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Egg-laying mammals (monotremes) are the only extant mammalian outgroup to therians (marsupial and eutherian animals) and provide key insights into mammalian evolution1,2. Here we generate and analyse reference genomes of the platypus (Ornithorhynchus anatinus) and echidna (Tachyglossus aculeatus), which represent the only two extant monotreme lineages. The nearly complete platypus genome assembly has anchored almost the entire genome onto chromosomes, markedly improving the genome continuity and gene annotation. Together with our echidna sequence, the genomes of the two species allow us to detect the ancestral and lineage-specific genomic changes that shape both monotreme and mammalian evolution. We provide evidence that the monotreme sex chromosome complex originated from an ancestral chromosome ring configuration. The formation of such a unique chromosome complex may have been facilitated by the unusually extensive interactions between the multi-X and multi-Y chromosomes that are shared by the autosomal homologues in humans. Further comparative genomic analyses unravel marked differences between monotremes and therians in haptoglobin genes, lactation genes and chemosensory receptor genes for smell and taste that underlie the ecological adaptation of monotremes.
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Evolución Biológica , Genoma , Ornitorrinco/genética , Tachyglossidae/genética , Animales , Femenino , Masculino , Mamíferos/genética , Filogenia , Cromosomas Sexuales/genéticaRESUMEN
Heteromorphic sex chromosomes (XY or ZW) present problems of gene dosage imbalance between sexes and with autosomes. A need for dosage compensation has long been thought to be critical in vertebrates. However, this was questioned by findings of unequal mRNA abundance measurements in monotreme mammals and birds. Here, we demonstrate unbalanced mRNA levels of X genes in platypus males and females and a correlation with differential loading of histone modifications. We also observed unbalanced transcripts of Z genes in chicken. Surprisingly, however, we found that protein abundance ratios were 1:1 between the sexes in both species, indicating a post-transcriptional layer of dosage compensation. We conclude that sex chromosome output is maintained in chicken and platypus (and perhaps many other non therian vertebrates) via a combination of transcriptional and post-transcriptional control, consistent with a critical importance of sex chromosome dosage compensation.
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Pollos , Compensación de Dosificación (Genética) , Ornitorrinco , Cromosomas Sexuales , Animales , Pollos/genética , Cromosomas Sexuales/genética , Masculino , Femenino , Ornitorrinco/genética , Transcripción Genética , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
Genetic sex determination (SD) in most vertebrates is controlled by a single master sex gene, which ensures a 1:1 sex ratio. However, more complex systems abound, and several have been ascribed to polygenic SD (PSD), in which many genes at different loci interact to produce the sexual phenotype. Here we examine claims for PSD in vertebrates, finding that most constitute transient states during sex chromosome turnover, or aberrant systems in species hybrids. To avoid confusion about terminology, we propose a consistent nomenclature for genetic SD systems.
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Procesos de Determinación del Sexo , Vertebrados , Animales , Procesos de Determinación del Sexo/genética , Vertebrados/genética , Cromosomas Sexuales/genética , Herencia Multifactorial/genética , FenotipoRESUMEN
The molecular mechanism of temperature-dependent sex determination (TSD) is a long-standing mystery. How is the thermal signal sensed, captured and transduced to regulate key sex genes? Although there is compelling evidence for pathways via which cells capture the temperature signal, there is no known mechanism by which cells transduce those thermal signals to affect gene expression. Here we propose a novel hypothesis we call 3D-TSD (the three dimensions of thermolabile sex determination). We postulate that the genome has capacity to remodel in response to temperature by changing 3D chromatin conformation, perhaps via temperature-sensitive transcriptional condensates. This could rewire enhancer-promoter interactions to alter the expression of key sex-determining genes. This hypothesis can accommodate monogenic or multigenic thermolabile sex-determining systems, and could be combined with upstream thermal sensing and transduction to the epigenome to commit gonadal fate.
