Diagnóstico pré-natal: retrospectiva

O Diagnóstico Pré-Natal (DPN) é um conjunto de técnicas destinado a investigar a saúde fetal ainda no período de vida intrauterina. É dirigido principalmente a casais com risco aumentado de gerar uma criança com uma anomalia genética ou congênita. Seu objetivo fundamental pressupõe a identificação de anomalias cromossômicas, malformações, doenças metabólicas mendelianas eoutras alterações circunstancialmente adquiridas durante a gestação e com repercussões sobre o fetoO Diagnóstico Pré-Natal (DPN) é um conjunto de técnicas destinado a investigar a saúde fetal ainda no período de vida intrauterina. É dirigido principalmente a casais com risco aumentado de gerar uma criança com uma anomalia genética ou congênita. Seu objetivo fundamental pressupõe a identificação de anomalias cromossômicas, malformações, doenças metabólicas mendelianas e outras alterações circunstancialmente adquiridas durante a gestação e com repercussões sobre o feto

Caracterización fenotípica y molecular de una familia colombiana con fenilcetonuria

Introduction: Phenylketonuria is a metabolic disorder characterized by severe neurological involvement and behavioral disorder, whose early diagnosis enables an effective treatment to avoid disease sequelae, thus changing the prognosis. Objective: To characterize a family with phenylketonuria in Colombia at clinical, biochemical and molecular levels. Materials and methods: The population consisted of seven individuals of a consanguineous family with four children with suggestive symptoms of phenylketonuria. After signing an informed consent, blood and urine samples were taken for colorimetric tests and high performance liquid and thin layer chromatographies. DNA extraction and sequencing of the 13 exons of the PAH gene were performed in all subjects. We designed primers for each exon with the Primer 3 software using automatic sequencing equipment Abiprism 3100 Avant. Sequences were analyzed using the SeqScape, v2.0, software. Results: We described the clinical and molecular characteristics of a Colombian family with phenylketonuria and confirmed the presence of the mutation c.398_401delATCA. We established a genotype-phenotype correlation, highlighting the interesting clinical variability found among the affected patients despite having the same mutation in all of them. Conclusions: Early recognition of this disease is very important to prevent its neurological and psychological sequelae, given that patients reach old age without diagnosis or proper management.Introducción. La fenilcetonuria es un trastorno metabólico caracterizado por un compromiso neurológico grave y por alteraciones del comportamiento. Su diagnóstico temprano permite establecer un tratamiento efectivo que evita las secuelas y modifica el pronóstico. Objetivo. Caracterizar a una familia con fenilcetonuria en Colombia, a nivel clínico, bioquímico y molecular. Materiales y métodos. Se estudió una población de siete individuos de una familia consanguínea en la que cuatro hijos presentaban signos clínicos sugestivos de fenilcetonuria. Una vez firmado el consentimiento informado, se tomaron muestras de sangre y orina para las pruebas colorimétricas, la cromatografía de capa fina y la cromatografía líquida de alta eficacia. Se extrajo el ADN y se secuenciaron los 13 exones del gen PAH de todos los sujetos estudiados. Se diseñaron iniciadores para cada exón con el programa Primer 3; la secuenciación automática se hizo con el equipo Abiprism 3100 Avant y, el análisis de las secuencias, con el programa SeqScape v2.0. Resultados. Se describieron las características clínicas y moleculares de una familia colombiana con fenilcetonuria en la que se identificó la mutación c.398_401delATCA; se presentó una correlación fenotipo-genotipo con una interesante variabilidad clínica entre los afectados, a pesar de tener la misma mutación. Conclusiones. Es importante el reconocimiento temprano de esta enfermedad para evitar sus secuelas neurológicas y psicológicas, pues los pacientes llegan a edades avanzadas sin diagnóstico ni tratamiento adecuados

Hipercolesterolemia familiar y diagnóstico. Revisión de la producción científica con apoyo de indicadores bibliométricos.

