Ophthalmic genetics in South America.

South America comprises of heterogeneous topographies, populations, and health care systems. Therefore, it is not surprising to see differences among the countries regarding expertise, education, and practices of ophthalmic genetics for patients with rare eye diseases. Nevertheless, common challenges such as limited genetics training in medical schools and among ophthalmologists, scarcity of diagnostic tools for phenotyping, and expensive genetic testing not covered by the public healthcare systems, are seen in all of them. Here, we provide a detailed report of the current status of ophthalmic genetics, described by the personal views of local ophthalmologists from Brazil, Colombia, Argentina, and Chile. By reporting our strengths and weaknesses as a region, we intend to highlight the need for guidelines on how to manage these patients aligned with public health policies. Our region contributes to research worldwide, with thousands of well diagnosed patients from a number of unique and genetically diverse populations. The constant expansion of ophthalmic genetics and molecular diagnostics requires us to join forces to collaborate across South America and with other countries to improve access to next-generation diagnostics and ultimately improve patient care.

[Autism. Genetic and biological aspects]. / Autismo. Aspectos genéticos y biológicos.

Autism is a neurodevelopmental disorder characterized by commitment to social interaction and communication, associated with interests restricted and stereotyped behaviors with a high population prevalence, neurobiological bases and high heritability. Its etiology is heterogeneous, numerous genetic bases, environmental factors and epigenetic mechanisms have been recognized. Advances in molecular genetics, as well as epidemiological studies of large cohorts, have made it possible to identify specific medical entities, as well as genes and environmental factors partially or totally linked in their pathogenesis. This knowledge, according to the clinical characteristics, allows to guide the complementary studies, the therapeutic conducts, to infer a clinical prognosis and to propitiate the familiar genetic advice. In this work, the most prevalent clinical characteristics identified are described; the specific medical entities that are strongly related to autism are stated, as well as the recognized genes, the possible environmental factors and the epidemiological results that allow family counseling.

El autismo es un trastorno del neurodesarrollo caracterizado por compromiso en la interacción social y la comunicación, asociado a intereses restringidos y conductas estereotipadas con gran prevalencia poblacional, bases neurobiológicas y alta heredabilidad. Su etiología es heterogénea y se han reconocido numerosas bases genéticas, factores ambientales y mecanismos epigenéticos. Los avances en la genética molecular, así como los estudios epidemiológicos de grandes cohortes, han posibilitado identificar entidades médicas específicas, así como genes y factores ambientales vinculados parcial o totalmente en su patogenia. Estos conocimientos, conforme las características clínicas, permiten orientar los estudios complementarios, las conductas terapéuticas, inferir un pronóstico clínico y propiciar el asesoramiento genético familiar. En este trabajo analizamos las características clínicas de los trastornos del espectro del autismo, las entidades médicas específicas que están fuertemente relacionadas a los mismos, así como los genes reconocidos, los posibles factores ambientales y los resultados epidemiológicos que permiten el adecuado asesoramiento familiar.

Case report: Novel SIN3A loss-of-function variant as causative for hypogonadotropic hypogonadism in Witteveen-Kolk syndrome.

Pubertal delay can be due to hypogonadotropic hypogonadism (HH), which may occur in association with anosmia or hyposmia and is known as Kallmann syndrome (OMIM #308700). Recently, hypogonadotropic hypogonadism has been suggested to overlap with Witteveen-Kolk syndrome (WITKOS, OMIM #613406) associated with 15q24 microdeletions encompassing SIN3A. Whether hypogonadotropic hypogonadism is due to haploinsufficiency of SIN3A or any of the other eight genes present in 15q24 is not known. We report the case of a female patient with delayed puberty associated with intellectual disability, behavior problems, dysmorphic facial features, and short stature, at the age of 14 years. Clinical, laboratory, and imaging assessments confirmed the diagnosis of Kallmann syndrome. Whole-exome sequencing identified a novel heterozygous frameshift variant, NM_001145358.2:c.3045_3046dup, NP_001138830.1:p.(Ile1016Argfs*6) in SIN3A, classified as pathogenic according to the American College of Medical Genetics and Genomics (ACMG/AMP) criteria. Reverse phenotyping led to the clinical diagnosis of WITKOS. No other variant was found in the 96 genes potentially related to hypogonadotropic hypogonadism. The analysis of the other contiguous seven genes to SIN3A in 15q24 did not reveal any clinically relevant variant. In conclusion, these findings point to SIN3A as the gene in 15q24 related to the reproductive phenotype in patients with overlapping WITKOS and Kallmann syndrome.

