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Resident PGY 2
Henry Ford Hospital
Learning Objective: Novel phenotype of hemolytic anemia with simultaneous mutations of SPTA1 c.6531-12C>T and SLC4A1 Pro868LeuCase: A 33-year-old male with no prior medical history presented with dizziness, diaphoresis and near syncope. On evaluation, hemoglobin was noted to be 6.1, Ultrasound of the abdomen showed splenomegaly measuring 18 cm. Anemia work up revealed a low haptoglobin <30, reticulocytosis, hyperbilirubinemia and high LDH. Coombs test was negative. Peripheral smear showed elliptocytosis without fragmented red blood cells. These findings were consistent with non-immune hemolytic anemia. Pertinent negative studies include monoclonal protein, antinuclear antibody, rheumatoid factor, Epstein Barr Virus, Cytomegalovirus, human immunodeficiency virus, and Coombs antibody. The patient was transfused packed red blood cells and hemoglobin improved to 9.7 prior to discharge from the hospital. He also underwent bone marrow biopsy that showed a hypercellular marrow and erythroid predominance, but with very mild dyserythropoiesis. Continued work up included hemoglobin electrophoresis, glucose-6-phosphate dehydrogenase, pyruvate kinase, and paroxysmal nocturnal hemoglobinuria all resulted negative. With the diagnosis of elliptocytosis, he underwent splenectomy which showed reactive splenomegaly and red pulp expansion. Following splenectomy, his hemoglobin normalized. Red blood cell membrane studies were also negative. Genetic testing revealed mutations of SPTA1 c.6531-12C>T and SLC4A1 Pro868Leu.Discussion: Mutation of SPTA1 c.6531-12C>T encodes for the protein spectrin and can cause a worse phenotype of hemolytic anemia in patients with elliptocytosis or poikilocytosis. SLC4A1 Pro868Leu is seen in acanthocytosis and encodes for band 3, a protein on the red blood cell membrane involved in ion exchange. These mutations have not been reported together before but we cannot rule out that even though they are not pathogenic standing alone, that they could cause hemolysis when found together. Of the various types of non-immune hemolytic anemias, aberrations in spectrin has been shown to be associated with various membrane defects ranging from spherocytosis to poikilocytosis1. Mutations in the anion exchanger SLC4A1 Pro868Leu has be shown to result in disturbances that can disrupt membrane ion equilibrium leading to acanthocytosis. Like this channel, SLC4AE is involved in ion exchange and connects to other proteins that compose the cytoskeleton of red blood cells, stabilizing the structure1. A mutation of this channel would lead to disturbance in the red cell membrane leading to abnormalities such as acanthocytosis. Mutation of SPTA1 c.6531-12C>T has been associated with a worse phenotype of hemolytic anemia in patient’s red cell membrane abnormalities. Many mutations in the SPTA1 gene affect the interaction sites of the alpha and beta spectrin molecules, leading to elliptocytosis2. Conversely, mutation at other sites can lead to pyropoikilocytosis and spherocytosis. The SPTA1 homozygous mutation showed signs of disruption at the cellular level whereas the heterozygous parents were absent of abnormalities clinically2. There are no cited cases of these two simultaneous mutations. Together these two heterozygous mutations in the same individual could lead an observable phenotype. This information can provide a proposed hypothesis for future research involving red cell membrane disorders. Furthermore, this information can be applied to future studies studying novel mutations and the impact on red cell membrane stability.
Nair, Vidhya; Cabrera-Fernandez, Diego; and Donthireddy, Vijayalakshmi, "Hemolytic anemia with mutations SPTA1 c.6531-12C>T and SLC4A1 Pro868Leu" (2019). Case Reports. 59.