Disorder Society.
Assuntos
Braço/fisiopatologia , Transtornos Neurológicos da Marcha/fisiopatologia , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Doença de Parkinson/diagnóstico , Doença de Parkinson/genética , Sintomas Prodrômicos , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Transtornos Neurológicos da Marcha/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/complicações , Doença de Parkinson/fisiopatologiaRESUMO
Although primary dystonia is defined by its characteristic motor manifestations, non-motor signs and symptoms have increasingly been recognized in this disorder. Recent neuroimaging studies have related the motor features of primary dystonia to connectivity changes in cerebello-thalamo-cortical pathways. It is not known, however, whether the non-motor manifestations of the disorder are associated with similar circuit abnormalities. To explore this possibility, we used functional magnetic resonance imaging to study primary dystonia and healthy volunteer subjects while they performed a motion perception task in which elliptical target trajectories were visually tracked on a computer screen. Prior functional magnetic resonance imaging studies of healthy subjects performing this task have revealed selective activation of motor regions during the perception of 'natural' versus 'unnatural' motion (defined respectively as trajectories with kinematic properties that either comply with or violate the two-thirds power law of motion). Several regions with significant connectivity changes in primary dystonia were situated in proximity to normal motion perception pathways, suggesting that abnormalities of these circuits may also be present in this disorder. To determine whether activation responses to natural versus unnatural motion in primary dystonia differ from normal, we used functional magnetic resonance imaging to study 10 DYT1 dystonia and 10 healthy control subjects at rest and during the perception of 'natural' and 'unnatural' motion. Both groups exhibited significant activation changes across perceptual conditions in the cerebellum, pons, and subthalamic nucleus. The two groups differed, however, in their responses to 'natural' versus 'unnatural' motion in these regions. In healthy subjects, regional activation was greater during the perception of natural (versus unnatural) motion (P < 0.05). By contrast, in DYT1 dystonia subjects, activation was relatively greater during the perception of unnatural (versus natural) motion (P < 0.01). To explore the microstructural basis for these functional changes, the regions with significant interaction effects (i.e. those with group differences in activation across perceptual conditions) were used as seeds for tractographic analysis of diffusion tensor imaging scans acquired in the same subjects. Fibre pathways specifically connecting each of the significant functional magnetic resonance imaging clusters to the cerebellum were reconstructed. Of the various reconstructed pathways that were analysed, the ponto-cerebellar projection alone differed between groups, with reduced fibre integrity in dystonia (P < 0.001). In aggregate, the findings suggest that the normal pattern of brain activation in response to motion perception is disrupted in DYT1 dystonia. Thus, it is unlikely that the circuit changes that underlie this disorder are limited to primary sensorimotor pathways.
Assuntos
Encéfalo/patologia , Encéfalo/fisiopatologia , Distonia Muscular Deformante/patologia , Distonia Muscular Deformante/fisiopatologia , Percepção de Movimento , Adulto , Mapeamento Encefálico , Estudos de Casos e Controles , Cerebelo/fisiopatologia , Imagem de Tensor de Difusão , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Vias Neurais/fisiopatologia , Ponte/fisiopatologia , Núcleo Subtalâmico/fisiopatologiaRESUMO
Dystonia is a brain disorder characterized by abnormal involuntary movements without defining neuropathological changes. The disease is often inherited as an autosomal-dominant trait with incomplete penetrance. Individuals with dystonia, whether inherited or sporadic, exhibit striking phenotypic variability, with marked differences in the somatic distribution and severity of clinical manifestations. In the current study, we used magnetic resonance diffusion tensor imaging to identify microstructural changes associated with specific limb manifestations. Functional MRI was used to localize specific limb regions within the somatosensory cortex. Microstructural integrity was preserved when assessed in subrolandic white matter regions somatotopically related to the clinically involved limbs, but was reduced in regions linked to clinically uninvolved (asymptomatic) body areas. Clinical manifestations were greatest in subjects with relatively intact microstructure in somatotopically relevant white matter regions. Tractography revealed significant phenotype-related differences in the visualized thalamocortical tracts while corticostriatal and corticospinal pathways did not differ between groups. Cerebellothalamic microstructural abnormalities were also seen in the dystonia subjects, but these changes were associated with genotype, rather than with phenotypic variation. The findings suggest that the thalamocortical motor system is a major determinant of dystonia phenotype. This pathway may represent a novel therapeutic target for individuals with refractory limb dystonia.
