RESUMO
D2C7-immunotoxin (IT), a dual-specific IT targeting wild-type epidermal growth factor receptor (EGFR) and mutant EGFR variant III (EGFRvIII) proteins, demonstrates encouraging survival outcomes in a subset of patients with glioblastoma. We hypothesized that immunosuppression in glioblastoma limits D2C7-IT efficacy. To improve the response rate and reverse immunosuppression, we combined D2C7-IT tumor cell killing with αCD40 costimulation of antigen-presenting cells. In murine glioma models, a single intratumoral injection of D2C7-IT+αCD40 treatment activated a proinflammatory phenotype in microglia and macrophages, promoted long-term tumor-specific CD8+ T cell immunity, and generated cures. D2C7-IT+αCD40 treatment increased intratumoral Slamf6+CD8+ T cells with a progenitor phenotype and decreased terminally exhausted CD8+ T cells. D2C7-IT+αCD40 treatment stimulated intratumoral CD8+ T cell proliferation and generated cures in glioma-bearing mice despite FTY720-induced peripheral T cell sequestration. Tumor transcriptome profiling established CD40 up-regulation, pattern recognition receptor, cell senescence, and immune response pathway activation as the drivers of D2C7-IT+αCD40 antitumor responses. To determine potential translation, immunohistochemistry staining confirmed CD40 expression in human GBM tissue sections. These promising preclinical data allowed us to initiate a phase 1 study with D2C7-IT+αhCD40 in patients with malignant glioma (NCT04547777) to further evaluate this treatment in humans.
Assuntos
Neoplasias Encefálicas , Glioblastoma , Glioma , Imunotoxinas , Humanos , Animais , Camundongos , Glioblastoma/patologia , Imunotoxinas/genética , Linfócitos T CD8-Positivos , Imunidade Adaptativa , Receptores ErbB/metabolismo , Linhagem Celular Tumoral , Neoplasias Encefálicas/terapiaRESUMO
BACKGROUND: Neonates and young children require efficacious magnetic resonance imaging (MRI) examinations but are potentially more susceptible to the short- and long-term adverse effects of gadolinium-based contrast agents due to the immaturity of their body functions. OBJECTIVE: To evaluate the acute safety and diagnostic efficacy of gadoteridol (ProHance) for contrast-enhanced MRI of the central nervous system (CNS) in children ≤2 years of age. MATERIALS AND METHODS: One hundred twenty-five children ≤2 years old (including 57 children <6 months old) who underwent contrast-enhanced MRI of the CNS with gadoteridol at 0.1 mmol/kg body weight were retrospectively enrolled at five imaging centers. Safety data were assessed for acute/subacute adverse events in the 48 h following gadoteridol administration and, when available, vital signs, electrocardiogram (ECG) and clinical laboratory values obtained from blood samples taken from 48 h before until 48 h following the MRI exam. The efficacy of gadoteridol-enhanced MRI compared to unenhanced MRI for disease diagnosis was evaluated prospectively by three blinded, unaffiliated readers. RESULTS: Thirteen changes of laboratory values (11 mild, 1 moderate, 1 unspecified) were reported as adverse events in 7 (5.6%) patients. A relationship to gadoteridol was deemed possible though doubtful for two of these adverse events in two patients (1.6%). There were no clinical adverse events, no serious adverse events and no clinically meaningful changes in vital signs or ECG recordings. Accurate differentiation of tumor from non-neoplastic disease, and exact matching of specific MRI-determined diagnoses with on-site final diagnoses, was achieved in significantly more patients by each reader following the evaluation of combined pre- and post-contrast images compared to pre-contrast images alone (84.6-88.0% vs. 70.9-76.9%; P≤0.006 and 67.5-79.5% vs. 47.0-66.7%; P≤0.011, respectively). CONCLUSION: Gadoteridol at 0.1 mmol/kg body weight is safe, well tolerated and effective for contrast-enhanced MRI of the CNS in children ≤2 years of age.