La Hipercolesterolemia Familiar (HF) es un trastorno genético que provoca el aumento del colesterol en la sangre y un incremento importante de desarrollo de ateroesclerosis. Objetivo: establecer el estado de la investigación en el tema de hipercolesterolemia familiar, revisar los principales documentos desarrollados en relación con la temática y explorar los posibles vacíos de conocimiento que surjan de este ejercicio académico con respecto al diagnóstico. Métodos: Se realizó una revisión con indicadores bibliométricos desde artículos de la base de datos de Web of Science, para el análisis se utilizaron los programas libres VOSviewer y Bibliometrix aplicación de R. Adicionalmente se revisaron los textos más citados. Resultados: Un total de 1102 artículos fueron hallados mediante los criterios de inclusión (HF y diagnóstico). Los autores más citados fueron Watts, GF. de Australia con n=32 publicaciones y 1279 citas, seguido por Kastelein, JP. de Holanda con n=28 publicaciones y 1157 citas, y Hegele, RA. de Canadá con n=30 publicaciones y 1003 citas asociadas a sus publicaciones. Discusión: La revisión indica producción importante en diagnóstico de HF en estos últimos diez años y progresos en el diagnóstico; sigue habiendo vacíos del conocimiento relacionados con la implementación de las políticas públicas, la falta de conocimiento sobre los riesgos de la HF en todos el personal interviniente y el desarrollo de las pruebas más efectivas y económicas

Clinical and genetic characterization of RDH12-retinal dystrophy in a South American cohort

Purpose: To characterize the largest cohort of individuals with RDH12-retinal dystrophy to date, and the first one from South America. // Design: Retrospective multicenter international study. // Subjects: 78 patients (66 families) with an inherited retinal dystrophy and biallelic variants in RDH12. // Methods: Review of clinical notes, ophthalmic images, and molecular diagnosis. // Main outcome measures: Visual function, retinal imaging and characteristics were evaluated and correlated. // Results: Thirty-seven individuals self-identified as Latino (51%) and 34 as White (47%). Mean age at the baseline visit was 19.8 ± 13 years old (6 months – 46 years old, median 18.5); 41 (53%) were children. Thirty-nine patients (50%) had subsequent visits, with mean follow-up of 6.8 + 7.3 years (0 – 29). Sixty-nine individuals (88%) had Leber congenital amaurosis/early onset severe retinal dystrophy (LCA/EOSRD). Macular and mid-peripheral atrophy was seen in all patients from 3 years of age. A novel retinal finding was a hyperautofluorescent ring in 2 young children with LCA. Eight variants (21%) were previously unreported and the most frequent variant was c.295C>A, p.Leu99Ile, present in 52 alleles of 32 probands. Individuals with LCA homozygous for p.Leu99Ile (31%) had a later age of onset, slower rate of BCVA decrease, the largest percentage of patients with mild visual impairment, and were predicted to reach legal blindness at an older age than the rest of the cohort. // Conclusions: By describing the largest molecularly confirmed cohort to date, improved understanding of disease progression was possible. Our detailed characterization aims to support research and the development of novel therapies that may have the potential to reduce or prevent vision loss in individuals with RDH12-associated retinal dystrophy

Utilizing ethnic-specific differences in minor allele frequency to recategorize reported pathogenic deafness variants

Q1Q1Artículo original445-453Ethnic-specific differences in minor allele frequency impact variant categorization for genetic screening of nonsyndromic hearing loss (NSHL) and other genetic disorders. We sought to evaluate all previously reported pathogenic NSHL variants in the context of a large number of controls from ethnically distinct populations sequenced with orthogonal massively parallel sequencing methods. We used HGMD, ClinVar, and dbSNP to generate a comprehensive list of reported pathogenic NSHL variants and re-evaluated these variants in the context of 8,595 individuals from 12 populations and 6 ethnically distinct major human evolutionary phylogenetic groups from three sources (Exome Variant Server, 1000 Genomes project, and a control set of individuals created for this study, the OtoDB). Of the 2,197 reported pathogenic deafness variants, 325 (14.8%) were present in at least one of the 8,595 controls, indicating a minor allele frequency (MAF) >0.00006. MAFs ranged as high as 0.72, a level incompatible with pathogenicity for a fully penetrant disease like NSHL. Based on these data, we established MAF thresholds of 0.005 for autosomal-recessive variants (excluding specific variants in GJB2) and 0.0005 for autosomal-dominant variants. Using these thresholds, we recategorized 93 (4.2%) of reported pathogenic variants as benign. Our data show that evaluation of reported pathogenic deafness variants using variant MAFs from multiple distinct ethnicities and sequenced by orthogonal methods provides a powerful filter for determining pathogenicity. The proposed MAF thresholds will facilitate clinical interpretation of variants identified in genetic testing for NSHL. All data are publicly available to facilitate interpretation of genetic variants causing deafness

