The interplay between drivers of erythropoiesis and iron homeostasis in rare hereditary anemias: Tipping the balance

Rare hereditary anemias (RHA) represent a group of disorders characterized by either impaired production of erythrocytes or decreased survival (i.e., hemolysis). In RHA, the regulation of iron metabolism and erythropoiesis is often disturbed, leading to iron overload or worsening of chronic anemia due to unavailability of iron for erythropoiesis. Whereas iron overload generally is a well-recognized complication in patients requiring regular blood transfusions, it is also a significant problem in a large proportion of patients with RHA that are not transfusion dependent. This indicates that RHA share disease-specific defects in erythroid development that are linked to intrinsic defects in iron metabolism. In this review, we discuss the key regulators involved in the interplay between iron and erythropoiesis and their importance in the spectrum of RHA

Untargeted metabolic profiling in dried blood spots identifies disease fingerprint for pyruvate kinase deficiency

The diagnostic evaluation and clinical characterization of rare hereditary anemia (RHA) is to date still challenging. In particular, there is little knowledge of the broad metabolic impact of many of the molecular defects underlying RHA. In this study we explored the potential of untargeted metabolomics to diagnose a relatively common type of RHA: pyruvate kinase deficiency (PKD). In total, 1,903 unique metabolite features were identified in dried blood spot samples from 16 PKD patients and 32 healthy controls. A metabolic fingerprint was identified using a machine learning algorithm, and subsequently a binary classification model was designed. The model showed high performance characteristics (AUC 0.990, 95% CI: 0.981-0.999) and an accurate class assignment was achieved for all newly added control (n=13) and patient samples, (n=6) with the exception of one patient (accuracy 94%). Important metabolites in the metabolic fingerprint included glycolytic intermediates, polyamines and several acyl carnitines. In general, the application of untargeted metabolomics in dried blood spots is a novel functional tool that holds promise for the diagnostic stratification and studies on the disease pathophysiology in RHA

Diamond Blackfan anemia & other hereditary red cell disorders: spotting phenotypes

Research in this thesis was conducted to contribute to the phenotypic characterization of hereditary anemias, in particular of Diamond-Blackfan anemia (DBA). Phenotyping is at the root of recognizing and understanding disorders by forming the contextual framework whereupon research and care can be commenced. The clinical phenotype that patients endure is the ultimate culmination of the genetic background and pathophysiological processes they evoke, and recognizing the phenotypic spectrum in these rare disorders is crucial for both the diagnostic evaluation as well as long term clinical treatment. In the first and third part of this thesis we focus on DBA, a rare bone marrow failure disorder with a broad range of underlying molecular defects and clinical phenotypes. Since registries have historically proven to be crucial in increasing disease understanding, we established the Dutch DBA Registry (DBAN) and created a comprehensive overview of 43 patients. Further on, we used DBAN to address iron overload, an important and understudied complication in DBA, and show that iron overload occurs often, even in patients wild only mildly elevated ferritin levels. In the second part of this thesis we explored the fairly uncharted omics layer of ‘metabolomics’ in the field of rare hereditary anemias. In the studies that are presented in this part of the thesis, we employed untargeted metabolomics to define disease specific metabolic signatures for the hereditary anemias pyruvate kinase deficiency, DBA and hereditary spherocytosis and show this could serve both future diagnostic potential as well as generate novel insights into the pathophysiology of these disorders

GATA-1 Defects in Diamond–Blackfan Anemia: Phenotypic Characterization Points to a Specific Subset of Disease

