RESUMO
Fibrosing mediastinitis is a rare benign condition, which can cause compression of the pulmonary or systemic vessels, tracheobronchial tree, coronary arteries or esophagus, leading to disabling clinical symptoms and even death. The case of a 26-year-old woman who presented with dyspnea is described. She was found to have 80% stenosis of the right pulmonary artery secondary to fibrosing mediastinitis. The stenosis was managed successfully with an endovascular Palmaz-Schatz stent, and the patient remains symptom-free 10 years later.
Assuntos
Angioplastia com Balão , Fibrose/complicações , Mediastinite/complicações , Doenças Vasculares Periféricas/terapia , Artéria Pulmonar , Adulto , Constrição Patológica , Feminino , Humanos , Doenças Vasculares Periféricas/etiologia , Stents , Resultado do TratamentoRESUMO
BACKGROUND: Rett syndrome (RTT) is an X linked neuro-developmental disorder affecting mostly girls. Mutations in the coding region of MECP2 are found in 80% of classic RTT patients. Until recently, the region encoding MECP2 was believed to comprise exons 2, 3, and 4 with the ATG start site located at the end of exon 2 (MeCP2_e2). METHODS: Recent reports of another mRNA transcript transcribed from exon 1 (MeCP2_e1) prompted us to screen exon 1 among RNA samples from 20 females with classic or atypical RTT. RESULTS: A previously reported 11 base pair deletion in exon 1 was detected in one subject with a milder phenotype. Although RNA expression for both protein isoforms was detected from the mutant allele, evaluation of MeCP2 protein in uncultured patient lymphocytes by immunocytochemistry revealed that MeCP2 protein production was restricted to only 74-76% of lymphocytes. X chromosome inactivation studies of genomic DNA revealed similar XCI ratios at the HUMARA locus (73:27 with HpaII and 74:26 with McrBC). We have demonstrated that translation but not transcription of the MeCP2_e2 isoform is ablated by the 11 nucleotide deletion, 103 nucleotides upstream of the e2 translation start site. CONCLUSIONS: These findings reveal that nucleotides within the deleted sequence in the 5'-UTR of the MeCP2_e2 transcript, while not required for transcription, are essential for translation.
Assuntos
Éxons , Proteína 2 de Ligação a Metil-CpG/genética , Biossíntese de Proteínas/fisiologia , Síndrome de Rett/genética , Adolescente , Adulto , Alelos , Sequência de Bases , Pré-Escolar , Feminino , Humanos , Lactente , Linfócitos/metabolismo , Proteína 2 de Ligação a Metil-CpG/biossíntese , Fenótipo , Isoformas de Proteínas/biossíntese , Isoformas de Proteínas/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Síndrome de Rett/diagnóstico , Análise de Sequência de RNA , Deleção de Sequência , Inativação do Cromossomo XRESUMO
BACKGROUND: Mutations in the E-cadherin (CDH1) gene are a well documented cause of hereditary diffuse gastric cancer (HDGC). Development of evidence based guidelines for CDH1 screening for HDGC have been complicated by its rarity, variable penetrance, and lack of founder mutations. METHODS: Forty three new gastric cancer (GC) families were ascertained from multiple sources. In 42 of these families at least one gastric cancer was pathologically confirmed to be a diffuse gastric cancer (DGC); the other family had intestinal type gastric cancers. Screening of the entire coding region of the CDH1 gene and all intron/exon boundaries was performed by bi-directional sequencing. RESULTS: Novel mutations were found in 13 of the 42 DGC families (31% overall). Twelve of these mutations occur among the 25 families with multiple cases of gastric cancer and with pathologic confirmation of diffuse gastric cancer phenotype in at least one individual under the age of 50 years. The mutations found include small insertions and deletions, splice site mutations, and three non-conservative amino acid substitutions (A298T, W409R, and R732Q). All three missense mutations conferred loss of E-cadherin function in in vitro assays. Multiple cases of breast cancers including pathologically confirmed lobular breast cancers were observed both in mutation positive and negative families. CONCLUSION: Germline truncating CDH1 mutations are found in 48% of families with multiple cases of gastric cancer and at least one documented case of DGC in an individual under 50 years of age. We recommend that these criteria be used for selecting families for CDH1 mutational analysis.
