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1.
N Engl J Med ; 385(22): 2059-2065, 2021 11 25.
Artículo en Inglés | MEDLINE | ID: mdl-34818480

RESUMEN

The integration of genomic testing into clinical care enables the use of individualized approaches to the management of rare diseases. We describe the use of belzutifan, a potent and selective small-molecule inhibitor of the protein hypoxia-inducible factor 2α (HIF2α), in a patient with polycythemia and multiple paragangliomas (the Pacak-Zhuang syndrome). The syndrome was caused in this patient by somatic mosaicism for an activating mutation in EPAS1. Treatment with belzutifan led to a rapid and sustained tumor response along with resolution of hypertension, headaches, and long-standing polycythemia. This case shows the application of a targeted therapy for the treatment of a patient with a rare tumor-predisposition syndrome. (Funded by the Morin Family Fund for Pediatric Cancer and Alex's Lemonade Stand Foundation.).


Asunto(s)
Neoplasias de las Glándulas Suprarrenales/tratamiento farmacológico , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/antagonistas & inhibidores , Indenos/uso terapéutico , Paraganglioma/tratamiento farmacológico , Policitemia/tratamiento farmacológico , Adolescente , Neoplasias de las Glándulas Suprarrenales/genética , Glándulas Suprarrenales/diagnóstico por imagen , Glándulas Suprarrenales/efectos de los fármacos , Glándulas Suprarrenales/patología , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Biomarcadores/sangre , Cromograninas/sangre , Femenino , Mutación con Ganancia de Función , Humanos , Indenos/efectos adversos , Imagen por Resonancia Magnética , Normetanefrina/sangre , Paraganglioma/genética , Policitemia/genética , Transducción de Señal , Síndrome , Secuenciación Completa del Genoma
2.
N Engl J Med ; 384(3): 205-215, 2021 01 21.
Artículo en Inglés | MEDLINE | ID: mdl-33283990

RESUMEN

BACKGROUND: Sickle cell disease is characterized by hemolytic anemia, pain, and progressive organ damage. A high level of erythrocyte fetal hemoglobin (HbF) comprising α- and γ-globins may ameliorate these manifestations by mitigating sickle hemoglobin polymerization and erythrocyte sickling. BCL11A is a repressor of γ-globin expression and HbF production in adult erythrocytes. Its down-regulation is a promising therapeutic strategy for induction of HbF. METHODS: We enrolled patients with sickle cell disease in a single-center, open-label pilot study. The investigational therapy involved infusion of autologous CD34+ cells transduced with the BCH-BB694 lentiviral vector, which encodes a short hairpin RNA (shRNA) targeting BCL11A mRNA embedded in a microRNA (shmiR), allowing erythroid lineage-specific knockdown. Patients were assessed for primary end points of engraftment and safety and for hematologic and clinical responses to treatment. RESULTS: As of October 2020, six patients had been followed for at least 6 months after receiving BCH-BB694 gene therapy; median follow-up was 18 months (range, 7 to 29). All patients had engraftment, and adverse events were consistent with effects of the preparative chemotherapy. All the patients who could be fully evaluated achieved robust and stable HbF induction (percentage HbF/(F+S) at most recent follow-up, 20.4 to 41.3%), with HbF broadly distributed in red cells (F-cells 58.9 to 93.6% of untransfused red cells) and HbF per F-cell of 9.0 to 18.6 pg per cell. Clinical manifestations of sickle cell disease were reduced or absent during the follow-up period. CONCLUSIONS: This study validates BCL11A inhibition as an effective target for HbF induction and provides preliminary evidence that shmiR-based gene knockdown offers a favorable risk-benefit profile in sickle cell disease. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT03282656).


Asunto(s)
Anemia de Células Falciformes/terapia , Hemoglobina Fetal/biosíntesis , Terapia Genética , Interferencia de ARN , Proteínas Represoras/genética , gamma-Globinas/metabolismo , Adolescente , Adulto , Anemia de Células Falciformes/genética , Niño , Regulación hacia Abajo , Femenino , Hemoglobina Fetal/genética , Técnicas de Silenciamiento del Gen , Vectores Genéticos , Humanos , Masculino , Proyectos Piloto , ARN Interferente Pequeño , Proteínas Represoras/metabolismo , Trasplante Autólogo , Adulto Joven , gamma-Globinas/genética
3.
Blood ; 140(13): 1470-1481, 2022 09 29.
Artículo en Inglés | MEDLINE | ID: mdl-35849650