[Autism and epigenetics. A model of explanation for the understanding of the genesis in autism spectrum disorders]. / Autismo y epigenética. Un modelo de explicación para la comprensión de la génesis en los trastornos del espectro autista.

Autism spectrum disorders are characterized by impairment of social integration and language development and restricted interests. Autism spectrum disorders manifest during childhood and may have a varying clinical expression over the years related to different therapeutic approaches, behavior-modifying drugs, and environmental factors, among others. So far, the genetic alterations identified are not sufficient to explain the genesis of all these processes, as many of the mutations found are also present in unaffected individuals. Findings on the underlying biological and pathophysiological mechanisms of entities strongly associated with autism spectrum disorders, such as Rett, fragile X, Angelman, and fetal alcohol syndromes, point to the role of epigenetic changes in disorders of neurodevelopment. Epigenetic phenomena are normal biological processes necessary for cell and thus human life, especially related to embryonic development. Different phenomena that affect epigenetic processes (changes that change operation or expression of a gene, without modifying the DNA structure) have also been shown to be important in the genesis of neurodevelopmental disorders. Alterations in the epigenetic mechanism may be reversible, which may explain the variation in the autism phenotype over time. Here we analyze the normal epigenetic mechanisms, autism spectrum disorders, their association with specific entities associated with altered epigenetic mechanisms, and possible therapeutic approaches targeting these alterations.

[Genetics of neurodevelopmental disorders. Practical aspects]. / Genética de los trastornos del neurodesarrollo. Aspectos prácticos.

Neurodevelopmental disorders (NDD) constitute a relevant group of pathologies, of childhood, with a biological basis and totally or partially genetic etiology. The recognition of the causal factors constitutes a challenge that has been perfected over the last decades, until obtaining an increasing diagnostic yield. The implementation of these technological advances can only be achieved through the formation of interdisciplinary work teams, which, following an orderly process, achieve a presumptive diagnosis, which is then certified using the techniques that for each of the cases are more profitable in terms of quality and cost. In this paper we list these procedures, based on different scenarios that highlight the extensive menu of possibilities and the need to manage them in a rational way, on well-founded scientific bases.

Los trastornos del neurodesarrollo (TND) constituyen un grupo relevante de enfermedades, con base biológica y etiología total o parcialmente genética. El reconocimiento de los factores causales constituye un reto cuyos resultados se han perfeccionado a lo largo de las últimas décadas, hasta obtener un rédito diagnóstico cada vez mayor. La implementación de estos avances tecnológicos solo puede lograrse mediante la conformación de equipos de trabajo interdisciplinarios, que siguiendo un proceso ordenado, logran un diagnóstico de presunción, que luego es certificado mediante las técnicas que, para cada uno de los casos, resulta más redituable en calidad y costo. En este trabajo, enumeramos estos procedimientos a partir de diferentes escenarios que ponen de relieve el extenso menú de posibilidades y la necesidad de administrar los mismos de un modo racional, sobre bases científicas debidamente fundadas.

[Epigenetic mechanisms involved in the genesis of autism]. / Mecanismos epigenéticos involucrados en la génesis del autismo.