Assuntos
Caderinas/genética , Testes Genéticos/métodos , Mutação em Linhagem Germinativa/genética , Neoplasias Gástricas/genética , Adolescente , Adulto , Idoso , Caderinas/fisiologia , Criança , Análise Mutacional de DNA/métodos , Feminino , Predisposição Genética para Doença/genética , Variação Genética/genética , Mutação em Linhagem Germinativa/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto/genética , Mutação de Sentido Incorreto/fisiologia , Linhagem , Neoplasias Gástricas/diagnósticoRESUMO
Syndromes of disordered 'chromatin remodeling' are unique in medicine because they arise from a general deregulation of DNA transcription caused by mutations in genes encoding enzymes which mediate changes in chromatin structure. Chromatin is the packaged form of DNA in the eukaryotic cell. It consists almost entirely of repeating units, called nucleosomes, in which short segments of DNA are wrapped tightly around a disk-like structure comprising two subunits of each of the histone proteins H2A, H2B, H3 and H4. Histone proteins are covalently modified by a number of different adducts (i.e. acetylation and phosphorylation) that regulate the tightness of the DNA-histone interactions. Mutations in genes encoding enzymes that mediate chromatin structure can result in a loss of proper regulation of chromatin structure, which in turn can result in deregulation of gene transcription and inappropriate protein expression. In this review we present examples of representative genetic diseases that arise as a consequence of disordered chromatin remodeling. These include: alpha-thalassemia/mental retardation syndrome, X-linked (ATR-X); Rett syndrome (RS); immunodeficiency-centromeric instability-facial anomalies syndrome (ICF); Rubinstein-Taybi syndrome (RSTS); and Coffin-Lowry syndrome (CLS).
Assuntos
Montagem e Desmontagem da Cromatina/genética , Doenças Genéticas Inatas/complicações , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Mutação/genética , Montagem e Desmontagem da Cromatina/fisiologia , Síndrome de Coffin-Lowry/complicações , Síndrome de Coffin-Lowry/diagnóstico , Síndrome de Coffin-Lowry/genética , Humanos , Deficiência Intelectual Ligada ao Cromossomo X/complicações , Deficiência Intelectual Ligada ao Cromossomo X/diagnóstico , Deficiência Intelectual Ligada ao Cromossomo X/genética , Mutação/fisiologia , Síndrome de Rett/complicações , Síndrome de Rett/diagnóstico , Síndrome de Rett/genética , Síndrome de Rubinstein-Taybi/complicações , Síndrome de Rubinstein-Taybi/diagnóstico , Síndrome de Rubinstein-Taybi/genética , Talassemia alfa/complicações , Talassemia alfa/diagnóstico , Talassemia alfa/genéticaRESUMO
Predictive and pre-natal testing for Huntington's Disease (HD) has been available since 1987. Initially this was offered by linkage analysis, which was surpassed by the advent of the direct mutation test for HD in 1993. Direct mutation analysis provided an accurate test that not only enhanced predictive and pre-natal testing, but also permitted the diagnostic testing of symptomatic individuals. The objective of this study was to investigate the uptake, utilization, and outcome of predictive, pre-natal and diagnostic testing in Canada from 1987 to April 1, 2000. A retrospective design was used; all Canadian medical genetics centres and their affiliated laboratories offering genetic testing for HD were invited to participate. A total of 15 of 22 centres (68.2%), currently offering or ever having offered genetic testing for HD, responded, providing data on test results, demographics, and clinical history. A total of 1061 predictive tests, 15 pre-natal tests, and 626 diagnostic tests were performed. The uptake for predictive testing was approximately 18% of the estimated at-risk Canadian population, ranging from 12.5% in the Maritimes to 20.7% in British Columbia. There appears to have been a decline in the rate of testing in recent years. Of the predictive tests, 45.0% of individuals were found to have an increased risk, and a preponderance of females (60.2%) sought testing. A greater proportion of those at < or = 25% risk sought predictive testing once direct CAG mutation analysis had become available (10.9% after mutation analysis vs 4.7% before mutation analysis, p = 0.0077). Very few pre-natal tests were requested. Of the 15 pre-natal tests, 12 had an increased risk, resulting in termination of pregnancy in all but one. Diagnostic testing identified 68.5% of individuals to be positive by mutation analysis, while 31.5% of those with HD-like symptoms were not found to have the HD mutation. The positive diagnostic tests included 24.5% of individuals with no known prior family history of HD.
