¿Un déficit nuclear en la enfermedad de Parkinson? / A core deficit in Parkinson disease?

Introducción: La enfermedad de Parkinson es un trastorno neurodegenerativo que lleva aparejados déficits motores, cognitivos y lingüísticos. Es importante esclarecer las causas de esta comorbilidad. Este trabajo tiene como objetivo determinar si dichos déficits pueden interpretarse como el resultado de la disfunción selectiva de capacidades computacionales primitivas, en particular, de una capacidad computacional sensible al contexto o de tipo 1 en la Jerarquía de Chomsky (una herramienta usada habitualmente en estudios de cognición comparada). Pacientes y métodos: Se seleccionó a 15 sujetos con enfermedad de Parkinson medicados y a 15 controles emparejados en edad y en años de escolarización. Se diseñó una batería de pruebas específicas para el experimento que evaluaban 3 dominios diferentes (motor, lingüístico y visuoespacial) y 2 tipos de capacidades computacionales distintas (sensible e insensible al contexto). Resultados: Se obtuvieron diferencias significativas entre ambos grupos solo en la prueba de tipo lingüístico que evaluaba la capacidad de computación sensible al contexto. Conclusiones: Los déficits de diferente naturaleza que caracterizan a la enfermedad de Parkinson no parecen explicarse por la afectación selectiva de una capacidad computacional básica que sería funcionalmente inespecífica. Resta por ver si las diferencias entre afectados y no afectados son significativas cuando se trata de sujetos no medicados y cuando las pruebas empleadas en la evaluación se ciñen a aspectos puramente formales. Idealmente, este tipo de primitivos computacionales podría ayudar a diagnosticar precozmente el trastorno

Introduction: Parkinson disease is a neurodegenerative condition involving motor, cognitive, and linguistic deficits. It is important to know why all these different deficits co-occur in the affected people. This paper aims to clarify whether these comorbid deficits result from the selective impairment of a computational primitive, namely, a context-sensitive computational ability according to Chomsky's Hierarchy (a well-established research tool in comparative neuroscience). Patients and methods: A total of 15 medicated subjects with Parkinson disease and 15 controls were selected. They were matched in age and education. A battery of tasks was designed to test 3 different domains (motor capacities, cognition, and language) and 2 different computational abilities (context-free and context-sensitive operations). Results: Significant differences between groups were observed only regarding the linguistic task involving context-sensitive computations (correferences). Conclusions: The observed deficits in our patients with Parkinson disease cannot be explained in terms of the selective impairment of one only unspecific, low-level computational process. At the same time, differences between patients and controls are expected to be greater if the former are not medicated. Moreover, we should pursue in the search of (this kind of) computational primitives than can be selectively impaired in people with Parkinson disease, because they may help to achieve an earlier diagnosis of this condition

[A core deficit in Parkinson disease?]. / ¿Un déficit nuclear en la enfermedad de Parkinson?

INTRODUCTION: Parkinson disease is a neurodegenerative condition involving motor, cognitive, and linguistic deficits. It is important to know why all these different deficits co-occur in the affected people. This paper aims to clarify whether these comorbid deficits result from the selective impairment of a computational primitive, namely, a context-sensitive computational ability according to Chomsky's Hierarchy (a well-established research tool in comparative neuroscience). PATIENTS AND METHODS: A total of 15 medicated subjects with Parkinson disease and 15 controls were selected. They were matched in age and education. A battery of tasks was designed to test 3 different domains (motor capacities, cognition, and language) and 2 different computational abilities (context-free and context-sensitive operations). RESULTS: Significant differences between groups were observed only regarding the linguistic task involving context-sensitive computations (correferences). CONCLUSIONS: The observed deficits in our patients with Parkinson disease cannot be explained in terms of the selective impairment of one only unspecific, low-level computational process. At the same time, differences between patients and controls are expected to be greater if the former are not medicated. Moreover, we should pursue in the search of (this kind of) computational primitives than can be selectively impaired in people with Parkinson disease, because they may help to achieve an earlier diagnosis of this condition.

Nuevas propuestas para el diagnóstico y la clasificación de los trastornos del lenguaje: ¿hemos incorporado los criterios idóneos? / New proposals for the diagnosis and classification of language disorders: have we incorporated the most suitable criteria?

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Aspectos problemáticos del análisis genético de los trastornos específicos del lenguaje: FOXP2 como paradigma / Problematic aspects of the genetic analysis of the specific disorders of the language: FOXP2 as paradigm

Introducción: El análisis genético de los trastornos específicos del lenguaje resulta del máximo interés, tanto para la práctica clínica como para la teoría lingüística. No obstante, un resultado casi universal de dicho análisis es que no parece existir una relación unívoca y obligada entre la mutación de determinados genes y la aparición de patologías concretas al término del desarrollo, ni por consiguiente, una relación causal directa entre el genotipo y el fenotipo. Objetivos: El presente trabajo se plantea evaluar esta clase de evidencias (utilizando como modelo, allí donde resulte ilustrativo, el gen FOXP2, considerado habitualmente como el «gen del lenguaje» por excelencia), proponer posibles causas que expliquen su recurrencia y discutir si tales explicaciones contribuyen realmente a esclarecer la genuina etiología de estos trastornos. Resultados: La clave para entender el intrincado (y a primera vista desconcertante) escenario resultante del análisis genético de los trastornos específicos del lenguaje radica en atender al verdadero papel que desempeñan los genes durante la ontogenia y, especialmente, al modo en que se regulan los procesos de desarrollo: lejos de erigirse en los agentes causales directos responsables en exclusividad de la aparición de los fenotipos, los genes constituyen uno más de los múltiples factores implicados.Conclusiones: La asunción de la complejidad de dicho papel, así como la conveniencia de considerar modelos alternativos del desarrollo, menos centrados en los genes (por paradójico que pueda parecer), permite explicar satisfactoriamente el modo en que las alteraciones génicas contribuyen a la aparición de este tipo de trastornos de la cognición (AU)

