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BACKGROUND: Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by persistent deficits in social communication and interaction. Common genetic variation appears to play a key role in the development of this condition. In this systematic review, we describe the relationship between genetic variations and autism. We created a gene dataset of the genes involved in the pathogenesis of autism and performed an over-representation analysis to evaluate the biological functions and molecular pathways that may explain the associations between these variants and the development of ASD. RESULTS: 177 studies and a gene set composed of 139 were included in this qualitative systematic review. Enriched pathways in the over-representation analysis using the KEGG pathway database were mostly associated with neurotransmitter receptors and their subunits. Major over-represented biological processes were social behavior, vocalization behavior, learning and memory. The enriched cellular component of the proteins encoded by the genes identified in this systematic review were the postsynaptic membrane and the cell junction. CONCLUSIONS: Among the biological processes that were examined, genes involved in synaptic integrity, neurotransmitter metabolism, and cell adhesion molecules were significantly involved in the development of autism.
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Trastorno del Espectro Autista/genética , Predisposición Genética a la Enfermedad/genética , Aprendizaje/fisiología , Polimorfismo Genético/genética , Pruebas Genéticas/métodos , Variación Genética/genética , HumanosRESUMEN
La mucopolisacaridosis de tipo VI (MPS VI) es una enfermedad de almacenamiento lisosomal resultante del déficit o ausencia de la arilsulfatasa B, que conduce a una acumulación patológica de dermatán-sulfato. Presenta un amplio espectro de síntomas, que van desde formas lentas hasta rápidamente progresivas. Los síntomas característicos son el compromiso esquelético, facies tosca, cardiopatía y compresión medular cervical. El diagnóstico se realiza por la determinación de glucosaminoglucanos en la orina y de la actividad enzimática en una gota de sangre seca, leucocitos o cultivo de fibroblastos. Actualmente, la terapia de reemplazo enzimático (TRE) con galsulfasa ha mostrado mejorar el compromiso esquelético y estabilizar la función respiratoria y cardíaca. El compromiso medular no suele responder a la TRE cuando ya se encuentra presente, por lo que la descompresión quirúrgica debe indicarse en forma temprana. El pronóstico varía en función del fenotipo y de la edad de inicio del tratamiento
Mucopolysaccharidosis VI (MPS VI) is a lysosomal storage disease associated with a deficiency or absence of arylsulfatase B leading to the abnormal accumulation of dermatan sulfate. MPS VI shows a wide spectrum of symptoms from slowly to rapidly progressing forms. The characteristic spectrum includes skeletal displasia, coarse facies, cardiomyopathy, pulmonary complications and spinal compression. Diagnosis generally requires measurement ofurinary glycosaminoglycans and arylsulfatase B enzyme activity in dried blood spot, leukocytes or cultured fibroblasts. Enzyme replacement therapy (ERT) with galsulfase is now widely available providing improvement in skeletal performance and stabilization in pulmonary and cardiac functioning. Spinal involvement does not respond to ERT when is present, surgical decompression should be indicated early. Prognosis is variable depending on the age of onset and age at initiation of ERT.
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Humanos , Niño , Mucopolisacaridosis VI/diagnóstico , Mucopolisacaridosis VI/tratamiento farmacológico , N-Acetilgalactosamina-4-Sulfatasa/uso terapéutico , Terapia de Reemplazo Enzimático , Progresión de la EnfermedadRESUMEN
Mucopolysaccharidosis VI (MPS VI) is a lysosomal storage disease associated with a deficiency or absence of arylsulfatase B leading to the abnormal accumulation of dermatan sulfate. MPS VI shows a wide spectrum of symptoms from slowly to rapidly progressing forms. The characteristic spectrum includes skeletal displasia, coarse facies, cardiomyopathy, pulmonary complications and spinal compression. Diagnosis generally requires measurement ofurinary glycosaminoglycans and arylsulfatase B enzyme activity in dried blood spot, leukocytes or cultured fibroblasts. Enzyme replacement therapy (ERT) with galsulfase is now widely available providing improvement in skeletal performance and stabilization in pulmonary and cardiac functioning. Spinal involvement does not respond to ERT when is present, surgical decompression should be indicated early. Prognosis is variable depending on the age of onset and age at initiation of ERT.