Assuntos
Doença de Huntington/diagnóstico , Doença de Huntington/genética , Diagnóstico Pré-Natal , Adolescente , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Canadá , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Gravidez , Estudos Retrospectivos , Expansão das Repetições de TrinucleotídeosRESUMO
The advent of the direct mutation test for Huntington disease (HD) has made it possible to identify a previously unrecognized symptomatic population of HD, including those with an atypical presentation or patients without a family history of HD. The present study investigated the uptake of this test in the province of British Columbia (BC), Canada and assessed the incidence rate and rate of identification of new mutations for HD. All symptomatic individuals residing in BC who were referred for the genetic test for HD between 1993 and 2000 (n=205) were analyzed for CAG expansion, baseline demographics and clinical data, and a family history of HD. A total of 141 (or 68.8%) had a CAG expansion > or =36. Of these, almost one-quarter (24.1%) did not have a family history of HD. An extensive chart review revealed that 11 patients (or 7.8%) had reliable information on both parents (who lived well into old age) and therefore possibly could represent new mutations for HD. This indicates a three to four times higher new mutation rate than previously reported. Our findings also show that the yearly incidence rate for HD was 6.9 per million, which is two times higher than previous incidence studies performed prior to the identification of the HD mutation. We also identified five persons with a clinical presentation of HD but without CAG expansion (genocopies) (2.4%).
Assuntos
Doença de Huntington/epidemiologia , Doença de Huntington/genética , Expansão das Repetições de Trinucleotídeos , Adolescente , Adulto , Fatores Etários , Idade de Início , Idoso , Colúmbia Britânica , Criança , Pré-Escolar , Saúde da Família , Pai , Feminino , Humanos , Doença de Huntington/diagnóstico , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Mães , Mutação , Análise de Sequência de DNA , Fatores Sexuais , Fatores de TempoRESUMO
OBJECTIVE: Machado-Joseph disease (MJD) reaches its highest prevalence world-wide in the Azores, thus constituting a public health problem in these islands. The aim of the study was thus to (1) determine the level of knowledge about the disease; (2) estimate the expected level of request for predictive testing, and (3) analyse the intentions of at-risk individuals concerning their reproductive decisions. METHODS: A questionnaire on these points was distributed to 42 affected and 36 at-risk individuals. RESULTS: As expected, the educational level of the respondents was significantly associated with the level of knowledge about the disease. The survey indicated that 83.3% of the at-risk individuals would make use of predictive test and that 77.8% would make use of prenatal diagnosis. Of the latter, 36.1% would terminate pregnancy if confronted with a positive result for the fetus. CONCLUSIONS: The level of knowledge about MJD in the Azorean families is considered to be fair. Although the actual behavior can prove to be different from the intentions put forward by at-risk individuals based solely on the results of this study we can estimate that the request for a predictive test would be quite high. The intentions expressed by at-risk individuals seem to indicate that the prenatal diagnosis will have an effect on their reproductive decisions. Results obtained certify the importance of implementing genetic testing for MJD in the Azores.