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Gónadas , Procesos de Determinación del Sexo , Procesos de Determinación del Sexo/genética , Cromatina , Temperatura , Regiones Promotoras Genéticas , Razón de MasculinidadRESUMEN
Pogona vitticeps has female heterogamety (ZZ/ZW), but the master sex-determining gene is unknown, as it is for all reptiles. We show that nr5a1 (Nuclear Receptor Subfamily 5 Group A Member 1), a gene that is essential in mammalian sex determination, has alleles on the Z and W chromosomes (Z-nr5a1 and W-nr5a1), which are both expressed and can recombine. Three transcript isoforms of Z-nr5a1 were detected in gonads of adult ZZ males, two of which encode a functional protein. However, ZW females produced 16 isoforms, most of which contained premature stop codons. The array of transcripts produced by the W-borne allele (W-nr5a1) is likely to produce truncated polypeptides that contain a structurally normal DNA-binding domain and could act as a competitive inhibitor to the full-length intact protein. We hypothesize that an altered configuration of the W chromosome affects the conformation of the primary transcript generating inhibitory W-borne isoforms that suppress testis determination. Under this hypothesis, the genetic sex determination (GSD) system of P. vitticeps is a W-borne dominant female-determining gene that may be controlled epigenetically.
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Alelos , Cromosomas/genética , Empalme del ARN , Procesos de Determinación del Sexo , Factor Esteroidogénico 1/genética , Secuencia de Aminoácidos , Animales , Cromosomas/química , Femenino , Dosificación de Gen , Lagartos , Masculino , Modelos Moleculares , Conformación Molecular , Conformación Proteica , Reptiles , Cromosomas Sexuales , Factores Sexuales , Factor Esteroidogénico 1/química , Relación Estructura-ActividadRESUMEN
Life on Earth has evolved from initial simplicity to the astounding complexity we experience today. Bacteria and archaea have largely excelled in metabolic diversification, but eukaryotes additionally display abundant morphological innovation. How have these innovations come about and what constraints are there on the origins of novelty and the continuing maintenance of biodiversity on Earth? The history of life and the code for the working parts of cells and systems are written in the genome. The Earth BioGenome Project has proposed that the genomes of all extant, named eukaryotes-about 2 million species-should be sequenced to high quality to produce a digital library of life on Earth, beginning with strategic phylogenetic, ecological, and high-impact priorities. Here we discuss why we should sequence all eukaryotic species, not just a representative few scattered across the many branches of the tree of life. We suggest that many questions of evolutionary and ecological significance will only be addressable when whole-genome data representing divergences at all of the branchings in the tree of life or all species in natural ecosystems are available. We envisage that a genomic tree of life will foster understanding of the ongoing processes of speciation, adaptation, and organismal dependencies within entire ecosystems. These explorations will resolve long-standing problems in phylogenetics, evolution, ecology, conservation, agriculture, bioindustry, and medicine.
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Secuencia de Bases/genética , Eucariontes/genética , Genómica/ética , Animales , Biodiversidad , Evolución Biológica , Ecología , Ecosistema , Genoma , Genómica/métodos , Humanos , FilogeniaRESUMEN
OBJECTIVE: The purpose of this study was to determine the frequency of myelin oligodendrocyte glycoprotein (MOG)-IgG and aquaporin-4 (AQP4)-IgG among patients with pediatric-onset multiple sclerosis (POMS) and healthy controls, to determine whether seropositive cases fulfilled their respective diagnostic criteria, to compare characteristics and outcomes in children with POMS versus MOG-IgG-associated disease (MOGAD), and identify clinical features associated with final diagnosis. METHODS: Patients with POMS and healthy controls were enrolled at 14 US sites through a prospective case-control study on POMS risk factors. Serum AQP4-IgG and MOG-IgG were assessed using live cell-based assays. RESULTS: AQP4-IgG was negative among all 1,196 participants, 493 with POMS and 703 healthy controls. MOG-IgG was positive in 30 of 493 cases (6%) and zero controls. Twenty-five of 30 patients positive with MOG-IgG (83%) had MOGAD, whereas 5 of 30 (17%) maintained a diagnosis of multiple sclerosis (MS) on re-review of records. MOGAD cases were more commonly in female patients (21/25 [84%] vs 301/468 [64%]; p = 0.044), younger age (mean = 8.2 ± 4.2 vs 14.7 ± 2.6 years; p < 0.001), more commonly had initial optic nerve symptoms (16/25 [64%] vs 129/391 [33%]; p = 0.002), or acute disseminated encephalomyelitis (ADEM; 8/25 [32%] vs 9/468 [2%]; p < 0.001), and less commonly had initial spinal cord symptoms (3/20 [15%] vs 194/381 [51%]; p = 0.002), serum Epstein-Barr virus (EBV) positivity (11/25 [44%] vs 445/468 [95%]; p < 0.001), or cerebrospinal fluid oligoclonal bands (5/25 [20%] vs 243/352 [69%]; p < 0.001). INTERPRETATION: MOG-IgG and AQP4-IgG were not identified among healthy controls confirming their high specificity for pediatric central nervous system (CNS) demyelinating disease. Five percent of those with prior POMS diagnoses ultimately had MOGAD; and none had AQP4-IgG positivity. Clinical features associated with a final diagnosis of MOGAD in those with suspected MS included initial ADEM phenotype, younger age at disease onset, and lack of EBV exposure. ANN NEUROL 2023;93:271-284.