RESUMEN

The phase 3 HESTIA3 study assessed the efficacy and safety of the reversible P2Y12 inhibitor ticagrelor vs placebo in preventing vaso-occlusive crises in pediatric patients with sickle cell disease (SCD). Patients aged 2 to 17 years were randomly assigned 1:1 to receive weight-based doses of ticagrelor or matching placebo. The primary end point was the rate of vaso-occlusive crises, a composite of painful crises and/or acute chest syndrome (ACS). Key secondary end points included number and duration of painful crises, number of ACS events, and number of vaso-occlusive crises requiring hospitalization or emergency department visits. Exploratory end points included the effect of ticagrelor on platelet activation. In total, 193 patients (ticagrelor, n = 101; placebo, n = 92) underwent randomization at 53 sites across 16 countries. The study was terminated 4 months before planned completion for lack of efficacy. Median ticagrelor exposure duration was 296.5 days. The primary end point was not met: estimated yearly incidence of vaso-occlusive crises was 2.74 in the ticagrelor group and 2.60 in the placebo group (rate ratio, 1.06; 95% confidence interval, 0.75-1.50; P = .7597). There was no evidence of efficacy for ticagrelor vs placebo across secondary end points. Median platelet inhibition with ticagrelor at 6 months was 34.9% predose and 55.7% at 2 hours' postdose. Nine patients (9%) in the ticagrelor group and eight patients (9%) in the placebo group had at least one bleeding event. In conclusion, no reduction of vaso-occlusive crises was seen with ticagrelor vs placebo in these pediatric patients with SCD. This trial was registered at www.clinicaltrials.gov as #NCT03615924.


Asunto(s)
Síndrome Torácico Agudo , Anemia de Células Falciformes , Síndrome Torácico Agudo/tratamiento farmacológico , Síndrome Torácico Agudo/etiología , Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/tratamiento farmacológico , Niño , Hemorragia/tratamiento farmacológico , Humanos , Dolor/tratamiento farmacológico , Inhibidores de Agregación Plaquetaria/efectos adversos , Ticagrelor/uso terapéutico
4.
Pediatr Blood Cancer ; 71(8): e31088, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38809385

RESUMEN

INTRODUCTION: Individuals with sickle cell disease (SCD) at increased risk for stroke should undergo annual stroke risk assessment using transcranial Doppler (TCD) screening between the ages of 2 and 16. Though this screening can significantly reduce morbidity associated with SCD, screening rates at Boston Children's Hospital (and nationwide) remain below the recommended 100% screening adherence rates. METHODS: Three plan-do-study-act (PDSA) cycles were designed and implemented. The Specific, Measurable, Achievable, Relevant, and Time-Bound (SMART) aim of our quality improvement (QI) initiative was to sustainably increase the proportion of eligible patients receiving a TCD within 15 months of their last TCD to greater than 95%. An interrupted time series (ITS) analysis was performed, comparing TCD adherence rates from PDSA Cycle 1 to those from PDSA Cycles 2 and 3. RESULTS: Mean TCD adherence increased across all three PDSA cycles, from a baseline of 67% in the first cycle (January 2015 to September 2020) to 92% in the third cycle (May 2021 to March 2023). In the ITS analysis of TCD adherence rates, there was a significant difference in the final TCD adherence rate achieved compared to the rate predicted, with a total estimated increase in adherence of 17.9% being attributable to the interventions from PDSA Cycles 2 and 3. DISCUSSION: Although other QI initiatives had demonstrated ability to increase adherence to TCD screening for patients with SCD, this is the first QI project to collect data over such a prolonged period of time to demonstrate a sustained increase in screening rates throughout the intervention (an 8-year period).


Asunto(s)
Anemia de Células Falciformes , Mejoramiento de la Calidad , Ultrasonografía Doppler Transcraneal , Humanos , Anemia de Células Falciformes/diagnóstico por imagen , Anemia de Células Falciformes/complicaciones , Ultrasonografía Doppler Transcraneal/métodos , Niño , Femenino , Masculino , Adolescente , Preescolar , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/prevención & control , Accidente Cerebrovascular/diagnóstico por imagen , Tamizaje Masivo/métodos , Tamizaje Masivo/normas , Estudios de Seguimiento , Pronóstico
5.
J Pediatr Hematol Oncol ; 46(5): e290-e295, 2024 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-38691085

RESUMEN

Ketorolac, a nonsteroidal anti-inflammatory drug, is used in combination with opioids to manage vaso-occlusive episodes (VOEs). The relationship between ketorolac use and kidney injury in pediatric patients with sickle cell disease (SCD) remains incompletely understood. We hypothesize that ketorolac is associated with acute kidney injury (AKI) in patients with SCD presenting with pain. All nonsurgical hospitalizations for VOEs treated with ketorolac between January 2014 and December 2022 were included. We used optimal matching methodology to identify control admissions (2:1 ratio) and used nonparametric tests to compare ketorolac administration between cases and controls. A total of 1319 encounters/253 patients were included in this study. AKI was noted in 1.1% of encounters and 5.5% of patients. Cases had significantly higher initial BUN than controls (9.0 vs. 6.0 mg/dL, P =0.012). In cases versus controls, there was significantly lower serum sodium (136.0 vs. 138.0 mmol/L, P =0.021). There was no association between ketorolac dose and development of AKI among children with SCD. Higher BUN and lower sodium in cases suggest that patients with AKI were more volume depleted on admission than controls. This highlights the need for strict assessment of fluid status upon admission for VOE.