Assuntos
Atitude Frente a Saúde , Testes Genéticos/psicologia , Conhecimentos, Atitudes e Prática em Saúde , Doença de Machado-Joseph/genética , Doença de Machado-Joseph/psicologia , Diagnóstico Pré-Natal/psicologia , Açores , Saúde da Família , Feminino , Aconselhamento Genético , Doenças Genéticas Inatas , Humanos , Intenção , Masculino , Portugal , Reprodução , Inquéritos e QuestionáriosRESUMO
Carnitine palmitoyltransferase I (CPT I) catalyzes the formation of acylcarnitine, the first step in the oxidation of long-chain fatty acids in mitochondria. The enzyme exists as liver (L-CPT I) and muscle (M-CPT I) isoforms that are encoded by separate genes. Genetic deficiency of L-CPT I, which has been reported in 16 patients from 13 families, is characterized by episodes of hypoketotic hypoglycemia beginning in early childhood and is usually associated with fasting or illness. To date, only two mutations associated with L-CPT I deficiency have been reported. In the present study we have identified and characterized the mutations underlying L-CPT I deficiency in six patients: five with classic symptoms of L-CPT I deficiency and one with symptoms that have not previously been associated with this disorder (muscle cramps and pain). Transfection of the mutant L-CPT I cDNAs in COS cells resulted in L-CPT I mRNA levels that were comparable to those expressed from the wild-type construct. Western blotting revealed lower levels of each of the mutant proteins, indicating that the low enzyme activity associated with these mutations was due, at least in part, to protein instability. The patient with atypical symptoms had approximately 20% of normal L-CPT I activity and was homozygous for a mutation (c.1436C-->T) that substituted leucine for proline at codon 479. Assays performed with his cultured skin fibroblasts indicated that this mutation confers partial resistance to the inhibitory effects of malonyl-CoA. The demonstration of L-CPT I deficiency in this patient suggests that the spectrum of clinical sequelae associated with loss or alteration of L-CPT I function may be broader than was previously recognized.
Assuntos
Carnitina O-Palmitoiltransferase/deficiência , Carnitina O-Palmitoiltransferase/genética , Hipoglicemia/genética , Malonil Coenzima A/metabolismo , Mutação/genética , Adulto , Animais , Células COS/metabolismo , Carnitina O-Palmitoiltransferase/metabolismo , Criança , DNA Complementar/genética , Estabilidade Enzimática , Jejum/metabolismo , Feminino , Fibroblastos/citologia , Fibroblastos/metabolismo , Humanos , Hipoglicemia/enzimologia , Hipoglicemia/etiologia , Lactente , Masculino , Valores de Referência , Pele/citologia , TransfecçãoRESUMO
BACKGROUND: Germ-line truncating mutations in the E-cadherin (CDH1) gene have been found in families with hereditary diffuse gastric cancer. These families are characterized by a highly penetrant susceptibility to diffuse gastric cancer with an autosomal dominant pattern of inheritance, predominantly in young persons. We describe genetic screening, surgical management, and pathological findings in young persons with truncating mutations in CDH1 from two unrelated families with hereditary diffuse gastric cancer. METHODS: Mutation-specific predictive genetic testing was performed by polymerase-chain-reaction amplification, followed by restriction-enzyme digestion and DNA sequencing in Family 1 and by heteroduplex analysis in Family 2. A total gastrectomy was performed prophylactically in five carriers of mutations who were between 22 and 40 years old. In each case, the entire mucosa of the stomach was extensively sampled for microscopical analysis. RESULTS: Superficial infiltrates of malignant signet-ring cells were identified in the surgical samples from all five persons who underwent gastrectomy. These early diffuse gastric cancers were multifocal in three of the five cases, and in one person infiltrates of malignant signet-ring cells were present in 65 of the 140 tissue blocks analyzed, representing in aggregate less than 2 percent of the gastric mucosa. CONCLUSIONS: We recommend genetic counseling and consideration of prophylactic gastrectomy in young, asymptomatic carriers of germ-line truncating CDH1 mutations who belong to families with highly penetrant hereditary diffuse gastric cancer.