Asunto(s)
Terapia de Reemplazo Enzimático , Mucopolisacaridosis VI/diagnóstico , Mucopolisacaridosis VI/tratamiento farmacológico , N-Acetilgalactosamina-4-Sulfatasa/uso terapéutico , Niño , Progresión de la Enfermedad , HumanosRESUMEN
Mucopolysaccharidosis VI (MPS VI) is a lysosomal storage disease associated with a deficiency or absence of arylsulfatase B leading to the abnormal accumulation of dermatan sulfate. MPS VI shows a wide spectrum of symptoms from slowly to rapidly progressing forms. The characteristic spectrum includes skeletal displasia, coarse facies, cardiomyopathy, pulmonary complications and spinal compression. Diagnosis generally requires measurement ofurinary glycosaminoglycans and arylsulfatase B enzyme activity in dried blood spot, leukocytes or cultured fibroblasts. Enzyme replacement therapy (ERT) with galsulfase is now widely available providing improvement in skeletal performance and stabilization in pulmonary and cardiac functioning. Spinal involvement does not respond to ERT when is present, surgical decompression should be indicated early. Prognosis is variable depending on the age of onset and age at initiation of ERT.
RESUMEN
Abstract Introduction: Fabry disease (FD) is a lysosomal storage disorder associated with marked cerebrovascular involvement. Conventional magnetic resonance imaging (MRI) shows different abnormalities, like white matter lesions that may already be present at an early stage in the disease. Aim: To present observations from a series of brain MRIs performed among a cohort of patients with FD and the relationship of imaging abnormalities with the presence of cardiovascular risk factors (CVRFs). Methods: A total of 70 patients with FD (43 women) were enrolled. The cardiac, renal, ophthalmic, and peripheral nerve functioning was assessed. The MRI evaluation included assessment for evidence of ischemia, microbleeds, pulvinar sign, Arnold-Chiari type 1 malformation, and vertebrobasilar dolichoectasia (VBD). The presence or absence of CVRFs was examined for all patients. Results: Renal involvement was found in 60%, cardiac compromise in 30%, cornea verticillata in 91.4%, and acroparesthesias in 87.1% of patients. Brain MRI analysis found evidence of cerebral ischemic injury in 25.9% of men and 30.2% of women. Vertebrobasilar dolichoectasia was observed in imaging from 55.5% of men and 34.8% of women. The logistic regression analysis adjusted for cardiovascular risks factors, using ischemia or VBD as a dependent variable, showed no statistically significant results. Discussion: Our results have demonstrated cerebrovascular involvement before the third decade in many patients with FD. This study is further evidence confirming that women are not just carriers of FD and should be followed clinically and evaluated comprehensively to monitor for disease burden and progression. Although silent brain ischemias in MRI should be included as a key feature for the diagnoses of FD, VBD is an earlier and frequent sign.
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Tay-Sachs disease (TSD) is a recessively inherited disorder caused by the deficient activity of hexosaminidase A due to mutations in the HEXA gene. Up to date there is no information regarding the molecular genetics of TSD in Argentinean patients. In the present study we have studied 17 Argentinean families affected by TSD, including 20 patients with the acute infantile form and 3 with the sub-acute form. Overall, we identified 14 different mutations accounting for 100% of the studied alleles. Eight mutations were novel: 5 were single base changes leading to drastic residue changes or truncated proteins, 2 were small deletions and one was an intronic mutation that may cause a splicing defect. Although the spectrum of mutations was highly heterogeneous, a high frequency of the c.459+5G>A mutation, previously described in different populations was found among the studied cohort. Haplotype analysis suggested that in these families the c.459+5G>A mutation might have arisen by a single mutational event.