Reducing the Clinical and Public Health Burden of Familial Hypercholesterolemia A Global Call to Action

Q1Q1Artículo completoE1-E13IMPORTANCE Familial hypercholesterolemia (FH) is an underdiagnosed and undertreated genetic disorder that leads to premature morbidity and mortality due to atherosclerotic cardiovascular disease. Familial hypercholesterolemia affects 1 in 200 to 250 people around the world of every race and ethnicity. The lack of general awareness of FH among the public and medical community has resulted in only 10% of the FH population being diagnosed and adequately treated. The World Health Organization recognized FH as a public health priority in 1998 during a consultation meeting in Geneva, Switzerland. The World Health Organization report highlighted 11 recommendations to address FH worldwide, from diagnosis and treatment to family screening and education. Research since the 1998 report has increased understanding and awareness of FH, particularly in specialty areas, such as cardiology and lipidology. However, in the past 20 years, there has been little progress in implementing the 11 recommendations to prevent premature atherosclerotic cardiovascular disease in an entire generation of families with FH. OBSERVATIONS In 2018, the Familial Hypercholesterolemia Foundation and the World Heart Federation convened the international FH community to update the 11 recommendations. Two meetings were held: one at the 2018 FH Foundation Global Summit and the other during the 2018 World Congress of Cardiology and Cardiovascular Health. Each meeting served as a platform for the FH community to examine the original recommendations, assess the gaps, and provide commentary on the revised recommendations. The Global Call to Action on Familial Hypercholesterolemia thus represents individuals with FH, advocacy leaders, scientific experts, policy makers, and the original authors of the 1998 World Health Organization report. Attendees from 40 countries brought perspectives on FH from low-, middle-, and high-income regions. Tables listing country-specific government support for FH care, existing country-specific and international FH scientific statements and guidelines, country-specific and international FH registries, and known FH advocacy organizations around the world were created. CONCLUSIONS AND RELEVANCE By adopting the 9 updated public policy recommendations created for this document, covering awareness; advocacy; screening, testing, and diagnosis; treatment; family-based care; registries; research; and cost and value, individual countries have the opportunity to prevent atherosclerotic heart disease in their citizens carrying a gene associated with FH and, likely, all those with severe hypercholesterolemia as well

Diagnóstico pré-natal: retrospectiva

O Diagnóstico Pré-Natal (DPN) é um conjunto de técnicas destinado a investigar a saúde fetal ainda no período de vida intrauterina. É dirigido principalmente a casais com risco aumentado de gerar uma criança com uma anomalia genética ou congênita. Seu objetivo fundamental pressupõe a identificação de anomalias cromossômicas, malformações, doenças metabólicas mendelianas eoutras alterações circunstancialmente adquiridas durante a gestação e com repercussões sobre o fetoO Diagnóstico Pré-Natal (DPN) é um conjunto de técnicas destinado a investigar a saúde fetal ainda no período de vida intrauterina. É dirigido principalmente a casais com risco aumentado de gerar uma criança com uma anomalia genética ou congênita. Seu objetivo fundamental pressupõe a identificação de anomalias cromossômicas, malformações, doenças metabólicas mendelianas e outras alterações circunstancialmente adquiridas durante a gestação e com repercussões sobre o feto