Autism is a neurobiological developmental disorder characterized by poor social interaction and communication, narrow interests, and stereotyped behaviors. It has been associated with disorders of synaptogenesis and multiple etiologies. The identification of the epigenetic factors involved in the genesis of autism allows a better understanding of the molecular mechanisms involved. Our objective was to analyze the epigenetic mechanisms related to the development of autism, specifying specific entities and their pathophysiological mechanisms. We analyze how DNA methylation disorders, histone modification, remodeling and chromosomal regulation mediated by non-coding RNA are related to various genetic syndromes such as fragile X, Rett, Pathias Mecp2, Phelam McDermid, prenatal toxins such as alcohol, valproic. acid, cannabis, and environmental toxins such as maternal stress, all associated with a higher prevalence of autism. In conclusion: the recognition of these mechanisms opens up new possibilities for prevention and it is likely that, in genetic entities, it will allow the development of specific treatments with modifications tailored to each entity.

El autismo es un trastorno del neurodesarrollo de base neurobiológica, caracterizado por alteración en la interacción social y la comunicación, intereses restringidos y conductas estereotipadas. Se relaciona con trastornos en la sinaptogénesis y a multiples etiologías. La identificación de factores epigenéticos implicados en la génesis del autismo permiten una mejor comprensión de los mecanismos moleculares involucrados. Nuestro objetivo fue analizar los mecanismos epigenéticos relacionados al desarrollo del autismo, puntualizando entidades específicas y sus mecanismos fisiopatológicos. Analizamos de qué manera se relacionan los trastornos en la metilación del ADN, la modificación de las histonas, la remodelación cromosómica y la regulación mediada por el ARN no codificantes con diversos síndromes genéticos como el frágil X, Rett, Mecp2patías, Phelam McDermid, tóxicos prenatales como el alcohol, ácido valproico, cannabis y ambientales cómo el estrés materno, todos ellos asociados a una mayor prevalencia de autismo. En conclusión, el reconocimiento de estos mecanismos abre nuevas posibilidades para la prevención, y probablemente en un futuro, en las entidades genéticas, permitirá el desarrollo de tratamientos específicos con modificaciones a la medida de cada entidad.

Clinical Spectrum and Tumour Risk Analysis in Patients with Beckwith-Wiedemann Syndrome Due to CDKN1C Pathogenic Variants.

Beckwith-Wiedemann syndrome spectrum (BWSp) is an overgrowth disorder caused by imprinting or genetic alterations at the 11p15.5 locus. Clinical features include overgrowth, macroglossia, neonatal hypoglycaemia, omphalocele, hemihyperplasia, cleft palate, and increased neoplasm incidence. The most common molecular defect observed is hypomethylation at the imprinting centre 2 (KCNQ1OT1:TSS DMR) in the maternal allele, which accounts for approximately 60% of cases, although CDKN1C pathogenic variants have been reported in 5-10% of patients, with a higher incidence in familial cases. In this study, we examined the clinical and molecular features of all cases of BWSp identified by the Spanish Overgrowth Registry Initiative with pathogenic or likely pathogenic CDKN1C variants, ascertained by Sanger sequencing or next-generation sequencing, with special focus on the neoplasm incidence, given that there is scarce knowledge of this feature in CDKN1C-associated BWSp. In total, we evaluated 21 cases of BWSp with CDKN1C variants; 19 were classified as classical BWS according to the BWSp scoring classification by Brioude et al. One of our patients developed a mediastinal ganglioneuroma. Our study adds evidence that tumour development in patients with BWSp and CDKN1C variants is infrequent, but it is extremely relevant to the patient's follow-up and supports the high heterogeneity of BWSp clinical features associated with CDKN1C variants.