Introduction: Genetic analysis of specific language disorders is of major interest for both clinical research and linguistic theory. However, the results of this analysis almost always do not show any univocal and compulsory relationships between particular gene mutations and particular disorders or a casual link between the genotype and the phenotype. Objectives: This paper will review this type of evidence (referring to the «language gene» FOXP2 as a leading example, where possible), try to suggest plausible reasons for such a perplexing output, and ultimately discuss if such reasons really explain the genuine aetiology of these conditions. Results: The key to disentangle and understand the puzzling scenario emerging from the genetic analysis of specific language disorders is to pay attention to the actual role played by genes during ontogeny and, in particular, to the way in which developmental processes are actually regulated: genes are not direct causal agents regarding the emergence of impaired or wild phenotypes, but just one among the diverse types of regulatory factors involved. Conclusions:When such a complex role as well as development models less focused on the genes are considered, the way in which genetic mutations really contribute to the emergence of these cognitive disorders is quite satisfactorily explained (AU)

[Problematic aspects of the genetic analysis of the specific disorders of the language: FOXP2 as paradigm]. / Aspectos problemáticos del análisis genético de los trastornos específicos del lenguaje: FOXP2 como paradigma.

INTRODUCTION: Genetic analysis of specific language disorders is of major interest for both clinical research and linguistic theory. However, the results of this analysis almost always do not show any univocal and compulsory relationships between particular gene mutations and particular disorders or a casual link between the genotype and the phenotype. OBJECTIVES: This paper will review this type of evidence (referring to the «language gene¼FOXP2 as a leading example, where possible), try to suggest plausible reasons for such a perplexing output, and ultimately discuss if such reasons really explain the genuine aetiology of these conditions. RESULTS: The key to disentangle and understand the puzzling scenario emerging from the genetic analysis of specific language disorders is to pay attention to the actual role played by genes during ontogeny and, in particular, to the way in which developmental processes are actually regulated: genes are not direct causal agents regarding the emergence of impaired or wild phenotypes, but just one among the diverse types of regulatory factors involved. CONCLUSIONS: When such a complex role as well as development models less focused on the genes are considered, the way in which genetic mutations really contribute to the emergence of these cognitive disorders is quite satisfactorily explained.

Neurobiología y neurogenética de la dislexia / Neurobiology and neurogenetics of dyslexia

Introducción: La dislexia es un trastorno cognitivo que lleva aparejada una competencia lectora reducida y que suele ser comórbido con otros que tienen como característica distintiva un déficit en la capacidad de aprendizaje y de adquisición de competencias específicas (fundamentalmente, trastorno específico del lenguaje, de los sonidos del habla o por déficit de atención e hiperactividad).Desarrollo: En el caso de la dislexia, el déficit nuclear parece corresponderse con una disfunción del componente fonológico de la memoria de trabajo verbal. El cerebro de los individuos disléxicos presenta diversos tipos de malformaciones estructurales, así como patrones anómalos de actividad cerebral durante las tareas de lectura y deletreo, que conciernen, entre otras, a las áreas que integran el dispositivo de procesamiento cuya actividad se ha asociado con estas actividades en la población no disléxica. Los genes identificados hasta la fecha cuya mutación parece constituir un componente causal (o un factor de riesgo) significativo en relación con el trastorno codifican proteínas que intervienen en la regulación de la migración de determinados linajes neuronales o del proceso de axonogénesis. La disminución del grado de expresión de los correspondientes genes ortólogos produce en el cerebro de los organismos modelo del trastorno alteraciones estructurales y funcionales semejantes a las observadas en los individuos disléxicos. Dichas alteraciones originan, a su vez, déficit auditivos y cognitivos que recapitulan satisfactoriamente los descritos en dichos individuos. Conclusiones: En conjunto, resulta plausible la hipótesis de que la dislexia vendría a ser, en diferentes niveles de complejidad biológica (genético, bioquímico, fisiológico, cognitivo), y en mayor o menor grado, un extremo del continuo de desarrollo que representa la capacidad de lectura en la población general; al mismo tiempo, algunos de los elementos que integran estos niveles (AU)