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Infecciones por Virus de Epstein-Barr , Esclerosis Múltiple , Neuromielitis Óptica , Femenino , Humanos , Glicoproteína Mielina-Oligodendrócito , Estudios de Casos y Controles , Herpesvirus Humano 4 , Acuaporina 4 , Autoanticuerpos , Inmunoglobulina GRESUMEN
BACKGROUND: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a recently described demyelinating disorder, and children represent about 50% of all cases. Almost half of the patients experience relapses, but very few studies have evaluated predictors of relapse risk, challenging clinical management. The study aimed to identify predictors at MOGAD onset that are associated with a relapsing course. METHODS: Prospectively collected data from paediatric patients with MOGAD seen by the US Network of Paediatric MS Centres were leveraged. Univariable and adjusted multivariable models were used to predict recurrent disease. RESULTS: We identified 326 MOGAD cases (mean age at first event 8.9 years [SD 4.3], 57% female, 77% white and 74% non-Hispanic) and 46% relapsed during a mean follow-up of 3.9 years (SD 4.1). In the adjusted multivariable model, female sex (HR 1.66, 95% CI 1.17 to 2.36, p=0.004) and Hispanic/Latino ethnicity (HR 1.77, 95% CI 1.19 to 2.64, p=0.005) were associated with a higher risk of relapsing MOGAD. Maintenance treatment initiated before a second event with rituximab (HR 0.25, 95% CI 0.07 to 0.92, p=0.037) or intravenous immunoglobulin (IVIG) (HR 0.35, 95% CI 0.14 to 0.88, p=0.026) was associated with lower risk of a second event in multivariable analyses. Conversely, maintenance steroids were associated with a higher estimated relapse risk (HR 1.76, 95% CI 0.90 to 3.45, p=0.097). CONCLUSION: Sex and ethnicity are associated with relapsing MOGAD. Use of rituximab or IVIG therapy shortly after onset is associated with a lower risk of the second event. Preventive treatment after a first event could be considered for those with a higher relapse risk.
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BACKGROUND AND OBJECTIVE: Prior Epstein-Barr virus (EBV) infection is associated with an increased risk of pediatric-onset multiple sclerosis (POMS) and adult-onset multiple sclerosis (MS). It has been challenging to elucidate the biological mechanisms underlying this association. We examined the interactions between candidate human leukocyte antigen (HLA) and non-HLA variants and childhood EBV infection as it may provide mechanistic insights into EBV-associated MS. METHODS: Cases and controls were enrolled in the Environmental and Genetic Risk Factors for Pediatric MS study of the US Network of Pediatric MS Centers. Participants were categorized as seropositive and seronegative for EBV-viral capsid antigen (VCA). The association between prior EBV infection and having POMS was estimated with logistic regression. Interactions between EBV serostatus, major HLA MS risk factors, and non-HLA POMS risk variants associated with response to EBV infection were also evaluated with logistic regression. Models were adjusted for sex, age, genetic ancestry, and the mother's education. Additive interactions were calculated using relative risk due to interaction (RERI) and attributable proportions (APs). RESULTS: A total of 473 POMS cases and 702 controls contributed to the analyses. Anti-VCA seropositivity was significantly higher in POMS cases compared to controls (94.6% vs 60.7%, p < 0.001). There was evidence for additive interaction between childhood EBV infection and the presence of the HLA-DRB1*15 allele (RERI = 10.25, 95% confidence interval (CI) = 3.78 to 16.72; AP = 0.61, 95% CI = 0.47 to 0.75). There was evidence for multiplicative interaction (p < 0.05) between childhood EBV infection and the presence of DRB1*15 alleles (odds ratio (OR) = 3.43, 95% CI = 1.06 to 11.07). Among the pediatric MS variants also associated with EBV infection, we detected evidence for additive interaction (p = 0.02) between prior EBV infection and the presence of the GG genotype in risk variant (rs2255214) within CD86 (AP = 0.30, 95% CI = 0.03 to 0.58). CONCLUSION: We report evidence for interactions between childhood EBV infection and DRB1*15 and the GG genotype of CD86 POMS risk variant. Our results suggest an important role of antigen-presenting cells (APCs) in EBV-associated POMS risk.