Genetic literacy and psychological adaptation in adolescents with genetic diseases / [Alfabetización genética y adaptación psicológica en adolescentes con enfermedades genéticas]

Introduction: Living with a genetic condition is complex and may be limiting for the adolescent. This situation is considered a stress factor and risk factor for the mental health of both the patient and his family. Objective: To study the levels of psychological adaptation and genetic literacy in adolescents with genetic diseases residing in Argentina. Methods: Correlational and quantitative design and cross sectional scope. The protocol consisted of an informed consent, a sociodemographic data questionnaire, and the Genetic Health Literacy Screening Tool (REAL G) and Psychological Adaptation Scale (PAS) instruments. The sampling was intentional and composed by 68 cases. Results: The REAL G indicated low levels of genetic literacy in all its components (decoding, familiarity, comprehension, arithmetic). Regarding psychological adaptation, an M = 4.02 (SD = 0.8) was found for the general scale and high scores for all the dimensions. Conclusion: Adolescents diagnosed with genetic diseases in Argentina have a good level of psychological adaptation to their disease, despite having low levels of genetic literacy.

Introducción: La convivencia con una condición genética es compleja y puede resultar limitante para el adolescente. Esta situación constituye un estresor y un factor de riesgo para la salud mental tanto del paciente como de su familia. Objetivo: Estudiar los niveles de adaptación psicológica y alfabetización genética en adolescentes con enfermedades genéticas, residentes en Argentina. Métodos: Alcance descriptivo correlacional, de diseño cuantitativo y corte transversal. El protocolo administrado consistió en un consentimiento informado, un cuestionario de datos socio-demográficos, y los instrumentos Genetic Health Literacy Screening Tool (REAL G) y  Psychological Adaptation Scale (PAS). El muestreo fue intencional y la muestra fue de 68 casos. Resultados: El REAL G indicó bajos niveles de de alfabetización genética en todos sus componentes (decodificación, familiaridad, comprensión, aritmética). En cuanto a la adaptación psicológica, se encontró una M=4,02 (DE= 0.8) para la escala general y puntuaciones elevadas para todas las dimensiones. Conclusión: Los adolescentes diagnosticados con enfermedades genéticas en Argentina poseen un buen nivel de adaptación psicológica a su enfermedad, a pesar de tener bajos niveles de alfabetización genética.

A few challenges in mucopolysaccharidosis type I. / Algunos desafíos en mucopolisacaridosis tipo I.

Here we describe the current challenges of mucopolysaccharidosis type I: the need for an adequate classification, establishing its relationship to therapeutic indications; an early diagnosis, from neonatal screening, its advantages and barriers, to clinical suspicion of severe and attenuated forms; spinal and eye disease care, from diagnosis to follow-up and treatment; allergic reactions caused by enzyme replacement therapy, their diagnosis and treatment. And lastly, transition to adult care.

Se describen como desafíos actuales en mucopolisacaridosis I la necesidad de una clasificación adecuada, vinculándola a las indicaciones terapéuticas; el diagnóstico temprano desde la pesquisa neonatal, sus ventajas y dificultades hasta la sospecha clínica de las formas grave y atenuada; el cuidado de la patología espinal y oftalmológica, desde el diagnóstico, el seguimiento y el tratamiento; las reacciones alérgicas por terapia de reemplazo enzimático, su diagnóstico y tratamiento. Por último, la transición hacia el cuidado adulto.

New recommendations for the care of patients with mucopolysaccharidosis type I. / Nuevas recomendaciones para el cuidado de los pacientes con mucopolisacaridosis tipo I.

Considering the advances made on mucopolysaccharidosis type I after the consensus study published by a group of experts in Argentina in 2008, recommendations about genetic testing, cardiological follow-up, airway care, hearing impairment detection, spinal and neurological conditions, as well as current treatments, were reviewed. Emphasis was placed on the need for early diagnosis and treatment, as well as an interdisciplinary follow-up.

Dados los avances sobre mucopolisacaridosis I con posterioridad al consenso publicado en la Argentina por un grupo de expertos en 2008, se revisan recomendaciones respecto a estudios genéticos, seguimiento cardiológico, cuidado de la vía aérea, alertas sobre aspectos auditivos, de la patología espinal y neurológica. Se hace revisión de la terapéutica actual y se enfatiza en la necesidad de un diagnóstico y tratamiento precoces, así como de un seguimiento interdisciplinario.