Definición de Subtipos del Síndrome de Usher en Población Colombiana

<h3>Resumen</h3><p><strong>Introducción.</strong> El Síndrome de Usher (USH), de herencia autosómica recesiva, se caracteriza por sordera congénita sensorial, Retinitis Pigmentosa y disfunción vestibular. Se conocen 3 tipos clínicos y 12 subtipos genéticos. En Colombia no se conocen las frecuencias de los subtipos genéticos ni las mutaciones más frecuentes.</p><p><strong>Objetivo.</strong> El objetivo de este trabajo fue definir el subtipo genético en 72 individuos con USH e identificar las mutaciones causantes de la enfermedad.</p><p><strong>Métodos</strong>. Se identificaron 72 individuos con USH de diferentes ciudades del país. Se realizó análisis de haplotipos para los 12 loci asociados a USH hasta el momento y análisis mutacional de los exones con mayor frecuencia de mutaciones reportadas en los genes USH.</p><p><strong>Resultados</strong>. Se logró definir el subtipo genético en 23 individuos y se identificó la mutación causal en 14. Se identifi caron dos mutaciones en el gen MYO7A, la p.R634X y la p.R1986X; y tres en el gen USH2A, la c.2299delG, la p.R334W, y la g.G129T.</p><p><strong>Conclusión.</strong> Se logró identificar el subtipo genético en el 31.9% y la mutación causal en el 19.4% de la población.</p><p><span>Palabras clave:</span> Síndrome de Usher, Retinitis Pigmentosa, Sordera, Hipoacusia Sensorial.</p><h3><span>Usher Syndrome Subtypes Definition in Colombian Population </span></h3><h3>Abstract</h3><p><strong>Introduction.</strong> Usher Syndrome (USH), is an autosomal recessive disorder characterized by the association of sensorineural hearing loss, retinitis pigmentosa (RP) and variable vestibular areflexia. Three clinical types and 12 genetic subtypes have been described. In Colombia, frequencies of genetic subtypes and more frequent mutations are unknown.</p><p><strong>Objective.</strong> The aim of this work was to defi ne the genetic subtype in Colombian population with USH.</p><p><strong>Methods.</strong> 72 individuals with USH were selected from different cities around the country. Haplotype analysis was performed to identify segregation to any of the 12 known USH loci. Mutational analysis of some exons was performed in USH genes.</p><p><strong>Results.</strong> Genetic subtype of 23 individuals and pathological mutation in 14 were identified. Two mutations were identifi ed in MYO7A gene, p.R634X and p.R1986X; and three in the USH2A gene, c.2299delG, p.R334W, and g.G129T.</p><p><strong>Conclusion</strong>. Genetic subtype was identified in 31.9% of the population and pathologic mutation in 19.4%.</p><p><span>Key words:</span> Usher Syndromes, Retinitis Pigmentosa, Deafness, Hearing Loss, Sensorineural.</p&gt

Caracterización fenotípica de la retinitis pigmentaria asociada a sordera

Introduction: There are several syndromes that associate retinitis pigmentosa with deafness or hearing loss. The most frequent is Usher syndrome, a genetic disorder of autosomal recessive inheritance, which, in some cases, is accompanied by vestibular dysfunction. However, there are cases of families that despite having retinitis pigmentosa associated with deafness, cannot be classified as Usher or other syndromes due to additional findings.Objective: To reassess the phenotypes of 103 families previously diagnosed as possible Usher syndrome and/or retinitis pigmentosa associated with deafness.Materials and methods: We conducted a descriptive and retrospective study by reviewing the medical records of 103 families with a probable clinical diagnosis of Usher syndrome and/or retinitis pigmentosa associated with deafness. Families whose clinical diagnosis did not correspond to the typical Usher syndrome were selected and evaluated ophthalmologically and audiologically. Demographic and clinical variables were analyzed.Results: We selected and then reevaluated 14 families and 55 individuals as they did not correspond to a clinical diagnosis of Usher syndrome; 13.6% of the families initially considered to have typical Usher syndrome were later diagnosed with retinitis pigmentosa associated with deafness, another ocular symptom associated with hearing loss, retinitis pigmentosa, or isolated hearing loss in the same family.Conclusions: Family studies are essential in cases where the symptoms do not match the typical Usher’ syndrome. In the cases of retinitis pigmentosa associated with deafness, a correct clinical diagnosis allows for focusing on the molecular analyses to establish a differential diagnosis. The need for nomenclature guidelines on these atypical findings is relevant to aid physicians and researchers in the best approach to these cases.Introducción. El síndrome de Usher es una alteración genética caracterizada por la asociación de retinitis pigmentaria y sordera. Sin embargo, hay casos con familias en las cuales, a pesar de presentarse dicha asociación, no se puede diagnosticar un síndrome de Usher ni ninguno otro.Objetivo. Reevaluar fenotípicamente a 103 familias con diagnóstico previo de posible síndrome de Usher o retinitis pigmentaria asociada con sordera.Materiales y métodos. Se revisaron las historias clínicas de 103 familias con un posible diagnóstico clínico de síndrome de Usher o retinitis pigmentaria asociada con sordera. Se seleccionaron las familias cuyo diagnóstico clínico no correspondía a un síndrome de Usher típico. Los afectados fueron valorados oftalmológica y audiológicamente. Se analizaron variables demográficas y clínicas.Resultados. Se reevaluaron 14 familias cuyo diagnóstico clínico no correspondía al de síndrome de Usher. De las familias con diagnóstico inicial de síndrome de Usher típico, el 13,6 % recibieron uno posterior de “retinitis pigmentaria asociada con sordera”, de “otro síntoma ocular asociado con hipoacusia”, o en forma aislada en una misma familia, de “retinitis pigmentaria” o “hipoacusia”.Conclusiones. Es fundamental el estudio familiar en los casos en que la clínica no concuerda con el diagnóstico de síndrome de Usher típico. En los pacientes con retinitis pigmentaria asociada con sordera, el diagnóstico clínico acertado permite enfocar los análisis moleculares y, así, establecer un diagnóstico diferencial. Es necesario elaborar guías de nomenclatura en los casos con estos hallazgos atípicos para orientar a médicos e investigadores en cuanto a su correcto manejo