Introduction: Dyslexia is a learning disability in which reading (but not any other) impairment is the most prominent symptom. There seems to be a high comorbidity among dyslexia and other learning disabilities, such as SLI, SSD or ADHD. Development: The nulear deficit in dyslexia appears to correspond to an impairment in phonological processing. Structural and functional studies in dyslexic readers converge to indicate the presence of malformations in the brain areas corresponding to the reading systems, but also a failure of these systems to function properly during reading. Genes linked (or associated) to dyslexia have been shown to be involved in neuronal migration and axon guidance during the formation of the cortex. In the developing cerebral neocortex of rats, local loss of function of most of these genes not only results in abnormal neuronal migration and neocortical and hippocampal malformations, but also in deficits related to auditory processing and learning. While the structural malformations resemble neuronal migration abnormalities observed in the brains of individuals with developmental dyslexia, processing/learning deficits also resemble deficits described in individuals affected by the disease.Conclusions: On the whole, dyslexia seems to be on a continuum with typical reading at different biological levels (genetic, biochemical, physiological, cognitive). Furthermore, certain elements belonging to some of these levels (mainly —some of the— genes linked or associated to the disease, but also —some of the— neuronal structures whose development is regulated by these genes) would simultaneously belong to those of other cognitive abilities, which give rise to diseases of a different nature (i.e. non- dyslexic impairments) when they are impaired (AU)

[Neurobiology and neurogenetics of dyslexia]. / Neurobiología y neurogenética de la dislexia.

INTRODUCTION: Dyslexia is a learning disability in which reading (but not any other) impairment is the most prominent symptom. There seems to be a high comorbidity among dyslexia and other learning disabilities, such as SLI, SSD or ADHD. DEVELOPMENT: The nulear deficit in dyslexia appears to correspond to an impairment in phonological processing. Structural and functional studies in dyslexic readers converge to indicate the presence of malformations in the brain areas corresponding to the reading systems, but also a failure of these systems to function properly during reading. Genes linked (or associated) to dyslexia have been shown to be involved in neuronal migration and axon guidance during the formation of the cortex. In the developing cerebral neocortex of rats, local loss of function of most of these genes not only results in abnormal neuronal migration and neocortical and hippocampal malformations, but also in deficits related to auditory processing and learning. While the structural malformations resemble neuronal migration abnormalities observed in the brains of individuals with developmental dyslexia, processing/learning deficits also resemble deficits described in individuals affected by the disease. CONCLUSIONS: On the whole, dyslexia seems to be on a continuum with typical reading at different biological levels (genetic, biochemical, physiological, cognitive). Furthermore, certain elements belonging to some of these levels (mainly -some of the- genes linked or associated to the disease, but also -some of the- neuronal structures whose development is regulated by these genes) would simultaneously belong to those of other cognitive abilities, which give rise to diseases of a different nature (i.e. non- dyslexic impairments) when they are impaired.

Dislexias evolutivas: qué pueden decirnos la neurología y la genética al respecto / Developmental dyslexias: what can neurology and genetics tell us about them?

La dislexia es un trastorno cognitivo que se caracteriza por una capacidad de lectura disminuida, causada, en buena medida, por una disfunción del componente fonológico de la memoria de trabajo verbal. Posee una significativa base genética y a nivel neurológico suele advertirse en los individuos afectados por el trastorno la presencia de malformaciones estructurales y patrones de actividad cerebral anómalos durante las tareas de lectura y deletreo. Hasta la fecha se han identificado diversos genes que cabe considerar como candidatos o como factores de riesgo para su aparición. En general, los productos codificados por estos genes intervienen en la regulación de la migración de determinados grupos neuronales o del crecimiento y la interconexión de sus axones. Su mutación da lugar en otros organismos a alteraciones estructurales y funcionales, así como a disfunciones auditivas y cognitivas, semejantes a las observadas en los individuos disléxicos. La comorbilidad que manifiesta la dislexia con otros trastornos cognitivos que afectan a la capacidad de adquisición de competencias específicas podría explicarse, en parte, por el hecho de que determinados genes relacionados con el trastorno podrían formar parte simultáneamente de los programas genéticos que intervienen en el desarrollo del sustrato neuronal de otras capacidades cognitivas, cuya disfunción da lugar a afecciones de diferente naturaleza clínica

Dyslexia is a learning disability in which reading (but not other) impairment is the most prominent symptom, feasibly caused by incorrect phonological processing. Typically, the brains of disabled readers show malformations and functional anomalies during reading. Currently, different genes have been linked (or associated) to dyslexia. Protein sencoded by them have probed to be involvedin neuronal migration and axon guidance during the formation of the cortex. In other organisms, local loss of function of most of these genes results in brain malformations and deficits related to auditory processing and learning, which resemble those observed in dyslexics. Dyslexia seems to be highly comorbid with other learning disabilities. Up to a point this comorbidity could be explained if some of these genes simultaneously regulate the development of neuronal structures relevant for other cognitive abilities, whose impairment is clinically described as a different disease

Dosis génica y lenguaje: a propósito de la región cromosómica 7q11.23 / Gene dosage and language: some issues concerning chromosome 7q11.23