Asunto(s)
Lesión Renal Aguda , Dolor Agudo , Anemia de Células Falciformes , Antiinflamatorios no Esteroideos , Ketorolaco , Humanos , Ketorolaco/efectos adversos , Ketorolaco/uso terapéutico , Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/tratamiento farmacológico , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/etiología , Masculino , Femenino , Niño , Antiinflamatorios no Esteroideos/efectos adversos , Adolescente , Dolor Agudo/tratamiento farmacológico , Dolor Agudo/etiología , Preescolar , Estudios de Casos y Controles , Estudios Retrospectivos , Factores de Riesgo
6.
Pediatr Blood Cancer ; 70(5): e30254, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-36861789

RESUMEN

BACKGROUND: Typical sickle cell disease (SCD) vaso-occlusive pain episode (VOE) management includes opioids, which are often inadequate and can be associated with significant side effects. Ketamine, a dissociative anesthetic, is a potentially effective adjunct to VOE management. OBJECTIVES: This study aimed to characterize ketamine use for VOE management in pediatric SCD. METHOD: This retrospective case series summarizes a single-center experience regarding the use of ketamine for inpatient management of pediatric VOE in 156 admissions from 2014 to 2020. RESULTS: Continuous low-dose ketamine infusion was most commonly prescribed to adolescents and young adults as an adjunct to opioids (median starting dose 2.0 µg/kg/min; median maximum dose 3.0 µg/kg/min). Ketamine was started a median of 13.7 hours after admission. Median ketamine infusion duration was 3 days. In most encounters, ketamine infusion was discontinued prior to opioid patient-controlled analgesia (PCA) discontinuation. The majority of encounters (79.3%) had a reduction in either PCA dose, continuous opioid infusion, or both while receiving ketamine. Low-dose ketamine infusion was associated with side effects noted in 21.8% (n = 34) of encounters. The most common side effects included dizziness (5.6%), hallucinations (5.1%), dissociation (2.6%), and sedation (1.9%). There were no reports of ketamine withdrawal. Most patients who received ketamine went on to receive it again during a subsequent admission. CONCLUSION: Further study is needed to determine the optimal timing of ketamine initiation and dosing. The variability of ketamine administration highlights the need for standardized protocols for ketamine use in VOE management.


Asunto(s)
Anemia de Células Falciformes , Ketamina , Adolescente , Adulto Joven , Humanos , Niño , Ketamina/efectos adversos , Analgésicos Opioides/efectos adversos , Estudios Retrospectivos , Dolor/tratamiento farmacológico , Dolor/etiología , Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/tratamiento farmacológico
7.
Pediatr Blood Cancer ; 70(1): e29961, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36094289

RESUMEN

Sickle cell disease (SCD) requires coordinated, specialized medical care for optimal outcomes. There are no United States (US) guidelines that define a pediatric comprehensive SCD program. We report a modified Delphi consensus-seeking process to determine essential, optimal, and suggested elements of a comprehensive pediatric SCD center. Nineteen pediatric SCD specialists participated from the US. Consensus was predefined as 2/3 agreement on each element's categorization. Twenty-six elements were considered essential (required for guideline-based SCD care), 10 were optimal (recommended but not required), and five were suggested. This work lays the foundation for a formal recognition process of pediatric comprehensive SCD centers.


Asunto(s)
Anemia de Células Falciformes , Niño , Humanos , Consenso , Anemia de Células Falciformes/terapia
8.
Hum Mutat ; 42(11): 1367-1383, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34298585

RESUMEN

The congenital sideroblastic anemias (CSAs) are a heterogeneous group of inherited disorders of erythropoiesis characterized by pathologic deposits of iron in the mitochondria of developing erythroblasts. Mutations in the mitochondrial glycine carrier SLC25A38 cause the most common recessive form of CSA. Nonetheless, the disease is still rare, there being fewer than 70 reported families. Here we describe the clinical phenotype and genotypes of 31 individuals from 24 families, including 11 novel mutations. We also review the spectrum of reported mutations and genotypes associated with the disease, describe the unique localization of missense mutations in transmembrane domains and account for the presence of several alleles in different populations.