Assuntos
Adenocarcinoma/genética , Caderinas/genética , Mutação em Linhagem Germinativa , Neoplasias Gástricas/genética , Adulto , Idade de Início , Carcinoma de Células em Anel de Sinete/genética , Feminino , Gastrectomia , Aconselhamento Genético , Testes Genéticos , Humanos , Masculino , Linhagem , Prevenção Primária , Estômago/patologia , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/prevenção & controle , Neoplasias Gástricas/cirurgiaRESUMO
The present study has investigated interaction at the cortical level in the human between two major components of flavor perception, pure chemical gustatory and lingual somatosensory perception. Twelve subjects participated in a functional magnetic resonance imaging study and tasted six stimuli, applied on the whole tongue, among which four were pure gustatory stimuli (NaCl, aspartame, quinine and HCl, pH 2.4 or 2.2) and two were both taste and lingual somatosensory stimuli, i.e. somato-gustatory stimuli (HCl, pH 1.6 or 1.5, and aluminum potassium sulfate). Functional images were acquired with an echo planar sequence on a 3 T system and were individually processed by correlation with the temporal perception profile. Both sets of stimuli showed activation in the same cortical areas, namely the insula, the rolandic operculum (base of the pre- and post-central gyri), the frontal operculum and the temporal operculum, confirming a wide overlap of taste and lingual somatosensory representations. However, the relative activation across areas and the analysis of co-activated areas across all runs for each set of stimuli allowed discrimination of taste and somatosensory modalities. Factor analysis of correspondences indicated different patterns of activation across the sub-insular and opercular regions, depending on the gustatory or somato-gustatory nature of the stimuli. For gustatory stimuli different activation patterns for the superior and inferior parts of the insula suggested a difference in function between these two insular sub-regions. Furthermore, the left inferior insula was co-activated with the left angular gyrus, a structure involved in semantic processing. In contrast, only somato-gustatory stimuli specifically produced a simultaneous and symmetrical activation of both the left and right rolandic opercula, which include a part of the sensory homunculus dedicated to the tactile representation of oral structures.
Assuntos
Mapeamento Encefálico , Córtex Somatossensorial/fisiologia , Paladar/fisiologia , Língua/fisiologia , Adulto , Córtex Cerebral/fisiologia , Feminino , Humanos , Imageamento por Ressonância Magnética/instrumentação , Masculino , Pessoa de Meia-Idade , Estimulação QuímicaRESUMO
The Rett syndrome (RS) is a peculiar, sporadic, atrophic disorder, almost entirely confined to females. After the first six months of life there is developmental slowing with reduced communication and head growth for about one year. This is followed by a rapid destructive stage with severe dementia and loss of hand skills (with frequent hand wringing), apraxia and ataxia, autistic features and irregular breathing with hyperventilation. Seizures often supervene. Subsequently there is some stabilization in a pseudo-stationary stage during the preschool to school years, associated with more emotional contact but also abnormalities of the autonomic and skeletal systems. After the age of 15-20 years, a late motor deterioration occurs with dystonia and frequent spasticity but seizures become milder. RS has generally been considered an X-linked disorder in which affected females represent a new mutation, with male lethality. Linkage studies suggested a critical region at Xq28. In 1999, mutations in the gene MECP2 encoding X-linked methyl cytosine-binding protein 2 (MeCP2) were found in a proportion of Rett girls. This protein can bind methylated DNA. Analyses are leading to much further investigation of mutants and their effects on genes. Neuropathological and electrophysiological studies of RS are described. Description of neurometabolic factors includes reduced levels of dopamine, serotonin, noradrenaline and choline acetyltransferase (ChAT) in brain, also estimation of nerve growth factors, endorphin, substance P, glutamate and other amino acids and their receptor levels. The results of neuroimaging are surveyed, including volumetric magnetic resonance imaging (MRI) and positron emission tomography (PET).
Assuntos
Síndrome de Rett/fisiopatologia , Animais , Eletroencefalografia , Humanos , Síndrome de Rett/genética , Síndrome de Rett/metabolismoRESUMO
Families with autosomal dominant inherited predisposition to gastric cancer have been described. More recently, germline E-cadherin/CDH1 mutations have been identified in hereditary diffuse gastric cancer kindred. The need to have protocols to manage and counsel these families in the clinic led a group of geneticists, gastroenterologists, surgeons, oncologists, pathologists, and molecular biologists to convene a workshop to produce consensus statements and guidelines for familial gastric cancer. Review of the available cancer pathology from people belonging to families with documented germline E-cadherin/CDH1 mutations confirmed that the gastric cancers were all of the diffuse type. Criteria to define the different types of familial gastric cancer syndromes were agreed. Foremost among these criteria was that review of histopathology should be part of the evaluation of any family with aggregation of gastric cancer cases. Guidelines for genetic testing and counselling in hereditary diffuse gastric cancer were produced. Finally, a proposed strategy for clinical management in families with high penetrance autosomal dominant predisposition to gastric cancer was defined.
