Subject(s)
Anemia, Sideroblastic/complications , Anemia, Sideroblastic/drug therapy , Anti-Bacterial Agents/adverse effects , Antitubercular Agents/therapeutic use , Ethambutol/therapeutic use , Linezolid/adverse effects , Seizures/etiology , Tuberculosis, Multidrug-Resistant , Anemia, Sideroblastic/blood , Anemia, Sideroblastic/etiology , Fatigue/etiology , Hemoglobins , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Tuberculosis, Multidrug-Resistant/complications , Tuberculosis, Multidrug-Resistant/drug therapySubject(s)
Anemia, Hypochromic , Anemia, Sideroblastic , Genetic Diseases, X-Linked , Iron Overload , Adult , Anemia, Hypochromic/blood , Anemia, Hypochromic/diagnosis , Anemia, Hypochromic/genetics , Anemia, Sideroblastic/blood , Anemia, Sideroblastic/diagnosis , Anemia, Sideroblastic/genetics , Diagnosis, Differential , Genetic Diseases, X-Linked/blood , Genetic Diseases, X-Linked/diagnosis , Genetic Diseases, X-Linked/genetics , Humans , Iron Overload/blood , Iron Overload/diagnosis , Iron Overload/genetics , MaleABSTRACT
Erythroferrone (ERFE), the erythroid regulator of iron metabolism, inhibits hepcidin to increase iron availability for erythropoiesis. ERFE plays a pathological role during ineffective erythropoiesis as occurs in X-linked sideroblastic anemia (XLSA) and ß-thalassemia. Its measurement might serve as an indicator of severity for these diseases. However, for reliable quantification of ERFE analytical characterization is indispensable to determine the assay's limitations and define proper methodology. We developed a sandwich ELISA for human serum ERFE using polyclonal antibodies and report its extensive analytical validation. This new assay showed, for the first time, the differentiation of XLSA and ß-thalassemia major patients from healthy controls (p = 0.03) and from each other (p<0.01), showing the assay provides biological plausible results. Despite poor dilution linearity, parallelism and recovery in patient serum matrix, which indicated presence of a matrix effect and/or different immunoreactivity of the antibodies to the recombinant standard and the endogenous analyte, our assay correlated well with two other existing ERFE ELISAs (both R2 = 0.83). Nevertheless, employment of one optimal dilution of all serum samples is warranted to obtain reliable results. When adequately performed, the assay can be used to further unravel the human erythropoiesis-hepcidin-iron axis in various disorders and assess the added diagnostic value of ERFE.
Subject(s)
Anemia, Sideroblastic/diagnosis , Peptide Hormones/analysis , beta-Thalassemia/diagnosis , Adult , Aged , Anemia/blood , Anemia/diagnosis , Anemia, Sideroblastic/blood , Cytokines/metabolism , Enzyme-Linked Immunosorbent Assay , Erythropoiesis , Female , Hepcidins/blood , Humans , Iron/metabolism , Iron Overload/diagnosis , Iron Overload/metabolism , Male , Middle Aged , Peptide Hormones/blood , beta-Thalassemia/bloodABSTRACT
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.