Asunto(s)
Anemia Sideroblástica/congénito , Genotipo , Proteínas de Transporte de Membrana Mitocondrial/genética , Mutación , Fenotipo , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Masculino
9.
Pediatr Blood Cancer ; 68(7): e28989, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-33788404

RESUMEN

Vaso-occlusive episodes (VOEs) are a common complication of sickle cell disease (SCD) and a significant cause of morbidity. Managing VOE pain can be difficult and complex. Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has been used to manage VOE pain. This systematic literature review synthesizes research published from 2010 to 2020 on the use of ketamine infusion to decrease VOE pain. The review demonstrates that ketamine, a safe and effective treatment for VOE pain, could be considered more widely. However, the significant variability among published clinical studies with regard to dosing, timing of initiation, duration of infusion, and timing of discontinuation highlights the need for standardized ketamine infusion protocols for the management of VOE pain. We conclude with a brief discussion of key components of a potential standardized protocol supported by the literature reviewed as well as areas for future investigation.


Asunto(s)
Anemia de Células Falciformes , Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/tratamiento farmacológico , Humanos , Ketamina , Dolor/tratamiento farmacológico , Dolor/etiología , Manejo del Dolor , Dimensión del Dolor
10.
J Inherit Metab Dis ; 43(4): 880-890, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32064623

RESUMEN

Congenital disorders of glycosylation (CDGs) are clinically heterogeneous disorders defined by a decreased ability to modify biomolecules with oligosaccharides. Critical disruptions in protein recognition, interaction, binding, and anchoring lead to broad physiological effects. Patients present with endocrinopathy, immunodeficiency, hepatopathy, coagulopathy, and neurodevelopmental impairment. Patients may experience mortality/morbidity associated with shock physiology that is frequently culture negative and poorly responsive to standard care. Oedema, pleural and pericardial effusions, ascites, proteinuria, and protein-losing enteropathy are observed with an exaggerated inflammatory response. The negative serum protein steady state results from several mechanisms including reduced hepatic synthesis and secretion, increased consumption, and extravasation. Disruption of the glycocalyx, a layer of glycosylated proteins that lines the endothelium preventing thrombosis and extravasation, is a suspected cause of endothelial dysfunction in CDG patients. We performed a retrospective review of CDG patients admitted to our institution with acute illness over the past 2 years. Longitudinal clinical and laboratory data collected during the sick and well states were assessed for biomarkers of inflammation and efficacy of interventions. Six patients representing 4 CDG subtypes and 14 hospitalisations were identified. Acute D-dimer elevation, proteinuria, decreased serum total protein levels, coagulation proteins, and albumin were observed with acute illness. Infusion of fresh frozen plasma, and in some cases protein C concentrate, was associated with clinical and biomarker improvement. This was notable with intra-patient comparison of treated vs untreated courses. Use of endothelial barrier support therapy may reduce endothelial permeability by restoring both regulatory serum protein homeostasis and supporting the glycocalyx and is likely a critical component of care for this population.


Asunto(s)
Trastornos Congénitos de Glicosilación/metabolismo , Trastornos Congénitos de Glicosilación/terapia , Células Endoteliales/metabolismo , Glicocálix/metabolismo , Trombosis/prevención & control , Biomarcadores/metabolismo , Permeabilidad Capilar/fisiología , Niño , Preescolar , Endotelio Vascular/metabolismo , Femenino , Productos de Degradación de Fibrina-Fibrinógeno/metabolismo , Humanos , Lactante , Masculino , Plasma , Estudios Retrospectivos
11.
N Engl J Med ; 374(7): 625-35, 2016 Feb 18.
Artículo en Inglés | MEDLINE | ID: mdl-26644172

RESUMEN

BACKGROUND: Sickle cell anemia is an inherited blood disorder that is characterized by painful vaso-occlusive crises, for which there are few treatment options. Platelets mediate intercellular adhesion and thrombosis during vaso-occlusion in sickle cell anemia, which suggests a role for antiplatelet agents in modifying disease events. METHODS: Children and adolescents 2 through 17 years of age with sickle cell anemia were randomly assigned to receive oral prasugrel or placebo for 9 to 24 months. The primary end point was the rate of vaso-occlusive crisis, a composite of painful crisis or acute chest syndrome. The secondary end points were the rate of sickle cell-related pain and the intensity of pain, which were assessed daily with the use of pain diaries. RESULTS: A total of 341 patients underwent randomization at 51 sites in 13 countries across the Americas, Europe, Asia, and Africa. The rate of vaso-occlusive crisis events per person-year was 2.30 in the prasugrel group and 2.77 in the placebo group (rate ratio, 0.83; 95% confidence interval, 0.66 to 1.05; P=0.12). There were no significant differences between the groups in the secondary end points of diary-reported events. The safety end points, including the frequency of bleeding events requiring medical intervention, of hemorrhagic and nonhemorrhagic adverse events that occurred while patients were taking prasugrel or placebo, and of discontinuations due to prasugrel or placebo, did not differ significantly between the groups. CONCLUSIONS: Among children and adolescents with sickle cell anemia, the rate of vaso-occlusive crisis was not significantly lower among those who received prasugrel than among those who received placebo. There were no significant between-group differences in the safety findings. (Funded by Daiichi Sankyo and Eli Lilly; ClinicalTrials.gov number, NCT01794000.).