Assuntos
Mapeamento Encefálico , Córtex Cerebral/patologia , Distonia/patologia , Distonia/fisiopatologia , Estatística como Assunto , Tálamo/patologia , Adulto , Análise de Variância , Córtex Cerebral/irrigação sanguínea , Imagem de Difusão por Ressonância Magnética , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Vias Neurais/irrigação sanguínea , Vias Neurais/fisiologia , Oxigênio/sangue , Fenótipo , Índice de Gravidade de Doença , Tálamo/irrigação sanguíneaRESUMO
The diagnosis of Parkinson's disease (PD) is usually not established until advanced neurodegeneration leads to clinically detectable symptoms. Previous blood PD transcriptome studies show low concordance, possibly resulting from the use of microarray technology, which has high measurement variation. The Leucine-rich repeat kinase 2 (LRRK2) G2019S mutation predisposes to PD. Using preclinical and clinical studies, we sought to develop a novel statistically motivated transcriptomic-based approach to identify a molecular signature in the blood of Ashkenazi Jewish PD patients, including LRRK2 mutation carriers. Using a digital gene expression platform to quantify 175 messenger RNA (mRNA) markers with low coefficients of variation (CV), we first compared whole-blood transcript levels in mouse models (1) overexpressing wild-type (WT) LRRK2, (2) overexpressing G2019S LRRK2, (3) lacking LRRK2 (knockout), and (4) and in WT controls. We then studied an Ashkenazi Jewish cohort of 34 symptomatic PD patients (both WT LRRK2 and G2019S LRRK2) and 32 asymptomatic controls. The expression profiles distinguished the four mouse groups with different genetic background. In patients, we detected significant differences in blood transcript levels both between individuals differing in LRRK2 genotype and between PD patients and controls. Discriminatory PD markers included genes associated with innate and adaptive immunity and inflammatory disease. Notably, gene expression patterns in levodopa-treated PD patients were significantly closer to those of healthy controls in a dose-dependent manner. We identify whole-blood mRNA signatures correlating with LRRK2 genotype and with PD disease state. This approach may provide insight into pathogenesis and a route to early disease detection.
Assuntos
Biomarcadores/sangue , Doença de Parkinson/sangue , Doença de Parkinson/diagnóstico , Proteínas Serina-Treonina Quinases/sangue , Proteínas Serina-Treonina Quinases/genética , RNA Mensageiro/sangue , Idoso , Idoso de 80 Anos ou mais , Animais , Estudos de Casos e Controles , Diagnóstico Precoce , Feminino , Expressão Gênica , Predisposição Genética para Doença , Heterozigoto , Humanos , Judeus/genética , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Mutação , Doença de Parkinson/genéticaRESUMO
BACKGROUND: Rapid eye movement sleep behavior disorder occurs with idiopathic Parkinson's disease (PD) and often precedes PD. Its frequency in LRRK2-PD and utility as a preclinical marker has not been established. METHODS: One hundred forty-four idiopathic PD, 142 LRRK2 G2019S mutation PD, 117 non-manifesting carriers, 93 related noncarriers, and 40 healthy controls completed the Rapid eye movement sleep Behavior Disorder Screening Questionnaire. RESULTS: Cut scores were met by 30.6% idiopathic PD, 19.7% LRRK2-PD, 6% nonmanifesting carriers, 20.4% related noncarriers, and 15% controls. The likelihood of abnormal scores was decreased in LRRK2-PD versus idiopathic PD (odds ratio = 0.55, P = 0.03), nonmanifesting carriers versus related noncarriers (OR = 0.25, P < 0.01), and PD of less than 3 years' duration, 1 of 19 LRRK2-PD versus 14 of 41 idiopathic PD (P < 0.05). CONCLUSIONS: A lower frequency of abnormal questionnaire scores is seen in LRRK2-PD, especially in early LRRK2-PD, and in nonmanifesting carriers. Therefore, the Rapid eye movement sleep Behavior Disorder Questionnaire is unlikely to serve as a preclinical marker for phenoconversion to PD.
Assuntos
Glutamina/genética , Mutação/genética , Doença de Parkinson/diagnóstico , Doença de Parkinson/genética , Proteínas Serina-Treonina Quinases/genética , Serina/genética , Privação do Sono/genética , Inquéritos e Questionários , Adulto , Idoso , Feminino , Humanos , Judaísmo , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Masculino , Pessoa de Meia-Idade , Privação do Sono/diagnósticoAssuntos
Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Doença de Parkinson/genética , Suicídio Consumado/estatística & dados numéricos , Adolescente , Adulto , Filho de Pais com Deficiência/estatística & dados numéricos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Pais , Doença de Parkinson/psicologia , Fatores de Risco , Irmãos , Adulto JovemRESUMO
A founder mutation in the Thanatos-associated (THAP) domain containing, apoptosis associated protein 1 (THAP1) gene causing primary dystonia was originally described in the Amish-Mennonites. However, there may be both genotypic and phenotypic heterogeneity of dystonia in this population that may also inform studies in other ethnic groups. Genotyping for THAP1 and for guanine nucleotide binding protein (G protein), α-activating activity polypeptide, olfactory type (GNAL) mutations and genotype-phenotype comparisons were performed for 76 individuals of Amish-Mennonites heritage with primary dystonia. Twenty-seven individuals had mutations in THAP1-most with the founder indel mutation-but two had different THAP1 mutations, 8 had mutations in GNAL, and 1 had a de novo GAG deletion in torsin 1A (TOR1A) (dystonia 1 [DYT1]). In the primary analysis comparing THAP1 carriers versus all non-THAP1, non-GNAL, non-TOR1A individuals, age at onset was lower in THAP1 carriers (mean age ± standard deviation, 15.5 ± 9.2 years [range, 5-38 years] vs. 39.2 ± 17.7 years [range, 1-70 years]; P < 0.001), and THAP1 carriers were more likely to have onset of dystonia in an arm (44.4% vs. 15.0%; P = 0.02) and to have arm involvement (88.9% vs. 22.5%; P < 0.01), leg involvement (51.9% vs. 10.0%; P = 0.01), and jaw/tongue involvement (33.3% vs. 7.5%; P = 0.02) involvement at their final examination. Carriers were less likely to have dystonia restricted to a single site (11.11% in carriers vs. 65.9% in noncarriers; P < 0.01) and were less likely to have dystonia onset in cervical regions (25.9% of THAP1 carriers vs. 52.5% of noncarriers; P = 0.04). Primary dystonia in the Amish-Mennonites is genetically diverse and includes not only the THAP1 indel founder mutation but also different mutations in THAP1 and GNAL as well as the TOR1A GAG deletion. Phenotype, particularly age at onset combined with final distribution, may be highly specific for the genetic etiology.
