RESUMO
Predicting pathogenic germline variants (PGVs) in breast cancer patients is important for selecting optimal therapeutics and implementing risk reduction strategies. However, PGV risk factors and the performance of prediction methods in the Japanese population remain unclear. We investigated clinicopathological risk factors using the Tyrer-Cuzick (TC) breast cancer risk evaluation tool to predict BRCA PGVs in unselected Japanese breast cancer patients (n = 1,995). Eleven breast cancer susceptibility genes were analyzed using target-capture sequencing in a previous study; the PGV prevalence in BRCA1, BRCA2, and PALB2 was 0.75%, 3.1%, and 0.45%, respectively. Significant associations were found between the presence of BRCA PGVs and early disease onset, number of familial cancer cases (up to third-degree relatives), triple-negative breast cancer patients under the age of 60, and ovarian cancer history (all P < .0001). In total, 816 patients (40.9%) satisfied the National Comprehensive Cancer Network (NCCN) guidelines for recommending multigene testing. The sensitivity and specificity of the NCCN criteria for discriminating PGV carriers from noncarriers were 71.3% and 60.7%, respectively. The TC model showed good discrimination for predicting BRCA PGVs (area under the curve, 0.75; 95% confidence interval, 0.69-0.81). Furthermore, use of the TC model with an optimized cutoff of TC score ≥0.16% in addition to the NCCN guidelines improved the predictive efficiency for high-risk groups (sensitivity, 77.2%; specificity, 54.8%; about 11 genes). Given the influence of ethnic differences on prediction, we consider that further studies are warranted to elucidate the role of environmental and genetic factors for realizing precise prediction.
Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Triagem de Portadores Genéticos/métodos , Mutação em Linhagem Germinativa , Neoplasias Ovarianas/genética , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Feminino , Predisposição Genética para Doença , Humanos , Japão , Pessoa de Meia-Idade , Taxa de Mutação , Linhagem , Vigilância da População , Medição de RiscoRESUMO
Genotype-first approach allows to systematically identify carriers of pathogenic variants in BRCA1/2 genes conferring a high risk of familial breast and ovarian cancer. Participants of the Estonian biobank have expressed support for the disclosure of clinically significant findings. With an Estonian biobank cohort, we applied a genotype-first approach, contacted carriers, and offered return of results with genetic counseling. We evaluated participants' responses to and the clinical utility of the reporting of actionable genetic findings. Twenty-two of 40 contacted carriers of 17 pathogenic BRCA1/2 variants responded and chose to receive results. Eight of these 22 participants qualified for high-risk assessment based on National Comprehensive Cancer Network criteria. Twenty of 21 counseled participants appreciated being contacted. Relatives of 10 participants underwent cascade screening. Five of 16 eligible female BRCA1/2 variant carriers chose to undergo risk-reducing surgery, and 10 adhered to surveillance recommendations over the 30-month follow-up period. We recommend the return of results to population-based biobank participants; this approach could be viewed as a model for population-wide genetic testing. The genotype-first approach permits the identification of individuals at high risk who would not be identified by application of an approach based on personal and family histories only.
Assuntos
Triagem de Portadores Genéticos/métodos , Aconselhamento Genético/psicologia , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Cooperação do Paciente , Atitude , Proteína BRCA1/genética , Proteína BRCA2/genética , Feminino , Triagem de Portadores Genéticos/ética , Aconselhamento Genético/normas , Síndrome Hereditária de Câncer de Mama e Ovário/diagnóstico , Síndrome Hereditária de Câncer de Mama e Ovário/psicologia , Síndrome Hereditária de Câncer de Mama e Ovário/cirurgia , Humanos , Mastectomia Profilática/psicologia , Mastectomia Profilática/estatística & dados numéricos , Revelação da VerdadeRESUMO
Dietary and supplemental intake of the ω-3 fatty acid docosahexaenoic acid (DHA) reduces risk of Alzheimer's disease (AD) and ameliorates symptoms. The apolipoprotein E ( APOE) 4 allele is the strongest risk factor for sporadic AD, exclusive of age. APOE4 carriers respond well to the DHA present in fish but do not respond as well to dietary supplements. The mechanisms behind this varied response remain unknown. I posit that the difference is that fish contain DHA in phospholipid form, whereas fish oil supplements do not. This influences whether DHA is metabolized to nonesterified DHA (free DHA) or a phospholipid form called lysophosphatidylcholine DHA (DHA-lysoPC). Free DHA is transported across the outer membrane leaflet of the blood-brain barrier (BBB) via passive diffusion, and DHA-lysoPC is transported across the inner membrane leaflet of the BBB via the major facilitator superfamily domain-containing protein 2A. I propose that APOE4 carriers have impaired brain transport of free DHA but not of DHA-lysoPC, as a consequence of a breakdown in the outer membrane leaflet of the BBB, putting them at increased risk for AD. Dietary sources of DHA in phospholipid form may provide a means to increase plasma levels of DHA-lysoPC, thereby decreasing the risk of AD.-Patrick, R. P. Role of phosphatidylcholine-DHA in preventing APOE4-associated Alzheimer's disease.
