RESUMO
Fanconi anemia (FA) is characterized by chromosome fragility, bone marrow failure (BMF) and predisposition to cancer. As reverse genetic mosaicism has been described as "natural gene therapy" in patients with FA, we sought to evaluate the clinical course of a cohort of FA mosaic patients followed at referral centers in Spain over a 30-year period. This cohort includes patients with a majority of T cells without chromosomal aberrations in the DEB-chromosomal breakage test. Relative to non-mosaic FA patients, we observed a higher proportion of adult patients in the cohort of mosaics, with a later age of hematologic onset and a milder evolution of (BMF). Consequently, the requirement for hematopoietic stem cell transplant (HSCT) was also lower. Additional studies allowed us to identify a sub-cohort of mosaic FA patients in whom the reversion was present in bone marrow (BM) progenitor cells leading to multilineage mosaicism. These multilineage mosaic patients are older, have a lower percentage of aberrant cells, have more stable hematology and none of them developed leukemia or myelodysplastic syndrome when compared to non-mosaics. In conclusion, our data indicate that reverse mosaicism is a good prognostic factor in FA and is associated with more favorable long-term clinical outcomes.
Assuntos
Anemia de Fanconi/terapia , Terapia Genética/métodos , Adolescente , Adulto , Criança , Anemia de Fanconi/genética , Humanos , Masculino , Mosaicismo , Adulto JovemRESUMO
BACKGROUND: Malaria transmission in Latin America is typically characterized as hypo-endemic and unstable with ~170 million inhabitants at risk of malaria infection. Although Colombia has witnessed an important decrease in malaria transmission, the disease remains a public health problem with an estimated ~10 million people currently living in areas with malaria risk and ~61,000 cases reported in 2012. This study aimed to establish the malaria prevalence in three endemic regions of Colombia to aid in designing new interventions for malaria elimination. METHODS: A cross-sectional survey was conducted in three regions of Colombia with different malaria epidemiological profiles: Tierralta (Ta), Tumaco (Tu) and Buenaventura (Bv). The Annual Parasite Index (API) was 10.7, 6.9 and 3.1, respectively. Participants were asked to respond to a sociodemographic questionnaire and then were bled to determine the Duffy genotype and the prevalence of malaria infection by microscopy and quantitative real-time PCR (qPCR). RESULTS: The study was conducted between October 2011 and January 2012. Eight sentinel sites with 1,169 subjects from 267 households were included. The overall prevalence of sub-microscopic infections measured by thick blood smear (TBS) was 0.3% (n=4) whereas by qPCR it was 9.7% (n=113), with a greater proportion (13%) in 40-50 years old individuals. Furthermore, different regions displayed different prevalence of sub-microscopic infections: Bv 12%, Ta 15%, and Tu 4%. From these 113 samples (qPCR), 74% were positive for P. vivax and 22% for P. falciparum, and 4% were mixed infections, which correlates to the overall parasite prevalence in Colombia. This study showed that in the southern Pacific coast of Colombia (Bv and Tu), around 56% of the population have a Duffy-negative genotype, compared to the northern region (Ta) where the percentage of Duffy-negative genotype is around 3%. CONCLUSIONS: Sub-microscopic infections are prevalent across different regions in Colombia, particularly in areas with relatively low transmission intensity. The poor microscopy results suggest the need for more sensitive diagnostic tools for detection of sub-microscopic infections. This study underscores the importance of conducting active case surveillance to more accurately determine malaria incidence, and highlights the need for updating the malaria guidelines to track and treat sub-microscopic malaria infections.
