Hereditary spherocytosis pathophysiology: Difference between revisions

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==Pathophysiology==
==Pathophysiology==
* The defects in hereditary spherocytosis lie in the cell membrane.<ref name="Bolton-Maggs2004">{{cite journal|last1=Bolton-Maggs|first1=P H B|title=Hereditary spherocytosis; new guidelines|journal=Archives of Disease in Childhood|volume=89|issue=9|year=2004|pages=809–812|issn=0003-9888|doi=10.1136/adc.2003.034587}}</ref>
* The defects in hereditary spherocytosis lie in the cell membrane.<ref name="Bolton-Maggs2004">{{cite journal|last1=Bolton-Maggs|first1=P H B|title=Hereditary spherocytosis; new guidelines|journal=Archives of Disease in Childhood|volume=89|issue=9|year=2004|pages=809–812|issn=0003-9888|doi=10.1136/adc.2003.034587}}</ref>
* The proteins essential for integrity of membrane structure lie immediately under the lipid bilayer, horizental aplha & beta spectrin molecules form heterodimers with linkage to vertical elements- ankyrin, proteins 4.1 & 4.2 and band 3 (a transmembrane protein).
* The proteins essential for integrity of cell membrane structure lie immediately under the lipid bilayer, horizontal alpha and beta spectrin molecules form heterodimers with linkage to vertical elements- ankyrin, proteins 4.1 and 4.2 and band 3 (a transmembrane protein).
* Different genes code for each of these proteins, therefore hereditary spherocytosis is a hetrogenous disorder which can result from a defect in any one of these proteins.
* Different genes code for each of these proteins, therefore hereditary spherocytosis is a heterogenous disorder that can result from a defect in any one of these proteins.
* The destabilization of membrane leads to both abnormal morphology and reduced red cell life span.
* The destabilization of membrane leads to both abnormal morphology and reduced red cell life span.
* The shorter the life span of red blood cells, the worse the clinical effects.
* The shorter the lifespan of red blood cells, the worse the clinical effects.
* Genetic defect and clinical severity tend to be fairly constant within a given family,but between family varies from mild asymptomatic hemolysis to severe continuous anemia with jaundice.
* The genetic defect and clinical severity tend to be fairly constant within a given family, but between families varies from mild asymptomatic hemolysis to severe continuous anemia with jaundice.
*The following four abnormalities in RBC membrane proteins have been identified in HS:
* The four RBC membrane protein abnormalities recognized in hereditary spherocytosis include; spectrin deficiency alone, combined spectrin & ankyrin deficiency, band 3 deficiency and band 4.2 deficiency.
** [[Spectrin]] deficiency alone  
* Spectrin deficiency:
** Combined [[spectrin]] and [[ankyrin]] deficiency
** Spectrin protein is a tetramer composed of alpha and beta dimers.<ref name="PerrottaDella Ragione2009">{{cite journal|last1=Perrotta|first1=S.|last2=Della Ragione|first2=F.|last3=Rossi|first3=F.|last4=Avvisati|first4=R. A.|last5=Di Pinto|first5=D.|last6=De Mieri|first6=G.|last7=Scianguetta|first7=S.|last8=Mancusi|first8=S.|last9=De Falco|first9=L.|last10=Marano|first10=V.|last11=Iolascon|first11=A.|title= -spectrinBari: a truncated  -chain responsible for dominant hereditary spherocytosis|journal=Haematologica|volume=94|issue=12|year=2009|pages=1753–1757|issn=0390-6078|doi=10.3324/haematol.2009.010124}}</ref><ref name="pmid19538529">{{cite journal| author=Maciag M, Płochocka D, Adamowicz-Salach A, Burzyńska B| title=Novel beta-spectrin mutations in hereditary spherocytosis associated with decreased levels of mRNA. | journal=Br J Haematol | year= 2009 | volume= 146 | issue= 3 | pages= 326-32 | pmid=19538529 | doi=10.1111/j.1365-2141.2009.07759.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19538529  }}</ref>
** [[Band 3|Band 3 deficiency]]
** The most frequent defect in hereditary spherocytosis is spectrin deficiency.
** [[Protein 4.2]] defects
** Mutations of alpha spectrin are associated with recessive forms of hereditary spherocytosis and beta spectrin mutations occur in autosomal dominant forms of hereditary spherocytosis.
 
