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2.
Curr Res Transl Med ; 72(1): 103438, 2024 03.
Artículo en Inglés | MEDLINE | ID: mdl-38244303

RESUMEN

Congenital sideroblastic anemia (CSA) is a group of disorders caused by different genetic mutations that result in low iron utilization and ineffective erythropoiesis. Current treatments are limited, and some patients do not respond to vitamin B6 therapy. Luspatercept is a novel erythropoietic maturation agent approved for adult ß-thalassemia and Myelodysplastic syndromes with ring sideroblasts (MDS-RS) associated with ineffective erythropoiesis. Here we report 2 patients with CSA due to mutations in ALAS2 and SLC25A38 genes who became unresponsive after a period of treatment with vitamin B6 and iron chelators but achieved transfusion independence and a markedly reduced spleen after combination with luspatercept.


Asunto(s)
Receptores de Activinas Tipo II , Anemia Sideroblástica , Enfermedades Genéticas Ligadas al Cromosoma X , Proteínas Recombinantes de Fusión , Adulto , Humanos , 5-Aminolevulinato Sintetasa , Receptores de Activinas Tipo II/efectos adversos , Anemia Sideroblástica/tratamiento farmacológico , Anemia Sideroblástica/genética , Anemia Sideroblástica/congénito , Fragmentos Fc de Inmunoglobulinas/efectos adversos , Proteínas Recombinantes de Fusión/efectos adversos , Vitamina B 6
5.
J Clin Immunol ; 43(4): 780-793, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-36729249

RESUMEN

PURPOSE: Sideroblastic anemia, immunodeficiency, periodic fevers, and developmental delay (SIFD) is an autosomal recessive syndrome caused by biallelic loss-of-function variant of tRNA nucleotidyl transferase 1 (TRNT1). Efficacious methods to treat SIFD are lacking. We identified two novel mutations in TRNT1 and an efficacious and novel therapy for SIFD. METHODS: We retrospectively summarized the clinical records of two patients with SIFD from different families and reviewed all published cases of SIFD. RESULTS: Both patients had periodic fever, developmental delay, rash, microcytic anemia, and B cell lymphopenia with infections. Whole-exome sequencing of patient 1 identified a previously unreported homozygous mutation of TRNT1 (c.706G > A/p.Glu236Lys). He received intravenous immunoglobulin (IVIG) replacement and antibiotics, but died at 1 year of age. Gene testing in patient 2 revealed compound heterozygous mutations (c.907C > G/p.Gln303Glu and c.88A > G/p.Met30Val) in TRNT1, the former of which is a novel mutation. Periodic fever was controlled in the first month after adalimumab therapy and IVIG replacement, but recurred in the second month. Adalimumab was discontinued and replaced with thalidomide, which controlled the periodic fever and normalized inflammatory markers effectively. A retrospective analysis of reported cases revealed 69 patients with SIFD carrying 46 mutations. The male: female ratio was 1: 1, and the mean age of onset was 3.0 months. The most common clinical manifestations in patients with SIFD were microcytic anemia (82.6%), hypogammaglobulinemia/B cell lymphopenia (75.4%), periodic fever (66.7%), and developmental delay (60.0%). In addition to the typical tetralogy, SIFD features several heterogeneous symptoms involving multiple systems. Corticosteroids, immunosuppressants, and anakinra have low efficacy, whereas etanercept suppressed fever and improved anemia in reports. Bone-marrow transplantation can be used to treat severe SIFD, but carries a high risk. In total, 28.2% (20/71) of reported patients died, mainly because of multi-organ failure. Biallelic mutations located in exon1-intron5 lead to more severe phenotypes and higher mortality. Furthermore, 15.5% (11/71) patients survived to adulthood. The symptoms could be resolved spontaneously in five patients. CONCLUSIONS: Thalidomide can control the inflammation of SIFD and represents a new treatment for SIFD.


