Genetic counseling to a DMD asymptomatic carrier: First case report in the Peruvian public healthcare system / Asesoramiento genético a una portadora asintomática de DMD: Primer caso reportado en el Sistema de Salud Pública del Perú

SUMMARY Duchenne muscular dystrophy (DMD) is a rapidly progressive dystrophinopathy with X-linked inheritance. This report describes a woman with a family history of male relatives affected by DMD, as she sought out genetic counseling about her concerns related to family planning and risks of eventually having children with the disease. We proposed her to get involved in a pilot program for carrier-status diagnosis and genetic counseling. This case illustrates the importance of a genetic counseling program for diagnosis of asymptomatic carriers in neurogenetic diseases, particularly in regions with low-resource settings. We discussed successes and misunderstandings faced throughout the process, supporting policies for present and future challenges from this and similar kinds of diagnoses.

RESUMEN La distrofia muscular de Duchenne (DMD) es una distrofinopatía rápidamente progresiva con herencia ligada al cromosoma X. Este reporte describe el caso de una mujer con historia familiar de hermano y sobrinos con DMD, que acudió a consulta para orientación e información sobre riesgos inherentes a una eventual planificación familiar. Le propusimos participar en un programa piloto de asesoramiento genético para determinar su estado de portador o no de la variante causal de DMD en la familia. Esta primera experiencia ilustra la importancia de tener un programa de asesoramiento genético para el diagnóstico de portadores asintomáticos de enfermedades neurogenéticas en regiones con bajos recursos. Se incluyen reflexiones y comentarios sobre aspectos positivos y retos presentados durante el proceso, las políticas de apoyo presente y futuro para el afronte de los complejos problemas planteados por éste y similares diagnósticos.

Costo-efectividad de la prueba de secuenciación del gen CFTR para portadores asintomáticos en la población colombiana / Cost-effectiveness of the CFTR gene-sequencing test for asymptomatic carriers in the Colombian population

Introducción. La fibrosis quística es una enfermedad genética de carácter autosómico recesivo clasificada como enfermedad huérfana de alto costo. Objetivo. Determinar la razón de costo-efectividad de la prueba diagnóstica de secuenciación del gen CFTR para los portadores asintomáticos familiares en primer, segundo y tercer grados de consanguinidad. Materiales y métodos. Se hizo una búsqueda sistemática sobre la evaluación de las características operativas de la prueba diagnóstica y los modelos de árbol de decisiones en estudios de costo-efectividad. Se elaboró un modelo de árbol de decisiones tomando como unidad de análisis la prevención de futuras concepciones. Los costos de la enfermedad se obtuvieron del reporte de alto costo del Ministerio de Salud de Colombia. Los costos de la prueba se obtuvieron de laboratorios nacionales. Se hizo un análisis de sensibilidad, determinístico y probabilístico, con la perspectiva del tercer pagador y horizonte a un año. Resultados. Se obtuvo una razón incremental de costo-efectividad (RICE) de USD$ 5.051,10 por obtener 10,89 % más de probabilidades de evitar el nacimiento de un niño enfermo con fibrosis quística por pareja. Para los familiares de segundo y tercer grados, se encontró una RICE de USD$ 19.380,94 y USD$ 55.913,53, respectivamente, al aplicar el PIB per cápita. Esta tecnología fue costo-efectiva en 39 %, 61,18 % y 74,36 % para 1, 2 y 3 PIB per cápita en familiares de primer grado de consanguinidad. Conclusiones. La prueba genética de detección de portadores del gen CFTR resultó costo-efectiva dependiendo del umbral de la disponibilidad de pagar, y de los supuestos y limitaciones establecidas en el modelo.

Introduction: Cystic fibrosis is an autosomal recessive genetic disease classified as a high- cost orphan disease. Objective: To determine the cost-effectiveness ratio of the diagnostic test for the CFTR gene-sequencing in asymptomatic family carriers in the first, second, and third degree of consanguinity. Materials and methods: We conducted a systematic search evaluating operative characteristics of the diagnostic test and decision-tree models in cost-effectiveness studies. A decision-tree model was elaborated taking prevention of future conceptions as a unit of analysis. We obtained the costs of the disease from the high-cost report of the Ministerio de Salud y Protección Social. The costs of the test were referenced by national laboratories. We carried out a deterministic and probabilistic sensitivity analysis with a third-payer perspective and a one-year horizon. Results: An ICER of USD$ 5051.10 was obtained as the incremental cost for obtaining 10.89% more probability of avoiding the birth of a child with cystic fibrosis per screened couple. For family members in second and third degrees, the ICER was USD$ 19,380.94 and USD$ 55,913.53, respectively, evidenced when applying the GDP per capita. This technology was cost-effective in 39%, 61.18%, and 74.36% for 1, 2, and 3 GDP per capita in first degree of consanguinity relatives. Conclusions: The genetic test for the detection of CFTR gene carriers was cost-effective depending on the threshold of availability to pay and the assumptions and limitations established in the model.