Assuntos
Doença de Alzheimer/metabolismo , Doença de Alzheimer/prevenção & controle , Apolipoproteína E4/metabolismo , Ácidos Docosa-Hexaenoicos/metabolismo , Fosfatidilcolinas/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Transporte Biológico , Encéfalo/metabolismo , Dieta , Interação Gene-Ambiente , Triagem de Portadores Genéticos , Predisposição Genética para Doença , HumanosRESUMO
Women carriers of mutations in the genes BRCA1 and BRCA2 coding for tumor suppressor proteins are at high risk of developing breast and ovarian cancers. Hereditary breast and ovarian cancers due to BRCA pathogenic mutations occur at earlier ages: mean age 43 years at diagnosis of breast cancer for BRCA1 mutations; onset of ovarian cancer up to 10-21% by age 50 years. Preventive strategies are then defined in the reproductive years. The National Comprehensive Cancer Network (NCCN) guidelines define that BRCA1/2 genetic testing should begin with the affected cancer individual (BRCA1/2 full sequencing); then, family members should be tested for the specific gene mutation found. A woman known to be a carrier needs a strict specific surveillance strategy to achieve early diagnosis. The NCCN proposes breast imageneological surveillance beginning at age 25 years; ovarian surveillance beginning at age 30-35 years. Concomitantly, risk-reducing strategies should be analyzed: surgical or pharmacological. When prophylactic bilateral salpingo-oophorectomy is performed before menopause, estrogen replacement therapy could be required. For BRCA, we review the risks of cancer in mutations carriers, criteria for genetic testing, surveillance and risk-reduction strategies, and the safety of prescribing hormone therapy when needed.
Assuntos
Neoplasias da Mama/prevenção & controle , Genes BRCA1 , Genes BRCA2 , Predisposição Genética para Doença , Neoplasias Ovarianas/prevenção & controle , Neoplasias da Mama/genética , Terapia de Reposição de Estrogênios , Feminino , Triagem de Portadores Genéticos , Aconselhamento Genético , Humanos , Mutação , Neoplasias Ovarianas/genética , Medição de Risco , Fatores de Risco , Salpingo-OoforectomiaRESUMO
KEY MESSAGE: 2n pollen formed by FDR in citrus. The Japanese local citrus cultivar, Nishiuchi Konatsu (Citrus tamurana hort. ex Tanaka; NK hereafter), has the ability to produce unreduced 2n pollen grains, allowing generation of polyploid progenies via sexual polyploidization. In this study, we developed a method of single-pollen genotyping for citrus and applied it to the analysis of transmission of heterozygosity in NK 2n pollen grains. Heterozygosity transmission was expressed as the percentage inheritance of a set of heterozygous alleles from the parent to the 2n gamete. The pathway of 2n pollen development was investigated by applying the observed heterozygosity transmission and genetic distance to two different map functions, for first division restitution (FDR) and second division restitution (SDR). The fit of the values observed for both functions was calculated, while virtually moving the centromere position. We screened for six heterozygous SSR (codominant microsatellite marker loci) in NK, all of which were expected to lie within the same linkage group. Pollen germination prior to DNA extraction was essential for this work, and 6-h incubation proved to be optimal for subsequent PCR amplification. Single-pollen genotyping unreduced NK 2n pollen grains revealed that heterozygosity transmission exceeded 50 % in all six alleles, and fitness tests indicated that the FDR map function better fitted the heterozygosity transmission observed rather than the SDR function. Our data thus strongly indicate that 2n pollen in NK is a result of first division restitution.
Assuntos
Citrus/genética , Triagem de Portadores Genéticos , Técnicas de Genotipagem , Pólen/genéticaRESUMO
OBJECTIVE: To discern presymptomatic changes in brain structure or function using advanced MRI in carriers of mutations predisposing to amyotrophic lateral sclerosis (ALS). METHODS: T1-weighted, diffusion weighted and resting state functional MRI data were acquired at 3â T for 12 asymptomatic mutation carriers (psALS), 12 age-matched controls and affected patients with ALS. Cortical thickness analysis, voxel-based morphometry, volumetric and shape analyses of subcortical structures, tract-based spatial statistics of metrics derived from the diffusion tensor, and resting state functional connectivity (FC) analyses were performed. RESULTS: Grey matter cortical thickness and shape analysis revealed significant atrophy in patients with ALS (but not psALS) compared with controls in the right primary motor cortex and right caudate. Comparison of diffusion tensor metrics showed widespread fractional anisotropy and radial diffusivity differences in patients with ALS compared to controls and the psALS group, encompassing parts of the corpus callosum, corticospinal tracts and superior longitudinal fasciculus. While FC in the resting-state sensorimotor network was similar in psALS and controls, FC between the cerebellum and a network comprising the precuneus, cingulate & middle frontal lobe was significantly higher in psALS and affected ALS compared to controls. CONCLUSIONS: Rather than structural brain changes, increased FC may be among the earliest detectable brain abnormalities in asymptomatic carriers of ALS-causing gene mutations. With replication and significant refinement, this technique has potential in the future assessment of neuroprotective strategies.
