Erythrocyte enzymopathies – hereditary nonspherocytic hemolytic anemias

Jacobasch G.

Biochemical and genetic basis of red cell enzyme deficiencies.
Baillieres Best Pract Res Clin Haematol. 2000 Mar;13(1):1-20.
Description: A review article that nicely describes the biochemical basis and clinical features of several erythrocyte enzymopathies. As many of these clinical syndromes are relatively rare, detailed references for each of them is beyond the scope of this reading list. This reference can provide summary of each of these disorders, as well as references for further reading. In fact, this particular issue of Ballière's Clinical Haematology is dedicated to red cell enzymopathies that lead to hemolysis.
PubMed citation number: 10916675

Glucose-6-phosphate dehydrogenase deficiency – the most common of all clinically significant enzymopathies

Comprehensive review

Beutler E.

G6PD deficiency.
Blood. 1994 Dec 1;84(11):3613-36
Description: One of, if not the, most comprehensive and well-written scholarly reviews of G6PD deficiency. It describes and reviews the evidence for pathophysiology, genetics, clinical manifestations, diagnosis, and treatment. It includes information pertinent to pediatric populations. It also provides excellent historical information about the process that led to the discovery of G6PD deficiency and the resultant insights into the epigenetics, population genetics, and evolutionary implications of this the most common enzymopathy.
PubMed citation number: 7949118

Pathophysiology

Alving AS, Carson PE, Flanagan CL, Ickes CE.

Enzymatic deficiency in primaquine-sensitive erythrocytes.
Science. 1956 Sep 14;124(3220):484-5.
Description: The landmark study reporting experimental evidence for lower levels of G6PD in individuals susceptible to hemolysis with exposure to primaquine.
PubMed citation number: 13360274

Genetics

Beutler E, Kuhl W, Vives-Corrons JL, Prchal JT.

Molecular heterogeneity of glucose-6-phosphate dehydrogenase A-.
Blood. 1989 Nov 15;74(7):2550-5.
Description: A population study of 29 males with the G-6-PD A- phenotype, demonstrating that all had both the mutation at nucleotide 376 that characterizes G-6-PD A+, and one of three additional mutations, suggesting that both mutations are needed for disease phenotype expression.
PubMed citation number: 25722880

Ruwende C, Hill A.

Glucose-6-phosphate dehydrogenase deficiency and malaria.
J Mol Med. 1998 Jul;76(8):581-8.
Description: A review that summarizes the available evidence for the now commonly held belief that G-6-PD deficiency confers a phenotypic advantage in malaria endemic areas
PubMed citation number: 9694435

Pyruvate kinase deficiency – the most common defect in the Embden-Meyerhoff Pathway leading to nonspherocytic hemolytic anemia

Comprehensive review

Zanella A, Bianchi P.
Red cell pyruvate kinase deficiency: from genetics to clinical manifestations.
Baillieres Best Pract Res Clin Haematol. 2000 Mar;13(1):57-81.
Description: A review of the biochemistry, genetics, pathophysiology, clinical manifestations, diagnosis, and therapy of this syndrome.
PubMed citation number: 1091667

Pathogenesis

Valentine WN, Tanaka KR, Miwa S.
A specific erythrocyte glycolytic enzyme defect (pyruvate kinase) in three subjects with congenital non-spherocytic hemolytic anemia.
Trans Assoc Am Physicians. 1961;74:100-10.
Description: The first report of pyruvate kinase deficiency as a cause of nonspherocytic hemolytic anemia.
PubMed citation number: 13924348

Pyrimidine 5’-nucleotidase deficiency – perhaps the third most common of the red cell enzymopathies associated with hemolysis

Genetics

Marinaki AM, Escuredo E, Duley JA, Simmonds HA, Amici A, Naponelli V, Magni G, Seip M, Ben-Bassat I, Harley EH, Thein SL, Rees DC.
Genetic basis of hemolytic anemia caused by pyrimidine 5' nucleotidase deficiency. Blood. 2001 Jun 1;97(11):3327-32.
Description: The first paper to describe the structure and location of the P 5’N-1 gene and the first to identify 3 mutations associated with the clinical syndrome.
PubMed citation number: 11369620

Paroxysmal nocturnal hemoglobinuria

Comprehensive reviews

Rosse WF.

Paroxysmal nocturnal hemoglobinuria as a molecular disease.
Medicine (Baltimore). 1997 Mar;76(2):63-93.
Description: A comprehensive, scholarly review of pathophysiology and clinical manifestations of PNH.
PubMed citation number: 9100736

Rosse WF, Ware RE.

The molecular basis of paroxysmal nocturnal hemoglobinuria.
Blood. 1995 Nov 1;86(9):3277-86.
Description: A review that nicely describes the evidence for the underlying defect in PNH from a molecular point of view. It also details several of the known mutations in the PIG-A gene.
PubMed citation number: 7579428

Pathogenesis

Takeda J, Miyata T, Kawagoe K, Iida Y, Endo Y, Fujita T, Takahashi M, Kitani T, Kinoshita T.