Asunto(s)
Síndrome Torácico Agudo/prevención & control , Anemia de Células Falciformes/tratamiento farmacológico , Dolor/prevención & control , Inhibidores de Agregación Plaquetaria/uso terapéutico , Clorhidrato de Prasugrel/uso terapéutico , Síndrome Torácico Agudo/etiología , Administración Oral , Adolescente , Anemia de Células Falciformes/complicaciones , Niño , Preescolar , Método Doble Ciego , Femenino , Hemorragia/inducido químicamente , Humanos , Masculino , Dolor/etiología , Enfermedades Vasculares Periféricas/etiología , Enfermedades Vasculares Periféricas/prevención & control , Inhibidores de Agregación Plaquetaria/efectos adversos , Clorhidrato de Prasugrel/efectos adversos
12.
Pediatr Hematol Oncol ; 36(6): 382-389, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31347415

RESUMEN

This study compared outcomes following total (TS) or partial splenectomy (PS) among patients with hereditary spherocytosis. Seventy-nine patients (TS = 33, PS = 46) were identified. The follow-up period was longer after PS (59.6 vs. 24.9 months, p < .001). Long-term adverse events occurred more frequently following PS (50% vs. 29%, p = .001). Anemia, jaundice, and fatigue recurred in six patients with PS, leading to five completion splenectomies. Hemoglobin was not different between PS and TS by 5 years post-procedure (12.3 vs. 13.4 g/dL, p = .25). Both PS and TS ameliorate symptoms and improve hematologic parameters. The rate of secondary surgery following PS should be considered when planning the initial surgical procedure.


Asunto(s)
Laboratorios/normas , Esferocitosis Hereditaria/cirugía , Esplenectomía/métodos , Niño , Femenino , Humanos , Masculino , Estudios Retrospectivos , Esferocitosis Hereditaria/patología , Resultado del Tratamiento
13.
Hum Mutat ; 39(3): 389-393, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-29288557

RESUMEN

Pyruvate kinase deficiency (PKD) is the most frequent red blood cell enzyme abnormality of the glycolytic pathway and the most common cause of hereditary nonspherocytic hemolytic anemia. Over 250 PKLR-gene mutations have been described, including missense/nonsense, splicing and regulatory mutations, small insertions, small and gross deletions, causing PKD and hemolytic anemia of variable severity. Alu retrotransposons are the most abundant mobile DNA sequences in the human genome, contributing to almost 11% of its mass. Alu insertions have been associated with a number of human diseases either by disrupting a coding region or a splice signal. Here, we report on two unrelated Middle Eastern patients, both born from consanguineous parents, with transfusion-dependent hemolytic anemia, where sequence analysis revealed a homozygous insertion of AluYb9 within exon 6 of the PKLR gene, causing precipitous decrease of PKLR RNA levels. This Alu element insertion consists a previously unrecognized mechanism underlying pathogenesis of PKD.


Asunto(s)
Elementos Alu/genética , Anemia Hemolítica Congénita no Esferocítica/genética , Mutagénesis Insercional , Piruvato Quinasa/deficiencia , Errores Innatos del Metabolismo del Piruvato/genética , Ancirinas/genética , Secuencia de Bases , Exones/genética , Femenino , Humanos , Lactante , Masculino , Medio Oriente , Piruvato Quinasa/genética
14.
Blood ; 128(15): 1913-1917, 2016 10 13.
Artículo en Inglés | MEDLINE | ID: mdl-27488349

RESUMEN

The congenital sideroblastic anemias (CSAs) are a heterogeneous group of inherited blood disorders characterized by pathological mitochondrial iron deposition in erythroid precursors. Each known cause has been attributed to a mutation in a protein associated with heme biosynthesis, iron-sulfur cluster biogenesis, mitochondrial translation, or a component of the mitochondrial respiratory chain. Here, we describe a recurring mutation, c.276_278del, p.F93del, in NDUFB11, a mitochondrial respiratory complex I-associated protein encoded on the X chromosome, in 5 males with a variably syndromic, normocytic CSA. The p.F93del mutation results in respiratory insufficiency and loss of complex I stability and activity in patient-derived fibroblasts. Targeted introduction of this allele into K562 erythroleukemia cells results in a proliferation defect with minimal effect on erythroid differentiation potential, suggesting the mechanism of anemia in this disorder.