Assuntos
Infecções Assintomáticas/epidemiologia , Malária Falciparum/epidemiologia , Plasmodium falciparum/isolamento & purificação , Plasmodium vivax/isolamento & purificação , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Colômbia/epidemiologia , Estudos Transversais , Feminino , Humanos , Lactente , Recém-Nascido , Malária Falciparum/parasitologia , Malária Vivax/epidemiologia , Malária Vivax/parasitologia , Masculino , Pessoa de Meia-Idade , Prevalência , Reação em Cadeia da Polimerase em Tempo Real , Adulto JovemRESUMO
Background: Moebius Syndrome (MBS) is a rare congenital neurological disorder characterized by paralysis of facial nerves, impairment of ocular abduction and other variable abnormalities. MBS has been attributed to both environmental and genetic factors as potential causes. Until now only two genes, PLXND1 and REV3L have been identified to cause MBS. Results: We present a 9-year-old male clinically diagnosed with MBS, presenting facial palsy, altered ocular mobility, microglossia, dental anomalies and congenital torticollis. Radiologically, he lacks both abducens nerves and shows altered symmetry of both facial and vestibulocochlear nerves. Whole-exome sequence identified a de novo missense variant c.643G>A; p.Gly215Arg in CHN1, encoding the α2-chimaerin protein. The p.Gly215Arg variant is located in the C1 domain of CHN1 where other pathogenic gain of function variants have been reported. Bioinformatic analysis and molecular structural modelling predict a deleterious effect of the missense variant on the protein function. Conclusion: Our findings support that pathogenic variants in the CHN1 gene may be responsible for different cranial congenital dysinnervation syndromes, including Moebius and Duane retraction syndromes. We propose to include CHN1 in the genetic diagnoses of MBS.
RESUMO
BACKGROUND: Less than 40% of patients with dilated cardiomyopathy (DCM) have a pathogenic/likely pathogenic genetic variant identified. TBX20 has been linked to congenital heart defects; although an association with left ventricular noncompaction (LVNC) and DCM has been proposed, it is still considered a gene with limited evidence for these phenotypes. This study sought to investigate the association between the TBX20 truncating variant (TBX20tv) and DCM/LVNC. METHODS: TBX20 was sequenced by next-generation sequencing in 7463 unrelated probands with a diagnosis of DCM or LVNC, 22â 773 probands of an internal comparison group (hypertrophic cardiomyopathy, channelopathies, or aortic diseases), and 124â 098 external controls (individuals from the gnomAD database). Enrichment of TBX20tv in DCM/LVNC was calculated, cosegregation was determined in selected families, and clinical characteristics and outcomes were analyzed in carriers. RESULTS: TBX20tv was enriched in DCM/LVNC (24/7463; 0.32%) compared with internal (1/22â 773; 0.004%) and external comparison groups (4/124â 098; 0.003%), with odds ratios of 73.23 (95% CI, 9.90-541.45; P<0.0001) and 99.76 (95% CI, 34.60-287.62; P<0.0001), respectively. TBX20tv was cosegregated with DCM/LVNC phenotype in 21 families for a combined logarythm of the odds score of 4.53 (strong linkage). Among 57 individuals with TBX20tv (49.1% men; mean age, 35.9±20.8 years), 41 (71.9%) exhibited DCM/LVNC, of whom 14 (34.1%) had also congenital heart defects. After a median follow-up of 6.9 (95% CI, 25-75:3.6-14.5) years, 9.7% of patients with DCM/LVNC had end-stage heart failure events and 4.8% experienced malignant ventricular arrhythmias. CONCLUSIONS: TBX20tv is associated with DCM/LVNC; congenital heart defect is also present in around one-third of cases. TBX20tv-associated DCM/LVNC is characterized by a nonaggressive phenotype, with a low incidence of major cardiovascular events. TBX20 should be considered a definitive gene for DCM and LVNC and routinely included in genetic testing panels for these phenotypes.