Assuntos
Esclerose Lateral Amiotrófica/diagnóstico por imagem , Esclerose Lateral Amiotrófica/genética , Encéfalo/diagnóstico por imagem , Imagem de Difusão por Ressonância Magnética , Predisposição Genética para Doença/genética , Interpretação de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Rede Nervosa/diagnóstico por imagem , Adulto , Idoso , Esclerose Lateral Amiotrófica/fisiopatologia , Encéfalo/fisiopatologia , Proteína C9orf72 , Cerebelo/diagnóstico por imagem , Cerebelo/fisiopatologia , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/fisiopatologia , Estudos de Coortes , Tomografia Computadorizada de Feixe Cônico , Corpo Caloso/diagnóstico por imagem , Corpo Caloso/fisiopatologia , Feminino , Lobo Frontal/diagnóstico por imagem , Lobo Frontal/fisiopatologia , Triagem de Portadores Genéticos , Giro do Cíngulo/diagnóstico por imagem , Giro do Cíngulo/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Rede Nervosa/fisiopatologia , Lobo Parietal/diagnóstico por imagem , Lobo Parietal/fisiopatologia , Proteínas/genética , Tratos Piramidais/diagnóstico por imagem , Tratos Piramidais/fisiopatologia , Superóxido Dismutase-1/genética , Adulto JovemRESUMO
BACKGROUND: Population carrier screening (PCS) has been available in Israel since 1999 and universally subsidized since 2008. We sought to evaluate its impact. METHODS: A retrospective review of governmental databanks, the national CF registry and CF centers. RESULTS: CF rate per 100,000 live births has decreased from 14.5 in 1990 to 6 in 2011. From 2004-2011 there were 95 CF births: 22 utilized PCS; 68 (72%) had 2 known CFTR mutations; 37% were pancreatic sufficient. At diagnosis, age was 6 (0-98) months; 53/95 had respiratory symptoms, 41/95 failure to thrive and 19/95 pseudomonas. Thirty-four (36%) were Arabs and 19 (20%) orthodox Jews, compared to 20% and 8% respectively, in the general population. CONCLUSIONS: PCS markedly reduced CF birth rates with a shift towards milder mutations, but was often avoided for cultural reasons. As children regularly have significant disease at diagnosis, we suggest a balanced approach, utilizing both PCS and newborn screening.
Assuntos
Fibrose Cística , Triagem Neonatal , Diagnóstico Pré-Natal , Adulto , Coeficiente de Natalidade , Fibrose Cística/diagnóstico , Fibrose Cística/etnologia , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Saúde da Família , Feminino , Triagem de Portadores Genéticos/métodos , Triagem de Portadores Genéticos/estatística & dados numéricos , Aconselhamento Genético/organização & administração , Humanos , Lactente , Recém-Nascido , Israel/epidemiologia , Masculino , Mutação , Programas Nacionais de Saúde/estatística & dados numéricos , Triagem Neonatal/métodos , Triagem Neonatal/tendências , Gravidez , Diagnóstico Pré-Natal/métodos , Diagnóstico Pré-Natal/tendências , Medição de Risco/métodosRESUMO
UNLABELLED: Acute necrotizing encephalopathy is a rare neurologic disease most often triggered by a febrile viral event affecting an otherwise healthy infant. The clinical course is characterized by rapid deterioration of the neurological condition that often leads to coma and requires intensive care. The diagnosis is usually suggested by MRI, which shows symmetrical and focal necrotic lesions of thalami. Acute necrotizing encephalopathy has been linked in recent studies to an autosomal-dominant mutation of the gene for the protein RAN-binding protein 2. CASE REPORT: We report three cases in siblings of Tunisian origin. Two of them presented with acute necrotizing encephalopathy at the age of 9 months in the immediate aftermath of a viral infection. The molecular study conducted in the family showed that both patients and their mother were carriers of the missense mutation gene RAN-binding protein 2. COMMENTS: Although the role of Ran BP2 protein is incompletely known, mutation of the RANBP2 gene causes rare, reversible central neurologic disorders. Suspected diagnosis is facilitated by MRI, which shows specific lesions of multifocal, symmetric involvement of the thalami, brainstem tegmentum, supratentorial white matter, and cerebellum. Due to the low frequency of the disease and its non-specific clinical presentation, the diagnosis of acute necrotizing encephalopathy is a major challenge, while preventative measures can be proposed in familial mutation.