Asunto(s)
Hexosaminidasa A/genética , Mutación , Enfermedad de Tay-Sachs/genética , Niño , Estudios de Cohortes , Femenino , Humanos , Lactante , MasculinoRESUMEN
Maroteaux-Lamy syndrome, or mucopolysaccharidosis VI (MPS VI), is an autosomal recessive lysosomal storage disorder caused by a deficiency of N-acetylgalactosamine-4-sulfatase or arylsulfatase B (ARSB). We aimed to analyze the spectrum of mutations responsible for the disorder in Spanish and Argentinian patients, not previously studied. We identified all the ARSB mutant alleles, nine of them novel, in 12 Spanish and 4 Argentinian patients. The new changes were as follows: six missense mutations: c.245T>G [p.L82R], c.413A>G [p.Y138C], c.719C>T [p.S240F], c.922G>A [p.G308R], c.1340G>T [p.C447F] and c.1415T>C [p.L472P]; one nonsense mutation: c.966G>A [p.W322X]; and two intronic changes involving splice sites: c.1142+2T>A, in the donor splice site of intron 5, which promotes skipping of exon 5, and c.1143-1G>C, which disrupts the acceptor site of intron 5, resulting in skipping of exon 6. We also report 10 previously described mutations as well as several non-pathogenic polymorphisms. Haplotype analysis indicated a common origin for most of the mutations found more than once. Most of the patients were compound heterozygotes, whereas only four of them were homozygous. These observations confirm the broad allelic heterogeneity of the disease, with 19 different mutations in 16 patients. However, the two most frequent mutations, c.1143-1G>C and c.1143-8T>G, present in both populations, accounted for one-third of the mutant alleles in this group of patients.
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Mucopolisacaridosis VI/genética , Mutación/genética , N-Acetilgalactosamina-4-Sulfatasa/genética , Argentina , Células Cultivadas , Análisis Mutacional de ADN , Fibroblastos/enzimología , Fibroblastos/patología , Haplotipos , Humanos , Mucopolisacaridosis VI/enzimología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , EspañaRESUMEN
Pompe disease is an autosomal recessive disorder caused by a deficiency in 1,4-alpha-glucosidase (EC.3.2.1.3), the enzyme required to hydrolyze lysosomal glycogen to glucose. While previous studies have focused on Pompe patients from Europe, the United States, and Taiwan, we have analyzed a group of South American Pompe patients to better understand the molecular basis of their disease. From 14 Argentinean patients diagnosed with either infantile or late-onset disease, we identified 14 distinct mutations in the acid alpha-glucosidase (GAA) gene including nine novel variants (c.236_246del, c.377G>A, c.1099T>C, c.1397T>G, c.1755-1G>A, c.1802C>G, c.1978C>T, c.2281delGinsAT, and c.2608C>T). Three different families displayed the c.377G>A allelic variant, suggesting a higher frequency among a subset of Argentineans. Comparison of patients with similar or identical variations in the GAA gene highlights the phenotypic diversity of late-onset disease and supports a role for other genetic and environmental factors in disease presentation.