Subject(s)
Anemia, Sideroblastic/blood , Chernobyl Nuclear Accident , Erythropoiesis/radiation effects , Iron/blood , Leukemia, Myeloid, Acute/blood , Precursor Cell Lymphoblastic Leukemia-Lymphoma/blood , Adolescent , Anemia, Sideroblastic/drug therapy , Anemia, Sideroblastic/etiology , Anemia, Sideroblastic/mortality , Antineoplastic Agents/therapeutic use , Bone Marrow/pathology , Bone Marrow/radiation effects , Child , Child, Preschool , Erythroid Cells/pathology , Erythroid Cells/radiation effects , Female , Humans , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/etiology , Leukemia, Myeloid, Acute/mortality , Male , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/etiology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/mortality , Prognosis , Radiation Exposure/adverse effects , Radiation, Ionizing , Recurrence , Remission Induction , Survival Analysis , Transferrin/metabolism , Ukraine/epidemiologyABSTRACT
INTRODUCTION: Myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) is a rare disease in the 2016 revised World Health Organization (WHO) classification. Diagnostic criteria include the following: persistent thrombocytosis (>450 × 109 /L) with clustering of atypical megakaryocytes, refractory anemia, dyserythropoiesis with ring sideroblasts, and the presence of the spliceosome factor 3b subunit (SF3B1) mutation. It is unclear if anemia should be a required criterion for this diagnosis as cases which show all other features of MDS/MPN-RS-T but without anemia exist. METHODS: We searched for borderline cases of MDS/MPN-RS-T in which refractory anemia was absent at diagnosis in two major academic institutes. RESULTS: Three cases without anemia were identified. These cases all showed other classic morphologic and clinical features of MDS/MPN-RS-T, including thrombocytosis, atypical megakaryocytes with clustering, and characteristic SF3B1 and JAK2 V617F mutations. CONCLUSION: Given these findings, the requirement of refractory anemia as a diagnostic criterion for MDS/MPN-RS-T should be re-evaluated. Removal of refractory anemia as a diagnostic criterion would incorporate current borderline cases and extend the spectrum of this disorder.
Subject(s)
Anemia, Sideroblastic/blood , Myelodysplastic-Myeloproliferative Diseases/blood , Myelodysplastic-Myeloproliferative Diseases/diagnosis , Thrombocytosis/blood , Aged, 80 and over , Anemia, Sideroblastic/etiology , Biomarkers , Biopsy , Bone Marrow/pathology , Bone Marrow Cells/pathology , Cytogenetic Analysis , Female , Flow Cytometry , High-Throughput Nucleotide Sequencing , Humans , Janus Kinase 2/genetics , Male , Middle Aged , Mutation , Myelodysplastic-Myeloproliferative Diseases/complications , Myelodysplastic-Myeloproliferative Diseases/etiology , Phosphoproteins/genetics , RNA Splicing Factors/genetics , Sequence Analysis, DNA , Thrombocytosis/etiologyABSTRACT
DISEASE OVERVIEW: Ring sideroblasts (RS) are erythroid precursors with abnormal perinuclear mitochondrial iron accumulation. Two myeloid neoplasms defined by the presence of RS, include refractory anemia with ring sideroblasts (RARS), now classified under myelodysplastic syndromes with RS (MDS-RS) and RARS with thrombocytosis (RARS-T); now called myelodysplastic/myeloproliferative neoplasm with RS and thrombocytosis (MDS/MPN-RS-T). DIAGNOSIS: MDS-RS is a lower-risk MDS, with single or multilineage dysplasia (SLD/MLD), <5% bone marrow (BM) blasts and ≥ 15% BM RS (≥5% in the presence of SF3B1 mutations). MDS/MPN-RS-T, now a formal entity in the MDS/MPN overlap syndromes, has diagnostic features of MDS-RS-SLD, along with a platelet count ≥450 × 10(9)/L and large atypical megakaryocytes. MUTATIONS AND KARYOTYPE: Mutations in SF3B1 are seen in ≥80% of patients with MDS-RS-SLD and MDS/MPN-RS-T, and strongly correlate with the presence of BM RS; MDS/MPN-RS-T patients also demonstrate JAK2V617F, ASXL1, DNMT3A, SETBP1, and TET2 mutations. Cytogenetic abnormalities are uncommon in both. RISK STRATIFICATION: Most patients with MDS-RS-SLD are stratified into lower-risk groups by the revised-IPSS. Disease outcome in MDS/MPN-RS-T is better than that of MDS-RS-SLD, but worse than that of essential thrombocythemia. Both diseases have a low risk of leukemic transformation. TREATMENT: Anemia and iron overload are complications seen in both and are managed similar to lower-risk MDS and MPN. The advent of luspatercept, a first-in-class erythroid maturation agent will tremendously boost the ability to manage anemia. Aspirin therapy is reasonable in MDS/MPN-RS-T, especially in the presence of JAK2V617F, but the value of platelet-lowering drugs remains uncertain.