Assuntos
Análise Mutacional de DNA , Emigrantes e Imigrantes , Genes Dominantes/genética , Leucoencefalite Hemorrágica Aguda/genética , Chaperonas Moleculares/genética , Mutação de Sentido Incorreto/genética , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Cerebelo/patologia , Aberrações Cromossômicas , Diagnóstico Diferencial , Progressão da Doença , Dominância Cerebral/fisiologia , França , Triagem de Portadores Genéticos , Humanos , Lactente , Leucoencefalite Hemorrágica Aguda/diagnóstico , Imageamento por Ressonância Magnética , Masculino , Exame Neurológico , Tegmento Mesencefálico/patologia , Tálamo/patologia , Tunísia/etnologia , Viroses/complicaçõesRESUMO
BACKGROUND: The diagnosis of mitochondrial disease requires a complex synthesis of clinical, biochemical, histological, and genetic investigations. An expanding number of mitochondrial diseases are being recognized, despite their phenotypic diversity, largely due to improvements in methods to detect mutations in affected individuals and the discovery of genes contributing to mitochondrial function. Improved understanding of the investigational pitfalls and the development of new laboratory methodologies that lead to a molecular diagnosis have necessitated the field to rapidly adopt changes to its diagnostic approach. SCOPE OF REVIEW: We review the clinical, investigational and genetic challenges that have resulted in shifts to the way we define and diagnose mitochondrial disease. Incorporation of changes, including the use of fibroblast growth factor 21 (FGF-21) and next generation sequencing techniques, may allow affected patients access to earlier molecular diagnosis and management. MAJOR CONCLUSIONS: There have been important shifts in the diagnostic paradigm for mitochondrial disease. Diagnosis of mitochondrial disease is no longer reliant on muscle biopsy alone, but should include clinical assessment accompanied by the use of serological biomarkers and genetic analysis. Because affected patients will be defined on a molecular basis, oligosymptomatic mutation carriers should be included in the spectrum of mitochondrial disease. Use of new techniques such as the measurement of serum FGF-21 levels and next-generation-sequencing protocols should simplify the diagnosis of mitochondrial disease. GENERAL SIGNIFICANCE: Improvements in the diagnostic pathway for mitochondrial disease will result in earlier, cheaper and more accurate methods to identify patients with mitochondrial disease. This article is part of a Special Issue entitled Frontiers of Mitochondrial Research.
Assuntos
Heterogeneidade Genética , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/genética , Análise Mutacional de DNA/métodos , Frequência do Gene , Triagem de Portadores Genéticos/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Doenças Mitocondriais/patologia , Técnicas de Diagnóstico Molecular , Músculo Esquelético/patologia , Mutação , FenótipoRESUMO
We cared for a term female newborn, who at 108 hours of age, with a total serum bilirubin of 15.4 mg/dL, was discharged from the hospital on home phototherapy. At a return appointment 44 hours later, her total serum bilirubin was 41.7 mg/dL and signs of acute kernicterus were present. Maternal/fetal blood group O/B incompatibility was identified, with a negative direct antiglobulin test, which was positive on retesting. She had abundant spherocytes on blood smear, and these persisted at follow-up, but neither parent had spherocytes identified. A heterozygous SLC4A1(E508K) mutation (gene encoding erythrocyte membrane protein band 3) was found, and in silico predicted to result in damaged erythrocyte cytoskeletal protein function. No mutations were identified in other red cell cytoskeleton genes (ANK1, SPTA1, SPTB, EPB41, EPB42) and the UGT1A1 promoter region was normal. Neurologic follow-up at 2 and 4 months showed developmental delays consistent with mild kernicterus.
Assuntos
Antiporters/genética , Incompatibilidade de Grupos Sanguíneos/sangue , Incompatibilidade de Grupos Sanguíneos/genética , Análise Mutacional de DNA , Kernicterus/sangue , Kernicterus/genética , Sistema ABO de Grupos Sanguíneos/genética , Bilirrubina/sangue , Deficiências do Desenvolvimento/sangue , Deficiências do Desenvolvimento/genética , Feminino , Seguimentos , Triagem de Portadores Genéticos , Humanos , Recém-Nascido , Proteínas de Membrana/genética , Regiões Promotoras Genéticas/genética , Proteínas de Protozoários/genética , Esferocitose Hereditária/sangue , Esferocitose Hereditária/genéticaRESUMO
BACKGROUND: Brugada syndrome is a genetic heart disease with autosomal dominant inheritance. Family screening commonly detects one parent responsible for transmission of the disease. AIMS: To describe atypical transmission of Brugada syndrome. METHODS: Between 2001 and 2007, systematic screening, including an electrocardiogram, ajmaline challenge and DNA sequencing of the SCN5A gene, of the first-degree relatives of 62 probands with Brugada syndrome was performed (Programme Hospitalier de Recherche Clinique). RESULTS: In two families, both parents transmitted Brugada syndrome to their offspring. In the first family, the proband presented Brugada electrocardiogram features with ajmaline challenge and carried a new SCN5A mutation (p.V1281F). The mutation was also identified in the mother, who had a type 1 aspect on inferior leads with ajmaline. The proband's father presented a typical Brugada electrocardiogram pattern on lead V2 with ajmaline and no SCN5A gene mutation. In the second family, the proband was a boy aged 2.5 years who had been resuscitated from sudden cardiac death. Ajmaline challenge revealed a typical Brugada electrocardiogram pattern in both parents but with no mutation in the genes studied. CONCLUSION: Family studies should always be exhaustive and discovery of one parent with Brugada syndrome does not eliminate the need for screening of the other parent.