Assuntos
Neoplasias Encefálicas , Compostos Heterocíclicos , Compostos Organometálicos , Encéfalo , Pré-Escolar , Meios de Contraste/efeitos adversos , Gadolínio/efeitos adversos , Compostos Heterocíclicos/efeitos adversos , Humanos , Lactente , Recém-Nascido , Imageamento por Ressonância Magnética , Compostos Organometálicos/efeitos adversos , Estudos RetrospectivosRESUMO
BACKGROUND: Paediatric low-grade glioma is the most common CNS tumour of childhood. Although overall survival is good, disease often recurs. No single universally accepted treatment exists for these patients; however, standard cytotoxic chemotherapies are generally used. We aimed to assess the activity of selumetinib, a MEK1/2 inhibitor, in these patients. METHODS: The Pediatric Brain Tumor Consortium performed a multicentre, phase 2 study in patients with paediatric low-grade glioma in 11 hospitals in the USA. Patients aged 3-21 years with a Lansky or Karnofsky performance score greater than 60 and the presence of recurrent, refractory, or progressive paediatric low-grade glioma after at least one standard therapy were eligible for inclusion. Patients were assigned to six unique strata according to histology, tumour location, NF1 status, and BRAF aberration status; herein, we report the results of strata 1 and 3. Stratum 1 comprised patients with WHO grade I pilocytic astrocytoma harbouring either one of the two most common BRAF aberrations (KIAA1549-BRAF fusion or the BRAFV600E [Val600Glu] mutation). Stratum 3 comprised patients with any neurofibromatosis type 1 (NF1)-associated paediatric low-grade glioma (WHO grades I and II). Selumetinib was provided as capsules given orally at the recommended phase 2 dose of 25 mg/m2 twice daily in 28-day courses for up to 26 courses. The primary endpoint was the proportion of patients with a stratum-specific objective response (partial response or complete response), as assessed by the local site and sustained for at least 8 weeks. All responses were reviewed centrally. All eligible patients who initiated treatment were evaluable for the activity and toxicity analyses. Although the trial is ongoing in other strata, enrolment and planned follow-up is complete for strata 1 and 3. This trial is registered with ClinicalTrials.gov, number NCT01089101. FINDINGS: Between July 25, 2013, and June 12, 2015, 25 eligible and evaluable patients were accrued to stratum 1, and between Aug 28, 2013, and June 25, 2015, 25 eligible and evaluable patients were accrued to stratum 3. In stratum 1, nine (36% [95% CI 18-57]) of 25 patients achieved a sustained partial response. The median follow-up for the 11 patients who had not had a progression event by Aug 9, 2018, was 36·40 months (IQR 21·72-45·59). In stratum 3, ten (40% [21-61]) of 25 patients achieved a sustained partial response; median follow-up was 48·60 months (IQR 39·14-51·31) for the 17 patients without a progression event by Aug 9, 2018. The most frequent grade 3 or worse adverse events were elevated creatine phosphokinase (five [10%]) and maculopapular rash (five [10%]). No treatment-realted deaths were reported. INTERPRETATION: Selumetinib is active in recurrent, refractory, or progressive pilocytic astrocytoma harbouring common BRAF aberrations and NF1-associated paediatric low-grade glioma. These results show that selumetinib could be an alternative to standard chemotherapy for these subgroups of patients, and have directly led to the development of two Children's Oncology Group phase 3 studies comparing standard chemotherapy to selumetinib in patients with newly diagnosed paediatric low-grade glioma both with and without NF1. FUNDING: National Cancer Institute Cancer Therapy Evaluation Program, the American Lebanese Syrian Associated Charities, and AstraZeneca.
Assuntos
Benzimidazóis/uso terapêutico , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Glioma/tratamento farmacológico , Adolescente , Neoplasias do Sistema Nervoso Central/genética , Neoplasias do Sistema Nervoso Central/patologia , Criança , Pré-Escolar , Progressão da Doença , Feminino , Glioma/genética , Glioma/patologia , Humanos , Masculino , Gradação de Tumores , Neoplasias Primárias Múltiplas/patologia , Neurofibromatose 1/patologia , Proteínas Proto-Oncogênicas B-raf/genética , Adulto JovemRESUMO
Dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI) is used to track the first pass of an exogenous, paramagnetic, nondiffusible contrast agent through brain tissue, and has emerged as a powerful tool in the characterization of brain tumor hemodynamics. DSC-MRI parameters can be helpful in many aspects, including tumor grading, prediction of treatment response, likelihood of malignant transformation, discrimination between tumor recurrence and radiation necrosis, and differentiation between true early progression and pseudoprogression. This review aims to provide a conceptual overview of the underlying principles of DSC-MRI of the brain for clinical neuroradiologists, scientists, or students wishing to improve their understanding of the technical aspects, pitfalls, and controversies of DSC perfusion MRI of the brain. Future consensus on image acquisition parameters and postprocessing of DSC-MRI will most likely allow this technique to be evaluated and used in high-quality multicenter studies and ultimately help guide clinical care.