Subject(s)
Anemia, Refractory , Mutation , Anemia, Refractory/blood , Anemia, Refractory/diagnosis , Anemia, Refractory/genetics , Anemia, Refractory/therapy , Anemia, Sideroblastic/blood , Anemia, Sideroblastic/diagnosis , Anemia, Sideroblastic/genetics , Anemia, Sideroblastic/therapy , Erythroblasts/metabolism , Female , Humans , Iron Overload/blood , Iron Overload/diagnosis , Iron Overload/genetics , Iron Overload/therapy , Male , Myelodysplastic-Myeloproliferative Diseases , Thrombocytosis/blood , Thrombocytosis/diagnosis , Thrombocytosis/genetics , Thrombocytosis/therapyABSTRACT
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.
Subject(s)
Anemia, Refractory/drug therapy , Anemia, Sideroblastic/drug therapy , Antimetabolites, Antineoplastic/therapeutic use , Azacitidine/therapeutic use , Aged , Aged, 80 and over , Anemia, Refractory/blood , Anemia, Sideroblastic/blood , Blood Component Transfusion/statistics & numerical data , Drug Administration Schedule , Feasibility Studies , Febrile Neutropenia/chemically induced , Febrile Neutropenia/epidemiology , Female , Humans , Japan/epidemiology , Male , Middle Aged , Prospective Studies , Thrombocytopenia/chemically induced , Thrombocytopenia/epidemiology , Treatment OutcomeABSTRACT
OBJECTIVES: To characterise the clinical features, immune manifestations and molecular mechanisms in a recently described autoinflammatory disease caused by mutations in TRNT1, a tRNA processing enzyme, and to explore the use of cytokine inhibitors in suppressing the inflammatory phenotype. METHODS: We studied nine patients with biallelic mutations in TRNT1 and the syndrome of congenital sideroblastic anaemia with immunodeficiency, fevers and developmental delay (SIFD). Genetic studies included whole exome sequencing (WES) and candidate gene screening. Patients' primary cells were used for deep RNA and tRNA sequencing, cytokine profiling, immunophenotyping, immunoblotting and electron microscopy (EM). RESULTS: We identified eight mutations in these nine patients, three of which have not been previously associated with SIFD. Three patients died in early childhood. Inflammatory cytokines, mainly interleukin (IL)-6, interferon gamma (IFN-γ) and IFN-induced cytokines were elevated in the serum, whereas tumour necrosis factor (TNF) and IL-1ß were present in tissue biopsies of patients with active inflammatory disease. Deep tRNA sequencing of patients' fibroblasts showed significant deficiency of mature cytosolic tRNAs. EM of bone marrow and skin biopsy samples revealed striking abnormalities across all cell types and a mix of necrotic and normal-appearing cells. By immunoprecipitation, we found evidence for dysregulation in protein clearance pathways. In 4/4 patients, treatment with a TNF inhibitor suppressed inflammation, reduced the need for blood transfusions and improved growth. CONCLUSIONS: Mutations of TRNT1 lead to a severe and often fatal syndrome, linking protein homeostasis and autoinflammation. Molecular diagnosis in early life will be crucial for initiating anti-TNF therapy, which might prevent some of the severe disease consequences.
Subject(s)
Anemia, Sideroblastic/genetics , Anti-Inflammatory Agents/therapeutic use , Genetic Diseases, X-Linked/genetics , Immunologic Deficiency Syndromes/genetics , Mutation , Nucleotidyltransferases/genetics , RNA, Transfer/genetics , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Adult , Anemia, Sideroblastic/blood , Child , Child, Preschool , Cytokines/blood , Cytokines/genetics , Developmental Disabilities/genetics , Female , Genetic Diseases, X-Linked/blood , Humans , Immunophenotyping , Male , Pedigree , Phenotype , Tumor Necrosis Factor-alpha/analysis , Exome SequencingABSTRACT
Sideroblastic anemias are anemic disorders characterized by the presence of ring sideroblasts in a patient's bone marrow. These disorders are typically divided into two types, congenital or acquired sideroblastic anemia. Recently, several genes were reported as responsible for congenital sideroblastic anemia; however, the relationship between the function of the gene products and ring sideroblasts is largely unclear. In this review article, we will focus on the iron metabolism in erythroid cells as well as in patients with congenital sideroblastic anemia.