Asunto(s)
Anemia Sideroblástica/genética , Secuencia de Bases , Cromosomas Humanos X/genética , Complejo I de Transporte de Electrón/genética , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Eliminación de Secuencia , Adolescente , Adulto , Anciano , Anemia Sideroblástica/metabolismo , Anemia Sideroblástica/patología , Niño , Preescolar , Cromosomas Humanos X/metabolismo , Complejo I de Transporte de Electrón/metabolismo , Femenino , Enfermedades Genéticas Ligadas al Cromosoma X/metabolismo , Humanos , Células K562 , Masculino , Persona de Mediana Edad
15.
Haematologica ; 103(12): 2008-2015, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30026338

RESUMEN

YARS2 variants have previously been described in patients with myopathy, lactic acidosis and sideroblastic anemia 2 (MLASA2). YARS2 encodes the mitochondrial tyrosyl-tRNA synthetase, which is responsible for conjugating tyrosine to its cognate mt-tRNA for mitochondrial protein synthesis. Here we describe 14 individuals from 11 families presenting with sideroblastic anemia and YARS2 variants that we identified using a sideroblastic anemia gene panel or exome sequencing. The phenotype of these patients ranged from MLASA to isolated congenital sideroblastic anemia. As in previous cases, inter- and intra-familial phenotypic variability was observed, however, this report includes the first cases with isolated sideroblastic anemia and patients with biallelic YARS2 variants that have no clinically ascertainable phenotype. We identified ten novel YARS2 variants and three previously reported variants. In vitro amino-acylation assays of five novel missense variants showed that three had less effect on the catalytic activity of YARS2 than the most commonly reported variant, p.(Phe52Leu), associated with MLASA2, which may explain the milder phenotypes in patients with these variants. However, the other two missense variants had a more severe effect on YARS2 catalytic efficiency. Several patients carried the common YARS2 c.572 G>T, p.(Gly191Val) variant (minor allele frequency =0.1259) in trans with a rare deleterious YARS2 variant. We have previously shown that the p.(Gly191Val) variant reduces YARS2 catalytic activity. Consequently, we suggest that biallelic YARS2 variants, including severe loss-of-function alleles in trans of the common p.(Gly191Val) variant, should be considered as a cause of isolated congenital sideroblastic anemia, as well as the MLASA syndromic phenotype.


Asunto(s)
Acidosis Láctica/genética , Anemia Sideroblástica/genética , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Mutación de Línea Germinal , Síndrome MELAS/genética , Proteínas Mitocondriales/genética , Tirosina-ARNt Ligasa/genética , Acidosis Láctica/enzimología , Adolescente , Anemia Sideroblástica/enzimología , Femenino , Estudios de Asociación Genética , Enfermedades Genéticas Ligadas al Cromosoma X/enzimología , Humanos , Lactante , Síndrome MELAS/enzimología , Masculino , Persona de Mediana Edad , Mutación Missense , Adulto Joven
16.
Am J Hematol ; 93(7): 943-952, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-29635754

RESUMEN

Red blood cell transfusions have become standard of care for the prevention of life-threatening anemia in patients with ß-thalassemia and sickle cell disease (SCD). However, frequent transfusions can lead to accumulation of iron that can result in liver cirrhosis, diabetes mellitus, arthritis, arrhythmias, cardiomyopathy, heart failure, and hypogonadotropic hypogonadism. Iron chelation therapy has been shown to reduce serum ferritin levels and liver iron content, but limitations of trial design have prevented any demonstration of improved survival. The objective of this systematic review was to investigate the impact of iron chelation therapy on overall and event-free survival in patients with ß-thalassemia and SCD. Eighteen articles discussing survival in ß-thalassemia and 3 in SCD were identified. Overall iron chelation therapy resulted in better overall survival, especially if it is instituted early and compliance is maintained. Comparative studies did not show any significant differences between available iron chelation agents, although there is evidence that deferiprone is better tolerated than deferoxamine and that compliance is more readily maintained with the newer oral drugs, deferiprone and deferasirox. Iron chelation therapy, particularly the second-generation oral agents, appears to be associated with improved overall and event-free survival in transfusion-dependent patients with ß-thalassemia and patients with SCD.


