RESUMEN
Hemophilia is characterized by bleeding diathesis, primarily affecting the joints. Prophylactic use of missing factor aims at limiting the number of bleeds and, in the long term, the risk of permanent joint damage. However, standard prophylactic regimens are usually applied empirically, not adjusting for variations in bleeding phenotype or drug metabolism. Aim of the present study was to evaluate the need for individualizing prophylaxis, with guidance of pharmacokinetic (PK) studies and joint ultrasound in a setting of everyday clinical practice. To evaluate adequacy of applied regimens, joint status was assessed using the Hemophilia Joint Health Score as well as ultrasound imaging, while PK studies were performed using the Web-Accessible Population Pharmacokinetic Service-Hemophilia. Imaging results were consistent with early joint damage in a large proportion of pediatric patients, whereas PK measures were indicative of inadequate prophylaxis in many cases-despite the limited number of bleeds reported by patients. The study revealed the need for prophylaxis adjustment in the majority of patients. Real world data confirm that traditional prophylaxis is often unable to achieve therapeutic goals, while an individualized approach, guided by the use of novel modalities, may be of great benefit to young hemophilia patients.
Asunto(s)
Hemofilia A , Niño , Factor VIII/uso terapéutico , Hemartrosis/diagnóstico por imagen , Hemartrosis/etiología , Hemartrosis/prevención & control , Hemofilia A/complicaciones , Hemofilia A/diagnóstico por imagen , Hemofilia A/tratamiento farmacológico , Hemorragia/tratamiento farmacológico , Hemorragia/etiología , Hemorragia/prevención & control , Humanos , Fenotipo , UltrasonografíaRESUMEN
The rare hemoglobin (Hb) variant Hb Natal [α140(HC2)Tyr-Argâ0 (HBA2: c.423C>A)], detected on the α2-globin gene, is characterized by a shortened polypeptide chain because of a premature stop codon formation in codon 140. Here, we report identification of the same genetic variation but in the corresponding position of the α1-globin gene, in a heterozygous state, in five members of a Greek family. All carriers of Hb Natal (ααNatal/αα) present with mild hematological and no clinical findings. This innocuous Hb variant was initially detected, in the context of the national prevention program for hemoglobinopathies, by high performance liquid chromatography (HPLC) and capillary electrophoresis (CE). Identification of the variant was performed by molecular analysis of the α-globin genes. This is the first description of a heterozygous Hb Natal in a Greek family, and the first description of this genetic variant on the HBA1 gene, worldwide.
Asunto(s)
Hemoglobinas Anormales , Talasemia alfa , Codón sin Sentido , Hemoglobina Glucada/genética , Grecia , Hemoglobinas Anormales/genética , Humanos , Globinas alfa/genética , Talasemia alfa/genéticaRESUMEN
We report the hematological data of the codon 7 (GAG>TAG (HBB: c.22G>T) mutation for the first time in two Albanian individuals from the region of Elbasan, who underwent genetic testing due to prenatal counseling and diagnosis for ß-thalassemia major (ß-TM) anemia. The phenotype was compatible with a typical ß0-thalassemia (ß0-thal) carrier but the hematological findings of the mutation has not been previously reported. The mutation involves the conversion of codon 7 GAG (Glu) into a translation termination codon (TAG), involving the replacement of guanine by thymine so that no ß chains are produced.
Asunto(s)
Emigrantes e Inmigrantes , Talasemia , Talasemia beta , Codón de Terminación , Análisis Mutacional de ADN , Genotipo , Grecia , Guanina , Humanos , Mutación , Talasemia/genética , Timina , Globinas beta/genética , Talasemia beta/diagnóstico , Talasemia beta/genéticaRESUMEN
Hb Adana (HBA2: c.179G>A) is found worldwide but is extremely rare and carriers are asymptomatic, with red cell indices similar to α+-thalassemia (α+-thal) carriers. First line screening tests are unable to detect the unstable hemoglobin (Hb). Coinheritance with the α-thal (-α3.7) deletion is herein presented and the challenges involving genetic counseling of couples carrying the mutations are discussed.