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Infecciones por Virus de Epstein-Barr , Esclerosis Múltiple , Adulto , Niño , Humanos , Infecciones por Virus de Epstein-Barr/complicaciones , Herpesvirus Humano 4 , Factores de Riesgo , Cadenas HLA-DRB1/genética , AnticuerposRESUMEN
BACKGROUND: Understanding nutrition's role in multiple sclerosis (MS) can guide recommendations and intervention-based studies. OBJECTIVE: Evaluate the association between nutrition and pediatric-onset MS outcomes. METHODS: Prospective longitudinal multicenter study conducted as part of the US Network of Pediatric MS centers. Predictors were collected using a food screener estimating intake of various dietary food groups (e.g. dairy and fruits) and additional calculated indices (e.g. Healthy Eating Index (HEI)). Outcomes included time-from-enrollment to clinical relapse, new magnetic resonance imaging (MRI) T2 lesions, and Expanded Disability Status Scale (EDSS) increase. RESULTS: 353 children with MS were enrolled (mean ± SD age 15.4 ± 2.9, follow-up 3.9 ± 2.6 years). Multivariable analysis demonstrated that increased dairy by 50% of recommended intake was associated with increased relapse risk by 41% (adjusted hazard ratio (HR) 1.41, 95% CI 1.07-1.86), and risk of T2 progression by 40% (1.40, 1.12-1.74). Increased intake of fruit or vegetable above recommended, and every five-point HEI increase decreased relapse risk by 25% (0.75, 0.60-0.95), 45% (0.55, 0.32-0.96), and 15% (0.84, 0.74-0.96), respectively. No associations were found with EDSS. CONCLUSION: This work supports the influence of dietary intake on MS course, particularly with dairy intake. Future prospective study is required to establish causation.
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Imagen por Resonancia Magnética , Esclerosis Múltiple , Humanos , Femenino , Masculino , Adolescente , Niño , Esclerosis Múltiple/diagnóstico por imagen , Estudios Longitudinales , Estudios Prospectivos , Progresión de la Enfermedad , Productos Lácteos , Dieta Saludable , Frutas , DietaRESUMEN
PURPOSE OF REVIEW: Multiple sclerosis (MS) is a chronic, immune-mediated demyelinating disorder of the central nervous system. Age is one of the most important factors in determining MS phenotype. This review provides an overview of how age influences MS clinical characteristics, pathology, and treatment. RECENT FINDINGS: New methods for measuring aging have improved our understanding of the aging process in MS. New studies have characterized the molecular and cellular composition of chronic active or smoldering plaques in MS. These lesions are important contributors to disability progression in MS. These studies highlight the important role of immunosenescence and the innate immune system in sustaining chronic inflammation. Given these changes in immune function, several studies have assessed optimal treatment strategies in aging individuals with MS. MS phenotype is intimately linked with chronologic age and immunosenescence. While there are many unanswered questions, there has been much progress in understanding this relationship which may lead to more effective treatments for progressive disease.
