New Genetic Abnormality in a Family with Suspected Congenital Sideroblastic Anemia
Prosjekt
- Prosjektnummer
- 911908
- Ansvarlig person
- Astrid Olsnes Kittang
- Institusjon
- Helse Bergen HF
- Prosjektkategori
- Korttidsprosjekt
- Helsekategori
- Blood, Cancer, Congenital Disorders
- Forskningsaktivitet
- 2. Aetiology, 4. Detection and Diagnosis
Rapporter
Anemia with presence of ring sideroblasts in the bone marrow is called sideroblastic anemia. It can be congenital (CSA) or neoplastic sideroblastic anemia (a type of myelodysplastic syndrome, MDS), the latter only cured by allogeous stem cell transplantation (ASCT). It is important to distinguish between CSA and MDS to select patients for ASCT.The presence of ring sideroblasts (RS) in the bone marrow of a patient whose haemoglobin level is below normal is called sideroblastic anemia. One discriminates between congenital sideroblastic anemia (CSA) and acquired anemia with ring sideroblasts, usually myelodysplastic syndromes (MDS) with RS. MDS is a group of clonal bone marrow stem cell diseases. Approximately one fourth of MDS-patients develop acute myeloid leukemia (AML), a blood cancer with poor prognosis, especially when arising secondarily to MDS. The only curative therapy for MDS is allogeneic stem cell transplantation (ASCT), an intensive therapy with treatment-related mortality in MDS between thirty and forty percent. Results are best when patients are transplanted before progression to AML, and younger patients with intermediate- or high-risk MDS should always be considered for ASCT. To ensure right selection of patients for ASCT it is of great importance to distinguish between patients who have mild CSA and patients with neoplastic sideroblastic anemia. In acquired anemia, RS can be a result of the action of toxins on the bone marrow, or they can be a feature associated with a dysplastic clone derived from a mutated bone marrow stem cell. In MDS, the subgroups RARS and RCMD-RS are distinguished from other MDS subgroups by the presence of 15 % or more RS. The splicing factor mutation SF3B1 is in the majority of MDS-cases associated with the presence of RS. CSA can be part of a hereditary syndrome with involvement of other organ systems (e.g. the central nervous system or endocrine organs), or it can be non-syndromic. There are two major groups of non-syndromic CSA, X-linked sideroblastic anemia (XLSA) (MIM ID # 300751), where the patients usually respond to treatment with pyridoxine, and autosomal recessive pyridoxine-refractory sideroblastic anemia (MIM ID #205950). Mutated genes identified in the latter form are GLRX5 (chromosome 14q32) and SLC25A38 (chromosome 3p22.1), whereas XLSA is defined by the presence of mutated ALAS2, located on chromosome Xp11.21. XLSA is usually a mild condition not requiring intensive treatment, whereas the pyridoxine-refractory types early become transfusion dependent with necessity of iron chelation or even ASCT. A young patient with the diagnosis of MDS with RS was consulted at the out-patient clinic at Haukeland University Hospital. There was a history of anemia in the family. The patients DNA was therefore exome sequenced in the diagnostic interest of searching for a potential new gene associated with CSA, which could let the patient live a relatively normal life without fearing the natural course of MDS or necessity of undergoing ASCT. The results from this analysis indicated a possible new germline mutation in the patient’s DNA. To confirm if the genetic aberration is associated with CSA, we will perform high-throughput sequencing of the total coding DNA (exome sequencing) of family members. Targeted sequencing did not show SF3B1-mutation. To search for functional defects to narrow the molecular genetic search, iron-dependent metabolism and mitochondrial function in cells from the index patient compared to patients with MDS and to healthy donors will be evaluated. Genetic anamnesis and counseling has been performed by Dr. Hildegunn Vetti. Medical student Mette Wold Eriksrud will write a student project thesis based on the findings. Our collaborators at Karolinska Institutet are prof. Eva Hellström-Lindberg and dr. Mohsen Karimi.