Assuntos
Caderinas/genética , Neoplasias Gástricas/genética , Gastrectomia , Aconselhamento Genético , Predisposição Genética para Doença , Guias como Assunto , Humanos , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/cirurgia , Neoplasias Gástricas/terapiaRESUMO
BACKGROUND: Medical spa spring waters (MSSWs) have been extensively used as adjunctive treatments for various skin conditions to provide skin comfort. We carried out a double-blind study to compare the sensory profile of four MSSWs with increasing mineral content. METHODS: A panel of 36 women, trained to perform comparative sensory analysis, applied in pairs four MSSWs with mineral contents of 0.2, 0.45, 5, and 11 g/L on the right and left cheeks. At baseline, 5 min, and 10 min after the applications, the subjects evaluated each water for the following factors using a computerized analog scale: freshness, mild stinging, softness, suppleness, and comfort of the skin. RESULTS: After 5 min, all four waters induced a sensation of freshness, irrespective of their mineral concentration. A mild stinging was also perceived with all four waters, with a magnitude that was dependent on the mineral density. After 10 min, softness, suppleness, and skin comfort were the prominent features induced by the waters, but the lower the mineral content, the greater these perceptions. Statistically significant differences were demonstrated between the 0.2 g/L group and the 5 and 11 g/L groups for stinging (P = 0.0001), softness and suppleness (P < 0.05), and skin comfort (P = 0.006) after 10 min. CONCLUSIONS: Our results indicate that the sensory effects provided by MSSWs when topically applied depend on their mineral concentration.
Assuntos
Balneologia , Águas Minerais , Sensação/fisiologia , Fenômenos Fisiológicos da Pele , Adulto , Método Duplo-Cego , Feminino , Humanos , Pessoa de Meia-Idade , Águas Minerais/administração & dosagem , Fenômenos Fisiológicos da Pele/efeitos dos fármacos , Água/análiseRESUMO
The syndrome of infantile spasms, hypsarrhythmia, and mental retardation (West syndrome) is a classical form of epilepsy, occurring in early infancy, which is etiologically heterogeneous. In rare families, West syndrome is an X-linked recessive condition, mapped to Xp11.4-Xpter (MIM 308350). We have identified a multi-generation family from Western Canada with this rare syndrome of infantile spasms, seen exclusively in male offspring from asymptomatic mothers, thereby confirming segregation as an X-linked recessive trait. Using highly polymorphic microsatellite CA-repeat probes evenly distributed over the entire X chromosome, linkage to markers DXS7110, DXS989, DXS1202, and DXS7106 was confirmed, with a maximum LOD score of 3.97 at a theta of 0.0. The identification of key recombinants refined the disease-containing interval between markers DXS1226 and the adrenal hypoplasia locus (AHC). This now maps the X-linked infantile spasms gene locus to chromosome Xp21.3-Xp22.1 and refines the interval containing the candidate gene to 7.0 cM. Furthermore, this interval overlaps several loci previously linked with either syndromic or non-syndromic X-linked mental retardation (XLMR), including one recognized locus implicated in neuroaxonal processing (radixin, RDXP2). Collectively, these studies lend strong support for the presence of one or more genes intrinsic to brain development and function, occurring within the critical interval defined between Xp21.3-Xp22.1.
Assuntos
Espasmos Infantis/genética , Cromossomo X/genética , Mapeamento Cromossômico , DNA/genética , Saúde da Família , Feminino , Ligação Genética , Genótipo , Humanos , Escore Lod , Masculino , Repetições de Microssatélites , LinhagemRESUMO
E-cadherin germ-line mutations have recently been described as a molecular basis for early-onset familial gastric cancer in Maori kindred. We screened 18 gastric cancer families of European origin for germ-line mutations to determine the proportion in which E-cadherin mutations occur and the clinical characteristics of the affected families. Truncating mutations were identified in three kindred with familial diffuse gastric cancer. In these families, the age of onset of gastric cancer was variable, the penetrance was incomplete, and one kindred contained individuals with cancers at other sites. Here, we show that a proportion of diffuse gastric cancer families of European origin have germ-line E-cadherin mutations; however, these mutations are absent in intestinal gastric cancer families.