La caracterización molecular de diversos trastornosgenómicos que cuentan entre sus síntomas distintivoscon determinadas disfunciones de carácter lingüísticoestá contribuyendo decisivamente a una mejor comprensióndel efecto que desempeña la dosis génicadentro del programa innato encargado de la regulacióndel desarrollo (y del funcionamiento) del «órganodel lenguaje». Un caso especialmente significativo aeste respecto concierne a un fragmento de alrededorde 1,5 Mb situado en la región cromosómica 7q11.23:mientras que su duplicación da lugar a distintos trastornosdel lenguaje que afectan eminentemente alcomponente expresivo del mismo, su deleción (queorigina el denominado síndrome de Williams-Beuren)parece, en cambio, afectar en mayor medida aotras funciones cognitivas. Dicho fragmento contienealrededor de treinta genes funcionales, algunos de loscuales cabría considerar candidatos principales paralas alteraciones de índole lingüística experimentadaspor los sujetos en los que el fragmento se halla duplicado/delecionado, y en los que se advierte, por consiguienteuna alteración de su dosis normal comoconsecuencia de los eventos de reordenación cromsómica.La consideración de otros trastornos semejantes(como el síndrome de la deleción del fragmento22q13.3 o los síndromes de Potocki-Lupski y Smith-Magenis) permitir perfilar la genuina naturaleza deaquel programa de desarrollo, que no se agota en lainformación que contiene la secuencia codificadorade los genes que lo integran, sino que depende deotros muchos factores, incluyendo la regulación precisade su patrón transcripcional(AU)

Molecular characterization of genomic disordersin which language impairment is a prominentsymptom decisively contributes to a betterunderstanding of the effect of gene dosage onthe development of the language organ. One ofthe most well-characterized deletion/duplicationsyndromes concer chromosome 7q11.23. Thecommon recurrent microdeletion/microduplicationaffects to a critical region of 1.5 Mb. Whenthis region is deleted (Williams-Beurensyndrome), language, but not other cognitiveabilities, seems to remain intact. Conversely,when this region is duplicated, a severe delay inexpressive speech emerges. The 1.5 Mb region isestimated to encompass nearly thirty functionalgenes, some of which have been tentatively linkedto differer of the cognitive and linguisticpecualiarities of the syndromes. A change ingene dosage has also been confirmed for some ofthese genes. The phenotypic and molecularanalysis of other similar genomic disorders (likechromosome 22q13.3 deletion syndrome orPotocki-Lupski/Smith-Magenis syndromes) clearlysuggests that not only gene sequences, butalso transcriptional profiles of the differentgenes involved, decisively shape the innate programmeresponsible for the development of thelanguage module(AU)

Genes, cognición y lenguaje: consideraciones a propósito del síndrome velocardiofacial / Genes, cognition, and language: some notes regarding velocardiofacial syndrome

Introducción. La identificación de diversos síndromes causadospor microdeleciones cromosómicas y su caracterización exhaustiva entérminos moleculares y clínicos está contribuyendo decisivamente adilucidar la genuina naturaleza de las relaciones existentes entre losgenes y la cognición.Desarrollo. El síndrome velocardiofacial es un trastorno causadopor la deleción de una pequeña región de una de las copias delcromosoma 22, la cual afecta en la mayoría de los casos a alrededorde 40 genes. Aunque la hemicigosis de dicha región da lugar adistintas alteraciones estructurales y funcionales en diferenteszonas del organismo, las que presentan una mayor relevancia sonlas que se observan en el sistema nervioso central, puesto que originanun complejo cuadro clínico que incluye entre sus síntomascaracterísticos diversos trastornos psiquiátricos, disfunciones cognitivasde diferente naturaleza y alcance, y distintos déficits deíndole lingüística.Conclusiones. La clonación y la caracterización molecular de losgenes presentes en el fragmento delecionado en este síndrome, asícomo la generación de modelos animales del mismo, están permitiendocomprender mejor sus manifestaciones clínicas, y tambiénentender con mayor exactitud el papel que desempeñan realmentelos genes en la emergencia y la operatividad de las diferentes capacidadescognitivas humanas: lejos de existir una causa directa, elefecto que los factores de naturaleza genética ejercen sobre las capacidadesse halla siempre condicionado por la influencia del contextomolecular y ontogenético, así como por la del ambiente en que sedesenvuelve el individuo (AU)

Introduction. Identification of different syndromes caused bychromosomic microdeletions and their exhaustive characterizationin molecular and clinical terms is decisively contributing to elucidatereal connections between genes and cognition.Development. The velocardiofacial syndrome is a disordercaused by a hemizygous deletion of chromosome 22q11.2, whichencompasses about 40 genes. Although the hemizygosis of thatregion gives rise to different structural and functional alterationsin difference zones of the body, those having the greatest relevanceare those observed in the central nervous system, sincethey give rise to a complex clinical picture. This clinical pictureincludes, among its characteristic symptoms, different psychiatricdisorders, cognitive impairments, and a delay in language acquisition.Conclusions. Cloning and molecular characterization ofgenes circumscribed to the deleted region in this syndrome andthe generation of animal models of it have greatly helped toobtain a better understanding of the clinical phenotype, as wellas the actual role performed by genes in the emergence of operationcapacity of the different human cognitive capacities. Farfrom there being a direct cause, the effect that the genetic factorshave on cognitive functions are always conditioned by themolecular and the ontogenetic background and also by the environmentthe body lives in (AU)

[Huntington's disease: molecular foundations and implications in the characterisation of the neuronal mechanisms responsible for linguistic processing]. / Enfermedad de Huntington: fundamentos moleculares e implicaciones para una caracterización de los mecanismos neuronales responsables del procesamiento lingüístico.