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Inmunosenescencia , Esclerosis Múltiple , Humanos , Esclerosis Múltiple/tratamiento farmacológico , Envejecimiento , Inflamación , Sistema Nervioso CentralRESUMEN
How temperature determines sex remains unknown. A recent hypothesis proposes that conserved cellular mechanisms (calcium and redox; 'CaRe' status) sense temperature and identify genes and regulatory pathways likely to be involved in driving sexual development. We take advantage of the unique sex determining system of the model organism, Pogona vitticeps, to assess predictions of this hypothesis. P. vitticeps has ZZ male: ZW female sex chromosomes whose influence can be overridden in genetic males by high temperatures, causing male-to-female sex reversal. We compare a developmental transcriptome series of ZWf females and temperature sex reversed ZZf females. We demonstrate that early developmental cascades differ dramatically between genetically driven and thermally driven females, later converging to produce a common outcome (ovaries). We show that genes proposed as regulators of thermosensitive sex determination play a role in temperature sex reversal. Our study greatly advances the search for the mechanisms by which temperature determines sex.
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Lagartos/genética , Cromosomas Sexuales/genética , Procesos de Determinación del Sexo/genética , Transcriptoma/genética , Animales , Femenino , Lagartos/crecimiento & desarrollo , Masculino , Análisis para Determinación del Sexo/métodos , Temperatura , Transcripción Genética/genéticaRESUMEN
Microchromosomes, once considered unimportant shreds of the chicken genome, are gene-rich elements with a high GC content and few transposable elements. Their origin has been debated for decades. We used cytological and whole-genome sequence comparisons, and chromosome conformation capture, to trace their origin and fate in genomes of reptiles, birds, and mammals. We find that microchromosomes as well as macrochromosomes are highly conserved across birds and share synteny with single small chromosomes of the chordate amphioxus, attesting to their origin as elements of an ancient animal genome. Turtles and squamates (snakes and lizards) share different subsets of ancestral microchromosomes, having independently lost microchromosomes by fusion with other microchromosomes or macrochromosomes. Patterns of fusions were quite different in different lineages. Cytological observations show that microchromosomes in all lineages are spatially separated into a central compartment at interphase and during mitosis and meiosis. This reflects higher interaction between microchromosomes than with macrochromosomes, as observed by chromosome conformation capture, and suggests some functional coherence. In highly rearranged genomes fused microchromosomes retain most ancestral characteristics, but these may erode over evolutionary time; surprisingly, de novo microchromosomes have rapidly adopted high interaction. Some chromosomes of early-branching monotreme mammals align to several bird microchromosomes, suggesting multiple microchromosome fusions in a mammalian ancestor. Subsequently, multiple rearrangements fueled the extraordinary karyotypic diversity of therian mammals. Thus, microchromosomes, far from being aberrant genetic elements, represent fundamental building blocks of amniote chromosomes, and it is mammals, rather than reptiles and birds, that are atypical.
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Evolución Biológica , Cordados/genética , Cromosomas de los Mamíferos , Genoma , Animales , Secuencia de Bases , Secuencia ConservadaRESUMEN
BACKGROUND: Sex determination is the process whereby the bipotential embryonic gonads become committed to differentiate into testes or ovaries. In genetic sex determination (GSD), the sex determining trigger is encoded by a gene on the sex chromosomes, which activates a network of downstream genes; in mammals these include SOX9, AMH and DMRT1 in the male pathway, and FOXL2 in the female pathway. Although mammalian and avian GSD systems have been well studied, few data are available for reptilian GSD systems. RESULTS: We conducted an unbiased transcriptome-wide analysis of gonad development throughout differentiation in central bearded dragon (Pogona vitticeps) embryos with GSD. We found that sex differentiation of transcriptomic profiles occurs at a very early stage, before the gonad consolidates as a body distinct from the gonad-kidney complex. The male pathway genes dmrt1 and amh and the female pathway gene foxl2 play a key role in early sex differentiation in P. vitticeps, but the central player of the mammalian male trajectory, sox9, is not differentially expressed in P. vitticeps at the bipotential stage. The most striking difference from GSD systems of other amniotes is the high expression of the male pathway genes amh and sox9 in female gonads during development. We propose that a default male trajectory progresses if not repressed by a W-linked dominant gene that tips the balance of gene expression towards the female trajectory. Further, weighted gene expression correlation network analysis revealed novel candidates for male and female sex differentiation. CONCLUSION: Our data reveal that interpretation of putative mechanisms of GSD in reptiles cannot solely depend on lessons drawn from mammals.