Asunto(s)
Anemia Sideroblástica , Síndromes de Inmunodeficiencia , Linfopenia , Masculino , Humanos , Femenino , Talidomida , Estudios Retrospectivos , Anemia Sideroblástica/diagnóstico , Anemia Sideroblástica/tratamiento farmacológico , Anemia Sideroblástica/genética , Adalimumab , Inmunoglobulinas Intravenosas/uso terapéutico , Síndromes de Inmunodeficiencia/genética , Fiebre/etiología , Fiebre/genética , Mutación/genética , Nucleotidiltransferasas/genética
6.
Pediatr Allergy Immunol Pulmonol ; 35(3): 129-132, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-36121781

RESUMEN

Introduction: Sideroblastic anemia with B cell immunodeficiency, periodic fevers, and developmental delay (SIFD) syndrome is caused by biallelic TRNT1 mutations. TRNT1 gene encodes a CCA-adding tRNA nucleotidyl transferase enzyme. Mutant TRNT1 results in immunodeficiency and anemia in various degrees, accompanied by several organ involvement. Case Presentation: We present here a 15-month old male, demonstrated brittle hair, growth hormone deficiency, recurrent fever, arthritis, recurrent infections, mild anemia, and hypogammaglobulinemia. The patient did not respond to colchicine treatment, and after establishing SIFD diagnosis with the presence of homozygote c.948-949delAAinsGG (p.Lys317Glu) mutation in TRNT1 gene, we commenced monthly intravenous immunoglobulin replacement and weekly subcutaneous etanercept. A rapid resolution of fever episodes and infections occurred after initiation of this treatment regimen. Afterward, both anemia and growth parameters have improved during follow-up. Conclusion: SIFD syndrome should be considered in patients with recurrent fever, arthritis, and growth retardation even in the absence of severe anemia and prominent hypogammaglobulinemia.


Asunto(s)
Agammaglobulinemia , Amiloidosis , Anemia Sideroblástica , Artritis , Síndromes de Inmunodeficiencia , Agammaglobulinemia/complicaciones , Agammaglobulinemia/tratamiento farmacológico , Agammaglobulinemia/genética , Amiloidosis/complicaciones , Anemia Sideroblástica/complicaciones , Anemia Sideroblástica/tratamiento farmacológico , Anemia Sideroblástica/genética , Artritis/complicaciones , Niño , Colchicina , Etanercept/uso terapéutico , Fiebre/complicaciones , Fiebre/tratamiento farmacológico , Hormona del Crecimiento , Humanos , Inmunoglobulinas Intravenosas , Síndromes de Inmunodeficiencia/complicaciones , Síndromes de Inmunodeficiencia/genética , Lactante , Masculino , Nucleotidiltransferasas/genética , ARN de Transferencia
8.
Leuk Lymphoma ; 63(1): 199-204, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34448437

RESUMEN

Myelodysplastic syndrome/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) is characterized by anemia, ring sideroblast erythroid precursors, and persistent thrombocytosis. Case reports suggest lenalidomide may be effective in treating MDS/MPN-RS-T. We evaluated a large series of patients with MDS/MPN-RS-T to compare hematological improvement (HI) response rates among different drug therapies including lenalidomide. We identified 167 patients with MDS/MPN-RS-T. Among the patients tested, 84% had SF3B1 mutations and 43% had JAK2 V617F mutations. The median OS for the cohort was 81 months. Overall, 76 patients (46%) received erythropoiesis-stimulating agents (ESAs), 47 patients (28%) received lenalidomide, and 45 patients (27%) received hypomethylating agents (HMAs). The HI rates were 58%, 53%, and 24%, respectively. The median duration of treatment was 11 months for lenalidomide compared to 6 months for HMAs. Rates of HI improvement were higher in patients with MDS/MPN-RS-T treated with ESAs or lenalidomide, in comparison to those treated with HMAs.