INTRODUCTION: Certain neuronal models of linguistic processing suggest that the basal ganglia play a key role in this processing, thanks to their integration within the so-called cortico-striato-cortical circuits. DEVELOPMENT: A comparative analysis, at a phenotypic and molecular level, of the pathologies, syndromes and disorders that entail a structural alteration and/or a dysfunction of the basal ganglia is essential for validating and optimising such models, as well as for achieving a suitable characterisation of the genetic program responsible for the development and functioning of the 'language organ'. One of the most significant pathologies in this respect is Huntington's disease, which is caused by the destruction of certain groups of neurons in the caudate nucleus. CONCLUSIONS: This type of analysis seems to confirm the hypothesis that, during linguistic processing, the basal ganglia would be responsible for planning and modulating the sequential tasks related to the so-called procedural (or computational or rule-applying) component of language. Equally plausible, however, is the hypothesis that, inside them, there would be regions that are specifically dedicated to processing the different (morphological and syntactical) rules that go to make up said component. Additionally, the nature of these subcortical structures and the function they perform would explain the simultaneous presence of an articulatory and a linguistic deficit in disorders in which the basal ganglia are affected. Lastly, this kind of analysis is also making it possible to characterise some of the genes that constitute the genetic program responsible for the development and functioning of this region of the brain and, by extension, of the 'language organ'.

Enfermedad de Huntington: fundamentos moleculares e implicaciones para una caracterización de los mecanismos neuronales responsables del procesamiento lingüístico / Huntington's disease: Molecular foundations and implications in the characterisation of the neuronal mechanisms responsible for linguistic processing

Introducción. Determinados modelos neuronales de procesamiento lingüístico sugieren que los ganglios basales desempeñan un papel fundamental durante aquél, merced a su integración en los denominados circuitos corticoestriatocorticales. Desarrollo. El análisis comparativo, a nivel fenotípico y molecular, de aquellas patologías, síndromes y afecciones que entrañan una alteración estructural y/o una disfunción de los ganglios basales resulta fundamental para la validación y la optimización de dichos modelos, así como para una adecuada caracterización del programa genético responsable del desarrollo y el funcionamiento del ‘órgano del lenguaje’. Una de las patologías más relevantes a este respecto es la enfermedad deHuntington, causada por la destrucción de determinados grupos neuronales del núcleo caudado. Conclusiones. Este tipo de análisis parece confirmar la hipótesis de que los ganglios basales se ocuparían durante el procesamiento lingüístico de la planificación y la modulación de las tareas secuenciales relacionadas con el denominado componente procedimental (o computacionalo de aplicación de reglas) del lenguaje, si bien resulta plausible la hipótesis de que dentro de ellos existirían regiones dedicadas específicamente al procesamiento de las diversas reglas (morfológicas y sintácticas) que integran dicho componente. La naturaleza y la función desempeñada por estas estructuras subcorticales explicaría, por otra parte, la presencia simultánea de un déficit articulatorio y uno lingüístico en aquellos trastornos en los que los ganglios basales se hallan afectados. Por último, este tipo de análisis está permitiendo también caracterizar algunos de los genes que integran el programa genético responsable del desarrollo y el funcionamiento de esta región cerebral y, por extensión, del ‘órgano del lenguaje’

Introduction. Certain neuronal models of linguistic processing suggest that the basal ganglia play a key role in this processing, thanks to their integration within the so-called cortico-striato-cortical circuits. Development. A comparative analysis, at a phenotypic and molecular level, of the pathologies, syndromes and disorders that entail a structural alterationand/or a dysfunction of the basal ganglia is essential for validating and optimising such models, as well as for achieving a suitable characterisation of the genetic program responsible for the development and functioning of the ‘language organ’. One of the most significant pathologies in this respect is Huntington’s disease, which is caused by the destruction of certaingroups of neurons in the caudate nucleus. Conclusions. This type of analysis seems to confirm the hypothesis that, during linguistic processing, the basal ganglia would be responsible for planning and modulating the sequential tasks related to the so-called procedural (or computational or rule-applying) component of language. Equally plausible, however, is the hypothesis that, inside them, there would be regions that are specifically dedicated to processing the different (morphological and syntactical) rules that go to make up said component. Additionally, the nature of these subcortical structures and the function they perform would explain the simultaneous presence of an articulatory and a linguistic deficit in disorders in which the basal ganglia are affected. Lastly, this kind of analysis is also making it possible to characterise some of the genes that constitute the genetic program responsible for the development and functioning of this region of the brain and, by extension, of the ‘language organ’

[FOXP2 and the molecular biology of language: new evidence. II. Molecular aspects and implications for the ontogenesis and phylogeny of language]. / FOXP2 y la biología molecular del lenguaje: nuevas evidencias. II. Aspectos moleculares e implicaciones para la ontogenia y la filogenia del lenguaje.