Assuntos
Síndrome de Brugada/genética , Heterozigoto , Mutação , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Adolescente , Adulto , Ajmalina , Antiarrítmicos , Síndrome de Brugada/complicações , Síndrome de Brugada/diagnóstico , Síndrome de Brugada/terapia , Pré-Escolar , Análise Mutacional de DNA , Morte Súbita Cardíaca/etiologia , Morte Súbita Cardíaca/prevenção & controle , Eletrocardiografia , Técnicas Eletrofisiológicas Cardíacas , Feminino , Triagem de Portadores Genéticos , Predisposição Genética para Doença , Testes Genéticos/métodos , Hereditariedade , Humanos , Masculino , Linhagem , Fenótipo , Valor Preditivo dos Testes , Ressuscitação , Adulto JovemRESUMO
Methylenetetrahydrofolate reductase (MTHFR) is essential for DNA biosynthesis and the epigenetic process of DNA methylation, and its gene polymorphisms have been implicated as risk factors for birth defects, neurological disorders, and cancers. However, reports on the association of MTHFR polymorphisms with autism spectrum disorders (ASD) are inconclusive. Therefore, we investigated the relationship of the MTHFR polymorphisms (C677T and A1298C) and the risk of ASD by meta-analysis. Up to December 2012, eight case-control studies involving 1672 patients with ASD and 6760 controls were included for meta-analysis. The results showed that the C677T polymorphism was associated with significantly increased ASD risk in all the comparison models [T vs. C allele (frequency of allele): odds ratio (OR) = 1.42, 95% confidence interval (CI): 1.09-1.85; CT vs. CC (heterozygote): OR = 1.48, 95% CI: 1.09-2.00; TT vs. CC (homozygote): OR = 1.86, 95% CI: 1.08-3.20; CT+TT vs. CC (dominant model): OR = 1.56, 95% CI: 1.12-2.18; and TT vs. CC+CT (recessive model): OR = 1.51, 95% CI: 1.02-2.22], whereas the A1298C polymorphism was found to be significantly associated with reduced ASD risk but only in a recessive model (CC vs. AA+AC: OR = 0.73, 95% CI: 0.56-0.97). In addition, we stratified the patient population based on whether they were from a country with food fortification of folic acid or not. The meta-analysis showed that the C677T polymorphism was found to be associated with ASD only in children from countries without food fortification. Our study indicated that the MTHFR C677T polymorphism contributes to increased ASD risk, and periconceptional folic acid may reduce ASD risk in those with MTHFR 677C>T polymorphism.
Assuntos
Transtornos Globais do Desenvolvimento Infantil/genética , Predisposição Genética para Doença/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo Genético/genética , Estudos de Casos e Controles , Criança , Transtornos Globais do Desenvolvimento Infantil/prevenção & controle , Comparação Transcultural , Países em Desenvolvimento , Epigênese Genética/genética , Ácido Fólico/administração & dosagem , Deficiência de Ácido Fólico/complicações , Deficiência de Ácido Fólico/genética , Alimentos Fortificados , Frequência do Gene , Triagem de Portadores Genéticos , Genótipo , Humanos , Fatores de RiscoRESUMO
Folate and vitamin B(12) metabolism are essential for de novo purine synthesis, and several defects in these pathways have been associated with immunodeficiency. Here we describe the occurrence of severe combined immunodeficiency (SCID) with megaloblastic anemia, leukopenia, atypical hemolytic uremic syndrome, and neurologic abnormalities in which hydroxocobalamin and folate therapy provided partial immune reconstitution. Whole exome sequencing identified compound heterozygous mutations in the MTHFD1 gene, which encodes a trifunctional protein essential for processing of single-carbon folate derivatives. We now report the immunologic details of this novel genetic cause of SCID and the response to targeted metabolic supplementation therapies. This finding expands the known metabolic causes of SCID and presents an important diagnostic consideration given the positive impact of therapy.