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Reptiles , Procesos de Determinación del Sexo , Diferenciación Sexual , Animales , Femenino , Masculino , Expresión Génica , Regulación del Desarrollo de la Expresión Génica , Gónadas/metabolismo , Reptiles/genética , Procesos de Determinación del Sexo/genética , Diferenciación Sexual/genética , Factor de Transcripción SOX9/genéticaRESUMEN
OBJECTIVE: A major challenge in multiple sclerosis (MS) research is the understanding of silent progression and Progressive MS. Using a novel method to accurately capture upper cervical cord area from legacy brain MRI scans we aimed to study the role of spinal cord and brain atrophy for silent progression and conversion to secondary progressive disease (SPMS). METHODS: From a single-center observational study, all RRMS (n = 360) and SPMS (n = 47) patients and 80 matched controls were evaluated. RRMS patient subsets who converted to SPMS (n = 54) or silently progressed (n = 159), respectively, during the 12-year observation period were compared to clinically matched RRMS patients remaining RRMS (n = 54) or stable (n = 147), respectively. From brain MRI, we assessed the value of brain and spinal cord measures to predict silent progression and SPMS conversion. RESULTS: Patients who developed SPMS showed faster cord atrophy rates (-2.19%/yr) at least 4 years before conversion compared to their RRMS matches (-0.88%/yr, p < 0.001). Spinal cord atrophy rates decelerated after conversion (-1.63%/yr, p = 0.010) towards those of SPMS patients from study entry (-1.04%). Each 1% faster spinal cord atrophy rate was associated with 69% (p < 0.0001) and 53% (p < 0.0001) shorter time to silent progression and SPMS conversion, respectively. INTERPRETATION: Silent progression and conversion to secondary progressive disease are predominantly related to cervical cord atrophy. This atrophy is often present from the earliest disease stages and predicts the speed of silent progression and conversion to Progressive MS. Diagnosis of SPMS is rather a late recognition of this neurodegenerative process than a distinct disease phase. ANN NEUROL 2022;91:268-281.
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Esclerosis Múltiple Recurrente-Remitente/diagnóstico por imagen , Esclerosis Múltiple Recurrente-Remitente/patología , Médula Espinal/patología , Adulto , Atrofia , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Progresión de la Enfermedad , Femenino , Foramen Magno/diagnóstico por imagen , Foramen Magno/patología , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Estudios Prospectivos , Médula Espinal/diagnóstico por imagenRESUMEN
BACKGROUND: We previously reported an association between household chemical exposures and an increased risk of paediatric-onset multiple sclerosis. METHODS: Using a case-control paediatric multiple sclerosis study, gene-environment interaction between exposure to household chemicals and genotypes for risk of paediatric-onset multiple sclerosis was estimated.Genetic risk factors of interest included the two major HLA multiple sclerosis risk factors, the presence of DRB1*15 and the absence of A*02, and multiple sclerosis risk variants within the metabolic pathways of common household toxic chemicals, including IL-6 (rs2069852), BCL-2 (rs2187163) and NFKB1 (rs7665090). RESULTS: 490 paediatric-onset multiple sclerosis cases and 716 controls were included in the analyses. Exposures to insect repellent for ticks or mosquitos (OR 1.47, 95% CI 1.06 to 2.04, p=0.019), weed control products (OR 2.15, 95% CI 1.51 to 3.07, p<0.001) and plant/tree insect or disease control products (OR 3.25, 95% CI 1.92 to 5.49, p<0.001) were associated with increased odds of paediatric-onset multiple sclerosis. There was significant additive interaction between exposure to weed control products and NFKB1 SNP GG (attributable proportions (AP) 0.48, 95% CI 0.10 to 0.87), and exposure to plant or disease control products and absence of HLA-A*02 (AP 0.56; 95% CI 0.03 to 1.08). There was a multiplicative interaction between exposure to weed control products and NFKB1 SNP GG genotype (OR 2.30, 95% CI 1.00 to 5.30) but not for other exposures and risk variants. No interactions were found with IL-6 and BCL-2 SNP GG genotypes. CONCLUSIONS: The presence of gene-environment interactions with household toxins supports their possible causal role in paediatric-onset multiple sclerosis.