INTRODUCTION: FOXP2 is the first gene linked to a hereditary variant of specific language impairment and seems to code for a transcriptional repressor that intervenes in the regulation of the development and the functioning of certain thalamic-cortical-striatal circuits. DEVELOPMENT: In the last three years, significant progress has been made in the determination of the structural and functional properties of the gene. These advances essentially have to do with the precise analysis of the most important structural motifs of the protein that it codes for and the main parameters that determine its interaction with DNA. They also concern the determination of the functional and behavioural properties in vivo of the main isoforms of the FOXP2 protein, the exact determination of the pattern of expression of new orthologues of the gene, and the identification of the different target genes for factor FOXP2. CONCLUSIONS: This new evidence suggests that protein FOXP2 protein has a high degree of versatility in vivo when it comes to binding to DNA; that its different isoforms are biologically functional; and that the FOXP2 gene is functional during embryonic development and during the adult phase. It also suggests that it is involved in the development and/or functioning of the thalamic-cortical-striatal circuits associated to motor planning, sequential behaviour and procedural learning (a significant saving in developmental terms of the regulatory mechanism in which the gene is involved), as well as the accuracy of the models of linguistic processing that consider language to be, to a large extent, the result of an interaction between certain cortical and subcortical structures.

[FOXP2 and the molecular biology of language: new evidence. I. Phenotypic aspects and animal models]. / FOXP2 y la biología molecular del lenguaje: nuevas evidencias. I. Aspectos fenotípicos y modelos animales.

INTRODUCTION: FOXP2 is the first gene linked to a hereditary variant of specific language impairment and seems to code for a transcriptional repressor that intervenes in the regulation of development and the functioning of certain thalamic-cortical-striatal circuits. DEVELOPMENT: In the last three years significant progress has been made in the analysis of the structural and functional properties of the gene. The most notable advances have been made in the genotypic and phenotypic characterisation of new alterations in its sequencing in human beings; the determination in vivo of the functional properties of the mutated proteins generated from said variants; the cloning and characterisation of new orthologues of the gene; the generation of the first knockout and knockdown organisms for it; and a more precise molecular characterisation of the biological role played by the orthologues corresponding to species that are also capable of learning the articulatory patterns of the vocalisations they use to communicate. CONCLUSIONS: The latest clinical evidence and that obtained from analysing animal models generated to date appear to suggest the presence of a 'sensory-motor disorder' as the central deficit behind the different phenotypes associated to the different mutations of the gene in the human species, the functionality of the gene FOXP2 during development of the embryo and during the adult phase, its involvement in the development and functioning of the thalamic-cortical-striatal circuits associated to motor planning, sequential behaviour and procedural learning, and significant old age, in developmental terms, of a part of the neuroanatomical substrate that is involved in processing linguistic stimuli in our species.

FOXP2 y la biología molecular del lenguaje: nuevas evidencias. II. Aspectos moleculares e implicaciones para la ontogenia y la filogenia del lenguaje / FOXP2 and the molecular biology of language: new evidence. II. Molecular aspects and implications for the ontogenesis and phylogeny of language

FOXP2 es el primer gen ligado a una variante hereditaria del trastorno específico del lenguaje y parececodificar un represor transcripcional que interviene en la regulación del desarrollo y del funcionamiento de determinados circuitos corticotalamoestriatales. Desarrollo. En los últimos tres años se han producido significativos avances en la determinación de las propiedades estructurales y funcionales del gen, que conciernen fundamentalmente al análisis preciso delos motivos estructurales más importantes de la proteína que codifica y de los parámetros más relevantes que determinan la interacción de ésta con el ADN; al esclarecimiento de las propiedades funcionales y del comportamiento in vivo de las principales isoformas de la misma; a la determinación exacta del patrón de expresión de nuevos ortólogos del gen; y a la identificación de diferentes genes diana para el factor FOXP2. Conclusiones. Estas nuevas evidencias sugieren una gran versatilidad in vivo por parte de la proteína FOXP2 a la hora de unirse al ADN; la funcionalidad biológica de sus diversas isoformas; la implicación del gen FOXP2 en el desarrollo y/o el funcionamiento de los circuitos corticotalamoestriatales asociados a la planificación motora, el comportamiento secuencial y el aprendizaje procedimental, tanto en la fase adulta como durante el desarrollo embrionario; una significativa conservación en términos evolutivos del mecanismo regulador en el que interviene el gen; y la idoneidad de los modelos de procesamiento lingüístico que consideran que el lenguaje es, en buena medida, el resultado de una interacción entre determinadas estructuras corticales y subcorticales (AU)

FOXP2 is the first gene linked to a hereditary variant of specific language impairment and seems tocode for a transcriptional repressor that intervenes in the regulation of the development and the functioning of certain thalamic-cortical-striatal circuits. Development. In the last three years, significant progress has been made in the determination of the structural and functional properties of the gene. These advances essentially have to do with the precise analysis of the most important structural motifs of the protein that it codes for and the main parameters that determine its interaction with DNA. They also concern the determination of the functional and behavioural properties in vivo of the main isoforms of the FOXP2 protein, the exact determination of the pattern of expression of new orthologues of the gene, and the identification of the different target genes for factor FOXP2. Conclusions. This new evidence suggests that protein FOXP2 protein has a high degree of versatility in vivo when it comes to binding to DNA; that its different isoforms are biologically functional; and that the FOXP2 gene is functional during embryonic development and during the adult phase. It also suggests that it is involved in the development and/or functioning of the thalamic-cortical-striatal circuits associated to motor planning, sequential behaviour and procedural learning (a significant saving in developmental terms of the regulatory mechanism in which the gene is involved), as well as the accuracy of the models of linguistic processing that consider language to be, to a large extent, the result of an interaction between certain cortical and subcortical structures (AU)