Assuntos
Análise Mutacional de DNA , Metilenotetra-Hidrofolato Desidrogenase (NADP)/genética , Imunodeficiência Combinada Severa/genética , 3-Hidroxiacil-CoA Desidrogenases/deficiência , 3-Hidroxiacil-CoA Desidrogenases/genética , Anemia Megaloblástica/diagnóstico , Anemia Megaloblástica/tratamento farmacológico , Anemia Megaloblástica/genética , Exame de Medula Óssea , Cardiomiopatias/diagnóstico , Cardiomiopatias/tratamento farmacológico , Cardiomiopatias/genética , Terapia Combinada , Combinação de Medicamentos , Quimioterapia Combinada , Exoma/genética , Feminino , Triagem de Portadores Genéticos , Humanos , Hidroxocobalamina/uso terapêutico , Imunização Passiva , Lactente , Recém-Nascido , Leucopenia/diagnóstico , Leucopenia/tratamento farmacológico , Leucopenia/genética , Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/tratamento farmacológico , Erros Inatos do Metabolismo Lipídico/genética , Antígenos de Histocompatibilidade Menor , Miopatias Mitocondriais , Proteína Mitocondrial Trifuncional/deficiência , Doenças do Sistema Nervoso , Infecções Oportunistas/diagnóstico , Infecções Oportunistas/tratamento farmacológico , Infecções Oportunistas/genética , Doenças do Sistema Nervoso Periférico/diagnóstico , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/genética , Pneumonia por Pneumocystis/diagnóstico , Pneumonia por Pneumocystis/tratamento farmacológico , Pneumonia por Pneumocystis/genética , Retinose Pigmentar/diagnóstico , Retinose Pigmentar/tratamento farmacológico , Retinose Pigmentar/genética , Rabdomiólise , Análise de Sequência de DNA , Imunodeficiência Combinada Severa/diagnóstico , Imunodeficiência Combinada Severa/tratamento farmacológico , Sulfadoxina/uso terapêutico , Trimetoprima/uso terapêutico , Vitamina B 12/uso terapêuticoRESUMO
OBJECTIVES: Beta thalassaemia major (ß-TM) and sickle-cell disease (SCD) are severe haemogobinopathies requiring life-lasting, advanced medical management. In the Mediterranean region, both conditions occur with high frequency. We assessed the efficacy of the National Program for the Prevention of Haemoglobinopathies in Greece during the last 30 yrs. METHODS: Data of affected births between 01/01/1980 and 31/12/2009 were collected in a nationwide scale, and expected vs. observed rates of new births were calculated and compared. In a subpopulation of affected births of Greek origin, the causes for occurrence of the new affected birth were also collected and analysed. RESULTS: Overall, the reduction in new cases was 81.1% and 84.6% for ß-TM and SCD, respectively. For ß-TM, a constant declining trend was recorded over the 30-yr period, whereas for SCD, a transient reversal was observed in the mid-1990s probably due to the significant influx of immigrants of African origin. Programme failure was 2.2 times more common among new ß-TM births of Greek origin compared to new SCD cases (P < 0.001). Unawareness and parental choice were more frequent in SCD compared to ß-TM (unawareness: OR = 1.4, P = 0.05, parental choice: OR = 1.9, P = 0.01). The main cause for programme failure was carrier misidentification and incorrect genetic advice for ß-TM and SCD, respectively. CONCLUSIONS: The ß-TM and SCD prevention programme in Greece has significantly reduced the numbers of new affected births. The outcomes could be optimised in groups of non-Greek origin, in carrier identification and by offering specialised genetic counselling.
Assuntos
Hemoglobinopatias/prevenção & controle , África/etnologia , Anemia Falciforme/epidemiologia , Anemia Falciforme/genética , Anemia Falciforme/história , Anemia Falciforme/prevenção & controle , Emigração e Imigração/história , Emigração e Imigração/tendências , Triagem de Portadores Genéticos , Aconselhamento Genético , Grécia/epidemiologia , Hemoglobinopatias/epidemiologia , Hemoglobinopatias/genética , Hemoglobinopatias/história , História do Século XX , História do Século XXI , Humanos , Recém-Nascido , Programas Nacionais de Saúde/história , Talassemia beta/epidemiologia , Talassemia beta/genética , Talassemia beta/história , Talassemia beta/prevenção & controleRESUMO
α-Amino adipic semialdehyde (α-AASA) accumulates in body fluids from patients with pyridoxine-dependent epilepsy because of mutations in antiquitin (ALDH7A1) and serves as the biomarker for this condition. We have recently found that the urinary excretion of α-AASA was also increased in molybdenum cofactor and sulfite oxidase deficiencies. The seizures in pyridoxine-dependent epilepsy are caused by lowered cerebral levels of pyridoxal-5-phosphate (PLP), the bioactive form of pyridoxine (vitamin B(6)), which can be corrected by the supplementation of pyridoxine. The nonenzymatic trapping of PLP by the cyclic form of α-AASA is causative for the lowered cerebral PLP levels. We describe 2 siblings with clinically evident pyridoxine-responsive seizures associated with increased urinary excretion of α-AASA. Subsequent metabolic investigations revealed several metabolic abnormities, all indicative for molybdenum cofactor deficiency. Molecular investigations indeed revealed a known homozygous mutation in the MOCS2 gene. Based upon the clinically evident pyridoxine-responsive seizures in these 2 siblings, we recommend considering pyridoxine supplementation to patients affected with molybdenum cofactor or sulfite oxidase deficiencies.