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Interacción Gen-Ambiente , Esclerosis Múltiple , Niño , Humanos , Esclerosis Múltiple/inducido químicamente , Esclerosis Múltiple/epidemiología , Esclerosis Múltiple/genética , Predisposición Genética a la Enfermedad/genética , Interleucina-6 , Cadenas HLA-DRB1/genética , Factores de Riesgo , Genotipo , Antígenos HLA , Estudios de Casos y Controles , Proteínas Proto-Oncogénicas c-bcl-2/genéticaRESUMEN
Multiple sclerosis (MS) is most likely to adopt a progressive clinical course during middle age or beyond, and the number of older adults with MS is steadily increasing. Developing new strategies to manage progressive forms of MS, which do not respond to currently available disease-modifying therapies (DMTs), will require a deeper understanding of the mechanisms by which biological aging interacts with pathogenic pathways to propel disability accumulation. In experimental autoimmune encephalomyelitis (EAE), a widely used preclinical mouse model of MS, middle-aged animals experience a more severe and protracted clinical course than their younger counterparts. This exacerbated disease course is accompanied by persistent neuroinflammation. Clinical studies of age-related biomarkers, such as telomere length, senescence markers, and DNA methylation, suggest that biological aging is accelerated in people with MS compared with age- and sex-matched healthy controls. Furthermore, distinguishing biological age from chronological may afford more precision in determining aging effects in MS. Here we review the current literature on aging biology and its impact on MS pathogenesis. Future research on this topic may lead to the development of novel biomarkers and senotherapy agents that slow neurological decline in people with progressive MS by targeting relevant aging-related pathways.
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Encefalomielitis Autoinmune Experimental , Esclerosis Múltiple Crónica Progresiva , Esclerosis Múltiple , Persona de Mediana Edad , Humanos , Ratones , Animales , Anciano , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple Crónica Progresiva/tratamiento farmacológico , Envejecimiento , Progresión de la Enfermedad , BiomarcadoresRESUMEN
OBJECTIVE: Cognitive involvement in pediatric multiple sclerosis (MS) relative to adult MS is less defined. This study advances our understanding by measuring cognitive performances in pediatric MS, adult MS, and pediatric healthy controls. METHODS: Consecutive relapsing pediatric MS participants from the United States Network of Pediatric MS Centers were compared with pediatric healthy controls and adults with relapsing MS. Participants were compared on two screening batteries: the Brief International Cognitive Assessment for MS and the Cogstate Brief Battery. Results were transformed to age-normative z scores. RESULTS: The pediatric groups (MS vs. Healthy Controls) did not differ on either battery's composite mean score or individual test scores (ps > 0.32), nor in the proportions impaired on either battery, Brief International Cognitive Assessment for MS (26% vs. 24%, p = 0.83); Cogstate Brief Battery (26% vs. 32%, p = 0.41). The pediatric versus adult MS group even after controlling for differences in disease duration performed better on the Brief International Cognition Assessment for MS composite (p = 0.03), Symbol Digit Modalities Test (p = 0.02), Rey Auditory Verbal Learning Test (p = 0.01), and Cogstate choice reaction time (p < 0.001). CONCLUSION: Pediatric MS patients do not differ from healthy pediatric controls on cognitive screens but perform better than adults with MS.
