Kelsey Uminski1, Donald S Houston2, Jessica N Hartley3, Jing Liu3, Geoffrey D E Cuvelier4, Sara J Israels4. 1. Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada. 2. Department of Internal Medicine, Section of Hematology and Medical Oncology, University of Manitoba, Winnipeg, Manitoba, Canada. 3. Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada. 4. Departments of Pediatric Hematology-Oncology, Cancer Care Manitoba, and Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba, Canada.
Abstract
BACKGROUND: Congenital sideroblastic anemia (CSA) constitutes an uncommon category of inherited anemia often associated with pathologic iron accumulation. Pathogenic variants in several genes have been identified as causative for CSA. Autosomal recessive pathogenic variants in the mitochondrial glycine transporter SLC25A38 have been implicated in a subset of patients with CSA. PROCEDURE: We describe seven individuals of Canadian Cree descent with a known or inferred homozygous novel founder missense variant in SLC25A38 (c.560G>A, p.Arg187Gln). RESULTS: All individuals presented as young children (median age 6 months) with severe microcytic, hypochromic anemia associated with pretransfusion iron overload, requiring red cell transfusion support and iron chelation. Six individuals received pyridoxine supplementation; two demonstrating transient partial responses. Three individuals underwent allogeneic hematopoietic stem cell transplantation (HSCT). One individual with significant iron loading died in the posttransplant period due to complications of sepsis. The other two individuals remain transfusion-free following HSCT. CONCLUSIONS: Despite a common genetic etiology, phenotypic variability was noted in this cohort. A transient response to pyridoxine was noted in two individuals but should not be considered a long-term therapeutic strategy. HSCT was curative when performed before significant iron loading occurred. Early identification of CSA and timely HSCT can result in excellent long-term outcomes.
BACKGROUND:Congenital sideroblastic anemia (CSA) constitutes an uncommon category of inherited anemia often associated with pathologic iron accumulation. Pathogenic variants in several genes have been identified as causative for CSA. Autosomal recessive pathogenic variants in the mitochondrial glycine transporter SLC25A38 have been implicated in a subset of patients with CSA. PROCEDURE: We describe seven individuals of Canadian Cree descent with a known or inferred homozygous novel founder missense variant in SLC25A38 (c.560G>A, p.Arg187Gln). RESULTS: All individuals presented as young children (median age 6 months) with severe microcytic, hypochromic anemia associated with pretransfusion iron overload, requiring red cell transfusion support and iron chelation. Six individuals received pyridoxine supplementation; two demonstrating transient partial responses. Three individuals underwent allogeneic hematopoietic stem cell transplantation (HSCT). One individual with significant iron loading died in the posttransplant period due to complications of sepsis. The other two individuals remain transfusion-free following HSCT. CONCLUSIONS: Despite a common genetic etiology, phenotypic variability was noted in this cohort. A transient response to pyridoxine was noted in two individuals but should not be considered a long-term therapeutic strategy. HSCT was curative when performed before significant iron loading occurred. Early identification of CSA and timely HSCT can result in excellent long-term outcomes.
Authors: Matthew M Heeney; Simon Berhe; Dean R Campagna; Joseph H Oved; Peter Kurre; Peter J Shaw; Juliana Teo; Mayada A Shanap; Hoda M Hassab; Bertil E Glader; Sanjay Shah; Ayami Yoshimi; Afshin Ameri; Joseph H Antin; Jeanne Boudreaux; Michael Briones; Kathryn E Dickerson; Conrad V Fernandez; Roula Farah; Henrik Hasle; Sioban B Keel; Timothy S Olson; Jacquelyn M Powers; Melissa J Rose; Akiko Shimamura; Sylvia S Bottomley; Mark D Fleming Journal: Hum Mutat Date: 2021-08-05 Impact factor: 4.878