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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 ? (SPTA1) or ?-spectrin (SPTB). Severe recessive HS is most commonly due to biallelic SPTA1 mutations. ?-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 ?-spectrin protein in their RBC cytoskeleton but was also affected by other factors. Patients carrying the low expression ?^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 ?-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.

SUBMITTER: Chonat S

PROVIDER: S-EPMC6617536 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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The Spectrum of SPTA1-Associated Hereditary Spherocytosis.

Chonat Satheesh S Risinger Mary M Sakthivel Haripriya H Niss Omar O Rothman Jennifer A JA Hsieh Loan L Chou Stella T ST Kwiatkowski Janet L JL Khandros Eugene E Gorman Matthew F MF Wells Donald T DT Maghathe Tamara T Dagaonkar Neha N Seu Katie G KG Zhang Kejian K Zhang Wenying W Kalfa Theodosia A TA

Frontiers in physiology 20190703

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 ...[more]

PMID: 31333484

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Project description:Hereditary spherocytosis (HS) is not a rare disease in the department of hematology; however, in the late stage of the disease, patients often have very severe cholestasis and are referred to the department of hepatology. Hepatologists may have trouble determining the source of cholestasis, causing treatment difficulties. We report two 20-year-old patients complaining of "skin and eyes turned to yellow". Patient 1 had no previous hematologic disorders, and patient 2 had a history of anemia without treatment. Laboratory tests suggested anemia and elevated bilirubin in both patients. The direct bilirubin levels were more significantly elevated than the indirect bilirubin levels in both patients, and the patients both suffered from abdominal pain and pancreatitis. However, the degree of anemia could not fully explain the jaundice. Magnetic resonance imaging findings suggested the presence of hepatosplenomegaly and gallstones. Genetic testing identified new mutations in the relevant genes, ultimately confirming the diagnosis of HS. The liver biopsy results for both patients showed obvious intrahepatic cholestasis. Patient 1 underwent splenectomy at a bilirubin level of 125.4 µmol/L, and the bilirubin level returned to normal after surgery, with a good prognosis. However, Patient 2 suffered from pancreatitis during hospitalization and was unable to undergo splenectomy. Endoscopic retrograde cholangiopancreatography was implemented, but the bilirubin level continued to rise, and Patient 2 ultimately gave up treatment and passed away. For hepatologists, identifying the source of jaundice (hemolysis, hepatocyte destruction, or biliary obstruction) is important for treatment, supplemented by liver biopsy and genetic testing if necessary. In the 2 cases covered in this article, early-stage HS caused hemolytic jaundice with predominantly elevated indirect bilirubin, and as the disease progressed, patients developed severe cholestasis probably related to transient biliary obstruction caused by gallstones and hepatocellular injury due to abnormal bilirubin metabolism. In addition, in patients with HS combined by intrahepatic cholestasis, early consideration of splenectomy may delay disease progression and achieve a better prognosis. Of course, this conclusion needs to be confirmed by more clinical studies.

Dataset Information

The Spectrum of SPTA1-Associated Hereditary Spherocytosis.

Publications

The Spectrum of <i>SPTA1</i>-Associated Hereditary Spherocytosis.

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