Assuntos
Ácido 2-Aminoadípico/análogos & derivados , Aldeído Desidrogenase/genética , Consanguinidade , Epilepsia/diagnóstico , Epilepsia/genética , Erros Inatos do Metabolismo dos Metais/diagnóstico , Erros Inatos do Metabolismo dos Metais/genética , Ácido 2-Aminoadípico/urina , Encéfalo/metabolismo , Encéfalo/patologia , Pré-Escolar , Análise Mutacional de DNA , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/tratamento farmacológico , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/urina , Diagnóstico Diferencial , Imagem de Difusão por Ressonância Magnética , Eletroencefalografia/efeitos dos fármacos , Epilepsia/tratamento farmacológico , Epilepsia/urina , Éxons/genética , Feminino , Triagem de Portadores Genéticos , Homozigoto , Humanos , Lactente , Recém-Nascido , Leucovorina/uso terapêutico , Masculino , Erros Inatos do Metabolismo dos Metais/tratamento farmacológico , Erros Inatos do Metabolismo dos Metais/urina , Molibdoferredoxina/genética , Molibdoferredoxina/urina , Exame Neurológico/efeitos dos fármacos , Fosfato de Piridoxal/deficiência , Fosfato de Piridoxal/metabolismo , Piridoxina/uso terapêutico , Análise de Sequência de DNA , Sulfurtransferases/genéticaRESUMO
Oxidative damage in brain cells is one of the factors hypothesized to be involved in the pathogenesis of schizophrenia. Glutathione S-transferase (GST) A1*B polymorphism, a genotype associated with a higher risk of oxidative damage, is associated with increased frequency of schizophrenia diagnosis. Thus, here we studied Glutathione S-transferase (GST) A1 polymorphism and diffusion tensor imaging-mean diffusivity (MD) data on deep grey matter brain structures in 56 patients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revised (DSM-IV-TR) schizophrenia. Clinical diagnosis and psychopathological symptom severity were assessed by using the Structured Clinical Interview for DSM-IV-TR (SCID-P) and the Scales for Assessment of Positive and Negative Symptoms (SAPS and SANS). Results confirmed that patients with schizophrenia who were carriers of the GSTA1 *B risk allele had an increased MD in bilateral thalami and increased severity of auditory and global hallucinations in comparison with non-B carriers. Thus, oxidative stress associated factors may be implicated in specific mechanisms of schizophrenia such as altered microstructure of the thalami and specific psychopathological features of auditory hallucinations.
Assuntos
Alelos , Imagem de Difusão por Ressonância Magnética , Dominância Cerebral/genética , Dominância Cerebral/fisiologia , Genótipo , Glutationa Transferase/genética , Interpretação de Imagem Assistida por Computador , Estresse Oxidativo/genética , Polimorfismo Genético/genética , Esquizofrenia/genética , Esquizofrenia/fisiopatologia , Psicologia do Esquizofrênico , Tálamo/fisiopatologia , Adulto , Feminino , Triagem de Portadores Genéticos , Predisposição Genética para Doença/genética , Alucinações/genética , Alucinações/psicologia , Humanos , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo/fisiologia , Regiões Promotoras Genéticas , Escalas de Graduação PsiquiátricaRESUMO
Pyridoxine-dependent epilepsy (PDE) was first described in 1954. The ALDH7A1 gene mutations resulting in α-aminoadipic semialdehyde dehydrogenase deficiency as a cause of PDE was identified only in 2005. Neonatal epileptic encephalopathy is the presenting feature in >50% of patients with classic PDE. We report the case of a 13-month-old girl with profound neonatal hypoglycemia (0.6 mmol/L; reference range >2.4), lactic acidosis (11 mmol/L; reference range <2), and bilateral symmetrical temporal lobe hemorrhages and thalamic changes on cranial MRI. She developed multifocal and myoclonic seizures refractory to multiple antiepileptic drugs that responded to pyridoxine. The diagnosis of α-aminoadipic semialdehyde dehydrogenase deficiency was confirmed based on the elevated urinary α-aminoadipic semialdehyde excretion, compound heterozygosity for a known splice mutation c.834G>A (p.Val278Val), and a novel putative pathogenic missense mutation c.1192G>C (p.Gly398Arg) in the ALDH7A1 gene. She has been seizure-free since 1.5 months of age on treatment with pyridoxine alone. She has motor delay and central hypotonia but normal language and social development at the age of 13 months. This case is the first description of a patient with PDE due to mutations in the ALDH7A1 gene who presented with profound neonatal hypoglycemia and lactic acidosis masquerading as a neonatal-onset gluconeogenesis defect. PDE should be included in the differential diagnosis of hypoglycemia and lactic acidosis in addition to medically refractory neonatal seizures.