[Osteoporosis-pseudoglioma Syndrome: a pediatric case of primary osteoporosis]. / Síndrome de osteoporosis-pseudoglioma: a propósito de un caso pediátrico de osteoporosis primaria.

Osteoporosis should be considered in children with severe chronic diseases or in association with some genetic diseases that bear an increased risk of bone fragility. Primary osteoporosis is an entity in which emerging aetiologies are being recognized. Its association with congenital retinal folds should guide the diagnosis to the Osteoporosis-Pseudoglioma syndrome (OMIM 259770), a rare disease (prevalence of 1/2 000 000), caused by the loss of function of the protein LRP5 (low-density lipoprotein receptor-related protein 5) resulting in the alteration of the Wnt/ß-catenin signalling pathway. We report the case of a child with congenital retinal folds, progressive loss of vision and multiple fractures whose clinical, biochemical and genetic studies confirmed the diagnosis of primary osteoporosis due to a novel homozygous inactivating variant in LRP5.

La osteoporosis es un trastorno para tener en cuenta en niños con patologías crónicas graves o con algunas enfermedades genéticas que predisponen al incremento de la fragilidad ósea. La osteoporosis primaria es una entidad con etiologías emergentes y puede ocurrir en forma sindrómica. La asociación con pliegues retinianos congénitos debe orientar al diagnóstico de osteoporosis-pseudoglioma (OMIM 259770), síndrome poco frecuente (prevalencia de 1/2 000 000), que se origina por la pérdida de función de la proteína LRP5 (low-density lipoprotein receptor-related protein 5) y compromete la vía de señalización de Wnt/ß-catenina. Se presenta el caso de un niño con pliegues retinianos congénitos, ceguera progresiva y múltiples fracturas cuyo estudio clínico, bioquímico y genético confirmó el diagnóstico de osteoporosis primaria debido a una nueva variante inactivante en el gen LRP5 en homocigosis.

[Genetic syndromes recognizable in the neonatal period]. / Síndromes genéticos reconocibles en el período neonatal.

The presence of a neonatal neurological lesion associated or not with dysmorphism or with a particular phenotype can be caused by a) prenatal infections (Group TORCH) toxic or teratotoxic agents (alcohol, cocain, antiepileptics, inhalants such as toluene, etc.), vascular defects or genetic anomalies; b) perinatal isquemic hypoxic lesions, infectious or metabolic disorders, etc. In this paper we analyze all entities of genetic origin neonatally recognizable by their phenotype which must be included in the differential diagnosis of all children neurologically compromised. In order to simplify the diagnosis, these entities will be divided according to the prevalence of the phenotype present at birth, dividing them into two large groups: 1) Genic alterations which include: Syndromes with characteristic facies and member malformations, Supra growth syndrome, Syndrome with neonatal growth deficit, Neuro-ectodermic syndromes, Syndromes with characteristic facies and ocular compromise, Syndromes with characteristic facies including those that bear MIM number, and 2) Chromosomal alterations (autosomal in number, mosaic, deletion, and sex chromosomes). The detection of these anomalies through phenotype studies involving congenital encephalopathies of genetic origin is of major importance because it will permit the orientation of specific diagnostic studies, the prevention of difficult and expensive maneuvers, and furthermore, it will offer adequate family counseling and control eventual complications.

Aging and Autism: Understanding, Intervention and Proposals to Improve Quality of Life.

BACKGROUND: The population with autism spectrum disorder (ASD) has been increasing and is currently estimated to be 1 in 58 births. The increased prevalence of ASD together with the lack of knowledge on the processes of aging in this population, the support needed at this stage of life, and the associated risk factors, have led to an urgent need for further research. METHODS: This study provides a review of the literature on social- and health-related conditions that may appear when persons with ASD grow old. RESULTS: In addition to the autism-related conditions, different neurological, genetic, and environmental factors may be involved in the process of aging. In this complex setting, this study provides proposals that may guide the development of support services that may improve the quality of life for aging people with ASD. CONCLUSION: Aging in ASD is emerging as a growing problem, which requires immediate planning and targetted treatment development.