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Trastornos del Conocimiento , Disfunción Cognitiva , Esclerosis Múltiple , Adulto , Humanos , Niño , Trastornos del Conocimiento/psicología , Esclerosis Múltiple/diagnóstico , Cognición , Pruebas Neuropsicológicas , Pruebas de Memoria y Aprendizaje , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/etiologíaRESUMEN
BACKGROUND: Rare genetic variants are emerging as important contributors to the heritability of multiple sclerosis (MS). Whether rare variants also contribute to pediatric-onset multiple sclerosis (POMS) is unknown. OBJECTIVE: To test whether genes harboring rare variants associated with adult-onset MS risk (PRF1, PRKRA, NLRP8, and HDAC7) and 52 major histocompatibility complex (MHC) genes are associated with POMS. METHODS: We analyzed DNA samples from 330 POMS cases and 306 controls from the US Network of Pediatric MS Centers and Kaiser Permanente Northern California for which Illumina ExomeChip genotypes were available. Using the gene-based method "SKAT-O," we tested the association between candidate genes and POMS risk. RESULTS: After correction for multiple comparisons, one adult-onset MS gene (PRF1, p = 2.70 × 10-3) and two MHC genes (BRD2, p = 5.89 × 10-5 and AGER, p = 7.96 × 10-5) were significantly associated with POMS. Results suggest these are independent of HLA-DRB1*1501. CONCLUSION: Findings support a role for rare coding variants in POMS susceptibility. In particular, rare minor alleles within PRF1 were more common among individuals with POMS compared to controls while the opposite was true for rare variants within significant MHC genes, BRD2 and AGER. These genes would not have been identified by common variant studies, emphasizing the merits of investigating rare genetic variation in complex diseases.
Asunto(s)
Esclerosis Múltiple , Niño , Adulto , Humanos , Esclerosis Múltiple/genética , Cadenas HLA-DRB1/genética , Alelos , Genotipo , Predisposición Genética a la EnfermedadRESUMEN
PURPOSE: Pediatric optic neuritis (ON) is a rare disease that has not been well characterized. The Pediatric ON Prospective Outcomes Study (PON1) was the first prospective study to our knowledge aiming to evaluate visual acuity (VA) outcomes, including VA, recurrence risk, and final diagnosis 2 years after enrollment. DESIGN: Nonrandomized observational study at 23 pediatric ophthalmology or neuro-ophthalmology clinics in the United States and Canada. PARTICIPANTS: A total of 28 (64%) of 44 children initially enrolled in PON1 (age 3-<16 years) who completed their 2-year study visit. METHODS: Participants were treated at the investigator's discretion. MAIN OUTCOMES MEASURES: Age-normal monocular high-contrast VA (HCVA). Secondary outcomes included low-contrast VA (LCVA), neuroimaging findings, and final diagnoses. RESULTS: A total of 28 participants completed the 2-year outcome with a median enrollment age of 10.3 years (range, 5-15); 46% were female, and 68% had unilateral ON at presentation. Final 2-year diagnoses included isolated ON (n = 11, 39%), myelin oligodendrocyte glycoprotein-associated demyelination (n = 8, 29%), multiple sclerosis (MS) (n = 4,14%), neuromyelitis optica spectrum disease (NMOSD) (n = 3, 11%), and acute disseminated encephalomyelitis (n = 2, 7%). Two participants (7%; 95% confidence interval [CI], 1-24) had subsequent recurrent ON (plus 1 participant who did not complete the 2-year visit); all had MS. Two other participants (7%) had a new episode in their unaffected eye. Mean presenting HCVA was 0.81 logarithm of the minimum angle of resolution (logMAR) (â¼20/125), improving to 0.14 logMAR (â¼20/25-2) at 6 months, 0.12 logMAR (â¼20/25-2) at 1 year, and 0.11 logMAR (20/25-1) at 2 years (95% CI, -0.08 to 0.3 [20/20+1-20/40-1]). Twenty-four participants (79%) had age-normal VA at 2 years (95% CI, 60-90); 21 participants (66%) had 20/20 vision or better. The 6 participants without age-normal VA had 2-year diagnoses of NMOSD (n = 2 participants, 3 eyes), MS (n = 2 participants, 2 eyes), and isolated ON (n = 2 participants, 3 eyes). Mean presenting LCVA was 1.45 logMAR (â¼20/500-2), improving to 0.78 logMAR (â¼20/125+2) at 6 months, 0.69 logMAR (â¼20/100+1) at 1 year, and 0.68 logMAR (â¼20/100+2) at 2 years (95% CI, 0.48-0.88 [20/50+1-20/150-1]). CONCLUSIONS: Despite poor VA at presentation, most children had marked improvement in VA by 6 months that was maintained over 2 years. Associated neurologic autoimmune diagnoses were common. Additional episodes of ON occurred in 5 (18%) of the participants (3 relapses and 2 new episodes).