Analysis of retinal nerve fiber layer thickness and macular thickness in unaffected female carrier of Leber hereditary optic neuropathy / 中华实验眼科杂志

Background Researches documented that retinal nerve fiber layer thickness (RNFLT) in unaffected carriers of Leber hereditary optic neuropathy (LHON) becomes thickened in different quadrants to different degrees.But the change of their macular thickness is still unclear.Objective This study was to clarify RNFLT and macular thickness by optical coherence tomography (OCT) in unaffected female carriers of LHON families.Methods Five female LHON patients (5 eyes) from 5 LHON families,eighteen unaffected female carriers (18eyes) from 18 LHON families and twenty-five age-matched healthy female controls (25 eyes) were included in this study.The patients and genetic carriers were diagnosed in PLA General Hospital from 2011 September to 2012 October.Regular ocular examination were performed followed by OCT measurement of retinas.The Optic Disc Cube 200×200 and Macular Cube 200×200 protocols were used during the OCT measurement.Average (360°) RNFLT,RNFLT at four quadrantic sections,cube average macular thickness and macular thickness of nine Early Treatment Diabetic Retinopathy Study (ETDRS) sub-areas were compared among the LHON genetic carriers,LHON patients and normal controls.Results Compared to the normal control group,significant reduced values were seen in temporal,superior,nasal and inferior side of sub-area macular thickness in the LHON female carriers (P=0.022,0.046,0.024,0.008).In addition,but no significant differences were found in cube average thickness,central subarea macular thickness,temporal,superior,nasal and inferior side of lateral sub-area macular thickness,average RNFLT,and temporal,superior,nasal and inferior quadrant RNFLT between the LHON female carriers and normal controls (P=0.102,0.051,0.238,0.663,0.1 10,0.104,0.419,0.371,0.158,0.063,0.563).Compared to the unaffected female carrier group,female patients showed significant reductions in cube average macular thickness,temporal,superior,nasal and inferior side of sub-area macular thickness,temporal,superior,nasal and inferior side of lateral sub-area mac ular thickness,average R NFLT and temporal,superior,and inferior quadrant RNFLT (P =0.000,0.000,0.000,0.007,0.002,0.002,0.000,0.000,0.040,0.000,0.016,0.000,0.000) except for the central subarea macular thickness and nasal quadrant RNFLT (P=0.388,0.580).Conclusions Unaffected LHON female carriers show a normal peripapillary RNFLT,but the macular thickness at medial sub-area is thinner.This first report offers an information of macular structure change in unaffected LHON female carriers,which suggest that macular damage appears prior to RNFLT change.

Aspectos Bioéticos y Legales de la Investigación Genética en Miembros Menores de Edad de una Familia con Adrenoleucodistrofia Ligada al X de Tucumán, Argentina / Bioethical and legal aspects of genetic research in underage memers of a familyy with x-linked adrenoleukodystrophy from tucumán, Arenntina / Aspecos bioéticoos e jurídicos da pesuisa genética em menores de idaade de uma família com adrenoleucodistrofia ligada ao cromossoma x (tucumán, Argentina)

El desarrollo de la Genética Humana ha puesto a disposición de la Medicina potentes recursos para Investigar los cambios en el material genético subyacentes a diversas enfermedades en pacientes individuales y sus familias. Semejante capacidad diagnóstica suele exceder en mucho a la capacidad de brindar una terapéutica específica, por lo que su utilidad médica reside en el perfeccionamiento del diagnóstico, la estimación del pronóstico clínico, y el cálculo del riesgo de recurrencia para futuros hermanos e hijos de un paciente dado; el paciente y/o su familia, por su parte, suelen buscar en el diagnóstico genético una certeza que les permita limitar su ansiedad. En Pediatría, el consenso mayoritario es que en los niños se justifica la investigación genética diagnóstica, que la investigación predictiva puede hacerse si la afección investigada permite una intervención médicamente beneficiosa durante la niñez, y que la del estado de portación debe diferirse hasta que el paciente alcance un cierto grado de madurez y competencia. El propósito de este trabajo es plantear los aspectos bioéticos y legales relacionados con la investigación de una familia que está segregando una mutación para adrenoleucodistrofia ligada al X, en la que por diversas circunstancias se estudió a menores de edad. Se discute la naturaleza de la enfermedad, el hecho de que tres de los individuos estudiados eran menores de edad, el rol proactivo de los padres en el proceso de toma de decisiones conducente a la investigación de tales miembros, y la existencia de un marco legal específico para la intervención.

