The Spectrum of SPTA1-Associated Hereditary Spherocytosis

Abstract

Hereditary spherocytosis (HS) is the most common red blood cell (RBC) membrane disorder causing hereditary hemolytic anemia. Patients with HS have defects in the genes coding for ankyrin ( ANK1 ), band 3 ( SLC4A1 ), protein 4.2 ( EPB42 ), and α ( SPTA1 ) or β-spectrin ( SPTB ). Severe recessive HS is most commonly due to biallelic SPTA1 mutations. α-spectrin is produced in excess in normal erythroid cells, therefore SPTA1 -associated HS ensues with mutations causing significant decrease of normal protein expression from both alleles. In this study, we systematically compared genetic, rheological, and protein expression data to the varying clinical presentation in eleven patients with SPTA1 -associated HS. The phenotype of HS in this group of patients ranged from moderately severe to severe transfusion-dependent anemia and up to hydrops fetalis which is typically fatal if transfusions are not initiated before term delivery. The pathogenicity of the mutations could be corroborated by reduced SPTA1 mRNA expression in the patients’ reticulocytes. The disease severity correlated to the level of α-spectrin protein in their RBC cytoskeleton but was also affected by other factors. Patients carrying the low expression α LEPRA allele in trans to a null SPTA1 mutation were not all transfusion dependent and their anemia improved or resolved with partial or total splenectomy, respectively. In contrast, patients with near-complete or complete α-spectrin deficiency have a history of having been salvaged from fatal hydrops fetalis , either because they were born prematurely and started transfusions early or because they had intrauterine transfusions. They have suboptimal reticulocytosis or reticulocytopenia and remain transfusion dependent even after splenectomy; these patients require either lifetime transfusions and iron chelation or stem cell transplant. Comprehensive genetic and phenotypic evaluation is critical to provide accurate diagnosis in patients with SPTA1 -associated HS and guide toward appropriate management.

Hereditary spherocytosis overlooked for 7 years in a pediatric patient with β-thalassemia trait and novel compound heterozygous mutations of SPTA1 gene

“…Therefore, a single heterozygous mutation in the SPTA1 gene can still synthesize enough α-spectrin to balance β-spectrin and maintain the erythrocyte skeleton, without obvious abnormal erythrocytes in the peripheral blood and clinical manifestations. Only homozygous or compound heterozygous mutations might be involved in the pathogenesis of recessive spectrum protein-deficient HS, and its severity is associated with the amount of α-spectrin in the erythrocyte membrane skeleton [19,20]. The production of <25% α-spectrin results in diseases [21].…”

Transcriptome Research of Key Modules and Hub Genes Associated with Primary Myelofibrosis by Weighted Co-expression Network Analysis.

“…EPB42, erythrocyte membrane protein band 4.2, was an ATP-binding protein which may regulate the correlation of protein 3 with ankyrin. It was reported that EPB42 could manipulate the shape and mechanical property of erythrocyte and have a high association with hereditary spherocytosis [40,41]. SLC4A1, the protein encoded by this gene was part of the anion exchanger family and was expressed in the erythrocyte plasma membrane.…”

How I approach hereditary hemolytic anemia and splenectomy

“…At initial consultation, prednisone wean was initiated and diagnosis was re‐evaluated by genetic testing, since reliable RBC phenotypic evaluation was not feasible due to his transfusion dependency. HHA gene panel demonstrated that he had autosomal recessive HS with biallelic SPTA1 mutations (a premature termination: c.5102A>T; p.L1701* in trans to the low expression PRAgue allele α LEPRA ) 6 . After discussions with the family regarding risks and benefits of partial versus total splenectomy, a partial splenectomy was performed.…”

“…Partial or total splenectomy in HS results, respectively, in improvement or complete resolution of anemia, except for the rare cases of complete alpha‐spectrin deficiency, due to biallelic null SPTA1 mutations, which have no improvement with splenectomy and are currently treated either with chronic transfusions and chelation or with hematopoietic stem cell transplant (HSCT) 6 . Based on data being collected from registries for rare diseases, splenectomy for severe PKD or CDA‐II may just offer a temporary transfusion relief during childhood, but typically does not correct anemia.…”

“…With the rationale that destruction of abnormal RBCs occurs as they pass through the interendothelial sinusoidal slits followed by phagocytosis by the macrophages of the splenic red‐pulp, 4 splenectomy has been used for decades with the aim to decrease hemolysis and improve anemia in HHAs. However, recent advancements in the field, including improved diagnostic work‐up with genetic testing that frequently enables pinpointing of the diagnosis, 5‐7 available follow‐up data on the efficacy of partial splenectomy in patients with HHA, 8‐11 and increased awareness of postsplenectomy vascular complications, such as thrombosis and pulmonary hypertension, 12 suggest that it is a good time to review the applicability, efficacy, safety, and choice of partial versus total splenectomy as therapeutic approach for the patients with HHA.…”