Asunto(s)
Anemia Sideroblástica , Enfermedades Mielodisplásicas-Mieloproliferativas , Neoplasias , Trombocitosis , Anemia Sideroblástica/diagnóstico , Anemia Sideroblástica/tratamiento farmacológico , Anemia Sideroblástica/etiología , Humanos , Mutación , Enfermedades Mielodisplásicas-Mieloproliferativas/complicaciones , Enfermedades Mielodisplásicas-Mieloproliferativas/diagnóstico , Enfermedades Mielodisplásicas-Mieloproliferativas/tratamiento farmacológico , Trombocitosis/tratamiento farmacológico , Trombocitosis/genética , Resultado del Tratamiento
10.
Probl Radiac Med Radiobiol ; 25: 390-401, 2020 Dec.
Artículo en Inglés, Ucraniano | MEDLINE | ID: mdl-33361849

RESUMEN

OBJECTIVE: To determine the influence of iron metabolism on the prognosis of acute lymphoblastic (ALL) and (AML)myeloblastic leukemia at the different phases of chemotherapy in children after Chоrnobyl accident. MATERIALS AND METHODS: 333 children (295 - ALL, 38 - AML) were examined at the stages of chemotherapy. Thecomparison group included 93 children without leukemia. Acute leukemia variants, patients survival, relapses, thenature of disease (live child or died), iron methabolism (morphometric parameters of erythrocytes, SI, SF, STf, TS),manifestations of dyserythropoiesis, bone marrow sideroblast and patients radiation dose were taken into account. RESULTS: In 295 patients with ALL the following variants of leukemia were established: pro-B-ALL in 23, «common¼type of ALL in 224, pre-B-ALL in 29, T-ALL in 19. Thirty eight patients were diagnosed with AML (11 - M1, 19 - M2,8 - M4). Doses of radiation in patients with AL were (2.78 ± 0.10) mSv and they did not correlate with clinical andhematological parameters, disease variant. Relapse rates and shorter survival were in patients with T-ALL, pro-B-ALLand AML with SF levels > 500 ng/ml (p < 0.05). The amount of children with normochromic-normocytic anemias andmanifestations of dysplasia of erythroid lineage elements was greater in the AML than in ALL. SF content in patientswas elevated during chemotherapy and was lower than the initial one only in the remission period. Transferrin wasreliably overloaded with iron: TS (70.2 ± 2.3) % compared with the control group (32.7 ± 2.1) %. Correlationbetween TS and survival of patients was detected (rs = -0.45). Direct correlation between the number of iron granules in erythrocariocytes and SF level (rs = 0.43) was established, indicating the phenomena of ineffective erythropoiesis. CONCLUSIONS: The negative influence of iron excess in the patients body on the hemopoiesis function, manifestations of ineffective erythropoiesis and the course of acute leukemia in children have been established. Changes inferrokinetic processes in children can be the basis of leukemоgenesis development.


Asunto(s)
Anemia Sideroblástica/sangre , Accidente Nuclear de Chernóbil , Eritropoyesis/efectos de la radiación , Hierro/sangre , Leucemia Mieloide Aguda/sangre , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangre , Adolescente , Anemia Sideroblástica/tratamiento farmacológico , Anemia Sideroblástica/etiología , Anemia Sideroblástica/mortalidad , Antineoplásicos/uso terapéutico , Médula Ósea/patología , Médula Ósea/efectos de la radiación , Niño , Preescolar , Células Eritroides/patología , Células Eritroides/efectos de la radiación , Femenino , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/etiología , Leucemia Mieloide Aguda/mortalidad , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiología , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Pronóstico , Exposición a la Radiación/efectos adversos , Radiación Ionizante , Recurrencia , Inducción de Remisión , Análisis de Supervivencia , Transferrina/metabolismo , Ucrania/epidemiología
12.
N Engl J Med ; 382(2): 140-151, 2020 01 09.
Artículo en Inglés | MEDLINE | ID: mdl-31914241