Subject(s)
Anemia, Sideroblastic/congenital , Anemia, Sideroblastic/genetics , Erythroid Cells/metabolism , Iron/metabolism , Acyl-CoA Dehydrogenase, Long-Chain/deficiency , Anemia, Sideroblastic/blood , Anemia, Sideroblastic/metabolism , Cerebellar Ataxia , Chromosomes, Human, X/genetics , Congenital Bone Marrow Failure Syndromes , Electron Transport Complex I/deficiency , Electron Transport Complex I/genetics , Female , Glutaredoxins/genetics , HSP70 Heat-Shock Proteins/genetics , Heme/biosynthesis , Humans , Lipid Metabolism, Inborn Errors , MELAS Syndrome , Male , Mitochondrial Diseases , Mitochondrial Membrane Transport Proteins/genetics , Mitochondrial Proteins/genetics , Muscular Diseases , MutationSubject(s)
Janus Kinase 2/genetics , Mutation , Myelodysplastic-Myeloproliferative Diseases/blood , Myelodysplastic-Myeloproliferative Diseases/genetics , Phosphoproteins/genetics , RNA Splicing Factors/genetics , Aged , Anemia, Sideroblastic/blood , Anemia, Sideroblastic/genetics , Erythroblasts/pathology , Female , Humans , Thrombocytosis/blood , Thrombocytosis/geneticsABSTRACT
Refractory anaemia with ring sideroblasts (RARS) is distinguished by hyperplastic inefficient erythropoiesis, aberrant mitochondrial ferritin accumulation and anaemia. Heterozygous mutations in the spliceosome gene SF3B1 are found in a majority of RARS cases. To explore the link between SF3B1 mutations and anaemia, we studied mutated RARS CD34(+) marrow cells with regard to transcriptome sequencing, splice patterns and mutational allele burden during erythroid differentiation. Transcriptome profiling during early erythroid differentiation revealed a marked up-regulation of genes involved in haemoglobin synthesis and in the oxidative phosphorylation process, and down-regulation of mitochondrial ABC transporters compared to normal bone marrow. Moreover, mis-splicing of genes involved in transcription regulation, particularly haemoglobin synthesis, was confirmed, indicating a compromised haemoglobinization during RARS erythropoiesis. In order to define the phase during which erythroid maturation of SF3B1 mutated cells is most affected, we assessed allele burden during erythroid differentiation in vitro and in vivo and found that SF3B1 mutated erythroblasts showed stable expansion until late erythroblast stage but that terminal maturation to reticulocytes was significantly reduced. In conclusion, SF3B1 mutated RARS progenitors display impaired splicing with potential downstream consequences for genes of key importance for haemoglobin synthesis and terminal erythroid differentiation.
Subject(s)
Anemia, Refractory/genetics , Anemia, Sideroblastic/genetics , Erythropoiesis/genetics , Hemoglobins/biosynthesis , Phosphoproteins/genetics , RNA Splicing/genetics , Ribonucleoprotein, U2 Small Nuclear/genetics , Aged , Aged, 80 and over , Anemia, Refractory/blood , Anemia, Sideroblastic/blood , Biological Transport/genetics , Gene Expression Profiling , Genes, Tumor Suppressor , Genetic Heterogeneity , Humans , Iron/metabolism , Phosphoproteins/physiology , Protein Isoforms/genetics , RNA Splicing Factors , RNA, Messenger/genetics , Ribonucleoprotein, U2 Small Nuclear/physiology , Sequence Analysis, RNA , Signal Transduction/geneticsABSTRACT
Sideroblastic anemias are a heterogeneous group of disorders characterized by anemia of varying severity and the presence of ringed sideroblasts in bone marrow. The most common form of inherited sideroblastic anemia is X-linked sideroblastic anemia (XLSA). In many XLSA patients, anemia responds variably to supplementation with pyridoxine (vitamin B6). We describe the case of a pregnant female with XLSA who had a novel mutation on the ALAS2 gene (c.1218G > T, p.Leu406Phe). Oral chelation therapy was contraindicated and high-dose vitamin B6 would have possible side effects in pregnancy. Serum hepcidin level was very low, indicating increased absorption of iron secondary to ineffective erythropoiesis. Therapy was begun with a low dose of pyridoxine that was increased post-partum. The patient's liver showed moderate iron deposits. During a subsequent 3-month period of pyridoxine supplementation, serum ferritin level and transferrin saturation decreased, hemoglobin content and serum hepcidin level normalized, and morphologic red cell abnormalities improved markedly. The patient responded well to treatment, showing the pyridoxine responsiveness of this novel ALAS2 mutation. The baby girl had the same mutation heterozygously, and although she was neither anemic nor showed abnormalities in a peripheral blood smear, she had a mild increment in RDW and her condition is now being followed.