** Spectrin deficiency can result from impaired synthesis of spectrin or from quantitative or qualitative defects in other proteins that integrate spectrin into the red cell membrane.  
* '''[[Spectrin]] deficiency:''' The most frequent defect in [[Hereditary spherocytosis|HS]] is [[spectrin]] deficiency. The [[biochemical]] nature and the severity of [[spectrin]] deficiency correlate with the extent of spherocytosis, the degree of abnormality on osmotic fragility test results, and the severity of [[hemolysis]].  [[Spectrin]] deficiency can result from impaired synthesis of spectrin or from [[quantitative]] or [[qualitative]] deficiencies of other proteins that integrate [[spectrin]] into the [[Red blood cell|red cell]] membrane. In the absence of those binding proteins, free spectrin is degraded, leading to [[spectrin]] deficiency.  The spectrin protein is a [[tetramer]] made up of alpha-beta dimers. [[Mutation|Mutations]] of alpha-spectrin are associated with [[recessive]] forms of [[Hereditary spherocytosis|HS]], whereas mutations of beta-[[spectrin]] occur in [[autosomal dominant]] forms of HS.<sup> </sup><ref name="PerrottaDella Ragione2009">{{cite journal|last1=Perrotta|first1=S.|last2=Della Ragione|first2=F.|last3=Rossi|first3=F.|last4=Avvisati|first4=R. A.|last5=Di Pinto|first5=D.|last6=De Mieri|first6=G.|last7=Scianguetta|first7=S.|last8=Mancusi|first8=S.|last9=De Falco|first9=L.|last10=Marano|first10=V.|last11=Iolascon|first11=A.|title= -spectrinBari: a truncated  -chain responsible for dominant hereditary spherocytosis|journal=Haematologica|volume=94|issue=12|year=2009|pages=1753–1757|issn=0390-6078|doi=10.3324/haematol.2009.010124}}</ref><ref name="pmid19538529">{{cite journal| author=Maciag M, Płochocka D, Adamowicz-Salach A, Burzyńska B| title=Novel beta-spectrin mutations in hereditary spherocytosis associated with decreased levels of mRNA. | journal=Br J Haematol | year= 2009 | volume= 146 | issue= 3 | pages= 326-32 | pmid=19538529 | doi=10.1111/j.1365-2141.2009.07759.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19538529  }}</ref> Synthesis of alpha-spectrin is threefold greater than that of beta-spectrin.
** Approximately 50% of patients with severe recessive hereditary spherocytosis have a point mutation at the codon (969) resulting in amino acid substitution (alanine/aspartic acid) at the corresponding site in apha spectrin protein leading to defective binding of spectrin to protein 4.1.
 