Asunto(s)
Hemoglobinas Anormales/genética , Heterocigoto , Eliminación de Secuencia , Índices de Eritrocitos , Femenino , Asesoramiento Genético , Grecia , Humanos , Masculino , Talasemia alfa/genéticaRESUMEN
Myosin heavy chain-9 (MYH9)-related disorders represent a heterogenous group of hereditary diseases caused by mutations in the gene encoding the heavy chain of nonmuscle myosin IIA. May-Hegglin anomaly and Fechtner, Sebastian, and Epstein syndromes are the four phenotypes of the disease, characterized by congenital macrothrombocytopenia and distinguished by different combinations of clinical signs that may include glomerulonephritis, sensorineural hearing loss, and presenile cataract. The spectrum of mutations responsible for the disease is wide and the existence of genotype-phenotype correlation remains a critical issue. We report the first case of an MYH9-RD in a patient of Greek origin presenting with macroscopic hematuria and presenile cataract caused by a p.R1165C mutation. The same mutation was present in the patient's father, who exhibited no extrahematological features of the disease. The p.R1165C mutation is one of the MYH9 alterations whose prognostic significance is still poorly defined. Thus, the patients described add to the limited existing data on the MYH9 mutations and their resultant phenotypes.
Asunto(s)
Catarata/diagnóstico , Catarata/genética , Hematuria/diagnóstico , Hematuria/genética , Proteínas Motoras Moleculares/genética , Cadenas Pesadas de Miosina/genética , Mutación Puntual/genética , Adolescente , Análisis Mutacional de ADN , Diagnóstico Diferencial , Grecia , Humanos , MasculinoRESUMEN
Thalassemic syndromes are characterized by clinical heterogenicity. For severe disease forms, lifelong blood transfusions remain the mainstay of therapy, while iron overload monitoring and adequate chelation treatment are required in order to ensure effective disease management. Compared to previous chelators, the new deferasirox film-coated tablet (DFX FCT) is considered to offer a more convenient and well-tolerated treatment scheme, aiming at better treatment-related and patient-related outcomes. The present study's objective was to prospectively evaluate the safety and efficacy of DFX FCT in children and adolescents with transfusion-dependent thalassemia. Data collected included patient demographics, hematology and biochemistry laboratory work up, magnetic resonance imaging of heart and liver for iron load, as well as ophthalmological and audiological examination prior to and a year following drug administration. Study results confirmed DFX FCT safety in older children in a manner similar to adults, but demonstrated increased frequency of adverse events in younger patients, mainly, involving liver function. With regards to efficacy, study results confirmed the preventive role of DFX FCT in iron loading of liver and heart, however, higher doses than generally recommended were required in order to ensure adequate chelation.
RESUMEN
Recent evidence supports the presence of renal dysfunction even among young patients with ß-thalassemia major. However, the possible genetic contribution has never been investigated. The aim of this study was to correlate the presence of Fok-I polymorphism of the vitamin D receptor gene with abnormal levels of early markers of renal impairment in children and young adults with thalassemia. Thirty-four patients (19 male and 15 female) with ß-thalassemia major on conventional treatment, with a mean decimal age of 14.62 ± 5.47 years (range: 5-22 years), were included in the study. Markers of renal function were determined in serum and in urine and patients were genotyped for Fok-I gene polymorphism. Genotype frequencies were similar to those previously reported for other populations: 47.06% of the patients were homozygous for the F allele, 41.18% were heterozygous, and 11.76% were homozygous for the f allele. A considerable number of patients demonstrated impaired renal function with increased serum cystatin C levels (29.41%), glomerular dysfunction with proteinuria (68%), as well as significant tubulopathy with hypercalciuria (73.08%), and increased levels of urinary ß(2)-microglobulin (29.41%). When patients were stratified according to Fok-I polymorphism, a significantly higher prevalence of abnormally increased serum levels of cystatin C was observed in patients being homozygous for the f allele (75%) compared with those being heterozygous (Ff) or homozygous for the F allele (14.29% and 31.25%, respectively, P = .02). Further studies are needed to confirm these preliminary results and elucidate the possible mechanisms involved.
