Paroxysmal nocturnal hemoglobinuria (PNH) is an uncommon acquired hemolytic anemia that often manifests with hemoglobinuria, abdominal pain, smooth muscle dystonias, fatigue, and thrombosis. The disease results from the expansion of hematopoietic stem cells harboring a mutation in the ... Paroxysmal nocturnal hemoglobinuria (PNH) is an uncommon acquired hemolytic anemia that often manifests with hemoglobinuria, abdominal pain, smooth muscle dystonias, fatigue, and thrombosis. The disease results from the expansion of hematopoietic stem cells harboring a mutation in the PIGA gene, which encodes a protein required for the biosynthesis of glycosylphosphatidylinositol (GPI), a lipid moiety that attaches dozens of proteins to the cell surface. Thus, PNH cells are deficient in cell surface GPI-anchored proteins. This deficiency on erythrocytes leads to intravascular hemolysis, since certain GPI-anchored proteins (i.e., CD55 (125240) and CD59 (107271)) normally function as complement regulators. Free hemoglobin released from intravascular hemolysis leads to circulating nitrous oxide depletion and is responsible for many of the clinical manifestations of PNH, including fatigue, erectile dysfunction, esophageal spasm, and thrombosis (review by Brodsky, 2008). - Genetic Heterogeneity of Paroxysmal Nocturnal Hemoglobinuria See also PNH2 (615399), which may be caused by germline and somatic mutation in the PIGT gene (610272) on chromosome 20q13.
PNH is characterized by complement-mediated hemolysis and cloned expansion of affected cells of various hematopoietic lineages that are thought to be derived from an abnormal multipotential hematopoietic stem cell (Rosse, 1989). Although not inherited, PNH is an acquired ... PNH is characterized by complement-mediated hemolysis and cloned expansion of affected cells of various hematopoietic lineages that are thought to be derived from an abnormal multipotential hematopoietic stem cell (Rosse, 1989). Although not inherited, PNH is an acquired genetic disorder. The affected clone endows all its descendants--red cells, leukocytes (including lymphocytes), and platelets--with the altered gene. These mutant cells arise side by side with normal elements, creating a hematologic mosaic in which the proportion of abnormal erythrocytes in the blood determines the severity of the disease. Its clinical hallmark, black urine on arising from sleep, is graphic testimony to intravascular hemolysis during the night. Hemolysis also occurs after blood from a patient with PNH is mixed with acidified serum or ordinary table sugar; this is the basis of the Ham and sugar-water tests for PNH. Biosynthesis of the GPI anchor is deficient in the affected cells from patients with PNH (Mahoney et al., 1992; Hirose et al., 1992), leading to deficient surface expression of multiple GPI-anchored proteins, such as decay-accelerated factor (CD55; 125240) and CD59 (107271), both of which play roles in the protection of red cells from the action of complement. Venous thrombosis, an increased incidence of leukemia arising from the affected cells, and a tendency for association with aplastic anemia (see 609135) are other features of the disease. Treatment of severe aplastic anemia with antithymocyte globulin (ADG) and cyclosporin leads to clinical remission in a large proportion of patients. As many as 10 to 57% of these patients, however, develop PNH. The secondary PNH tends to be more indolent than classic PNH. Nagarajan et al. (1995) studied 4 patients with this form of secondary PNH. All 4 of their aplastic patients who developed PNH had a negative Ham test at diagnosis of aplastic anemia. A positive Ham test developed within 3 months after ATG/cyclosporine administration in 2 of the 4; after immunosuppressive therapy, 1 developed a positive test at 6 months and another at 18 months. All 4 patients remained transfusion-independent with no thrombotic episodes after mean follow-up of 30 months. A mutation in the PIGA gene was identified in each of the 4. Nagarajan et al. (1995) concluded that the seeming indolent nature of secondary PNH merely reflects early detection. On the basis of a group of 80 consecutive patients with PNH who were referred to Hammersmith Hospital, London, between 1940 and 1970, Hillmen et al. (1995) defined the natural history of this disorder. The median age of patients at the time of diagnosis was 42 years (range, 16 to 75), and the median survival after diagnosis was 10 years, with 22 patients (28%) surviving for 25 years. Sixty patients had died; 28 of the 48 patients for whom the cause of death was known died from either venous thrombosis or hemorrhage. Thirty-one patients (39%) had one or more episodes of venous thrombosis during their illness. OF