Subject(s)
5-Aminolevulinate Synthetase/genetics , Anemia, Sideroblastic/genetics , Anemia, Sideroblastic/therapy , Genetic Diseases, X-Linked/genetics , Genetic Diseases, X-Linked/therapy , Pregnancy Complications, Hematologic/genetics , Pregnancy Complications, Hematologic/therapy , Adult , Anemia, Sideroblastic/blood , Anemia, Sideroblastic/complications , Female , Genetic Diseases, X-Linked/blood , Genetic Diseases, X-Linked/complications , Hematologic Tests , Hepcidins/blood , Humans , Infant, Newborn , Iron/blood , Iron Overload/blood , Iron Overload/complications , Mutation , Pregnancy , Pregnancy Complications, Hematologic/blood , Pyridoxine/therapeutic use , Vitamin B Complex/therapeutic useSubject(s)
Anemia, Sideroblastic/genetics , Frameshift Mutation , Genetic Diseases, X-Linked/genetics , Mitochondrial Membrane Transport Proteins/genetics , Anemia, Sideroblastic/blood , Anemia, Sideroblastic/diagnosis , Anemia, Sideroblastic/therapy , Biomarkers/blood , Blood Transfusion , Bone Marrow Examination , DNA Mutational Analysis , Female , Genetic Diseases, X-Linked/blood , Genetic Diseases, X-Linked/diagnosis , Genetic Diseases, X-Linked/therapy , Genetic Predisposition to Disease , Humans , Infant , PhenotypeABSTRACT
BACKGROUND: The presence of somatic mutations in splicing factor 3b subunit 1 (SF3B1) in patients with Myelodysplastic syndromes with ring sideroblasts (MDS-RS) highlights the importance of the RNA-splicing machinery in MDS. We previously reported the presence of bone marrow (BM) RS in Sf3b1 heterozygous (Sf3b1 (+/-)) mice which are rarely found in mouse models of MDS. Sf3b1 (+/-) mice were originally engineered to study the interaction between polycomb genes and other proteins. METHODS: We used routine blood tests and histopathologic analysis of BM, spleen, and liver to evaluate the hematologic and morphologic characteristics of Sf3b1 (+/-) mice in the context of MDS by comparing the long term follow-up (15 months) of Sf3b1 (+/-) and Sf3b1 (+/+) mice. We then performed a comprehensive RNA-sequencing analysis to evaluate the transcriptome of BM cells from Sf3b1 (+/-) and Sf3b1 (+/+) mice. RESULTS: Sf3b1 (+/-) exhibited macrocytic anemia (MCV: 49.5 ± 1.6 vs 47.2 ± 1.4; Hgb: 5.5 ± 1.7 vs 7.2 ± 1.0) and thrombocytosis (PLTs: 911.4 ± 212.1 vs 878.4 ± 240.9) compared to Sf3b1 (+/+) mice. BM analysis showed dyserythropoiesis and occasional RS in Sf3b1 (+/-) mice. The splenic architecture showed increased megakaryocytes with hyperchromatic nuclei, and evidence of extramedullary hematopoiesis. RNA-sequencing showed higher expression of a gene set containing Jak2 in Sf3b1 (+/-) compared to Sf3b1 (+/+). CONCLUSIONS: Our study indicates that Sf3b1 (+/-) mice manifest features of low risk MDS-RS and may be relevant for preclinical therapeutic studies.
