Clinical Characterization of a Novel Mutation in SLC25A38 Resulting in Congenital Sideroblastic Anemia in a Canadian First Nations Population

Introduction: Congenital sideroblastic anemia (CSA) is an uncommon cause of inherited anemia characterized by pathologic iron accumulation. Severity of anemia and blood transfusion requirements are variable. Aberrations in iron-heme metabolism that underpin CSA result in iron overload, often preceding transfusion. The only curative therapy for CSA is hematopoietic stem cell transplantation (HSCT), offered to select patients with severe transfusion dependent anemia. Mutations in several genes have been identified to be responsible for CSA. Mutations in SLC25A38, encoding a mitochondrial glycine transporter required for heme biosynthesis, are a rare cause of CSA. Homozygosity for a novel founder missense mutation in SLC25A38 (c.560G>A) has been detected in a Canadian First Nations Northern Cree population. The associated phenotype is a severe anemia presenting in infancy and characterized by ineffective erythropoiesis and iron loading. The natural history and treatment outcomes of CSA caused by the c.560G>A mutation have not been described.

Objectives: (1) To characterize the clinical features in patients homozygous for this founder mutation, including propensity to iron loading and (2) to describe the treatment course and outcomes for red cell transfusion, iron chelation, pyridoxine supplementation and HSCT.

Methods: A retrospective chart review was conducted at the Winnipeg Health Sciences Centre and CancerCare Manitoba of all affected individuals homozygous for the c.560G>A mutation in SLC25A38.

Results: Seven affected individuals (three females and four males) were identified. Comorbidities including dextrocardia, hypertrophic cardiomyopathy, rheumatoid arthritis and global developmental delay were noted in three members of the kindred, but there was no evidence of a syndromic form of CSA. The median age of presentation with anemia was 6 months (24 days - 4.4 years). The median age of CSA diagnosis was 1.5 years (6 months - 22 years). Alternative causes of anemia were initially suspected in five of the seven patients: iron deficiency, resulting in oral iron supplementation, and alpha thalassemia. Uniformly, individuals presented with a microcytic, hypochromic anemia, with elevated ferritin prior to first red cell transfusion. All affected individuals required red cell transfusion support, with six of seven patients requiring chronic transfusions at a median frequency of every four weeks. One individual, though chronically anemic, did not require regular transfusion support until the age of 20 years. One patient carried a successful pregnancy with transfusion support, but delivered prematurely. For all individuals, iron chelation was recommended, with six individuals starting chelation within three years of initiation of transfusions. Hepatic, cardiac, pituitary and pancreatic iron overload, and resultant organ dysfunction were noted in two subjects who did not adhere to chelation; one died of neutropenic sepsis after starting deferiprone for cardiac iron overload. Six individuals were given trials of pyridoxine supplementation, with two demonstrating a transient partial response with a rise in reticulocyte count and decrease in transfusion frequency. Three individuals underwent allogeneic HSCT (two from matched sibling donors, and one from a matched unrelated donor), at 5.5 years, 7.2 years, and 28 years. The oldest and most iron-loaded of the three died in the post-transplant period due to complications of sepsis. The other two individuals remain transfusion free, at 9 months and 15.6 years post-HSCT.

Conclusions: A novel founder mutation in SLC25A38 causing CSA among individuals of Canadian First Nations Northern Cree descent results in a severe transfusion-dependent anemia. Despite a common genetic etiology, phenotypic variability was noted, with one individual having marked tolerance to anemia. A partial transient response to pyridoxine was noted in two individuals, raising the question of an alternative role for SLC25A38 in heme biosynthesis. HSCT, when performed before significant iron overloading, was beneficial. Characterization of this phenotype and evidence of successful HSCT may assist clinicians in identifying affected individuals with CSA and initiating timely and effective treatment.