Asunto(s)
Alelos , Frecuencia de los Genes , Enfermedades Renales/genética , Polimorfismo de Longitud del Fragmento de Restricción , Receptores de Calcitriol/genética , Talasemia beta/genética , Adolescente , Adulto , Biomarcadores/sangre , Biomarcadores/orina , Calcio/orina , Niño , Preescolar , Cistatina C/sangre , Femenino , Genotipo , Mesangio Glomerular/metabolismo , Humanos , Enfermedades Renales/sangre , Enfermedades Renales/orina , Masculino , Proteinuria/sangre , Proteinuria/orina , Receptores de Calcitriol/metabolismo , Microglobulina beta-2/orina , Talasemia beta/sangre , Talasemia beta/orinaRESUMEN
There are limited studies on renal involvement in beta-thalassemia, mainly involving patients on deferoxamine, reporting both glomerular and tubular dysfunction. The aim of the present study was to investigate renal involvement in young thalassemia patients, using both conventional and early markers of renal dysfunction, and to correlate findings to iron chelation therapy. Forty-two patients aged 4-23 years were studied and, for analysis purposes, were divided into two groups based on chelation therapy (group A receiving deferasirox and group B receiving deferoxamine and deferiprone combination therapy). In addition to conventional renal biochemistries, creatinine clearance, estimated glomerular filtration rate, serum cystatin C (Cys C), fractional excretion of sodium, tubular phosphorus reabsorption and urine calcium, protein, beta(2)-microglobulin (beta(2)-MG) and glucose levels were measured. A considerable number of patients demonstrated impaired renal function with elevated Cys C levels (36%), glomerular dysfunction with proteinuria (24%) and tubulopathy with hypercalciuria (35.5%) and elevated excretion of beta(2)-MG (33.5%). Renal involvement seems to be present even in young patients with beta-thalassemia, therefore, routine use of early markers of renal dysfunction is recommended. Further studies are needed in order to investigate the role of new chelators in tubular function parameters.
Asunto(s)
Benzoatos/efectos adversos , Deferoxamina/efectos adversos , Quelantes del Hierro/efectos adversos , Enfermedades Renales/complicaciones , Piridonas/efectos adversos , Triazoles/efectos adversos , Talasemia beta/tratamiento farmacológico , Adolescente , Adulto , Benzoatos/uso terapéutico , Biomarcadores/sangre , Biomarcadores/orina , Terapia por Quelación/efectos adversos , Niño , Preescolar , Cistatina C/sangre , Deferasirox , Deferiprona , Deferoxamina/uso terapéutico , Quimioterapia Combinada , Diagnóstico Precoz , Femenino , Humanos , Hipercalciuria , Quelantes del Hierro/uso terapéutico , Enfermedades Renales/sangre , Enfermedades Renales/inducido químicamente , Enfermedades Renales/orina , Pruebas de Función Renal , Masculino , Proteinuria , Piridonas/uso terapéutico , Triazoles/uso terapéutico , Adulto Joven , Microglobulina beta-2/orina , Talasemia beta/sangre , Talasemia beta/complicaciones , Talasemia beta/orinaRESUMEN
Sickle cell disease (SCD) is associated with increased risk of cardiovascular disease, although blood pressure (BP) levels have been reported to be lower in SCD patients compared to general population. Aims of the present study were to investigate the prevalence of BP phenotypes and levels of arterial stiffness in pediatric patients with SCD and to assess the differences with children at risk for hypertension. We included in the study 16 pediatric SCD (HbS/ß-thalassemia, S/ß-thal) patients and 16 consecutive children at risk for hypertension referred to our hypertension clinic that served as high-risk controls. All patients underwent ambulatory BP monitoring and measurement of carotid-femoral pulse wave velocity (PWV). S/ß-thal patients had lower office systolic BP than the high-risk control group (115.43 ± 10.03 vs 123.37 ± 11.92, P = .05) but presented similar levels of day and night ambulatory BP. Office hypertension was found in 12.5% of the S/ß-thal patients and in 43.8% of the high-risk controls (P = .06), while 18.8% of the S/ß-thal patients and 25% of the high-risk controls presented hypertension by ambulatory BP levels (P = .21). All of the S/ß-thal patients with ambulatory hypertension had night hypertension (one combined night and day hypertension) with office normotension (masked hypertension). S/ß-thal patients and high-risk controls presented equal prevalence of masked hypertension (18.8%). Children and adolescents with S/ß-thal present similar prevalence of BP phenotypes and levels of PWV with children at risk for hypertension. A significant number of children and adolescents with S/ß-thal may have masked nighttime hypertension despite normal office BP levels.