* Akyrin deficiency
** The excess alpha chains normally are degraded. [[Heterozygous|Heterozygotes]] for alpha-spectrin defects produce sufficient normal alpha-spectrin to balance normal beta-spectrin production. Defects of beta-spectrin are more likely to be expressed in the [[heterozygous]] state because synthesis of beta-spectrin is the rate-limiting factor.  Red cell membranes isolated from individuals with [[autosomal recessive]] [[Hereditary spherocytosis|HS]] have only 40-50% of the normal amount of spectrin (relative to band protein 3). In the [[autosomal dominant]] form of [[Hereditary spherocytosis|HS]], red cell spectrin levels range from 60-80% of normal. Approximately 50% of patients with severe [[recessive]] [[Hereditary spherocytosis|HS]] have a [[point mutation]] at codon (969) that results in an amino acid [[substitution]] ([[alanine]] [Ala]/[[aspartic acid]] [Asp]) at the corresponding site in the alpha-spectrin protein. This leads to a defective binding of spectrin to protein 4.1. [[Mutations]] involving the alpha-spectrin beta-spectrin gene also occur, each resulting in spectrin deficiency. Several other beta-spectrin mutations have been identified. Some of these mutations result in impaired beta-spectrin synthesis. Others produce unstable beta-spectrins or abnormal beta-spectrins that do not bind to ankyrin and undergo [[proteolytic]] degradation. 
** Ankyrin is the principal binding site for spectrin on the red blood cell membrane.
** '''[[Ankyrin]] defects:''' [[Hereditary spherocytosis|HS]] is described in patients with [[Chromosomal translocation|translocation]] of [[Chromosome 8 (human)|chromosome 8]] or [[deletion]] of the [[short arm]] of [[Chromosome 8 (human)|chromosome 8]], where the [[ankyrin]] gene is located. Patients with [[Hereditary spherocytosis|HS]] and [[deletion]] of [[Chromosome 8 (human)|chromosome 8]] have a decrease in [[Red cells|red cell]] [[ankyrin]] content. [[Ankyrin]] is the principal [[binding site]] for [[spectrin]] on the red cell membrane. Studies of [[cytoskeletal protein]] assembly in [[Reticulocyte|reticulocytes]] indicate that [[ankyrin]] deficiency leads to decreased incorporation of [[spectrin]]. In [[Hereditary spherocytosis|HS]] caused by [[ankyrin]] deficiency, a proportional decrease in [[spectrin]] content occurs, although spectrin synthesis is normal. Of particular interest, 75-80% of patients with [[autosomal dominant]] HS have combined spectrin and ankyrin deficiency and the two proteins are diminished equally.
** Ankyrin gene is located on chromosome 8, therefore translocation of chromosome 8 or deletion of short arm of chromosome 8 can lead to hereditary spherocytosis.
** '''[[Band 3]] deficiency:''' [[Band 3]] deficiency has been recognized in 10-20% of patients with mild-to-moderate [[autosomal dominant]] [[Hereditary Spherocytosis|HS]]. These patients also have a proportionate decrease in [[protein 4.2]] content on the [[erythrocyte]] membrane. In some individuals with [[Hereditary spherocytosis|HS]] who are deficient in [[band 3]], the deficiency is considerably greater in older RBCs. This suggests that band 3 protein is unstable.
** Ankyrin deficiency leads to decreased incorporation of spectrin, leading to a proportional decrease in spectrin content as well despite the normal synthesis of spectrin.