Assuntos
Cardiomiopatia Dilatada , Cardiopatias Congênitas , Masculino , Humanos , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Feminino , Cardiomiopatia Dilatada/patologia , Cardiopatias Congênitas/genética , Arritmias Cardíacas , Fenótipo , Proteínas com Domínio T/genéticaRESUMO
Neurodevelopmental disorders (NDDs) affect 2-5% of the population and approximately 50% of cases are due to genetic factors. Since de novo pathogenic variants account for the majority of cases, a gene panel including 460 dominant and X-linked genes was designed and applied to 398 patients affected by intellectual disability (ID)/global developmental delay (GDD) and/or autism (ASD). Pathogenic variants were identified in 83 different genes showing the high genetic heterogeneity of NDDs. A molecular diagnosis was established in 28.6% of patients after high-depth sequencing and stringent variant filtering. Compared to other available gene panel solutions for NDD molecular diagnosis, our panel has a higher diagnostic yield for both ID/GDD and ASD. As reported previously, a significantly higher diagnostic yield was observed: (i) in patients affected by ID/GDD compared to those affected only by ASD, and (ii) in females despite the higher proportion of males among our patients. No differences in diagnostic rates were found between patients affected by different levels of ID severity. Interestingly, patients harboring pathogenic variants presented different phenotypic features, suggesting that deep phenotypic profiling may help in predicting the presence of a pathogenic variant. Despite the high performance of our panel, whole exome-sequencing (WES) approaches may represent a more robust solution. For this reason, we propose the list of genes included in our customized gene panel and the variant filtering procedure presented here as a first-tier approach for the molecular diagnosis of NDDs in WES studies.
Assuntos
Transtorno Autístico , Deficiência Intelectual , Transtornos do Neurodesenvolvimento , Masculino , Feminino , Humanos , Genes Ligados ao Cromossomo X , Transtornos do Neurodesenvolvimento/diagnóstico , Transtornos do Neurodesenvolvimento/genética , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Testes Genéticos , Transtorno Autístico/genéticaRESUMO
Malaria is the most important parasitic disease worldwide, responsible for an estimated 225 million clinical cases each year. It mainly affects children, pregnant women and non-immune adults who frequently die victims of cerebral manifestations and anaemia. Although the contribution of the American continent to the global malaria burden is only around 1.2 million clinical cases annually, there are 170 million inhabitants living at risk of malaria transmission in this region. On the African continent, where Plasmodium falciparum is the most prevalent human malaria parasite, anaemia is responsible for about half of the malaria-related deaths. Conversely, in Latin America (LA), malaria-related anaemia appears to be uncommon, though there is a limited knowledge about its real prevalence. This may be partially explained by several factors, including that the overall malaria burden in LA is significantly lower than that of Africa, that Plasmodium vivax, the predominant Plasmodium species in the region, appears to display a different clinical spectrus and most likely because better health services in LA prevent the development of severe malaria cases. With the aim of contributing to the understanding of the real importance of malaria-related anaemia in LA, we discuss here a revision of the available literature on the subject and the usefulness of experimental animal models, including New World monkeys, particularly for the study of the mechanisms involved in the pathogenesis of malaria.
Assuntos
Anemia/parasitologia , Malária Falciparum/complicações , Malária Vivax/complicações , Animais , Modelos Animais de Doenças , Feminino , Humanos , América Latina , Malária Falciparum/parasitologia , Malária Vivax/parasitologia , Plasmodium falciparum/patogenicidade , Plasmodium vivax/patogenicidade , Platirrinos , GravidezRESUMO
Discrepant results have been published by studies comparing deaths by suicide with attempted suicides. This study aimed to determine factors associated with suicides and attempted suicides in Andalusia (Spain) between 2007 and 2013, comparing sex, age, year, and suicide method between these populations. A retrospective study was conducted of data on deaths by suicide and attempted suicides over a seven-year period, calculating the sex and age rates for each behavior. Adjusted Poisson regression was used to analyze the association with study variables, and incidence rate ratios were estimated. During the seven-year study period, 20,254 attempted suicides and 5202 deaths by suicide were recorded. The prevalence of attempted suicide did not differ between the sexes, whereas the prevalence of deaths by suicide was three-fold higher among males than among females and increased with higher age. The most frequently used method was the same in males and females for suicide attempts, but differed between the sexes for suicides. The combined influence of sex and age was greater in the model for death by suicide than in the model for attempted suicide. The key differentiating factor was the method used, while the finding of greatest concern was the suicide behavior among the elderly. Preventive strategies should take these differences into account.