Assuntos
Proteínas Reguladoras de Apoptose/genética , Proteínas de Ligação a DNA/genética , Distúrbios Distônicos/genética , Subunidades alfa de Proteínas de Ligação ao GTP/genética , Predisposição Genética para Doença/genética , Chaperonas Moleculares/genética , Mutação/genética , Proteínas Nucleares/genética , Adolescente , Adulto , Idoso , Amish , Criança , Pré-Escolar , Análise Mutacional de DNA , Distúrbios Distônicos/etnologia , Saúde da Família , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Adulto JovemAssuntos
Estimulação Encefálica Profunda , Distonia/cirurgia , Distúrbios Distônicos/terapia , Subunidades alfa de Proteínas de Ligação ao GTP/genética , Adulto , Estimulação Encefálica Profunda/métodos , Distúrbios Distônicos/genética , Feminino , Globo Pálido/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Resultado do TratamentoRESUMO
Background: LRRK2 variants have been associated with immune dysregulation as well as immune-related disorders such as IBD. A possible relationship between multiple sclerosis (MS) and LRRK2 PD has also been suggested. Further, neuropathologic studies of homozygous LRRK2 G2019S carriers with Parkinson's disease (PD) are rare, and there are no systematic reports of clinical features in those cases. Methods: We investigated the co-occurrence of PD and MS in our research cohort and report on two cases of MS in LRRK2 PD as well as neuropathological findings for one. Results: MS preceded PD in 1.4% (2/138) of participants with LRRK2 G2019S variants, and in none (0/638) with idiopathic PD (p = 0.03). One case with MS and PD was a LRRK2 G2019S homozygous carrier, and neuropathology showed evidence of substantia nigra pars compacta degeneration and pallor without Lewy deposition, as well as multiple white matter lesions consistent with MS-related demyelination. Discussion: The increased prevalence of MS in LRRK2 PD further supports an important role for immune function for LRRK2 PD. This co-occurrence, while rare, suggests that MS may be an expression of the LRRK2 G2019S variant that includes both MS and PD, with MS predating features diagnostic of PD. The neuropathology suggests that the MS-related effects occurred independent of synuclein deposition. Importantly, and in addition, the neuropathological results not only support the MS diagnosis, but provide further evidence that Lewy body pathology may be absent even in homozygote LRRK2 carriers.
RESUMO
The G2019S mutation in the leucine-rich repeat kinase 2 (LRRK2) gene is a major risk factor for the development of Parkinson's disease (PD). LRRK2, although ubiquitously expressed, is highly abundant in cells of the innate immune system. Given the importance of central and peripheral immune cells in the development of PD, we sought to investigate the consequences of the G2019S mutation on microglial and monocyte transcriptome and function. We have generated large-scale transcriptomic profiles of isogenic human induced microglial cells (iMGLs) and patient derived monocytes carrying the G2019S mutation under baseline culture conditions and following exposure to the proinflammatory factors IFNγ and LPS. We demonstrate that the G2019S mutation exerts a profound impact on the transcriptomic profile of these myeloid cells, and describe corresponding functional differences in iMGLs. The G2019S mutation led to an upregulation in lipid metabolism and phagolysosomal pathway genes in untreated and LPS/IFNγ stimulated iMGLs, which was accompanied by an increased phagocytic capacity of myelin debris. We also identified dysregulation of cell cycle genes, with a downregulation of the E2F4 regulon. Transcriptomic characterization of human-derived monocytes carrying the G2019S mutation confirmed alteration in lipid metabolism associated genes. Altogether, these findings reveal the influence of G2019S on the dysregulation of the myeloid cell transcriptome under proinflammatory conditions.
RESUMO
With increasing understanding of dystonia genetic etiologies and pathophysiology there has been renewed scrutiny and reappraisal of dystonia classification schemes and nomenclature. One important category that includes both clinical and etiologic criteria is primary dystonia. This editorialized review discusses the impact of recent findings on primary dystonia criteria and argues that it remains useful in clinical and research practice. © 2013 Movement Disorder Society.