RESUMEN

BACKGROUND: Patients with anemia and lower-risk myelodysplastic syndromes in whom erythropoiesis-stimulating agent therapy is not effective generally become dependent on red-cell transfusions. Luspatercept, a recombinant fusion protein that binds transforming growth factor ß superfamily ligands to reduce SMAD2 and SMAD3 signaling, showed promising results in a phase 2 study. METHODS: In a double-blind, placebo-controlled, phase 3 trial, we randomly assigned patients with very-low-risk, low-risk, or intermediate-risk myelodysplastic syndromes (defined according to the Revised International Prognostic Scoring System) with ring sideroblasts who had been receiving regular red-cell transfusions to receive either luspatercept (at a dose of 1.0 up to 1.75 mg per kilogram of body weight) or placebo, administered subcutaneously every 3 weeks. The primary end point was transfusion independence for 8 weeks or longer during weeks 1 through 24, and the key secondary end point was transfusion independence for 12 weeks or longer, assessed during both weeks 1 through 24 and weeks 1 through 48. RESULTS: Of the 229 patients enrolled, 153 were randomly assigned to receive luspatercept and 76 to receive placebo; the baseline characteristics of the patients were balanced. Transfusion independence for 8 weeks or longer was observed in 38% of the patients in the luspatercept group, as compared with 13% of those in the placebo group (P<0.001). A higher percentage of patients in the luspatercept group than in the placebo group met the key secondary end point (28% vs. 8% for weeks 1 through 24, and 33% vs. 12% for weeks 1 through 48; P<0.001 for both comparisons). The most common luspatercept-associated adverse events (of any grade) included fatigue, diarrhea, asthenia, nausea, and dizziness. The incidence of adverse events decreased over time. CONCLUSIONS: Luspatercept reduced the severity of anemia in patients with lower-risk myelodysplastic syndromes with ring sideroblasts who had been receiving regular red-cell transfusions and who had disease that was refractory to or unlikely to respond to erythropoiesis-stimulating agents or who had discontinued such agents owing to an adverse event. (Funded by Celgene and Acceleron Pharma; MEDALIST ClinicalTrials.gov number, NCT02631070; EudraCT number, 2015-003454-41.).


Asunto(s)
Receptores de Activinas Tipo II/uso terapéutico , Anemia Sideroblástica/tratamiento farmacológico , Transfusión de Eritrocitos , Hematínicos/uso terapéutico , Fragmentos Fc de Inmunoglobulinas/uso terapéutico , Síndromes Mielodisplásicos/tratamiento farmacológico , Proteínas Recombinantes de Fusión/uso terapéutico , Receptores de Activinas Tipo II/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Anemia Sideroblástica/terapia , Método Doble Ciego , Femenino , Hematínicos/efectos adversos , Hemoglobinas/análisis , Humanos , Fragmentos Fc de Inmunoglobulinas/efectos adversos , Infusiones Subcutáneas , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/terapia , Proteínas Recombinantes de Fusión/efectos adversos
13.
Rev Med Interne ; 40(7): 462-465, 2019 Jul.
Artículo en Francés | MEDLINE | ID: mdl-31133329

RESUMEN

INTRODUCTION: Sideroblastic anemia is a rare cause of microcytic anemia, which is characterized by ring sideroblasts on bone marrow aspirate. This anemia can be congenital or acquired. CASE REPORT: We report the case of an alcoholic 49-year-old man who presented with a severe microcytic sideroblastic anemia related to pyridoxine (B6 vitamin) deficiency. Acid folic deficiency was associated. The blood count normalized within one month after vitamin supplementation. CONCLUSION: Pyridoxine deficiency must be sought in sideroblastic anemia in patients at risk.


