What are the causes of hereditary spherocytosis?

Causes of Hereditary Spherocytosis

Hereditary spherocytosis is caused by genetic mutations in red blood cell membrane proteins, specifically in genes encoding ankyrin-1 (ANK1), alpha-spectrin (SPTA1), beta-spectrin (SPTB), band 3/anion exchanger 1 (SLC4A1), and protein 4.2 (EPB42). 1, 2

Genetic Basis and Inheritance Patterns

The molecular defects underlying hereditary spherocytosis reside in proteins responsible for vertical interactions between the membrane skeleton and the lipid bilayer. 2 These defects lead to loss of red cell surface area, spheroidal shape, and reduced membrane elasticity and mechanical stability. 2

Inheritance patterns:

• Autosomal dominant in 75% of cases - most commonly associated with ANK1, SPTA1, SPTB, and SLC4A1 mutations 2
• Autosomal recessive or nondominant in 25% of cases - primarily found with ANK1, SPTA1, and SPTB gene mutations 2
• De novo mutations occur - documented cases include spontaneous band 3 mutations (such as M663K substitution in exon 16) that arise without parental transmission 3

Specific Protein Defects

Alpha-spectrin (SPTA1) mutations:

• Severe recessive hereditary spherocytosis most commonly results from biallelic SPTA1 mutations 1
• Disease occurs when mutations cause significant decrease of normal protein expression from both alleles, since α-spectrin is normally produced in excess 1
• Clinical severity correlates with the level of α-spectrin protein in the RBC cytoskeleton 1
• Patients carrying the low expression αLEPRA allele in trans to a null SPTA1 mutation may have less severe disease 1
• Near-complete or complete α-spectrin deficiency presents with hydrops fetalis and requires intrauterine or early postnatal transfusions 1

Band 3/Anion exchanger 1 (SLC4A1) mutations:

• Point mutations such as 2102 T>C changing methionine at position 663 to lysine have been identified 3
• Band 3 deficiency can be detected by flow cytometry showing reduced protein content 3

Ankyrin-1 (ANK1) mutations:

• Commonly associated with both dominant and recessive inheritance patterns 2, 4
• Protein deficiencies can be demonstrated by polyacrylamide gel electrophoresis 4

Clinical Implications of Genetic Variants

Disease severity varies based on specific mutations:

• Moderately severe to severe transfusion-dependent anemia occurs with different SPTA1 variants 1
• Hydrops fetalis represents the most severe presentation, typically fatal without early transfusion 1
• Patients with suboptimal reticulocytosis or reticulocytopenia remain transfusion dependent even after splenectomy 1
• Novel mutations such as SPTA1 c.7134+5G>A (intronic) may influence disease severity, particularly when compound heterozygous with pathogenic variants 5

Important Clinical Caveat

Comprehensive genetic and phenotypic evaluation is critical because the same genetic mutation can manifest differently in family members - one sibling may have severe transfusion-dependent disease while another remains asymptomatic despite carrying the same heterozygous mutation. 5 This underscores the importance of genetic testing combined with clinical assessment rather than relying solely on family history to predict disease severity.