** '''[[Protein 4.2]] (pallidin) deficiency:''' Hereditary [[hemolytic anemia]] has been described in patients with a complete deficiency of [[protein 4.2]]. RBC morphology in these cases is characterized by [[Spherocyte|spherocytes]], [[Elliptocyte|elliptocytes]], or sphero-ovalocytes. Deficiency of [[protein 4.2]] in [[Hereditary spherocytosis|HS]] is relatively common in Japan. One [[mutation]] that appears to be common in the Japanese population (resulting in [[protein 4.2]] Nippon) is associated in the [[homozygous]] state with a [[Red cells|red cell]] morphology described as [[Spherocyte|spherocytic]], ovalocytic, and [[Elliptocyte|elliptocytic]]. Another [[mutant]] [[protein 4.2]] (protein 4.2 Lisboa) is caused by a deletion that results in a complete absence of protein 4.2. This is associated with a typical [[Hereditary spherocytosis|HS]] [[phenotype]].
* Band 3 deficiency
** '''[[Aquaporin 1|Aquaporin-1]]:''' In addition to abnormal levels of proteins affected by [[mutations]], patients with [[Hereditary spherocytosis|HS]] may demonstrate aberrant distribution of other proteins in [[erythrocytes]]. Crisp et al found reduced expression of the water channel protein [[Aquaporin 1|aquaporin-1 (AQP1)]] in the membranes of erythrocytes from patients with HS, compared with normal controls. The [[AQP1]] content in [[erythrocyte]] membranes correlated with the clinical severity of HS.<sup> [7]</sup> 
** Band 3 deficiency is seen in 10-20% of patients with mild to moderate autosomal dominant hereditary spherocytosis.
** '''Red blood cell antibodies:''' Using a mitogen-stimulated direct [[antiglobulin test]], Zaninoni and colleagues found RBC antibodies in 61% of patients with HS. Patients with RBC-bound IgG of more than 250 ng/mL (the positive threshold of [[autoimmune hemolytic anemia]]) had increased numbers of [[Spherocyte|spherocytes]] and mainly had [[spectrin]] deficiency. These researchers concluded that the more evident hemolytic pattern in patients with RBC autoantibodies suggests that these [[antibodies]] have a pathogenic role in RBC opsonization and removal by the [[spleen]].<ref name="pmid26259504">{{cite journal| author=Zaninoni A, Vercellati C, Imperiali FG, Marcello AP, Fattizzo B, Fermo E et al.| title=Detection of red blood cell antibodies in mitogen-stimulated cultures from patients with hereditary spherocytosis. | journal=Transfusion | year= 2015 | volume= 55 | issue= 12 | pages= 2930-8 | pmid=26259504 | doi=10.1111/trf.13257 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26259504  }}</ref>
** Band 3 deficiency is considerably greater in older RBCs due to unstable nature of band 3 protein.
* Band 4.2 (Pallidin) Deficiency
** Protein 4.2 deficiency leads to abnormal RBC morphology including spherocytes, elliptocytes or sphero-ovalocytes.
** Its deficiency is relatively common in japan.
** A point mutation causing complete absence of protein 4.2 is associated with typical hereditary spherocytosis phenoype.
* Red Blood Cell Antibodies
** Zaninoni et all found RBC antibodies in 61% of patients with hereditary spherocytosis using a mitogen stimulated direct antiglobulin test.<ref name="pmid26259504">{{cite journal| author=Zaninoni A, Vercellati C, Imperiali FG, Marcello AP, Fattizzo B, Fermo E et al.| title=Detection of red blood cell antibodies in mitogen-stimulated cultures from patients with hereditary spherocytosis. | journal=Transfusion | year= 2015 | volume= 55 | issue= 12 | pages= 2930-8 | pmid=26259504 | doi=10.1111/trf.13257 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26259504  }}</ref>
** They concluded that the more evident hemolytic pattern in patients with RBC autoantibodies suggests that these antibodies have a pathogenic role in RBC opsonization and removal by spleen.