FOXP2 y la biología molecular del lenguaje: nuevas evidencias. I. Aspectos fenotípicos y modelos animales / FOXP2 and the molecular biology of language: new evidence. I. Phenotypic aspects and animal models

FOXP2 es el primer gen ligado a una variante hereditaria del trastorno específico del lenguaje y parececodificar un represor transcripcional que intervendría en la regulación del desarrollo y del funcionamiento de determinados circuitos corticotalamoestriatales. Desarrollo. En los últimos tres años se han producido significativos avances en el análisis de las propiedades estructurales y funcionales del gen, en particular, en lo que atañe a la caracterización genotípicay fenotípica de nuevas alteraciones de su secuencia en el ser humano, la determinación de las propiedades funcionales in vivo de las proteínas mutadas generadas a partir de dichas variantes, la clonación y caracterización de nuevos ortólogos delgen, la generación de los primeros organismos knockout y knockdown para éste, y una caracterización molecular más precisa del papel biológico desempeñado por los ortólogos correspondientes a especies que también son capaces de aprender los patrones articulatorios de las vocalizaciones que emplean para comunicarse. Conclusiones. Las nuevas evidencias clínicas ylas procedentes del análisis de los modelos animales generados hasta la fecha parecen sugerir la presencia de un ‘trastorno sensorimotor’ como déficit nuclear de los distintos fenotipos asociados a las diversas mutaciones del gen en la especie humana,la funcionalidad del gen FOXP2 durante el desarrollo embrionario y durante la fase adulta, su implicación en el desarrollo y funcionamiento de los circuitos corticotalamoestriatales asociados a la planificación motora, el comportamiento secuencialy el aprendizaje procedimental, y una significativa antigüedad, en términos evolutivos, de una parte del sustrato neuroanatómico que en nuestra especie interviene en el procesamiento de estímulos lingüísticos

FOXP2 is the first gene linked to a hereditary variant of specific language impairment and seems tocode for a transcriptional repressor that intervenes in the regulation of development and the functioning of certain thalamiccortical- striatal circuits. Development. In the last three years significant progress has been made in the analysis of thestructural and functional properties of the gene. The most notable advances have been made in the genotypic and phenotypic characterisation of new alterations in its sequencing in human beings; the determination in vivo of the functional propertiesof the mutated proteins generated from said variants; the cloning and characterisation of new orthologues of the gene; the generation of the first knockout and knockdown organisms for it; and a more precise molecular characterisation of the biological role played by the orthologues corresponding to species that are also capable of learning the articulatory patternsof the vocalisations they use to communicate. Conclusions. The latest clinical evidence and that obtained from analysing animal models generated to date appear to suggest the presence of a 'sensory-motor disorder' as the central deficit behind thedifferent phenotypes associated to the different mutations of the gene in the human species, the functionality of the gene FOXP2 during development of the embryo and during the adult phase, its involvement in the development and functioning ofthe thalamic-cortical-striatal circuits associated to motor planning, sequential behaviour and procedural learning, and significant old age, in developmental terms, of a part of the neuroanatomical substrate that is involved in processing linguisticstimuli in our species

[Autism and language: some molecular aspects]. / Autismo y lenguaje: aspectos moleculares.

INTRODUCTION: Autism is a cognitive disorder that includes among its distinguishing symptoms a deficit in the pragmatic component of language. Yet, it seems that there are certain subtypes where other deficiencies have been seen to affect the phonological, lexical, syntactical and morphological components of language. DEVELOPMENT: Linkage and association analyses aimed at identifying the genes that constitute causal or risk factors for the disorder have allowed researchers to identify certain loci that appear to be linked or associated to a statistically significant degree with autism endophenotypes of a linguistic nature. CONCLUSIONS: The target genes in this type of analysis play a number of different biological roles related with the development and functioning of the nervous system. On certain occasions, the loci thus identified coincide with others that had previously been linked to diverse language disorders (one paradigmatic case would be that of the chromosomal region 7q31 in relation to specific language disorder). This suggests that such disorders and autism might share a partially common genetic foundation that would account for the similarities observed between them at the phenotypic level.

Autismo y lenguaje: aspectos moleculares / Autism and language: some molecular aspects

El autismo es un trastorno cognitivo que incluye entre sus síntomas distintivos un déficit en el componentepragmático del lenguaje. Sin embargo, parecen existir determinados subtipos en los que se advierten además otros déficit que afectan a los componentes fonológico, léxico, sintáctico y morfológico del lenguaje. Desarrollo. Los análisis de ligamientoy de asociación encaminados a identificar los genes que constituyen factores causales o de riesgo para el trastorno han permitido caracterizar determinados loci que aparecen ligados o asociados de forma estadísticamente significativa con endofenotipos del autismo de carácter lingüístico. Conclusiones. Los genes a los que apunta este tipo de análisis desempeñan diversos papeles biológicos, relacionados con el desarrollo y el funcionamiento del sistema nervioso. En determinadas ocasiones, los loci identificados coinciden con otros que se habían vinculado previamente con distintos trastornos del lenguaje (un caso paradigmático sería el de la región cromosómica 7q31 en relación con el trastorno específico del lenguaje), lo quesugiere que dichos trastornos y el autismo podrían compartir una base genética parcialmente común, que explicaría las semejanzas que se advierten entre ellos a nivel fenotípico