Assuntos
Acidose Láctica/diagnóstico , Epilepsia/diagnóstico , Hipoglicemia/diagnóstico , Ácido 2-Aminoadípico/análogos & derivados , Ácido 2-Aminoadípico/deficiência , Ácido 2-Aminoadípico/genética , Aldeído Desidrogenase/genética , Alelos , Anticonvulsivantes/uso terapêutico , Encéfalo/patologia , Análise Mutacional de DNA , Imagem de Difusão por Ressonância Magnética , Eletroencefalografia/efeitos dos fármacos , Epilepsia/genética , Feminino , Seguimentos , Triagem de Portadores Genéticos , Humanos , Lactente , Recém-Nascido , Infusões Intravenosas , Imageamento por Ressonância Magnética , Mutação de Sentido Incorreto , Piridoxina/uso terapêutico , Lobo Temporal/patologia , Tálamo/patologiaRESUMO
HISTORY: A 42-year-old man was found to have a four to six fold increase in the level of plasma ferritin since four years. In the age of 10 he had undergone unilateral resection of a dysplastic kidney associated with systemic hypertension. He had also developed recurrent venous thromboses caused by atresia of the inferior vena cava with azygos continuation, known since 23 years. Iron overload or hemochromatosis had been excluded, but despite numerous investigations the exact cause of the hyperferritinemia had not been elucidated. The patient, his grandfather, his mother and a brother had undergone cataract surgeries in both eyes. He presented at admission with prominent veins over the abdomen a postthrombotic syndrome. INVESTIGATION: Laboratory tests revealed a ferritin level 6 times above the upper limit of normal, but iron, transferrin saturation, and transferrin levels were normal. The patient was on oral anticoagulation (INR 2.2). Molecular genetic tests revealed heterozygous mutation IRE+ 32 G > T. DIAGNOSIS, TREATMENT AND COURSE: The findings indicated a hereditary hyperferritinemia cataract syndrome with an autosomal dominant trait. As functions of other organs are not affected, bilateral cataract surgery is "curative". CONCLUSION: Early and correct diagnosis avoids unnecessary diagnostic and therapeutic interventions, such as extended and repeated laboratory tests, liver biopsies, phlebotomies and chelation therapy.
Assuntos
Catarata/congênito , Distúrbios do Metabolismo do Ferro/congênito , Adulto , Catarata/sangue , Catarata/diagnóstico , Catarata/genética , Extração de Catarata , Aberrações Cromossômicas , Análise Mutacional de DNA , Ferritinas/sangue , Genes Dominantes/genética , Triagem de Portadores Genéticos , Testes Genéticos , Humanos , Hipertensão Renal/sangue , Hipertensão Renal/diagnóstico , Hipertensão Renal/genética , Ferro/sangue , Distúrbios do Metabolismo do Ferro/sangue , Distúrbios do Metabolismo do Ferro/diagnóstico , Distúrbios do Metabolismo do Ferro/genética , Proteínas Reguladoras de Ferro/genética , Rim/anormalidades , Masculino , Fenótipo , Síndrome Pós-Trombótica/sangue , Síndrome Pós-Trombótica/diagnóstico , Síndrome Pós-Trombótica/genética , Transferrina/metabolismo , Veia Cava Inferior/anormalidades , Trombose Venosa/sangue , Trombose Venosa/diagnóstico , Trombose Venosa/genéticaRESUMO
PREMISE OF THE STUDY: The development of compound microsatellite markers was conducted in Dysosma pleiantha to investigate genetic diversity and population genetic structure of this threatened medicinal plant. METHODS AND RESULTS: Using the compound microsatellite marker technique, 14 microsatellite markers that were successfully amplified showed polymorphism when tested on 38 individuals from three populations in eastern China. Overall, the number of alleles per locus ranged from 2 to 14, with an average of 7.71 alleles per locus. CONCLUSIONS: These results indicate that these microsatellite markers are adequate for detecting and characterizing population genetic structure and genetic diversity in Dysosma pleiantha.
Assuntos
Berberidaceae/genética , DNA de Plantas/análise , Triagem de Portadores Genéticos/métodos , Repetições de Microssatélites , Polimorfismo Genético , Alelos , Sequência de Bases , Berberidaceae/metabolismo , China , Primers do DNA/genética , DNA de Plantas/genética , Espécies em Perigo de Extinção , Escherichia coli/genética , Escherichia coli/metabolismo , Frequência do Gene , Biblioteca Gênica , Loci Gênicos , Genótipo , Dados de Sequência MolecularRESUMO
PREMISE OF THE STUDY: Microsatellite primers were developed for a Chinese traditional herb, Panax notoginseng, to investigate its genetic diversity and cultivar breeding. METHODS AND RESULTS: Twelve polymorphic microsatellite loci were isolated from the microsatellite-enriched genomic library of Panax notoginseng. The polymorphisms were assessed in two populations and an assemblage containing individuals from the entire distribution area. The number of alleles per locus ranged from 3 to 12, with a mean of 5.8; the observed and expected heterozygosity values ranged from 0.0411 to 0.8472 and from 0.0804 to 0.7653, respectively. CONCLUSIONS: These new microsatellite markers will be useful for investigating the genetic diversity of this cultivated Panax notoginseng as well as assist in cultivar breeding.