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Enfermedad del Almacenamiento de Glucógeno Tipo II/epidemiología , Enfermedad del Almacenamiento de Glucógeno Tipo II/genética , Mutación , alfa-Glucosidasas/genética , Adolescente , Adulto , Edad de Inicio , Argentina/epidemiología , Niño , Preescolar , Análisis Mutacional de ADN , Femenino , Genotipo , Humanos , Lactante , Masculino , Persona de Mediana Edad , alfa-Glucosidasas/metabolismoRESUMEN
Doce de 21 pacientes con trastorno mental grave (mayoritariamente con esquizofrenia) clínicamente estabilizados pudieron realizar con continuidad un Programa de rehabilitación laboral, en la modalidad de empleo con apoyo, consistente en distribución de correspondencia durante 2 años y 6 meses. La mejoría en el rendimiento laboral fue significativa en varias áreas, aunque posiblemente con un ritmo de aprendizaje relativamente lento. Se expone la conceptualización y puesta en práctica del Programa, la modaliad de selección de usuarios, el proceso de capacitación, la evaluación del rendimiento laboral, así como también datos socio-demográficos y clínicos. Se destaca el gradualismo, el manejo del estrés y la labor del equipo capacitador como aspectos cruciales del Programa. Se correlaciona los resultados con hipótesis explicativas, jerarquizándose entre ellas la perspectiva del desarrollo adulto del paciente con esquizofrenia. Por último, se concluye en la necesidad de realizar nuevas experiencias de este tipo de rehabilitación laboral a fin de extraer conclusiones de mayor significación. (AU)
Asunto(s)
Humanos , Femenino , Masculino , Adulto , Persona de Mediana Edad , Rehabilitación Vocacional/tendencias , Trastornos Mentales , Esquizofrenia , Desarrollo de ProgramaRESUMEN
Doce de 21 pacientes con trastorno mental grave (mayoritariamente con esquizofrenia) clínicamente estabilizados pudieron realizar con continuidad un Programa de rehabilitación laboral, en la modalidad de empleo con apoyo, consistente en distribución de correspondencia durante 2 años y 6 meses. La mejoría en el rendimiento laboral fue significativa en varias áreas, aunque posiblemente con un ritmo de aprendizaje relativamente lento. Se expone la conceptualización y puesta en práctica del Programa, la modaliad de selección de usuarios, el proceso de capacitación, la evaluación del rendimiento laboral, así como también datos socio-demográficos y clínicos. Se destaca el gradualismo, el manejo del estrés y la labor del equipo capacitador como aspectos cruciales del Programa. Se correlaciona los resultados con hipótesis explicativas, jerarquizándose entre ellas la perspectiva del "desarrollo adulto" del paciente con esquizofrenia. Por último, se concluye en la necesidad de realizar nuevas experiencias de este tipo de rehabilitación laboral a fin de extraer conclusiones de mayor significación.
Asunto(s)
Masculino , Femenino , Adulto , Humanos , Persona de Mediana Edad , Esquizofrenia , Desarrollo de Programa , Trastornos Mentales , Rehabilitación Vocacional/tendenciasRESUMEN
BACKGROUND: Glycogen storage disease II is characterized by a deficiency of the lysosomal enzyme acid alpha-glucosidase. Currently, glycogen storage disease II is diagnosed by demonstrating the virtual absence or a marked reduction of acid alpha-glucosidase activity in muscle biopsies, cultured fibroblasts, or purified lymphocytes. Early diagnosis and treatment of glycogen storage disease II are considered to be critical for maximum efficacy of the enzyme replacement therapies that are in development. However, these existing diagnostic methods are not suited for newborn screening. We developed an assay useful for newborn screening for glycogen storage disease II. METHODS: A series of three enzyme assays to measure the alpha-glucosidase activities in dried blood spots on filter paper was developed. The measurement of acid alpha-glucosidase activity with minimal interference by other alpha-glucosidases was accomplished using maltose as an inhibitor. The method was used on samples from glycogen storage disease II patients, obligate heterozygotes, and healthy controls. RESULTS: Glycogen storage disease II patients were distinguished from carriers and healthy controls using the series of enzyme assays. CONCLUSIONS: We developed a simple and noninvasive screening method for glycogen storage disease II. The method could be incorporated into newborn screening.