Subject(s)
Anemia, Sideroblastic/genetics , Phosphoproteins/genetics , Ribonucleoprotein, U2 Small Nuclear/genetics , Anemia, Sideroblastic/blood , Animals , Disease Models, Animal , Female , Genotype , Haploinsufficiency/genetics , Humans , Male , Mice , Mice, Transgenic , Phosphoproteins/blood , RNA Splicing , RNA Splicing Factors , Ribonucleoprotein, U2 Small Nuclear/blood , Risk FactorsSubject(s)
5-Aminolevulinate Synthetase/genetics , Anemia, Sideroblastic/genetics , Genetic Diseases, X-Linked/genetics , Mutation, Missense/genetics , Anemia, Sideroblastic/blood , Child , Chromosomes, Human, X/genetics , Erythrocytes , Genetic Diseases, X-Linked/blood , Hemizygote , Heterozygote , Humans , MaleABSTRACT
BACKGROUND: X-linked sideroblastic anaemia (XLSA; OMIM#300751) is the most common inherited form of sideroblastic anaemia and is associated with several mutations in the erythroid specific 5-aminolevulinate synthase gene (ALAS2). This gene encodes for aminolevulinic acid synthase 2 (ALAS2), the catalytic enzyme involved in the first en rate-limiting step of haem biosynthesis.1-3 The disorder is characterised by mostly mild hypochromic microcytic anaemia with bone marrow ring sideroblasts. Even untransfused patients with mild or no anaemia are at risk for severe systemic iron overload due to ineffective erythropoiesis. To date, 61 different ALAS2 mutations have been reported in 120 families with XLSA. Descriptions of molecularly confirmed case series from the Netherlands, however, are lacking. METHODS: We reviewed age of presentation, clinical and biochemical features, ALASâ2 defects and treatment characteristics of 15 Dutch patients from 11 unrelated families diagnosed with XLSA. RESULTS AND CONCLUSIONS: In one family a novel pathogenic c.1412G>A (p.Cys471Tyr) mutation was found. All other families shared the previously described c.1355G>A (p.Arg452His) mutation. Haplotype analysis in seven probands with the p.Arg452His mutation strongly suggests that six of them were ancestrally related. Nevertheless, their phenotype was very different. Our patients illustrate the phenotypical heterogeneity in the presentation of XLSA patients, the effectiveness of treatment regimens and the various pitfalls associated with the diagnosis, follow-up and treatment of the disease. A timely diagnosis avoids unnecessary investigations and allows adequate treatment that can prevent systemic iron load with subsequent severe life-threatening complications. Therefore, we suggest considering XLSA in both male and female patients with unexplained iron overload and÷or (mild) microcytic anaemia, also at older age.
Subject(s)
5-Aminolevulinate Synthetase/genetics , Anemia, Sideroblastic/epidemiology , Anemia, Sideroblastic/genetics , Genetic Diseases, X-Linked/epidemiology , Genetic Diseases, X-Linked/genetics , Adolescent , Adult , Age of Onset , Aged , Anemia, Sideroblastic/blood , Canthaxanthin , Child , Child, Preschool , Drug Combinations , Erythrocyte Indices , Female , Ferritins/blood , Genetic Diseases, X-Linked/blood , Genotype , Hemoglobins/metabolism , Humans , Male , Middle Aged , Mutation , Netherlands/epidemiology , Pyridoxine/therapeutic use , Vitamin B Complex/therapeutic use , Young Adult , beta CaroteneABSTRACT
X-linked sideroblastic anemia (XLSA) is the most common form of congenital sideroblastic anemia. In affected males, it is uniformly associated with partial loss-of-function missense mutations in the erythroid-specific heme biosynthesis protein 5-aminolevulinate synthase 2 (ALAS2). Here, we report five families with XLSA owing to mutations in a GATA transcription factor binding site located in a transcriptional enhancer element in intron 1 of the ALAS2 gene. As such, this study defines a new class of mutations that should be evaluated in patients undergoing genetic testing for a suspected diagnosis of XLSA.