Autism is a cognitive disorder that includes among its distinguishing symptoms a deficit in the pragmaticcomponent of language. Yet, it seems that there are certain subtypes where other deficiencies have been seen to affect the phonological, lexical, syntactical and morphological components of language. Development. Linkage and association analyses aimed at identifying the genes that constitute causal or risk factors for the disorder have allowed researchers toidentify certain loci that appear to be linked or associated to a statistically significant degree with autism endophenotypes of a linguistic nature. Conclusions. The target genes in this type of analysis play a number of different biological roles relatedwith the development and functioning of the nervous system. On certain occasions, the loci thus identified coincide with others that had previously been linked to diverse language disorders (one paradigmatic case would be that of the chromosomal region 7q31 in relation to specific language disorder). This suggests that such disorders and autism might share a partiallycommon genetic foundation that would account for the similarities observed between them at the phenotypic lev

[The molecular bases of dyslexia]. / Bases moleculares de la dislexia.

INTRODUCTION: The recent identification and cloning of the first genes with a mutation linked to dyslexia is starting to allow researchers to achieve a more precise characterisation of both the disorder itself and the functioning of the neuronal circuits responsible for the ability to read and spell. DEVELOPMENT: The dyslexia-related genes that have been characterised to date appear to be involved in controlling the migration of certain neuronal lineages, as well as in regulating axonal growth. Furthermore, there seems to be a satisfactory match between their dysfunction and some of the structural and functional anomalies detected in individuals affected by the disorder. In some cases there has been a positive selection of certain modifications to their sequencing during the recent developmental history of the human kind. CONCLUSIONS: Molecular analysis of the endophenotypes associated with dyslexia and the search for the alleles that make the individual susceptible to the disorder (apart from the search for the genes that have a direct influence in the disorder, which researchers are beginning identify) will make it possible, some time in the future, to reach a more precise characterisation of the components of the genetic regulation programme that modulates the organisation and activity of the neuronal centres related to the capacity to read. Many of these centres are likely to be common to other programmes governing the development of neuronal circuits linked to linguistic processing and the learning and acquisition of new capacities. It will also make it possible to carry out a more exact assessment of how this programme is affected by the molecular and ontogenetic context, as well as by the environment in which the individual grows up.

Bases moleculares de la dislexia / The molecular bases of dyslexia

La reciente identificación y clonación de los primeros genes cuya mutación se ha asociado a la dislexiaestá comenzando a permitir una caracterización más precisa del trastorno, pero también del programa genético que regula el desarrollo y el funcionamiento de los circuitos neuronales responsables de la capacidad de lectura y deletreo. Desarrollo.Los genes relacionados con la dislexia caracterizados hasta la fecha parecen estar involucrados en el control de la migración de determinados linajes neuronales, así como en la regulación del crecimiento axonal; su disfunción parece casar satisfactoriamentecon algunas de las anomalías estructurales y funcionales detectadas en los individuos afectados por el trastorno.En algunos casos se ha producido una selección positiva de determinadas modificaciones de su secuencia durante lareciente historia evolutiva de la especie humana. Conclusiones. El análisis molecular de los endofenotipos asociados a la dislexia y la búsqueda de los alelos que confieran susceptibilidad a ésta (al margen de la búsqueda de los genes que influyen directamenteen el trastorno, los cuales ya se han comenzado a identificar) permitirán, en un futuro, caracterizar con mayor precisión los componentes del programa de regulación genética que modula la organización y la actividad de los centros neuronalesrelacionados con la capacidad de lectura, muchos de los cuales serán, probablemente, comunes a otros programas dedesarrollo de circuitos neuronales vinculados al procesamiento lingüístico, el aprendizaje y la adquisición de nuevas capacidades,y valorar de este modo en su justa medida el efecto que sobre dicho programa ejerce el contexto molecular y ontogenético, así como el ambiente en el cual crece el individuo

The recent identification and cloning of the first genes with a mutation linked to dyslexia is starting toallow researchers to achieve a more precise characterisation of both the disorder itself and the functioning of the neuronalcircuits responsible for the ability to read and spell. Development. The dyslexia-related genes that have been characterised to date appear to be involved in controlling the migration of certain neuronal lineages, as well as in regulating axonal growth.Furthermore, there seems to be a satisfactory match between their dysfunction and some of the structural and functional anomalies detected in individuals affected by the disorder. In some cases there has been a positive selection of certain modifications to their sequencing during the recent developmental history of the human kind. Conclusions. Molecular analysisof the endophenotypes associated with dyslexia and the search for the alleles that make the individual susceptible to the disorder (apart from the search for the genes that have a direct influence in the disorder, which researchers are beginning identify) will make it possible, some time in the future, to reach a more precise characterisation of the components of thegenetic regulation programme that modulates the organisation and activity of the neuronal centres related to the capacity to read. Many of these centres are likely to be common to other programmes governing the development of neuronal circuitslinked to linguistic processing and the learning and acquisition of new capacities. It will also make it possible to carry out a more exact assessment of how this programme is affected by the molecular and ontogenetic context, as well as by theenvironment in which the individual grows up