A homozygous mutation in the highly conserved Tyr60 of the mature IGF1 peptide broadens the spectrum of IGF1 deficiency.

BACKGROUND: IGF1 is a key factor in fetal and postnatal growth. To date, only three homozygous IGF1 gene defects leading to complete or partial loss of IGF1 activity have been reported in three short patients born small for gestational age. We describe the fourth patient with severe short stature presenting a novel homozygous IGF1 gene mutation. RESULTS: We report a boy born from consanguineous parents at 40 weeks of gestational age with intrauterine growth restriction and severe postnatal growth failure. Physical examination revealed proportionate short stature, microcephaly, facial dysmorphism, bilateral sensorineural deafness and mild global developmental delay. Basal growth hormone (GH) fluctuated from 0.2 to 29 ng/mL, while IGF1 levels ranged from -1.15 to 2.95 SDS. IGFBP3 was normal-high. SNP array delimited chromosomal regions of homozygosity, including 12q23.2 where IGF1 is located. IGF1 screening by HRM revealed a homozygous missense variant NM_000618.4(IGF1):c.322T>C, p.(Tyr108His). The change of the highly conserved Tyr60 in the mature IGF1 peptide was consistently predicted as pathogenic by multiple bioinformatic tools. Tyr60 has been described to be critical for IGF1 interaction with type 1 IGF receptor (IGF1R). In vitro, HEK293T cells showed a marked reduction of IGF1R phosphorylation after stimulation with serum from the patient as compared to sera from age-matched controls. Mutant IGF1 was also less efficient in inducing cell growth. CONCLUSION: The present report broadens the spectrum of clinical and biochemical presentation of homozygous IGF1 defects and underscores the variability these patients may present depending on the IGF/IGF1R pathway activity.

[Pervasive developmental disorders. Clinical and genetics aspects]. / Trastornos generalizados del desarrollo. Aspectos clínicos y genéticos.

Pervasive developmental disorders (PDD) encompass a heterogeneous group of children with deficits of verbal and non-verbal language, social communication, and with a restricted repertoire of activities or repetitive behaviours. The frequency in general population is considered 27.5/10,000. In this study, we analyzed the clinical and genetic aspects of Autism, Asperger Syndrome, PDD Not Otherwise Specified, Rett Syndrome and Childhood Disintegrative Disorder. We analyzed clinical, behavioural and neuropsychological features. We revised different medical genetics associated conditions and divided the genetics aspects of pervasive developmental disorders into two groups: Syndromic forms (around 20%) and non syndromic forms (currently proposed to be 80%). The early recognition of pervasive developmental disorders and the diagnosis of specific associated syndromes allow early therapy, correct genetic counselling, and follow up anticipating possible complications related to the entity. Finally, although the genetic bases of autism have not yet been identified, the following candidate genes have been proposed: 15q, 2q, 17q, 7q, 12q, and X related genes, among others; which are analyzed in this study and will allow a better understanding of these disorders in the future.

Genética de los trastornos del neurodesarrollo. Aspectos prácticos / Genetics of neurodevelopmental disorders. Practical aspects

Resumen Los trastornos del neurodesarrollo (TND) constituyen un grupo relevante de enfermedades, con base biológica y etiología total o parcialmente genética. El reconocimiento de los factores causales cons tituye un reto cuyos resultados se han perfeccionado a lo largo de las últimas décadas, hasta obtener un rédito diagnóstico cada vez mayor. La implementación de estos avances tecnológicos solo puede lograrse mediante la conformación de equipos de trabajo interdisciplinarios, que siguiendo un proceso ordenado, logran un diag nóstico de presunción, que luego es certificado mediante las técnicas que, para cada uno de los casos, resulta más redituable en calidad y costo. En este trabajo, enumeramos estos procedimientos a partir de diferentes escenarios que ponen de relieve el extenso menú de posibilidades y la necesidad de administrar los mismos de un modo racional, sobre bases científicas debidamente fundadas.