Assuntos
Neoplasias Encefálicas/diagnóstico , Imageamento por Ressonância Magnética/métodos , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Meios de Contraste , Progressão da Doença , Hemodinâmica , Humanos , Gradação de Tumores , Recidiva Local de Neoplasia/diagnósticoRESUMO
OBJECTIVE: The purpose of this study was to measure the organ doses and estimate the effective dose for the standard brain perfusion CT protocol and erroneous protocols. MATERIALS AND METHODS: An anthropomorphic phantom with metal oxide semiconductor field effect transistor (MOSFET) detectors was scanned on a 64-MDCT scanner. Protocol 1 used a standard brain perfusion protocol with 80 kVp and fixed tube current of 200 mA. Protocol 2 used 120 kVp and fixed tube current of 200 mA. Protocol 3 used 120 kVp with automatic tube current modulation (noise index, 2.4; minimum, 100 mA; maximum, 520 mA). RESULTS: Compared with protocol 1, the effective dose was 2.8 times higher with protocol 2 and 7.8 times higher with protocol 3. For all protocols, the peak dose was highest in the skin, followed by the brain and calvarial marrow. Compared with protocol 1, the peak skin dose was 2.6 times higher with protocol 2 and 6.7 times higher with protocol 3. The peak skin dose for protocol 3 exceeded 3 Gy. The ocular lens received significant scatter radiation: 177 mGy for protocol 2 and 435 mGy for protocol 3, which were 4.6 and 11.3 times the dose for protocol 1, respectively. CONCLUSION: Compared with the standard protocol, erroneous protocols of increasing the tube potential from 80 kVp to 120 kVp will lead to a three- to fivefold increase in organ doses, and concurrent use of high peak kilovoltage with incorrectly programmed tube current modulation can increase dose to organs by 7- to 11-fold. Tube current modulation with a low noise index can lead to doses to the skin and ocular lens that are close to thresholds for tissue reactions.
Assuntos
Encéfalo/diagnóstico por imagem , Doses de Radiação , Radiometria/métodos , Tomografia Computadorizada por Raios X/métodos , Humanos , Imagens de Fantasmas , Tomografia Computadorizada por Raios X/instrumentaçãoRESUMO
OBJECTIVE: This article addresses questions that radiologists frequently ask when planning, performing, processing, and interpreting MRI perfusion studies in CNS imaging. CONCLUSION: Perfusion MRI is a promising tool in assessing stroke, brain tumors, and neurodegenerative diseases. Most of the impediments that have limited the use of per-fusion MRI can be overcome to allow integration of these methods into modern neuroimaging protocols.
Assuntos
Doenças do Sistema Nervoso Central/diagnóstico , Imageamento por Ressonância Magnética/métodos , Neuroimagem/métodos , Doenças do Sistema Nervoso Central/patologia , Meios de Contraste , Humanos , Aumento da Imagem/métodos , Interpretação de Imagem Assistida por Computador/métodosRESUMO
OBJECTIVE: This and its companion article address the 10 most frequently asked questions that radiologists face when planning, performing, processing, and interpreting different MR perfusion studies in CNS imaging. CONCLUSION: Perfusion MRI is a promising tool in assessing stroke, brain tumors, and patients with neurodegenerative diseases. Most of the impediments that have limited the use of perfusion MRI can be overcome to allow integration of these methods into modern neuroimaging protocols.
Assuntos
Encefalopatias/diagnóstico , Encéfalo/irrigação sanguínea , Meios de Contraste , Angiografia por Ressonância Magnética/métodos , Meios de Contraste/administração & dosagem , Meios de Contraste/efeitos adversos , Gadolínio , Gadolínio DTPA/efeitos adversos , Humanos , Injeções Intravenosas , Angiografia por Ressonância Magnética/efeitos adversos , Compostos Organometálicos/efeitos adversosRESUMO
The purpose of this study was to measure organ doses and the effective dose (ED) using a three-dimensional rotational X-ray (3D-RX) system and to determine the ED conversion factor from the dose area product (DAP) for skull, spine and biliary protocols. A commercial 3D-RX imaging system was used to simulate the protocols with the adult female anthropomorphic phantom. Twenty MOSFET detectors were used to measure the absorbed doses at various organ locations. The ED was calculated for each protocol and the corresponding DAP was obtained. The skin dose was the highest for all the protocols. The second highest organ doses were those of the brain for the skull, the intestine for the spine and the kidney for the biliary protocol. The ED was 0.4-0.9, 4.2-8.4 and 3.2-4.6 mSv, and the ED conversion factor was 0.06-0.09, 0.18-0.31 and 0.13-0.23 mSv Gy(-1) cm(-2) for each protocol, respectively. This data may be used to estimate the patient ED for those protocols in the 3D-RX.