Anemia with presence of ring sideroblasts in the bone marrow is called sideroblastic anemia. It can be congenital (CSA) or neoplastic sideroblastic anemia (a type of myelodysplastic syndrome, MDS), the latter only cured by allogeous stem cell transplantation (ASCT). It is important to distinguish between CSA and MDS to select patients for ASCT.The presence of ring sideroblasts in the bone marrow of a patient whose haemoglobin level is below normal is called sideroblastic anemia. One discriminates between congenital sideroblastic anemia (CSA) and acquired anemia with ring sideroblasts, usually myelodysplastic syndromes (MDS) with ring sideroblasts. MDS is a group of clonal bone marrow stem cell diseases. Approximately one fourth of MDS-patients develop acute myeloid leukemia (AML), a blood cancer with poor prognosis, especially when arising secondarily to MDS. The only curative therapy for MDS is allogeneic stem cell transplantation (ASCT), an intensive therapy with treatment-related mortality in MDS between thirty and forty percent. Results are usually best when patients are transplanted before progression to AML, and younger patients with intermediate- or high-risk MDS should always be considered for ASCT. To ensure the right selection of patients for ASCT it is of great importance to distinguish between patients who have mild CSA and patients with neoplastic sideroblastic anemia. Ring sideroblasts are defined as erythroid precursor cells (called normoblasts or erythroblasts) containing more than four iron granules surrounding at least one third of the circumference of the nucleus, as seen by iron staining. In acquired anemia, these cells can be a result of the action of toxins on the bone marrow, or they can be a feature associated with a dysplastic clone derived from a mutated bone marrow stem cell. In MDS, the subgroups RARS and RCMD-RS are distinguished from other MDS subgroups by the presence of 15 % or more ring sideroblasts. The splicing factor mutation SF3B1 is in the majority of MDS-cases associated with the presence of ring sideroblasts. CSA can be part of a hereditary syndrome with involvement of other organ systems (e.g. the central nervous system or endocrine organs), or it can be non-syndromic. There are two major groups of non-syndromic CSA, X-linked sideroblastic anemia (XLSA) (MIM ID # 300751), where the patients usually respond to treatment with pyridoxine, and autosomal recessive pyridoxine-refractory sideroblastic anemia (MIM ID #205950). Mutated genes identified in the latter form are GLRX5 (chromosome 14q32) and SLC25A38 (chromosome 3p22.1), whereas XLSA is defined by the presence of mutated ALAS2, located on chromosome Xp11.21. XLSA is usually a mild condition not requiring intensive treatment, whereas the pyridoxine-refractory types early become transfusion dependent with necessity of iron chelation or even ASCT. A young patient with the diagnosis of MDS was consulted at the out-patient clinic at Haukeland University Hospital. There was a history of anemia in the family. The patients DNA was therefore exome sequenced in the diagnostic interest of searching for a potential new gene associated with CSA, which could let the patient live a relatively normal life without fearing the natural course of MDS or necessity of undergoing ASCT. The results from this analysis indicated a possible new germline mutation in the patient’s DNA. To confirm if the genetic aberration is associated with CSA, we will perform high-throughput sequencing of the total coding DNA (exome sequencing) of family members. Genetic anamnesis and counseling has been performed by Dr. Hildegunn Vetti.Medical student Mette Wold Eriksrud will write a student project thesis based on the findings, and has so far been involved in microscopic evaluation of bone marrow from the family members.
Deltagere
- Hildegunn Høberg Vetti Prosjektdeltaker
- Astrid Olsnes Kittang Prosjektleder
- Mette Wold Eriksrud Prosjektdeltaker
eRapport er utarbeidet av Sølvi Lerfald og Reidar Thorstensen, Regionalt kompetansesenter for klinisk forskning, Helse Vest RHF, og videreutvikles av de fire RHF-ene i fellesskap, med støtte fra Helse Vest IKT
Alle henvendelser rettes til Faglig rapportering, Helse Vest