Abstract Neurodevelopmental disorders (NDD) constitute a relevant group of pathologies, of childhood, with a biological basis and totally or partially genetic etiology. The recognition of the causal factors constitutes a challenge that has been perfected over the last decades, until obtaining an increasing diagnostic yield. The implementation of these technological advances can only be achieved through the formation of interdisciplinary work teams, which, following an or derly process, achieve a presumptive diagnosis, which is then certified using the techniques that for each of the cases are more profitable in terms of quality and cost. In this paper we list these procedures, based on different scenarios that highlight the extensive menu of possibilities and the need to manage them in a rational way, on well-founded scientific bases.

Mecanismos epigenéticos involucrados en la génesis del autismo / Epigenetic mechanisms involved in the genesis of autism

Resumen El autismo es un trastorno del neurodesarrollo de base neurobiológica, caracterizado por alteración en la interacción social y la comunicación, intereses restringidos y conductas estereotipadas. Se relaciona con trastornos en la sinaptogénesis y a multiples etiologías. La identificación de factores epigenéticos implicados en la génesis del autismo permiten una mejor comprensión de los mecanismos moleculares invo lucrados. Nuestro objetivo fue analizar los mecanismos epigenéticos relacionados al desarrollo del autismo, puntualizando entidades específicas y sus mecanismos fisiopatológicos. Analizamos de qué manera se rela cionan los trastornos en la metilación del ADN, la modificación de las histonas, la remodelación cromosómica y la regulación mediada por el ARN no codificantes con diversos síndromes genéticos como el frágil X, Rett, Mecp2patías, Phelam McDermid, tóxicos prenatales como el alcohol, ácido valproico, cannabis y ambientales cómo el estrés materno, todos ellos asociados a una mayor prevalencia de autismo. En conclusión, el recono cimiento de estos mecanismos abre nuevas posibilidades para la prevención, y probablemente en un futuro, en las entidades genéticas, permitirá el desarrollo de tratamientos específicos con modificaciones a la medida de cada entidad.

Abstract Autism is a neurobiological developmental disorder characterized by poor social interaction and communication, narrow interests, and stereotyped behaviors. It has been associated with disorders of synaptogenesis and multiple etiologies. The iden tification of the epigenetic factors involved in the genesis of autism allows a better understanding of the molecular mechanisms involved. Our objective was to analyze the epigenetic mechanisms related to the development of autism, specifying specific entities and their pathophysiological mechanisms. We analyze how DNA methylation disorders, histone modification, remodeling and chromosomal regulation mediated by non-coding RNA are related to various genetic syndromes such as fragile X, Rett, Pathias Mecp2, Phelam McDermid, prenatal toxins such as alcohol, valproic. acid, cannabis, and environmental toxins such as maternal stress, all associated with a higher prevalence of autism. In conclusion: the recognition of these mechanisms opens up new possibilities for preven tion and it is likely that, in genetic entities, it will allow the development of specific treatments with modifications tailored to each entity.

Nuevas recomendaciones para el cuidado de los pacientes con mucopolisacaridosis tipo I / New recommendations for the care of patients with mucopolysaccharidosis type I

Dados los avances sobre mucopolisacaridosis Icon posterioridad al consenso publicado en la Argentina por un grupo de expertos en 2008, se revisan recomendaciones respecto a estudios genéticos, seguimiento cardiológico, cuidado de la vía aérea, alertas sobre aspectos auditivos, de la patología espinal y neurológica. Se hace revisión de la terapéutica actual y se enfatiza en la necesidad de un diagnóstico y tratamiento precoces, así como de un seguimiento interdisciplinario