Assuntos
Imageamento Tridimensional , Doses de Radiação , Proteção Radiológica/métodos , Tomografia Computadorizada por Raios X , Vísceras , Contagem Corporal Total/métodos , Adulto , Algoritmos , Simulação por Computador , Feminino , Humanos , Modelos Biológicos , Imagens de Fantasmas , Eficiência Biológica Relativa , RotaçãoRESUMO
OBJECT: Inadvertent catheterization of brachiocephalic arteries (carotid artery, subclavian artery, or vertebral artery) during attempted placement of a central venous catheter can have potentially disastrous complications. While removal of the catheter in the operating room is almost always an option, there are circumstances in which a less invasive approach may be more appropriate. The authors present their experience using endovascular techniques for removal of inadvertently placed central venous catheters to elucidate potential options for successful nonsurgical management. METHODS: The authors reviewed their database of interventional procedures that occurred between January 1, 2000, and February 1, 2009. All cases referred for management of suspected brachiocephalic arterial catheterization or arterial injury after attempted placement of a central venous catheter were included. Medical records and radiological imaging were reviewed to determine patient demographics, clinical situation, methods for removal, as well as clinical and imaging follow-up. RESULTS: A total of 13 patients, ranging in age from 31 to 88 years old, were referred to interventional radiology for management of suspected inadvertent arterial catheterization of the brachiocephalic arteries. Angiography confirmed arterial catheterization in 9 patients. Three patients were referred after developing uncontrolled hemorrhage or expanding hematomas following attempted catheterization. One patient who had an arterial waveform after placement of an internal jugular catheter was found to have early venous filling from a dialysis fistula requiring no intervention. Ten patients were treated in the interventional suite using angiographically monitored manual pressure (1 patient), balloon tamponade (3 patients), use of a percutaneous closure device (1 patient), stent grafting (4 patients), or embolization of the injured vessel alone (1 patient). One patient was taken to the operating room for removal of the inadvertently placed catheter due to vessel thrombosis. No procedural complications were encountered, and no patient required sacrifice of a major brachiocephalic vessel. CONCLUSIONS: Angiographic evaluation of patients who underwent inadvertent catheterization of brachiocephalic arteries or their branches allowed successful endovascular treatment or excluded the need for intervention in 12 (92%) of 13 patients. The choice and use of specific endovascular techniques should be dictated by patient factors and the vessel inadvertently catheterized.
Assuntos
Lesões das Artérias Carótidas , Cateterismo Venoso Central/efeitos adversos , Procedimentos Endovasculares/métodos , Erros Médicos , Artéria Subclávia/lesões , Adulto , Idoso , Idoso de 80 Anos ou mais , Angiografia , Oclusão com Balão , Embolização Terapêutica , Feminino , Seguimentos , Hemorragia/etiologia , Hemorragia/prevenção & controle , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , StentsRESUMO
BACKGROUND: Folate metabolism pathway genes have been examined for association with neural tube defects (NTDs) because folic acid supplementation reduces the risk of this debilitating birth defect. Most studies addressed these genes individually, often with different populations providing conflicting results. OBJECTIVES: Our study evaluates several folate pathway genes for association with human NTDs, incorporating an environmental cofactor: maternal folate supplementation. METHODS: In 304 Caucasian American NTD families with myelomeningocele or anencephaly, we examined 28 polymorphisms in 11 genes: folate receptor 1, folate receptor 2, solute carrier family 19 member 1, transcobalamin II, methylenetetrahydrofolate dehydrogenase 1, serine hydroxymethyl-transferase 1, 5,10-methylenetetrahydrofolate reductase (MTHFR), 5-methyltetrahydrofolate-homo-cysteine methyltransferase, 5-methyltetrahydrofolate-homocysteine methyltransferase reductase, betaine-homocysteine methyltransferase (BHMT), and cystathionine-beta-synthase. RESULTS: Only single nucleotide polymorphisms (SNPs) in BHMT were significantly associated in the overall data set; this significance was strongest when mothers took folate-containing nutritional supplements before conception. The BHMT SNP rs3733890 was more significant when the data were stratified by preferential transmission of the MTHFR rs1801133 thermolabile T allele from parent to offspring. Other SNPs in folate pathway genes were marginally significant in some analyses when stratified by maternal supplementation, MTHFR, or BHMT allele transmission. CONCLUSIONS: BHMT rs3733890 is significantly associated in our data set, whereas MTHFR rs1801133 is not a major risk factor. Further investigation of folate and methionine cycle genes will require extensive SNP genotyping and/or resequencing to identify novel variants, inclusion of environmental factors, and investigation of gene-gene interactions in large data sets.