Human Genetics development has furnished Medicine with potent resources to investigate changes in genetic material underneath a host of diseases in individual patients and their families. Such a diagnostic capability usually exceeds greatly the capability of specific therapeutic intervention, so its medical usefulness lies in perfecting the diagnosis, estimating the clinical prognosis and calculating the risk of recurrence among future sibs and children of a certain patient; on the other hand, the patient and/or his/her family usually look into genetic diagnosis for a certainty that enables them to limit their anxiety. In Pediatrics, the majority consensus is that children may be submitted to genetic research with diagnostic purposes, that predictive research might be done if the disease in question is amenable of a medically beneficial intervention during childhood, and that carrier state determination should be deferred until the patient reaches maturity and competence. The goal of this work is to review bioethical and legal aspects of the genetic investigation of a Tucumanian family segregating a mutation for X-linked adrenoleukodystrophy, in which for various reasons underage individuals were studied. We discuss the nature of the disease, the fact that three of the research subjects were underage, the proactive role of the family in the decision-making process leading to research those members, and the local existence of a specific legal frame for this intervention.

O desenvolvimento da genética humana tem dotado de recursos poderosos à medicina para pesquisar mudanças no material genético, subjacentes a diversas doenças nos pacientes e nas famílias. Essa capacidade de diagnóstico é muitas vezes maior do que a capacidade de fornecer uma terapia específica; portanto, sua utilidade médica está no aperfeiçoamento do diagnóstico, a estimativa do prognóstico clínico e o cálculo do risco de recorrência para irmãos e filhos de determinado paciente. O paciente e sua família tendem a visar no diagnóstico uma segurança genética que lhes permita limitar sua ansiedade. Em Pediatria, o consenso da maioria justifica a pesquisa genética diagnóstica em crianças, assinala que a pesquisa preditiva pode levar-se a cabo se a condição permite uma intervenção medicamente benéfica durante a infância e afirma que la solução ao estado de portador deverá pospor-se até que o paciente atinge determinada maturidade e competência. O objetivo deste trabalho é apresentar aspectos bioéticos e jurídicos relacionados com a pesquisa em de uma família que está segregando uma mutação para adrenoleucodistrofia ligada ao cromossoma X, na que por diversas razões foram estudados menores.Discute-se a natureza da doença, o fato que três dos indivíduos foram menores, o papel proativo dos pais no processo decisório -em quanto à pesquisa desses membros- e a existência de um quadro jurídico específico para a intervenção.

Modification of Polyethyleneimine as a Genetic Carrier / 中国药房

OBJECTIVE:To study the cytotoxicity of the graft polymer after polyethyleneimine (PEI) had been modified by polyoxyethylene stearate (POES) and the property of the carrier,grafted-polymer/DNA complexes. METHODS: To modify PEI by conjugating PEI to POES with succinimidyl carbonate method. Structural analysis of synthesized polymer was performed by using 1H-NMR. Agarose gel electrophoresis (AGE) behavior of the graft polymer/DNA complexes was observed with particle size and zeta potential measured. The cytotoxicity of the graft polymer was evaluated by MTT method. The pGL3-lus served as a reporter gene,and the luciferase activity was determined to evaluate the transfection efficiency of grafted-polymer/DNA on Hela cells. RESULTS: 1H-NMR showed that the graft polymer had high purity. AGE showed that the DNA-wrapping ability of the graft polymer were increased with the increase of N/P ratios,and decreased with the increase of the POES graft number. The size of complexes was below 300 nm,and the zeta potential of the complexes increased with the increase of N/P ratios. The graft polymer showed significantly lower cytotoxicity than PEI. The graft polymer with lower POES graft number had higher transfection efficiency. CONCLUSIONS: The POES-modified PEI can be used as an effective non-viral genetic carrier.