Deficiency of alpha-spectrin synthesis in burst-forming units-erythroid in lethal hereditary spherocytosis

Whitfield, CF; Follweiler, JB; Lopresti‐Morrow, Lori; Miller, BA

doi:10.1182/blood.v78.11.3043.bloodjournal78113043

Cited by 8 publications

(9 citation statements)

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“…α LEPRA in trans to a null SPTA1 allele (leading to a total α-spectrin production of about 8%) has been shown to cause severe autosomal recessive HS, with anemia and jaundice that resolve with splenectomy (Wichterle et al, 1996; Delaunay et al, 2004). Complete α-spectrin deficiency has been shown to cause lethal anemia in utero (Whitfield et al, 1991).…”

Section: Introductionmentioning

confidence: 99%

The Spectrum of SPTA1-Associated Hereditary Spherocytosis

et al. 2019

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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.

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Section: Introductionmentioning

confidence: 99%

The Spectrum of SPTA1-Associated Hereditary Spherocytosis

et al. 2019

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“…Some patients with the syndrome of hereditary pyropoikilocytosis (HPP) [1][2][3][4]32] are doubly heterozygous for two different types of mutant ␣-spectrin genes: an ␣-spectrin gene encoding a structural ␣-chain variant associated with hereditary elliptocytosis (HE), and a second gene associated with markedly decreased accumulation of ␣-spectrin chains and concomitant marked deficiency of ␣-spectrin mRNA [33,34]. Two infants with hydrops fetalis due to severe nonimmune hemolytic anemia were born in a family in which one parent had apparently typical dominant HS and the other parent was hematologically normal [35]. Peripheral blood BFU-E-derived erythroid precursor cells cultured in vitro from one of the infants displayed total absence of ␣-spectrin chain synthesis [35].…”

Section: Discussionmentioning

confidence: 99%

Amino-acid substitution in α-spectrin commonly coinherited with nondominant hereditary spherocytosis

et al. 1997

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Nondominant hereditary spherocytosis (ndHS) is a disorder characterized in some patients by severe hemolytic anemia and marked deficiency of erythrocyte spectrin. This report describes the identification of a variant spectrin chain, ␣-spectrin Bughill or ␣ BH , that is associated with this disorder in a number of patients. Tryptic maps of spectrin from affected individuals revealed an acidic shift in isoelectric point of the ␣II domain peptides at 46 kD and 35 kD. A point mutation at codon 970 of the ␣-spectrin gene (GCT→GAT), that changes the encoded amino acid from an alanine to an aspartic acid, was identified in genomic DNA of affected patients. The ␣ BH variant was present in 8 patients with ndHS from five different kindreds but was absent in 4 patients from two other kindreds. The 8 ndHS patients with the ␣ BH variant appeared to be homozygous for the ␣ BH variant by analysis of peptide maps of limited tryptic digests of erythrocyte spectrin. However, following genomic DNA analysis, only 2 of these patients were true homozygotes, whereas 6 were found to be doubly heterozygous for the ␣ BH allele and a second, presumably abnormal, ␣-spectrin gene. These results suggest that, in these 6 patients, the second ␣-spectrin allele is in fact associated with one or more genetic defect(s), causing decreased accumulation of ␣-spectrin. The pattern of transmission of the ␣ BH allele in certain families suggests that the ␣ BH amino-acid substitution is not itself responsible for ndHS but is more likely a polymorphic variant that, in some but not all cases, is in linkage disequilibrium with another uncharacterized ␣-spectrin gene defect that itself is a cause of ndHS. Am.

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“…Asymptomatic HS may also be uncovered (usually in childhood) after an aplastic crisis, particularly when associated with Parvovirus B19 (Summerfield & Wyatt, 1985; Lefrere et al , 1986; Cohen et al , 1991), or influenza infection (Jensson et al , 1977). Hydrops fetalis or stillbirth can occur when a fetus has inherited defects in membrane proteins from both parents (Whitfield et al , 1991; Gallagher et al , 1995). Very mild HS may be first detected during investigation of asymptomatic relatives of a known case or during pregnancy (Kohler et al , 1960; Pajor et al , 1993).…”

Section: Age At Diagnosismentioning

confidence: 99%

Guidelines for the diagnosis and management of hereditary spherocytosis

et al. 2004

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SummaryHereditary spherocytosis (HS) is a heterogeneous group of disorders with regard to clinical severity, protein defects and mode of inheritance. It is relatively common in Caucasian populations; most affected individuals have mild or only moderate haemolysis. There is usually a family history, and a typical clinical and laboratory picture so that the diagnosis is often easily made without additional laboratory tests. Atypical cases may require measurement of erythrocyte membrane proteins to clarify the nature of the membrane disorder and in the absence of a family history, occasionally molecular genetic analysis will help to determine whether inheritance is recessive or non-dominant. It is particularly important to rule out stomatocytosis where splenectomy is contraindicated because of the thrombotic risk. Mild HS can be managed without folate supplements and does not require splenectomy. Moderately and severely affected individuals are likely to benefit from splenectomy, which should be performed after the age of 6 years and with appropriate counselling about the infection risk. In all cases careful dialogue between doctor, patient and the family is essential. Laparoscopic surgery, when performed by experienced surgeons, can result in a shorter hospital stay and less pain.Keywords: spherocytosis, hereditary, splenectomy, child, erythrocyte membrane.Hereditary spherocytosis (HS) was described in 1871 and the first recorded splenectomy was performed soon after. It is the commonest cause of inherited chronic haemolysis in Northern Europe and North America with a quoted incidence of 1 in 5000 births (Morton et al, 1962). However, studies of osmotic fragility in blood donors suggest the existence of extremely mild or subclinical forms (Godal & Heisto, 1981;Eber et al, 1992), raising the prevalence of HS to 1 in 2000 . HS has also been found in other ethnic groups (in Africa, Algeria, Tunisia, Egypt, Japan, North India and Brazil). There are only rare cases reported in the black population. In the last 15 years significant progress has been made in the understanding of the biochemical and molecular genetic basis of HS. The definitions of the types of evidence and the grading recommendations used in this guideline are listed in Appendix. Search strategyIn addition to personal archives and consultation of standard textbooks (together with relevant cited references therein), the writing group searched Medline and Embase to identify relevant literature including meta-analyses (none found), reviews and original papers in any language, using the following key words and combinations of them: hereditary spherocytosis; red cell membrane; spectrin, ankyrin, band 3, spherocytes; haemolysis; folate; folic acid; splenectomy; splenectomy in haematological

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Deficiency of alpha-spectrin synthesis in burst-forming units-erythroid in lethal hereditary spherocytosis

Cited by 8 publications

References 0 publications

The Spectrum of SPTA1-Associated Hereditary Spherocytosis

The Spectrum of SPTA1-Associated Hereditary Spherocytosis

Amino-acid substitution in α-spectrin commonly coinherited with nondominant hereditary spherocytosis

Guidelines for the diagnosis and management of hereditary spherocytosis

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