==References==
==References==

Revision as of 15:16, 29 November 2018

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

There is intrinsic defects in erythrocyte membrane proteins that result in RBC cytoskeleton instability. Loss of erythrocyte surface area leads to the spherical shape of RBCs (spherocytes), which are culled rapidly from the circulation by the spleen. Hemolysis mainly confined to the spleen and, therefore, is extravascular. Splenomegaly commonly develops.

Pathophysiology

  • The defects in hereditary spherocytosis lie in the cell membrane.[1]
  • The proteins essential for integrity of cell membrane structure lie immediately under the lipid bilayer, horizontal alpha and beta spectrin molecules form heterodimers with linkage to vertical elements- ankyrin, proteins 4.1 and 4.2 and band 3 (a transmembrane protein).
  • Different genes code for each of these proteins, therefore hereditary spherocytosis is a heterogenous disorder that can result from a defect in any one of these proteins.
  • The destabilization of membrane leads to both abnormal morphology and reduced red cell life span.
  • The shorter the lifespan of red blood cells, the worse the clinical effects.
  • The genetic defect and clinical severity tend to be fairly constant within a given family, but between families varies from mild asymptomatic hemolysis to severe continuous anemia with jaundice.
  • The four RBC membrane protein abnormalities recognized in hereditary spherocytosis include; spectrin deficiency alone, combined spectrin & ankyrin deficiency, band 3 deficiency and band 4.2 deficiency.
  • Spectrin deficiency:
    • Spectrin protein is a tetramer composed of alpha and beta dimers.[2][3]
    • The most frequent defect in hereditary spherocytosis is spectrin deficiency.
    • Mutations of alpha spectrin are associated with recessive forms of hereditary spherocytosis and beta spectrin mutations occur in autosomal dominant forms of hereditary spherocytosis.
    • Spectrin deficiency can result from impaired synthesis of spectrin or from quantitative or qualitative defects in other proteins that integrate spectrin into the red cell membrane.
    • Approximately 50% of patients with severe recessive hereditary spherocytosis have a point mutation at the codon (969) resulting in amino acid substitution (alanine/aspartic acid) at the corresponding site in apha spectrin protein leading to defective binding of spectrin to protein 4.1.
  • Akyrin deficiency
    • Ankyrin is the principal binding site for spectrin on the red blood cell membrane.
    • Ankyrin gene is located on chromosome 8, therefore translocation of chromosome 8 or deletion of short arm of chromosome 8 can lead to hereditary spherocytosis.
    • Ankyrin deficiency leads to decreased incorporation of spectrin, leading to a proportional decrease in spectrin content as well despite the normal synthesis of spectrin.
  • Band 3 deficiency
    • Band 3 deficiency is seen in 10-20% of patients with mild to moderate autosomal dominant hereditary spherocytosis.
    • Band 3 deficiency is considerably greater in older RBCs due to unstable nature of band 3 protein.
  • Band 4.2 (Pallidin) Deficiency
    • Protein 4.2 deficiency leads to abnormal RBC morphology including spherocytes, elliptocytes or sphero-ovalocytes.
    • Its deficiency is relatively common in japan.
    • A point mutation causing complete absence of protein 4.2 is associated with typical hereditary spherocytosis phenoype.
  • Red Blood Cell Antibodies
    • Zaninoni et all found RBC antibodies in 61% of patients with hereditary spherocytosis using a mitogen stimulated direct antiglobulin test.[4]
    • They concluded that the more evident hemolytic pattern in patients with RBC autoantibodies suggests that these antibodies have a pathogenic role in RBC opsonization and removal by spleen.

References

  1. ↑ Bolton-Maggs, P H B (2004). "Hereditary spherocytosis; new guidelines". Archives of Disease in Childhood. 89 (9): 809–812. doi:10.1136/adc.2003.034587. ISSN 0003-9888.
  2. ↑ Perrotta, S.; Della Ragione, F.; Rossi, F.; Avvisati, R. A.; Di Pinto, D.; De Mieri, G.; Scianguetta, S.; Mancusi, S.; De Falco, L.; Marano, V.; Iolascon, A. (2009). "-spectrinBari: a truncated  -chain responsible for dominant hereditary spherocytosis". Haematologica. 94 (12): 1753–1757. doi:10.3324/haematol.2009.010124. ISSN 0390-6078.
  3. ↑ Maciag M, Płochocka D, Adamowicz-Salach A, Burzyńska B (2009). "Novel beta-spectrin mutations in hereditary spherocytosis associated with decreased levels of mRNA". Br J Haematol. 146 (3): 326–32. doi:10.1111/j.1365-2141.2009.07759.x. PMID 19538529.
  4. ↑ Zaninoni A, Vercellati C, Imperiali FG, Marcello AP, Fattizzo B, Fermo E; et al. (2015). "Detection of red blood cell antibodies in mitogen-stimulated cultures from patients with hereditary spherocytosis". Transfusion. 55 (12): 2930–8. doi:10.1111/trf.13257. PMID 26259504.

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