Assuntos
Ácido Fólico/metabolismo , Defeitos do Tubo Neural/genética , Alelos , Suplementos Nutricionais , Ácido Fólico/administração & dosagem , Humanos , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Computed tomography angiography (CTA) is a rapidly developing technology with great potential. This is particularly true for evaluating neurovascular disease. Clinical stroke because of atherosclerotic disease of the carotid and vertebral arteries is a common examination indication; areas of stenosis, and soft and calcified plaque along the entire vessel, not only at the carotid bifurcation, permit a full assessment of the patient's disease process. Other diseases including dissection, trauma, intracranial stenosis, thrombosis, and aneurysms can be readily diagnosed. Although duplex ultrasound may be a first line examination in many patients, both magnetic resonance angiography (MRA) and CTA offer distinct advantages over it. CTA and MRA are both highly accurate but CTA has several key advantages. CTA has been advanced by the development of improved multidetector CT (MDCT) and workstations that postprocess the data. Methods to obtain quality CTA images and to rapidly analyze the data for abnormalities are the subject of this chapter. In addition, evolving techniques in future CT scanners and workstations, and developing methods of vulnerable plaque and CT perfusion imaging are discussed.
Assuntos
Isquemia Encefálica/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Transtornos Cerebrovasculares/diagnóstico por imagem , Estenose Coronária/diagnóstico por imagem , Displasia Fibromuscular/diagnóstico por imagem , Pescoço/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodosRESUMO
PURPOSE: Neural tube defects (NTDs) are a group of widely varying congenital malformations resulting from incomplete or improper fusion of the neural tube during embryonic development. NTDs are traditionally classified by the presence or absence of a layer of skin covering the spinal defect. Although a genetic component has been well established in the etiology of open NTDs, studies examining the genetics of closed NTDs such as lipomyelomeningocele are rare. We and others have previously observed families in which multiple members were affected with a broad spectrum of NTDs, suggesting the possibility of a common genetic etiology. METHODS: We calculated the sibling recurrence risk in 52 pedigrees in which the proband was diagnosed with lipomyelomeningocele (LMM), defining recurrence broadly to include both closed and open neural tube defects. RESULTS: Although no recurrences of LMM were observed among younger siblings, one younger sibling had myelomeningocele, yielding an estimate of recurrence risk of 0.04 (95% CI 0.01-0.20). When all siblings of the proband were included, two additional affected siblings were identified, one with anencephaly and another with fatty filum, yielding an estimate of recurrence risk of 0.043 (95% CI 0.01-0.12). CONCLUSIONS: Although the sample size is small, these data are not inconsistent with recurrence risks for myelomeningocele, ranging from 2% to 5% in siblings. These data suggest the underlying genetic basis for closed defects may be the same or closely related to that for myelomeningocele in some families, although a larger sample will be necessary before these data are appropriate for use in a clinical setting. Further characterizations, including whether risk for recurrence of NTDs or LMM in families in which the proband is affected with LMM are altered by folate supplementation, may shed light on the underlying genetics.