the 35 patients who survived for 10 years or more, 12 had a spontaneous clinical recovery. No PNH-affected cells were found among the erythrocytes or neutrophils of the patients in prolonged remission, but a few PNH-affected lymphocytes were detectable in 3 of the 4 patients tested. Leukemia did not develop in any of the patients. The patients had been treated with supportive measures, such as oral anticoagulant therapy after established thromboses and transfusions. Hillmen et al. (1995) stated that the occurrence of spontaneous long-term remission must be taken into account when considering potentially dangerous treatments, such as bone marrow transplantation (BMT). Platelet transfusion should be given, as appropriate, and long-term anticoagulation therapy should be considered for all patients. Socie et al. (1996) reported a case-control study on the 7 factors that they found to be significantly associated with survival in PNH patients (6 negative and 1 positive). Risk factors affecting 220 patients in the French population (diagnosed by a positive Ham test) were used in this multivariate analysis. The 6 factors associated with decreased survival were the development of thrombosis, progression to pancytopenia, myelodysplastic syndrome or acute leukemia, age over 55 years at diagnosis, multiple attempts at treatment, and thrombocytopenia at diagnosis. The only protective factor found was, surprisingly, a history of aplastic anemia antedating the diagnosis of PNH. The mean survival was found to be 15 years. Paroxysmal nocturnal hemoglobinuria is rare in children. Van den Heuvel-Eibrink et al. (2005) reported 11 Dutch pediatric PNH patients with a median age of 12 years. In 7 cases, PNH was associated with aplastic anemia and in 4 with myelodysplastic syndrome. Information on the molecular defect was not provided. - Reviews Reviews on PNH were provided by Yeh and Rosse (1994) and Rosse (1996). In the title of a review of PNH, Nishimura et al. (1999) referred to the paradox in referring to the disorder as an 'acquired genetic disease.' Brodsky (2008) reviewed advances in the diagnosis and therapy of PNH.
Ueda et al. (1992) established affected B-lymphocyte cell lines from 2 patients with PNH, and Takahashi et al. (1993) demonstrated that the early step of GPI anchor biosynthesis was deficient in these cells. Complementation analysis by somatic cell ... Ueda et al. (1992) established affected B-lymphocyte cell lines from 2 patients with PNH, and Takahashi et al. (1993) demonstrated that the early step of GPI anchor biosynthesis was deficient in these cells. Complementation analysis by somatic cell hybridization with GPI-deficient mutant cell lines showed that these PNH cell lines belonged to complementation class A, which is known not to synthesize GlcNAc-PI. Takeda et al. (1993) found that transfection of PIGA cDNA into affected B-lymphoblastoid cell lines restored their surface expression of GPI-anchored proteins. Further analysis demonstrated that the PIGA transcript was missing or present in very small amount in cell lines established from 1 patient, but that in a cell line established from another patient, deletion of thymine in a 5-prime splice site (311770.0001) was associated with deletion of a PIGA exon located immediately 5-prime to the abnormal splice donor site. Since the PIGA gene resides on chromosome Xp22.1, and 1 of the patients studied was female, Takeda et al. (1993) concluded that the mutant PIGA gene must reside on the active X chromosome. Affected cell lines established from 5 other patients with PNH were shown to belong to complementation group class A, indicating that the target gene is the same in most, if not all, patients with PNH. This can account for the behavior of the deficiency as a dominant in hemizygous males and in females with the mutant gene on the active X chromosome in a given lymphoblastoid cell line. Rosse (1993) indicated that all cases of PNH appear to have a defect in the PIGA gene, but the causative mutation has in all instances been unique. That many different mutations of PIGA may result in PNH may not be surprising since they arise as somatic mutations. Rosse (1993) suggested that a germline mutation resulting in defects in this biosynthetic pathway would be lethal. Bessler et al. (1994) reviewed the evidence that PNH is caused by somatic mutations in the PIGA gene. They demonstrated a somatic point mutation in 4 cases which, with the 2 mutations reported by Takeda et al. (1993), brought to 6 the number in which formal proof of the absence of normal PIGA gene product has been shown to produce the PNH phenotype. For further information on somatic mutations in the PIGA gene in patients with PNH, see MOLECULAR GENETICS in 311770.