Assuntos
Tentativa de Suicídio/estatística & dados numéricos , Suicídio Consumado/estatística & dados numéricos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Espanha/epidemiologia , Adulto JovemRESUMO
Marfan syndrome (MFS) is an autosomal dominantly inherited connective tissue disorder, mostly caused by mutations in the fibrillin-1 (FBN1) gene. We, by using targeted next-generation sequence analysis, identified a novel intronic FBN1 mutation (the c.2678-15C>A variant) in a MFS patient with aortic dilatation. The computational predictions showed that the heterozygous c.2678-15C>A intronic variant might influence the splicing process by differentially affecting canonical versus cryptic splice site utilization within intron 22 of the FBN1 gene. RT-PCR and Western blot analyses, using FBN1 minigenes transfected into HeLa and COS-7 cells, revealed that the c.2678-15C>A variant disrupts normal splicing of intron 22 leading to aberrant 13-nt intron 22 inclusion, frameshift, and premature termination codon. Collectively, the results strongly suggest that the c.2678-15C>A variant could lead to haploinsufficiency of the FBN1 functional protein and structural connective tissue fragility in MFS complicated by aorta dilation, a finding that further expands on the genetic basis of aortic pathology.
Assuntos
Fibrilina-1/genética , Íntrons/genética , Síndrome de Marfan/genética , Mutação , Adulto , Aorta/patologia , Dilatação Patológica , Heterozigoto , Humanos , Masculino , Proteínas dos MicrofilamentosRESUMO
OBJECTIVE: To analyze the number and characteristics of suicide attempts by reviewing records of the public emergency healthcare service information system. METHOD: A retrospective observational study was conducted of emergency telephone calls received between January 1 2007 and December 31 2013 throughout the Andalusia region (Southern Spain). Cases were selected based on phone operator or healthcare team labeling. Data were analyzed on the characteristics of the individuals, the timing and severity of attempts, their prioritization, and their outcome. RESULTS: Between January 1 2007 and December 31 2013, 20.942 calls related to suicide attempts were recorded, a rate of 34.7 attempts per 100,000 inhabitants. Most cases were classified by the public emergency healthcare service (Empresa Pública de Emergencias Sanitarias, EPES) as code X84 (The International Statistical Classification of Diseases, tenth revision, ICD-10) or 305(The International Statistical Classification of Diseases, ninth revision, ICD-9). Attempts were more frequent in the 35-49-year age group and there were similar proportions of males and females. The lowest number of calls for suicide attempts were in 2007 and the highest in 2013. Calls were more frequent during the summer months, at weekends, and between 16:00 and 23:00 h. The likelihood of evacuation to the hospital emergency department was almost two-fold lower in over 65-yr-olds than in younger individuals. Significant (Æ¿ = 0.001) gender differences were found in call outcome and prioritization. The most influential factor for evacuation to a hospital emergency department was the code assigned by the attending healthcare team. CONCLUSIONS: Information obtained from extra-hospital emergency services provides valuable data on the characteristics and timing of calls related to suicide attempts, complementing information from hospital emergency departments or population surveys. There is a need to standardize the definition and recording of a suicide attempt.