Phenotypic characterization of retinitis pigmentosa associated with deafness

Introducción. El síndrome de Usher es una alteración genética caracterizada por la asociación de retinitis pigmentaria y sordera. Sin embargo, hay casos con familias en las cuales, a pesar de presentarse dicha asociación, no se puede diagnosticar un síndrome de Usher ni ninguno otro. Objetivo. Reevaluar fenotípicamente a 103 familias con diagnóstico previo de posible síndrome de Usher o retinitis pigmentaria asociada con sordera. Materiales y métodos. Se revisaron las historias clínicas de 103 familias con un posible diagnóstico clínico de síndrome de Usher o retinitis pigmentaria asociada con sordera. Se seleccionaron las familias cuyo diagnóstico clínico no correspondía a un síndrome de Usher típico. Los afectados fueron valorados oftalmológica y audiológicamente. Se analizaron variables demográficas y clínicas. Resultados. Se reevaluaron 14 familias cuyo diagnóstico clínico no correspondía al de síndrome de Usher. De las familias con diagnóstico inicial de síndrome de Usher típico, el 13,6 % recibieron uno posterior de “retinitis pigmentaria asociada con sordera”, de “otro síntoma ocular asociado con hipoacusia”, o en forma aislada en una misma familia, de “retinitis pigmentaria” o “hipoacusia”. Conclusiones. Es fundamental el estudio familiar en los casos en que la clínica no concuerda con el diagnóstico de síndrome de Usher típico. En los pacientes con retinitis pigmentaria asociada con sordera, el diagnóstico clínico acertado permite enfocar los análisis moleculares y, así, establecer un diagnóstico diferencial. Es necesario elaborar guías de nomenclatura en los casos con estos hallazgos atípicos para orientar a médicos e investigadores en cuanto a su correcto manejo.Q4Q3Introduction: There are several syndromes that associate retinitis pigmentosa with deafness or hearing loss. The most frequent is Usher syndrome, a genetic disorder of autosomal recessive inheritance, which, in some cases, is accompanied by vestibular dysfunction. However, there are cases of families that despite having retinitis pigmentosa associated with deafness, cannot be classified as Usher or other syndromes due to additional findings. Objective: To reassess the phenotypes of 103 families previously diagnosed as possible Usher syndrome and/or retinitis pigmentosa associated with deafness. Materials and methods: We conducted a descriptive and retrospective study by reviewing the medical records of 103 families with a probable clinical diagnosis of Usher syndrome and/or retinitis pigmentosa associated with deafness. Families whose clinical diagnosis did not correspond to the typical Usher syndrome were selected and evaluated ophthalmologically and audiologically. Demographic and clinical variables were analyzed. Results: We selected and then reevaluated 14 families and 55 individuals as they did not correspond to a clinical diagnosis of Usher syndrome; 13.6% of the families initially considered to have typical Usher syndrome were later diagnosed with retinitis pigmentosa associated with deafness, another ocular symptom associated with hearing loss, retinitis pigmentosa, or isolated hearing loss in the same family. Conclusions: Family studies are essential in cases where the symptoms do not match the typical Usher’ syndrome. In the cases of retinitis pigmentosa associated with deafness, a correct clinical diagnosis allows for focusing on the molecular analyses to establish a differential diagnosis. The need for nomenclature guidelines on these atypical findings is relevant to aid physicians and researchers in the best approach to these cases.https://orcid.org/0000-0001-5439-5560https://orcid.org/0000-0001-9380-0792https://orcid.org/0000-0002-3925-1451https://orcid.org/0000-0001-8297-3970Revista Nacional - IndexadaBN