Considering the advances made on mucopolysaccharidosis type I after the consensus study published by a group of experts in Argentina in 2008, recommendations about genetic testing, cardiological follow-up, airway care, hearing impairment detection, spinal and neurological conditions, as well as current treatments, were reviewed. Emphasis was placed on the need for early diagnosis and treatment, as well as an interdisciplinary follow-up

Algunos desafíos en mucopolisacaridosis tipo I / A few challenges in mucopolysaccharidosis type I

Se describen como desafíos actuales en mucopolisacaridosis I la necesidad de una clasificación adecuada, vinculándola a las indicaciones terapéuticas; el diagnóstico temprano desde la pesquisa neonatal, sus ventajas y dificultades hasta la sospecha clínica de las formas grave y atenuada; el cuidado de la patología espinal y oftalmológica, desde el diagnóstico, el seguimiento y el tratamiento; las reacciones alérgicas por terapia de reemplazo enzimático, su diagnóstico y tratamiento. Por último, la transición hacia el cuidado adulto

Here we describe the current challenges of mucopolysaccharidosis type I: the need for an adequate classification, establishing its relationship to therapeutic indications; an early diagnosis, from neonatal screening, its advantages and barriers, to clinical suspicion of severe and attenuated forms; spinal and eye disease care, from diagnosis to follow-up and treatment; allergic reactions caused by enzyme replacement therapy, their diagnosis and treatment. And lastly, transition to adult care

[Therapeutic approaches in autism spectrum disorders]. / Abordajes terapéuticos en los trastornos del espectro autista.

Autistic spectrum disorders affect one out of every 68 persons, with a 4:1 dominance in males. Since they are dysfunctions rather than irreversible injuries to the central nervous system, which can be attributed to deficits in the neuronal networks and synaptogenesis and are modifiable thanks to the plasticity of the brain, starting therapy as early as possible is essential for more favourable progress. Very few treatments are backed by solid scientific evidence. We will analyse the therapeutic approaches oriented towards improving autism spectrum disorders which showed a clinical improvement that can be related to neurophysiological or functional changes in the central nervous system. We will classify the behavioural educational treatments and those in the research phase into a hierarchy, highlighting the neurogenetic entities with a high prevalence of autism, in which their pathophysiology and molecular base are known, that attempt to modify the consequences of those alterations by means of pharmacological agents. These entities include fragile X syndrome (GABAergic and metabotropic glutamate receptor inhibitors), tuberous sclerosis (mTOR inhibitors), Phelan-McDermid syndrome and Rett syndrome (insulin-like growth factor 1 inhibitors). Oxytocin, which has been shown to improve social cognition in persons with autism spectrum disorders, is analysed separately.

TITLE: Abordajes terapeuticos en los trastornos del espectro autista.Los trastornos del espectro autista afectan a una de cada 68 personas, con predominio de 4 a 1 en varones. Por tratarse de disfunciones y no lesiones irreversibles del sistema nervioso central, atribuibles a defectos en las redes neuronales y la sinaptogenesis, modificables gracias a la plasticidad cerebral, la precocidad en el inicio terapeutico es fundamental para una mejor evolucion. Son pocos los tratamientos que cuentan con clara evidencia cientifica. Analizaremos abordajes terapeuticos orientados a mejorar los trastornos del espectro autista que demostraron una mejoria clinica relacionable a cambios neurofisiologicos o funcionales en el sistema nervioso central. Jerarquizaremos los tratamientos educativos conductuales y aquellos en etapa de investigacion, puntualizando las entidades neurogeneticas con alta prevalencia de autismo, en las cuales se conoce su fisiopatologia y base molecular, que intentan modificar a traves de farmacos las consecuencias de dichas alteraciones, incluyendo el sindrome X fragil (gabergicos e inhibidores del receptor metabotropico del glutamato), la esclerosis tuberosa (inhibidores del mTOR), el sindrome de Phelan-McDermid y el sindrome de Rett (inhibidores del desarrollo insulinico-1). Separadamente se analiza la oxitocina, que ha demostrando una mejoria en la cognicion social en personas con trastornos del espectro autista.