Assuntos
Tentativa de Suicídio , Adulto , Fatores Etários , Idoso , Estudos Transversais , Serviços Médicos de Emergência , Serviço Hospitalar de Emergência/estatística & dados numéricos , Feminino , Sistemas de Informação em Saúde , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Prontuários Médicos , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Fatores Sexuais , Espanha/epidemiologia , Tentativa de Suicídio/estatística & dados numéricos , TelefoneAssuntos
Aracnodactilia , Craniossinostoses , Síndrome de Marfan , Dilatação , Humanos , Síndrome de Marfan/diagnósticoAssuntos
Síndrome de Brugada/genética , DNA/genética , Predisposição Genética para Doença , Mutação , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Canal de Sódio Disparado por Voltagem NAV1.8/genética , Adolescente , Síndrome de Brugada/metabolismo , Análise Mutacional de DNA , Eletrocardiografia , Humanos , Masculino , Canal de Sódio Disparado por Voltagem NAV1.5/metabolismo , Canal de Sódio Disparado por Voltagem NAV1.8/metabolismo , LinhagemAssuntos
DNA/genética , Fibrilina-1/genética , Prolapso da Valva Mitral/genética , Mutação , Miopia/genética , Dermatopatias/genética , Adolescente , Adulto , Criança , Análise Mutacional de DNA , Feminino , Fibrilina-1/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Prolapso da Valva Mitral/diagnóstico , Prolapso da Valva Mitral/metabolismo , Miopia/diagnóstico , Miopia/metabolismo , Linhagem , Fenótipo , Dermatopatias/diagnóstico , Dermatopatias/metabolismo , Tomografia Computadorizada por Raios X , Adulto JovemRESUMO
Resumen Las cardiopatías familiares son un grupo de enfermedades con alta heterogeneidad clínica y genética. Debido a que pueden heredarse y a su asociación con la muerte súbita, se recomienda efectuar un estudio clínico y genético del individuo afectado y su familia a través de una unidad especializada. Con la implementación de la secuenciación masiva se ha facilitado el acceso a los estudios genéticos en la práctica clínica de forma más rutinaria. Sin embargo, dada la gran cantidad de información obtenida se hacen necesarios el análisis y la interpretación adecuada de los resultados para garantizar un diagnóstico correcto. Este nuevo modelo de medicina amplía nuestra comprensión sobre estas patologías, gracias a que optimiza el diagnóstico, da una mejor aproximación pronóstica de los pacientes e identifica individuos asintomáticos en riesgo. Este artículo pretende realizar una revisión de la arquitectura genética de las enfermedades cardíacas hereditarias y proporcionar un enfoque práctico acerca de la utilidad de la Medicina genómica en el diagnóstico, la estratificación del riesgo y el estudio familiar en pacientes con este tipo de patologías.
Abstract The familial heart diseases are a group of diseases with high clinical and genomic heterogeneity. As they can be inherited and are associated with sudden death, it is recommended to perform a clinical and genetic study of the individual affected, as well as the family, in a specialised unit. The implementation of massive sequencing has meant that access to genetic studies is available in the most routine clinical practice. However, due to the large amount of information obtained, the results have to analysed and interpreted to ensure a correct diagnosis. This new medicine model widens the understanding of these diseases, as due to the diagnosis being optimised, it provides a more accurate prognosis for the patients, and identifies asymptomatic individuals at risk. A review is presented on the genetic architecture of heritable heart disease and provides a practical approach on the usefulness of Genomic Medicine in the diagnosis, risk stratification, and the familial study in patients with these types of heart diseases.
Assuntos
Humanos , Morte Súbita Cardíaca , Cardiomiopatias , Fenótipo , Sequenciamento Completo do Genoma , GenótipoRESUMO
Latin America contributes 1-1.2 million clinical malaria cases to the global malaria burden of about 300 million per year. In 21 malaria endemic countries, the population at risk in this region represents less than 10% of the total population exposed worldwide. Factors such as rapid deforestation, inadequate agricultural practices, climate change, political instability, and both increasing parasite drug resistance and vector resistance to insecticides contribute to malaria transmission. Recently, several malaria endemic countries have experienced a significant reduction in numbers of malaria cases. This is most likely due to actions taken by National Malaria Control Programs (NMCP) with the support from international funding agencies. We describe here the research strategies and activities to be undertaken by the Centro Latino Americano de Investigación en Malaria (CLAIM), a new research center established for the non-Amazonian region of Latin America by the National Institute of Allergy and Infectious Diseases (NIAID). Throughout a network of countries in the region, initially including Colombia, Guatemala, Panama, and Peru, CLAIM will address major gaps in our understanding of changing malaria epidemiology, vector biology and control, and clinical malaria mainly due to Plasmodium vivax. In close partnership with NMCPs, CLAIM seeks to conduct research on how and why malaria is decreasing in many countries of the region as a basis for developing and implementing new strategies that will accelerate malaria elimination.