Asunto(s)
Anemia Sideroblástica/tratamiento farmacológico , Deficiencia de Vitamina B 6/tratamiento farmacológico , Vitamina B 6/uso terapéutico , Alcoholismo/complicaciones , Alcoholismo/diagnóstico , Alcoholismo/tratamiento farmacológico , Anemia Sideroblástica/complicaciones , Anemia Sideroblástica/diagnóstico , Humanos , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Deficiencia de Vitamina B 6/complicaciones , Deficiencia de Vitamina B 6/diagnóstico
14.
Cancer Sci ; 109(10): 3209-3215, 2018 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-30007103

RESUMEN

Although azacitidine is the first-line drug for higher-risk myelodysplastic syndrome (MDS) patients, its efficacy for lower-risk MDS remains unestablished. Therefore, we conducted a prospective study to examine the efficacy and safety of a 5-day regimen of azacitidine (AZA-5) for lower-risk MDS. The primary endpoint was hematological improvement (HI) after 4 courses of therapy. A total of 51 patients with lower-risk MDS based on the French-American-British (FAB) classification (44 patients with refractory anemia [RA] and 7 patients with refractory anemia with ringed sideroblasts [RARS]) were enrolled from 6 centers in Japan. The median age was 75 years (range: 51-88). These patients received AZA-5 (75 mg/m2 ; once daily for 5 sequential days). The median number of AZA-5 courses was 8 (range: 1-57), and 45 patients (88.2%) received more than 4 courses. HI and transfusion independency were seen in 24 patients (47.1%) and 11 patients (39.2%), respectively. A total of 11 patients (21.6%) achieved complete remission or marrow remission. WT1 mRNA levels were not significantly correlated with therapy response. Grade 3 or 4 neutropenia and thrombocytopenia occurred in 26 (51.0%) and 11 (21.5%) patients, respectively. Nonhematological grade 3 or 4 adverse events were observed in 9 patients (17.6%). Together, these results indicate that AZA-5 is feasible and effective for lower-risk MDS patients as well as for higher-risk MDS patients.


Asunto(s)
Anemia Refractaria/tratamiento farmacológico , Anemia Sideroblástica/tratamiento farmacológico , Antimetabolitos Antineoplásicos/uso terapéutico , Azacitidina/uso terapéutico , Anciano , Anciano de 80 o más Años , Anemia Refractaria/sangre , Anemia Sideroblástica/sangre , Transfusión de Componentes Sanguíneos/estadística & datos numéricos , Esquema de Medicación , Estudios de Factibilidad , Neutropenia Febril/inducido químicamente , Neutropenia Febril/epidemiología , Femenino , Humanos , Japón/epidemiología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Trombocitopenia/inducido químicamente , Trombocitopenia/epidemiología , Resultado del Tratamiento
18.
Ann Clin Lab Sci ; 47(3): 319-322, 2017 May.
Artículo en Inglés | MEDLINE | ID: mdl-28667034

RESUMEN

We report a novel ALAS2 gene mutation c.1315A>G (p.Lys439Glu) identified in a family, which caused evidently different hematologic phenotypes. The proband was a 17-year-old man with severe microcytic hypochromic anemia, excessive ring sideroblasts in the bone marrow, and iron overload. A hemizygous ALAS2 mutation in exon 9, c.1315A>G (p.Lys439Glu), was identified through sequence analysis. We assume that this amino acid substitution affects the enzymatic activity of ALAS2 by affecting its interaction with the cofactor pyridoxal 5'-phosphate, since the patient was responsive to pyridoxine treatment. This novel mutation likely accounts for variable hematologic phenotypes in the family of this patient: his 15-year-old hemizygous brother was asymptomatic, while his heterozygous mother was mildly anemic.


Asunto(s)
5-Aminolevulinato Sintetasa/genética , Anemia Sideroblástica/genética , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Mutación Missense , Piridoxina/uso terapéutico , 5-Aminolevulinato Sintetasa/metabolismo , Adolescente , Anemia Sideroblástica/tratamiento farmacológico , Femenino , Enfermedades Genéticas Ligadas al Cromosoma X/tratamiento farmacológico , Heterocigoto , Humanos , Sobrecarga de Hierro/genética , Masculino , Linaje , Fenotipo , Fosfato de Piridoxal/metabolismo
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