Asunto(s)
Anemia de Células Falciformes/tratamiento farmacológico , Quelantes del Hierro/uso terapéutico , Talasemia beta/tratamiento farmacológico , Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/mortalidad , Transfusión Sanguínea , Deferiprona/efectos adversos , Deferiprona/uso terapéutico , Deferoxamina/efectos adversos , Deferoxamina/uso terapéutico , Humanos , Quelantes del Hierro/efectos adversos , Cumplimiento de la Medicación , Análisis de Supervivencia , Talasemia beta/mortalidad
17.
Lancet ; 387(10019): 661-670, 2016 Feb 13.
Artículo en Inglés | MEDLINE | ID: mdl-26670617

RESUMEN

BACKGROUND: For children with sickle cell anaemia and high transcranial doppler (TCD) flow velocities, regular blood transfusions can effectively prevent primary stroke, but must be continued indefinitely. The efficacy of hydroxycarbamide (hydroxyurea) in this setting is unknown; we performed the TWiTCH trial to compare hydroxyurea with standard transfusions. METHODS: TWiTCH was a multicentre, phase 3, randomised, open-label, non-inferiority trial done at 26 paediatric hospitals and health centres in the USA and Canada. We enrolled children with sickle cell anaemia who were aged 4-16 years and had abnormal TCD flow velocities (≥ 200 cm/s) but no severe vasculopathy. After screening, eligible participants were randomly assigned 1:1 to continue standard transfusions (standard group) or hydroxycarbamide (alternative group). Randomisation was done at a central site, stratified by site with a block size of four, and an adaptive randomisation scheme was used to balance the covariates of baseline age and TCD velocity. The study was open-label, but TCD examinations were read centrally by observers masked to treatment assignment and previous TCD results. Participants assigned to standard treatment continued to receive monthly transfusions to maintain 30% sickle haemoglobin or lower, while those assigned to the alternative treatment started oral hydroxycarbamide at 20 mg/kg per day, which was escalated to each participant's maximum tolerated dose. The treatment period lasted 24 months from randomisation. The primary study endpoint was the 24 month TCD velocity calculated from a general linear mixed model, with the non-inferiority margin set at 15 cm/s. The primary analysis was done in the intention-to-treat population and safety was assessed in all patients who received at least one dose of assigned treatment. This study is registered with ClinicalTrials.gov, number NCT01425307. FINDINGS: Between Sept 20, 2011, and April 17, 2013, 159 patients consented and enrolled in TWiTCH. 121 participants passed screening and were then randomly assigned to treatment (61 to transfusions and 60 to hydroxycarbamide). At the first scheduled interim analysis, non-inferiority was shown and the sponsor terminated the study. Final model-based TCD velocities were 143 cm/s (95% CI 140-146) in children who received standard transfusions and 138 cm/s (135-142) in those who received hydroxycarbamide, with a difference of 4·54 (0·10-8·98). Non-inferiority (p=8·82 × 10(-16)) and post-hoc superiority (p=0·023) were met. Of 29 new neurological events adjudicated centrally by masked reviewers, no strokes were identified, but three transient ischaemic attacks occurred in each group. Magnetic resonance brain imaging and angiography (MRI and MRA) at exit showed no new cerebral infarcts in either treatment group, but worsened vasculopathy in one participant who received standard transfusions. 23 severe adverse events in nine (15%) patients were reported for hydroxycarbamide and ten serious adverse events in six (10%) patients were reported for standard transfusions. The most common serious adverse event in both groups was vaso-occlusive pain (11 events in five [8%] patients with hydroxycarbamide and three events in one [2%] patient for transfusions). INTERPRETATION: For high-risk children with sickle cell anaemia and abnormal TCD velocities who have received at least 1 year of transfusions, and have no MRA-defined severe vasculopathy, hydroxycarbamide treatment can substitute for chronic transfusions to maintain TCD velocities and help to prevent primary stroke. FUNDING: National Heart, Lung, and Blood Institute, National Institutes of Health.


Asunto(s)
Anemia de Células Falciformes/tratamiento farmacológico , Antidrepanocíticos/uso terapéutico , Transfusión Sanguínea/métodos , Hidroxiurea/uso terapéutico , Adolescente , Anemia de Células Falciformes/fisiopatología , Velocidad del Flujo Sanguíneo , Circulación Cerebrovascular/fisiología , Niño , Preescolar , Terapia Combinada , Sustitución de Medicamentos , Femenino , Humanos , Masculino , Accidente Cerebrovascular/etiología , Resultado del Tratamiento , Ultrasonografía Doppler Transcraneal
18.
Blood ; 126(25): 2734-8, 2015 Dec 17.
Artículo en Inglés | MEDLINE | ID: mdl-26491070

RESUMEN

The congenital sideroblastic anemias (CSAs) are relatively uncommon diseases characterized by defects in mitochondrial heme synthesis, iron-sulfur (Fe-S) cluster biogenesis, or protein synthesis. Here we demonstrate that mutations in HSPA9, a mitochondrial HSP70 homolog located in the chromosome 5q deletion syndrome 5q33 critical deletion interval and involved in mitochondrial Fe-S biogenesis, result in CSA inherited as an autosomal recessive trait. In a fraction of patients with just 1 severe loss-of-function allele, expression of the clinical phenotype is associated with a common coding single nucleotide polymorphism in trans that correlates with reduced messenger RNA expression and results in a pseudodominant pattern of inheritance.