Assuntos
Erradicação de Doenças/métodos , Erradicação de Doenças/organização & administração , Projetos de Pesquisa Epidemiológica , Malária/prevenção & controle , Animais , Atenção à Saúde/organização & administração , Resistência a Medicamentos , Variação Genética , Humanos , Imidazóis/farmacologia , Insetos Vetores/parasitologia , Insetos Vetores/fisiologia , Cooperação Internacional , América Latina/epidemiologia , Malária/epidemiologia , Malária/imunologia , Malária/parasitologia , Vacinas Antimaláricas/administração & dosagem , Vacinas Antimaláricas/imunologia , Programas Nacionais de Saúde/organização & administração , Niacina/análogos & derivados , Niacina/farmacologia , Plasmodium/efeitos dos fármacos , Plasmodium/genética , Plasmodium/imunologia , Plasmodium/patogenicidade , Fatores SocioeconômicosRESUMO
Objetivo: identificar las enfermedades más frecuentes de los niños del programa familia canguro, así como los antecedentes sociodemográficos y ginecobstétricos de la madre y características relacionadas con el recién nacido. Metodología: se realizó un estudio cuantitativo descriptivo en una muestra no probabilística a conveniencia, en el que se revisaron 86 historias clínicas de niños que fueron atendidos en el programa familia canguro de junio a diciembre de 2009, con un peso menor de 2 500 gr y con menos de 37 semanas de edad gestacional. Resultados: el promedio de edad de las madres fue de 26 ± 6.6 años. Un 50.2% pertenecía al estrato 2; 44.4% tenía secundaria completa; 40.7% está conformado por primigestantes y al 54.3% se le practicó cesárea. El promedio del peso de los niños al nacer fue de 1 715 ± 490 gramos. La edad gestacional en promedio fue de 33 ± 7.8 semanas. El 8.1% de los niños presentó bronquiolitis, 7% ictericia, 7% reflujo gastroesofágico y un 66.3% no presentó morbilidad. Conclusiones: el estudio mostró una baja frecuencia de enfermedades en los neonatos del programa madre-canguro de la Clínica Universitaria Bolivariana.
Objective: to identify the most frequent diseases in children of the kangaroo family program, as well as the mother Ìs sociodemographic and gynecobstetric background and characteristics related to the new born. Methods: a descriptive quantitative study was made in a convinient nonprobabilístic sample, in which 86 medical histories of children who attended the kangaroo family program from June to December 2009 were reviewed, with a weight less than 2500 grams and with less than 37 weeks of gestational age. Results: the average age of the mothers was 26 ± 6.6 years old. 50.2% belonged to a socioeconomic status 2; 44.4% had completed secondary school; 40.7% were primiparous and 54.3% underwent caesarean. The average weight of the newborns was 1 715 ± 490 gr. The average gestational age was 33 ± 7.8 weeks. 8.1% of the children presented bronchiolitis, 7% jaundice, 7% Gastroesophageal reflux and 66.3% did not present any morbidityConclusions: the study showed a low frequency of diseases in infants of the mother kangaroo program of the Bolivarian University Clinic
Assuntos
Humanos , Feminino , Gravidez , Recém-Nascido , Lactente , Método Canguru , Bronquiolite , Idade Gestacional , MorbidadeRESUMO
Malaria is the most important parasitic disease worldwide, responsible for an estimated 225 million clinical cases each year. It mainly affects children, pregnant women and non-immune adults who frequently die victims of cerebral manifestations and anaemia. Although the contribution of the American continent to the global malaria burden is only around 1.2 million clinical cases annually, there are 170 million inhabitants living at risk of malaria transmission in this region. On the African continent, where Plasmodium falciparum is the most prevalent human malaria parasite, anaemia is responsible for about half of the malaria-related deaths. Conversely, in Latin America (LA), malaria-related anaemia appears to be uncommon, though there is a limited knowledge about its real prevalence. This may be partially explained by several factors, including that the overall malaria burden in LA is significantly lower than that of Africa, that Plasmodium vivax, the predominant Plasmodium species in the region, appears to display a different clinical spectrus and most likely because better health services in LA prevent the development of severe malaria cases. With the aim of contributing to the understanding of the real importance of malaria-related anaemia in LA, we discuss here a revision of the available literature on the subject and the usefulness of experimental animal models, including New World monkeys, particularly for the study of the mechanisms involved in the pathogenesis of malaria.