Assuntos
Predisposição Genética para Doença/genética , Meningomielocele/genética , Linhagem , Irmãos , Estudos de Casos e Controles , Feminino , Testes Genéticos , Humanos , Masculino , Defeitos do Tubo Neural/genética , Fatores de RiscoRESUMO
BACKGROUND: Neural tube defects (NTDs) are the second most common birth defects, after congenital heart defects. Telomerase, the reverse transcriptase that maintains telomere DNA, has been shown to be important for neural tube development and bilateral symmetry in the brain. In knockout mice null for the telomerase RNA component (TERC), telomere loss results in the failure of neural tube closure, primarily at the forebrain and midbrain. METHODS: We investigated TERC for variants that may predispose to human NTDs in 477 NTD cases with a variety of phenotypic presentations. RESULTS: Two novel single nucleotide polymorphisms were identified in the human TERC sequence but showed no association with the NTD phenotype. CONCLUSIONS: Variants in TERC are unlikely to be a major risk factor for the most common form of human NTDs, lumbosacral myelomeningocele.
Assuntos
Defeitos do Tubo Neural/enzimologia , RNA/genética , Telomerase/genética , Animais , Primers do DNA , Feminino , Amplificação de Genes , Variação Genética , Cardiopatias Congênitas , Humanos , Camundongos , Camundongos Knockout , Defeitos do Tubo Neural/epidemiologia , Reação em Cadeia da Polimerase , Polimorfismo de Nucleotídeo Único/genética , Gravidez , Telomerase/deficiênciaRESUMO
OBJECTIVE: To determine whether there are magnetic resonance imaging (MRI) characteristics of fatty fila that are correlated with neurological deficits, especially in the presence of a normal-level conus medullaris. METHODS: Lumbosacral MRI scans were reviewed for patients with fatty fila who were treated at Duke University Medical Center during a 5-year period. The patients were divided into three groups. Group I patients (n = 5) had fatty fila that were incidentally detected during evaluations for metastases or infections. Group II patients (n = 16) exhibited isolated low back pain but were in neurologically intact condition. Group III patients (n = 15) exhibited neurological impairments consistent with distal spinal cord dysfunction. Several characteristics were measured on the MRI scans, including the location of the conus medullaris, the filum thickness, and the distance of fat from the conus. These results were assessed for statistically significant correlation with the presence of clinical symptoms. RESULTS: The majority of patients in all three groups demonstrated the normal conus position (L2 or above) and thickened fila. The distance of fat from the conus was the only parameter that demonstrated a statistically significant difference among the groups. CONCLUSION: The following findings were noted: 1) patients were likely to exhibit neurological deficits at a younger age (<22 yr in Group III versus 47 yr in Groups I and II); 2) a conus level below L2 was associated with neurological deficits (Group III); 3) filum thickness was not correlated with clinical presentation; 4) fat in the filum within 13 mm of the conus medullaris was most predictive of neurological deficits (Group III).
Assuntos
Tecido Adiposo/patologia , Cauda Equina/patologia , Imageamento por Ressonância Magnética , Doenças do Sistema Nervoso/etiologia , Medula Espinal/patologia , Adulto , Idoso , Cauda Equina/anormalidades , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso/patologia , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Estudos RetrospectivosRESUMO
Neural tube defects (NTD) are a common birth defect, with both genetic and environmental contributions to their etiology. In mouse, null mutations in Noggin result in fully-penetrant NTDs. We investigated Noggin for mutations that may predispose to human NTDs in 202 NTD cases. One variant allele was identified in a male patient with myelomeningocele. The patient's father and a sibling also carried the variant allele, but neither was affected with an open NTD. DNA sequencing confirmed a C1064A missense mutation predicted to result in the conversion of residue 84 from proline to histidine. The variant found in the NTD patient is a newly identified variant, the role of which is uncertain.
Assuntos
Proteínas Morfogenéticas Ósseas/genética , Predisposição Genética para Doença , Mutação , Defeitos do Tubo Neural/genética , Proteínas de Transporte , Cromatografia Líquida de Alta Pressão , Feminino , Humanos , Masculino , Meningomielocele/genéticaRESUMO
We investigated the T locus as a candidate gene in a series of patients and families with lumbosacral myelomeningocele. Single-strand conformation polymorphism (SSCP) analysis was used to identify sequence variation in all 8 exons and in intron 7 of this locus. We found evidence of substantial polymorphism within this locus, as previously reported [Papapetrou et al., 1999, J Med Genet 36:208-213], and moderately significant evidence of linkage disequilibrium with the CacI polymorphism of exon 8. However, when the locus was considered as a whole, with all single nucleotide polymorphisms (SNPs) integrated into a haplotype, there was no evidence for linkage disequilibrium. In addition, we did not identify any new sequence variants. Thus, we conclude that the T locus is not a major locus for human NTDs in this sample.