Asunto(s)
Anemia Sideroblástica/genética , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Proteínas HSP70 de Choque Térmico/genética , Proteínas Mitocondriales/genética , Adulto , Anciano , Secuencia de Bases , Análisis Mutacional de ADN , Femenino , Genotipo , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Mutación , Análisis de Secuencia por Matrices de Oligonucleótidos , Linaje , Polimorfismo de Nucleótido Simple , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Adulto Joven
19.
Pediatr Blood Cancer ; 64(5)2017 05.
Artículo en Inglés | MEDLINE | ID: mdl-27808451

RESUMEN

Symptomatic ß-thalassemia is one of the globally most common inherited disorders. The initial clinical presentation is variable. Although common hematological analyses are typically sufficient to diagnose the disease, sometimes the diagnosis can be more challenging. We describe a series of patients with ß-thalassemia whose diagnosis was delayed, required bone marrow examination in one affected member of each family, and revealed ringed sideroblasts, highlighting the association of this morphological finding with these disorders. Thus, in the absence of characteristic congenital sideroblastic mutations or causes of acquired sideroblastic anemia, the presence of ringed sideroblasts should raise the suspicion of ß-thalassemia.


Asunto(s)
Anemia Sideroblástica/patología , Células de la Médula Ósea/patología , Eritroblastos/patología , Talasemia beta/patología , Adolescente , Adulto , Anemia Sideroblástica/diagnóstico , Células de la Médula Ósea/citología , Examen de la Médula Ósea , Niño , Eritroblastos/citología , Eritrocitos Anormales , Femenino , Enfermedades Hematológicas/complicaciones , Humanos , Lactante , Masculino , Talasemia beta/diagnóstico
20.
Clin Trials ; 14(6): 563-571, 2017 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-28743191

RESUMEN

BACKGROUND/AIMS: Patients with sickle cell anemia can experience recurrent pain episodes, which affect quality of life. The reported prevalence of pain is higher in studies using patient diaries than in healthcare facility utilization data. Determining Effects of Platelet Inhibition on Vaso-Occlusive Events was a multinational study that assessed the efficacy and safety of prasugrel in reducing the rate of vaso-occlusive events in children with sickle cell anemia (NCT01794000) and included an electronic patient-reported outcome diary to record pain occurrence. We aimed to capture diary completion rates and compliance in children who used the electronic patient-reported outcome diary during the Determining Effects of Platelet Inhibition on Vaso-Occlusive Events study and examine factors contributing to diary completion rates and compliance. METHODS: Daily electronic patient-reported outcome diary data were collected for up to 9 months in Determining Effects of Platelet Inhibition on Vaso-Occlusive Events participants aged 4 to <18 years in Africa, the Americas, Europe, and the Middle East. The questionnaires were available in 11 languages/dialects for collecting subjective (pain intensity, activity interference) and objective (study drug use, analgesic use, school attendance) data. Pain intensity was measured using the Faces Pain Scale-Revised. Data were entered by participants or caregivers and transferred wirelessly each day to a central database. Diary completion rates were the number of daily diary entries divided by the total number of expected daily diary entries. Percentages of participants who were compliant with the diary (≥80% diary completion) were calculated. RESULTS: A total of 311 participants received a diary; 268 provided diary data through Month 9. Diary completion rates and compliance were high throughout the collection period and across all groups and regions, despite no games being included on the device. For subjective data, the overall completion rate was 94.4%, and 92.6% of participants were compliant. For objective data, the overall completion rate was 93.3%, and 89.7% of participants were compliant. Completion rates and compliance differed significantly by age and region and were higher for 4 to <12 year olds and very much higher for participants from Africa and the Middle East. Caregivers almost always entered data for participants <6 years and rarely entered data for participants ≥12 years. Comparing participant-entered and caregiver-entered data, pain intensity score data were more consistent for 4 to <12 year olds than older children, but pain intensity scores for older children were higher when entered by caregivers. CONCLUSION: With appropriate design, participant training, and sufficient monitoring, an electronic patient-reported outcome diary can capture daily sickle cell-related pain data in large multinational studies. Providing a mechanism for caregiver reporting is particularly valuable for participants <6 years and may also facilitate compliance in older children who experience high levels of pain.


Asunto(s)
Anemia de Células Falciformes/complicaciones , Dimensión del Dolor/métodos , Dolor/epidemiología , Cooperación del Paciente/estadística & datos numéricos , Calidad de Vida , Autoinforme/estadística & datos numéricos , Adolescente , África , Factores de Edad , Cuidadores/estadística & datos numéricos , Niño , Preescolar , Computadoras de Mano , Europa (Continente) , Femenino , Humanos , Masculino , Medio Oriente , Dolor/etiología , Método Simple Ciego , Estados Unidos
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