Metabolic Enzyme Deficiency Hemolytic Anemias and Paroxysmal Nocturnal Hemoglobinuria
Enzyme Deficiencies
PATHOPHYSIOLOGY
Enzymatic deficiency in primaquine-sensitive erythrocytes
Carson PE, Flanagan CL, Ickes CE, Alving AS.
Science. 1956;124:484-485.
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
A specific erythrocyte glycolytic enzyme defect (pyruvate kinase) in three subjects with congenital non-spherocytic hemolytic anemia.
Valentine WN, Tanaka KR, Miwa S.
Trans Assoc Am Physicians. 1961;74:100-110.
Description: The first report of pyruvate kinase deficiency as a cause of nonspherocytic hemolytic anemia. PubMed citation number: 13924348
Molecular heterogeneity of glucose-6-phosphate dehydrogenase A-.
Beutler E, Kuhl W, Vives-Corrons J-L, Prchal JT.
Blood. 1989;74:2550-2555.
Description: A population study of 29 males with the G-6-PD A- phenotype that demonstrates 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
Glucose-6-phosphate dehydrogenase deficiency and malaria.
Ruwende C, Hill A.
J Mol Med. 1998;76:581-588.
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
Genetic basis of hemolytic anemia caused by pyrimidine 5' nucleotidase deficiency.
Marinaki AM, Escuredo E, Duley JA, et al.
Blood. 2001;97:3327-3332.
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
REVIEW
G6PD deficiency.
Beutler E.
Blood. 1994;84:3613-3636.
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
Biochemical and genetic basis of red cell enzyme deficiencies.
Jacobasch G.
Baillieres Best Pract Res Clin Haematol. 2000;13:1-20.
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
Red cell pyruvate kinase deficiency: from genetics to clinical manifestations.
Zanella A, Bianchi P.
Baillieres Best Pract Res Clin Haematol. 2000;13:57- 81.
Description: A review of the biochemistry, genetics, pathophysiology, clinical manifestations, diagnosis, and therapy of this syndrome.
PubMed citation number: 10916678
Paroxysmal nocturnal hemoglobinuria
PATHOGENESIS
Paroxysmal nocturnal hemoglobinuria with onset in childhood and adolescence.
Ware RE, Hall SE, Rosse WF.
N Engl J Med. 1991;325:991-996.
Description: A clinical study in which data from patients less than 21 years old were retrospectively analyzed; 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
Deficiency of the GPI anchor caused by a somatic mutation of the PIG-A gene in paroxysmal nocturnal hemoglobinuria.
Takeda J, Miyata T, Kawagoe K, et al.
Cell. 1993;73:703-711.
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
Specific defect in N-acetylglucosamine incorporation in the biosynthesis of the glycosylphosphatidylinositol anchor in cloned cell lines from patients with paroxysmal nocturnal hemoglobinuria.
Hillmen P, Bessler M, Mason PJ, Watkins WM, Luzzatto L.
Proc Natl Acad Sci U S A. 1993;90:5272-5276.
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
The molecular basis of paroxysmal nocturnal hemoglobinuria.
Rosse WF, Ware RE.
Blood. 1995;86:3277-3286.
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
Natural history of paroxysmal nocturnal hemoglobinuria.
Hillmen P, Lewis SM, Bessler M, Luzzatto L, Dacie JV.
N Engl J Med. 1995;333:1253-1258.
Description: A single institution’s experience with 80 patients diagnosed with PNH (by a positive Ham test) between 1940 and 1970, which documents their presenting symptoms, complications, survival, and associated conditions.
PubMed citation number: 7566002
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.
Mortazavi Y, Merk B, McIntosh J, Marsh JCW, Schrezenmeier H, Rutherford TR, for the BIOMED II Pathophysiology and Treatment of Aplastic Anaemia Study Group.
Blood. 2003;101:2833-2841.
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, which has also been identified in PNH patients. An identical 5-bp deletion was found in 15 of 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
Molecular genetics of paroxysmal nocturnal hemoglobinuria.
Inoue N, Murakami Y, Kinoshita T.
Int J Hematol. 2003;77:107-112.
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
DIAGNOSIS
Paroxysmal nocturnal hemoglobinuria cells in patients with bone marrow failure syndromes.
Dunn DE, Tanawattanacharoen P, Boccuni P, et al.
Ann Intern Med. 1999;131:401-408.
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
TREATMENT
Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria.
Hillmen P, Hall C, Marsh JCW, et al.
N Engl J Med. 2004;350:552-559.
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
REVIEW
Paroxysmal nocturnal hemoglobinuria as a molecular disease.
Rosse WF.
Medicine (Baltimore). 1997;76:63-93.
Description: A comprehensive, scholarly review of pathophysiology and clinical manifestations of PNH. PubMed citation number: 9100736