Deficiency of the GPI anchor caused by a somatic mutation of the PIG-A gene in paroxysmal nocturnal hemoglobinuria.
Cell. 1993 May 21;73(4):703-11
Description: This is the seminal study in which somatic mutation of the PIG-A gene is identified as the underlying defect in loss of GPI-anchored proteins and in the hemolysis of PNH.
PubMed citation number: 8500164

Hillmen P, Bessler M, Mason PJ, Watkins WM, Luzzatto L.

Specific defect in N-acetylglucosamine incorporation in the biosynthesis of the glycosylphosphatidylinositol anchor in cloned cell lines from patients with paroxysmal nocturnal hemoglobinuria.
Proc Natl Acad Sci U S A. 1993 Jun 1;90(11):5272-6.
Description: In vitro study demonstrating that it is the step in which N-acetylglucosamine is added to phosphatidylinositol that is defective in the synthesis of the glycosylphosphotidyl inositol anchor, the pathogenic defect in PNH.
PubMed citation number: 8389477

Inoue N, Murakami Y, Kinoshita T.

Molecular genetics of paroxysmal nocturnal hemoglobinuria.
Int J Hematol. 2003 Feb;77(2):107-12.
Description: A review that summarizes the evidence to date for mechanisms of clonal expansion of the abnormal GPI-deficient cells in the setting of PNH. It includes descriptions of the hypotheses that PNH cells are resistant to immune-mediated destruction and that they must also harbor other as yet unidentified defects in order to achieve predominance over the progeny of normal stem cells in the marrow.
PubMed citation number: 12627844

Mortazavi Y, Merk B, McIntosh J, Marsh JC, Schrezenmeier H, Rutherford TR; BIOMED II Pathophysiology and Treatment of Aplastic Anaemia Study Group.

The spectrum of PIG-A gene mutations in aplastic anemia/paroxysmal nocturnal hemoglobinuria (AA/PNH): a high incidence of multiple mutations and evidence of a mutational hot spot.
Blood. 2003 Apr 1;101(7):2833-41. Epub 2002 Nov 07.
Description: Clinical study of patients with aplastic anemia and PNH-type GPI-anchor deficient clones in which PIG-A gene mutations were analyzed. Several patients were found to have multiple clones as has also been identified in PNH patients. An identical 5-bp deletion was found in 15/40 patients, suggesting a mutational “hot spot.” The authors suggest that a process of hypermutation of the PIG-A gene may be present in aplastic anemia stem cells.
PubMed citation number: 12424196

Diagnosis and clinical features

Dunn DE, Tanawattanacharoen P, Boccuni P, Nagakura S, Green SW, Kirby MR, Kumar MS, Rosenfeld S, Young NS.

Paroxysmal nocturnal hemoglobinuria cells in patients with bone marrow failure syndromes.
Ann Intern Med. 1999 Sep 21;131(6):401-8.
Description: A clinical study in which a well-designed flow cytometry protocol was demonstrated to be superior to the Ham test for detection of cells lacking GPI-anchored proteins. In this study, cells typical of PNH were detected in about 20% of patients with myelodysplasia or aplastic anemia, revealing the overlap between these syndromes. See the associated editorial on page 467 of the same issue.
PubMed citation number: 10498555

 

Hillmen P, Lewis SM, Bessler M, Luzzatto L, Dacie JV.

Natural history of paroxysmal nocturnal hemoglobinuria.
N Engl J Med. 1995 Nov 9;333(19):1253-8.
Description: A single institution’s experience with 80 patients diagnosed with PNH (by a positive Ham’s test) between 1940 and 1970, which documents their presenting symptoms, complications, survival, and associated conditions.
PubMed citation number: 7566002

 

Ware RE, Hall SE, Rosse WF.

Paroxysmal nocturnal hemoglobinuria with onset in childhood and adolescence.
N Engl J Med. 1991 Oct 3;325(14):991-6.
Description: A clinical study in which data from patients less than 21 years old were retrospectively analyzed and it was found that younger patients presenting with PNH were more likely to present with and progress to bone marrow failure than older patients.
PubMed citation number: 1886636

Treatment

Hillmen P, Hall C, Marsh JC, Elebute M, Bombara MP, Petro BE, Cullen MJ, Richards SJ, Rollins SA, Mojcik CF, Rother RP.

Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria.
N Engl J Med. 2004 Feb 5;350(6):552-9.
Description: Recent clinical trial of 11 transfusion dependent patients with PNH treated with Eculizumab, a recombinant humanized monoclonal antibody against terminal complement protein C5. In this trial, treatment reduced intravascular hemolysis, hemoglobinuria, and the need for transfusion, with an associated improvement in the quality of life.
PubMed citation number: 14762182

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