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Enfermedad del Almacenamiento de Glucógeno Tipo II/sangre , Enfermedad del Almacenamiento de Glucógeno Tipo II/diagnóstico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Tampones (Química) , Niño , Preescolar , Diagnóstico Diferencial , Femenino , Filtración , Glucano 1,4-alfa-Glucosidasa/antagonistas & inhibidores , Enfermedad del Almacenamiento de Glucógeno Tipo II/enzimología , Inhibidores de Glicósido Hidrolasas , Humanos , Concentración de Iones de Hidrógeno , Indicadores y Reactivos , Lactante , Recién Nacido , Masculino , Maltosa/química , Maltosa/farmacología , Persona de Mediana Edad , Tamizaje Neonatal , Papel , Manejo de EspecímenesRESUMEN
BACKGROUND: Tay-Sachs disease (TSD), Sandhoff disease (SD) and variants are caused by deficient activity of the lysosomal enzymes hexosaminidase A (HA) and total hexosaminidase (TH) (hexosaminidase A plus B), respectively. For diagnosis, these enzymes are usually measured in plasma or extracts of leukocytes. We describe methods for the assay of hexosaminidase A and total hexosaminidase activities in dried blood spots (DBSs) on filter paper. MATERIALS AND METHODS: We studied 163 healthy controls, 9 Tay-Sachs patients, 4 Sandhoff patients, 18 obligate carriers and the newborn-screening cards from two patients with Tay-Sachs and one patient with Sandhoff disease. To tubes containing a 3-mm-diameter blood spot, we added elution liquid and substrate solution. After incubation at 37 degrees C, the amount of hydrolyzed product was compared with a calibrator to allow the quantification of enzyme activity. RESULTS AND CONCLUSIONS: The described methodology is useful to distinguish patients with Tay-Sachs disease or Sandhoff disease from carriers and controls using samples that are sufficiently stable to be transported to the testing laboratory by mail. The diagnosis of both diseases from a newborn-screening card (NSC) was clearly demonstrated, even after storage for up to 38 months at room temperature. The newborn-screening card has been added to the biological materials that allow the identification of patients with Tay-Sachs disease and Sandhoff disease.
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Tamizaje Neonatal/métodos , Enfermedad de Sandhoff/enzimología , Enfermedad de Tay-Sachs/enzimología , Adulto , Sangre Fetal/enzimología , Pruebas Hematológicas , Hexosaminidasa A , Humanos , Recién Nacido , Valores de Referencia , Estudios Retrospectivos , Enfermedad de Sandhoff/sangre , Enfermedad de Tay-Sachs/sangre , beta-N-Acetilhexosaminidasas/sangreRESUMEN
BACKGROUND: Gaucher disease (GD) and Niemann-Pick (NP) disease are caused by deficient activity of the lysosomal enzymes acid beta-D-glucosidase (ABG) and acid sphingomyelinase (ASM), respectively. For diagnosis, these enzymes are usually measured in the extracts of leukocytes or cultured fibroblasts. Chitotriosidase (CTE), a chitinolytic enzyme, is markedly increased in the plasma of Gaucher patients. We describe methods for the assay of acid beta-D-glucosidase, acid sphingomyelinase, chitotriosidase, and alpha-N-acetyl-galactosaminidase (NAGA) as a control enzyme in blood spots that were dried onto filter paper. METHODS: To tubes containing a 3 mm-diameter blood spot, we added elution liquid and substrate solution. After incubation at 37 degrees C, the amount of hydrolyzed product was compared with a calibrator to allow the quantification of enzyme activity. We examined 80 healthy controls, 54 Gaucher patients, 8 Niemann-Pick patients, 27 obligate carriers, and the newborn-screening cards (NSC) from a case of Gaucher and a case of Niemann-Pick disease. RESULTS AND CONCLUSION: The described methodology is useful to identify Gaucher and Niemann-Pick patients and controls, using samples that are sufficiently stable to be transported to the testing laboratory by mail. The diagnosis of both diseases on a newborn-screening card was clearly established. The newborn-screening card has been added to the biological materials that allow the identification of patients with Gaucher and Niemann-Pick diseases.