Asunto(s)
Anemia de Células Falciformes , Hipertensión , Talasemia beta , Adolescente , Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/diagnóstico , Anemia de Células Falciformes/epidemiología , Presión Sanguínea , Monitoreo Ambulatorio de la Presión Arterial , Niño , Humanos , Hipertensión/diagnóstico , Hipertensión/epidemiología , Análisis de la Onda del Pulso , Talasemia beta/complicaciones , Talasemia beta/diagnóstico , Talasemia beta/epidemiologíaAsunto(s)
Benzoatos/efectos adversos , Terapia por Quelación/efectos adversos , Quelantes del Hierro/efectos adversos , Sobrecarga de Hierro/tratamiento farmacológico , Nefrolitiasis/inducido químicamente , Reacción a la Transfusión , Triazoles/efectos adversos , Talasemia beta/complicaciones , Adulto , Benzoatos/uso terapéutico , Niño , Preescolar , Deferasirox , Deferiprona , Femenino , Grecia/epidemiología , Humanos , Hipercalciuria/etiología , Hiperuricemia/etiología , Quelantes del Hierro/uso terapéutico , Sobrecarga de Hierro/etiología , Masculino , Nefrolitiasis/sangre , Nefrolitiasis/epidemiología , Nefrolitiasis/etiología , Complicaciones Posoperatorias/sangre , Complicaciones Posoperatorias/inducido químicamente , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Piridonas/uso terapéutico , Esplenectomía , Triazoles/uso terapéutico , Adulto Joven , Talasemia beta/sangre , Talasemia beta/cirugía , Talasemia beta/terapiaAsunto(s)
Hierro/metabolismo , Pruebas de Función Respiratoria/métodos , Talasemia beta/metabolismo , Adolescente , Adulto , Femenino , Humanos , Sobrecarga de Hierro , Hígado/metabolismo , Imagen por Resonancia Magnética , Masculino , Miocardio/metabolismo , Pruebas de Función Respiratoria/instrumentación , Adulto Joven , Talasemia beta/epidemiologíaRESUMEN
Beta thalassemia is known to be characterized by a hypercoagulable state, with prothrombotic factors present and thrombotic event development in a number of patients. The aim of the present study was to evaluate subclinical involvement of the central nervous system (CNS) in young patients with thalassemia intermedia, the use of nonimaging, noninvasive laboratory methods for detecting relevant abnormalities, and the frequency and possible correlation of coagulation abnormalities with CNS lesions. In this cross-sectional study, 24 young patients with thalassemia intermedia were evaluated (mean age 12 ± 4.6 years, range 4.5-20 years). Patients underwent neurological examination, inherited and acquired coagulation defect testing, as well as neurophysiologic and neuroimaging evaluation. Patients aged 6-16 also had intelligence scores measured. With regards to coagulation, a decrease in antithrombin III (ATIII), protein C and protein S activity was found in 4.1, 54.16 and 45.8% of patients, respectively. Increased D-dimers, as well as thrombin-antithrombin complex (TAT) and prothrombin fragment (F1 + 2) values were found in 12.5, 62.5 and 8.33% of patients, respectively. Heterozygosity and homozygosity for the methylenetetrahydrofolate reductase mutation was found in 45.8 and 12.5% of patients, whereas heterozygosity for factor V Leiden and G20210FII was found in 8.33 and 12.5% of patients, respectively, with increased prevalence compared to Greek population. Neuroimaging evaluation was normal in all patients. Neurophysiologic evaluation revealed abnormal findings in 33.3% of patients on electroencephalogram (EEG), 16% on brain auditory-evoked potentials (BAEPs) and 4.12% on somatosensory evoked potentials (SEPs). Visual-evoked potentials (VEPs) were normal in all patients. A statistically significant difference was found between low protein C values, as well as high platelet counts, with abnormal EEG findings (P = 0.004 and P = 0.039, respectively). Transcranial Doppler (TCD) measurements revealed increased peak systolic velocities in anterior and posterior cerebral arteries and in basilar artery in 57, 38 and 41% of patients, respectively, as compared to healthy population values. On the contrary, decreased mean velocities were found both on middle cerebral artery and pars terminalis of internal carotid examination in 28.5% of patients. Patients with pathological findings on TCD study had lower hematocrit (P = 0.049) and younger age (P = 0.001) than patients with normal measurements. With regards to intelligence scores, mean intelligence quotient (IQ) was 100 ± 19.1, with 11.7% of patients demonstrating IQ below 85. The study results confirm the early presence of hemostatic changes in patients with thalassemia intermedia. Additionally, they demonstrate subclinical CNS involvement starting at childhood. For such involvement detection, in addition to neuroimaging, neurophysiological and neuropsychological evaluation is warranted.