Diamond–Blackfan anemia (DBA) is one of the inherited bone marrow failure syndromes marked by erythroid hypoplasia. Underlying variants in ribosomal protein (RP) genes account for 80% of cases, thereby classifying DBA as a ribosomopathy. In addition to RP genes, extremely rare variants in non-RP genes, including GATA1, the master transcription factor in erythropoiesis, have been reported in recent years in patients with a DBA-like phenotype. Subsequently, a pivotal role for GATA-1 in DBA pathophysiology was established by studies showing the impaired translation of GATA1 mRNA downstream of the RP haploinsufficiency. Here, we report on a patient from the Dutch DBA registry, in which we found a novel hemizygous variant in GATA1 (c.220+2T>C), and an Iranian patient with a previously reported variant in the initiation codon of GATA1 (c.2T>C). Although clinical features were concordant with DBA, the bone marrow morphology in both patients was not typical for DBA, showing moderate erythropoietic activity with signs of dyserythropoiesis and dysmegakaryopoiesis. This motivated us to re-evaluate the clinical characteristics of previously reported cases, which resulted in the comprehensive characterization of 18 patients with an inherited GATA-1 defect in exon 2 that is presented in this case-series. In addition, we re-investigated the bone marrow aspirate of one of the previously published cases. Altogether, our observations suggest that DBA caused by GATA1 defects is characterized by distinct phenotypic characteristics, including dyserythropoiesis and dysmegakaryopoiesis, and therefore represents a distinct phenotype within the DBA disease spectrum, which might need specific clinical management

The postgraduate medical education pathway: an international comparison

An at first sight seemingly coherent, global medical workforce, with clearly recognizable specialities, subspecialties and primary care doctors, appears at a closer look quite variable. Even within the most progressive countries as to the development of medical education, with educators who regularly meet at conferences and share major journals about medical education, the differences in structures and regulations are big. This contribution focuses on the preparation, admission policy, duration, examinations, and national competency frameworks in postgraduate speciality training in Germany, the USA, Canada, the UK, Australia and the Netherlands. While general objectives for postgraduate training programs have not been very clear, only recently competency-frameworks, created in a limited number of countries, serve harmonize objectives. This process appears to be a challenge and the recent creation of milestones for the reporting on progress of individual trainees (in the US and in Canada in different ways) and the adoption of entrustable professional activities, a most recent concept that is quickly spreading internationally as a framework for teaching and assessing in the clinical workplace is an interesting and hopeful development, but time will tell whether true harmonization across countries will happen

The Interplay between Drivers of Erythropoiesis and Iron Homeostasis in Rare Hereditary Anemias: Tipping the Balance

Rare hereditary anemias (RHA) represent a group of disorders characterized by either impaired production of erythrocytes or decreased survival (i.e., hemolysis). In RHA, the regulation of iron metabolism and erythropoiesis is often disturbed, leading to iron overload or worsening of chronic anemia due to unavailability of iron for erythropoiesis. Whereas iron overload generally is a well-recognized complication in patients requiring regular blood transfusions, it is also a significant problem in a large proportion of patients with RHA that are not transfusion dependent. This indicates that RHA share disease-specific defects in erythroid development that are linked to intrinsic defects in iron metabolism. In this review, we discuss the key regulators involved in the interplay between iron and erythropoiesis and their importance in the spectrum of RHA

GATA-1 Defects in Diamond-Blackfan Anemia : Phenotypic Characterization Points to a Specific Subset of Disease

Diamond-Blackfan anemia (DBA) is one of the inherited bone marrow failure syndromes marked by erythroid hypoplasia. Underlying variants in ribosomal protein (RP) genes account for 80% of cases, thereby classifying DBA as a ribosomopathy. In addition to RP genes, extremely rare variants in non-RP genes, including GATA1, the master transcription factor in erythropoiesis, have been reported in recent years in patients with a DBA-like phenotype. Subsequently, a pivotal role for GATA-1 in DBA pathophysiology was established by studies showing the impaired translation of GATA1 mRNA downstream of the RP haploinsufficiency. Here, we report on a patient from the Dutch DBA registry, in which we found a novel hemizygous variant in GATA1 (c.220+2T>C), and an Iranian patient with a previously reported variant in the initiation codon of GATA1 (c.2T>C). Although clinical features were concordant with DBA, the bone marrow morphology in both patients was not typical for DBA, showing moderate erythropoietic activity with signs of dyserythropoiesis and dysmegakaryopoiesis. This motivated us to re-evaluate the clinical characteristics of previously reported cases, which resulted in the comprehensive characterization of 18 patients with an inherited GATA-1 defect in exon 2 that is presented in this case-series. In addition, we re-investigated the bone marrow aspirate of one of the previously published cases. Altogether, our observations suggest that DBA caused by GATA1 defects is characterized by distinct phenotypic characteristics, including dyserythropoiesis and dysmegakaryopoiesis, and therefore represents a distinct phenotype within the DBA disease spectrum, which might need specific clinical management