ORPHA: 447; DO: 0060284;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xp22.2 | Paroxysmal nocturnal hemoglobinuria, somatic | 300818 | 3 | PIGA | 311770 |
A number sign (#) is used with this entry because susceptibility to paroxysmal nocturnal hemoglobinuria-1 (PNH1) is conferred by somatic mutation in the PIGA gene (311770) on chromosome Xp22.
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 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.
Using FISH, Takeda et al. (1993) demonstrated that the PIGA gene, which harbors somatic mutations in patients with PNH, resides on chromosome Xp22.1.
Ware et al. (1994) suggested that the autosomal location of genes other than PIGA that are involved in GPI anchor biosynthesis would explain why all patients with PNH have a defect in the X-linked PIGA gene. For the disorder to be caused by mutation in 1 of the autosomal genes, the hematopoietic cell would need to acquire clonal mutation of both alleles.
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.
Shen et al. (2014) provided evidence that PIGA-mutant cells derived from patients with PNH acquire stepwise somatic mutations in additional genes that provide an intrinsic growth advantage for clonal cells. Whole-exome sequencing of PIGA-mutant and PIGA-nonmutant cells from 12 patients and targeted deep sequencing of cells derived from 36 other patients showed that many PIGA-mutant cells harbored somatic mutations in multiple additional genes, including genes known to be involved in myeloid neoplasms, such as TET2 (612839), SUZ12 (606245), U2AF1 (191317), and JAK2 (147796). Some of these additional somatic mutations occurred before the PIGA mutations. The findings suggested that PNH involves stepwise clonal evolution derived from a singular stem cell clone, similar to that observed in hematopoietic malignancies. Shen et al. (2014) suggested that the additional clonal somatic mutations may modify the behavior of the PIGA clone and thus may explain the variable clinical courses observed in patients with PNH.
For further information on somatic mutations in the PIGA gene in patients with PNH, see MOLECULAR GENETICS in 311770.
Bessler et al. (1994) reported an elegant series of experiments in 2 patients with PNH, each of whom had 2 independently arising PNH clonal lines. All 4 clones had an entirely separate mutational basis. Bessler et al. (1994) presented these observations as further support for positive selection of PNH clones with inhibition of normal hematopoiesis. With regard to the known association between PNH and aplastic anemia, their suggestion was that aplastic anemia inhibits normal hematopoiesis but that PNH cell clones are unaffected by this inhibition. Hematopoiesis, albeit of an abnormal clone, continues--an example of gene therapy in the wild.
Luzzatto and Bessler (1996) and Luzzatto et al. (1997) reviewed the topic of PNH and gave a survey of the more than 100 somatic mutations in the PIGA gene that had been identified in patients with this disorder. Luzzatto et al. (1997) concluded that 2 different causes are required to give the clinical phenotype of PNH: one (A) that we now understand, namely a somatic mutation in the PIGA gene; and one (B) that can only be defined as a specific type of bone marrow failure. The implications of this testable model are that A alone would produce PNH clones of no clinical significance, which may be lurking in normal people, whereas B alone would give the clinical picture of aplastic anemia. It is only when A and B coexist in the same person that we see a clinical phenotype of PNH. PNH is hypothesized to have a conditional growth or survival advantage and environment that is injurious to hematopoietic cells through a GPI-mediated mechanism (Rotoli and Luzzatto, 1989). For instance, if the damage was caused by autoreactive T cells or by natural killer cells, as has been suggested to be the case in aplastic anemia, one could speculate that this happens by virtue of these cells triggering an apoptotic pathway by interacting with a GPI-linked molecule normally present on the surface of hematopoietic stem cells. Under this hypothesis, it is obvious that PNH cells, being invulnerable to this special kind of injury, would be at an advantage as long as the offending T cells or natural killer cells are present; whereas they would revert to being neutral or even at a disadvantage once such offending cells are no longer present.
Although many of the clinical manifestations (e.g., hemolytic anemia) of PNH can be explained by a deficiency of GPI-anchored complement regulatory proteins such as CD59 and CD55, it was unclear why PNH clonal cells dominate hematopoiesis and why they are prone to evolve into acute leukemia. Brodsky et al. (1997) found that PIGA mutations confer survival advantage by making cells relatively resistant to apoptotic death. When placed in serum-free medium, granulocytes and affected CD34(+) cells from PNH patients survive longer than their normal counterparts. PNH cells were also relatively resistant to apoptosis induced by ionizing irradiation. Replacement of the normal PIGA gene in PNH cell lines reversed the cellular resistance to apoptosis. Brodsky et al. (1997) speculated that apoptosis inhibition may be the principal mechanism by which PNH cells maintain a growth advantage over normal progenitors and could play a role in the propensity of this disease to transform into more aggressive hematologic disorders. The work also suggested that GPI anchors are important in regulating apoptosis.
The clinical association between PNH and acquired aplastic anemia (AAA), and the observation that, as in AAA, PNH patients have decreased hematopoietic progenitors, may be taken to suggest a common pathogenetic process. There is strong evidence that AAA is an autoimmune disease and, as for AAA, bone marrow failure in PNH can be treated successfully with immunosuppression; thus, autoimmunity is likely to play a role in PNH as well. Specifically, it has been hypothesized that an autoimmune attack on normal stem cells targets a GPI-linked molecule and therefore preferentially spares the PNH stem cell, which thus has a growth or survival advantage (or both) in this abnormal environment. Using flow cytometric analysis of granulocytes, Araten et al. (1999) identified cells that had the PNH phenotype (lack of expression of proteins linked to the membrane by a GPI anchor) at an average frequency of 22 per million in 9 normal individuals. These rare cells were collected by flow sorting, and exons 2 and 6 of the PIGA gene were amplified by nested PCR. The authors identified PIGA mutations in 6 cases. PNH red blood cells also were identified at a frequency of 8 per million. Thus, small clones with PIGA mutations existed commonly in normal individuals, showing clearly that PIGA gene mutations are not sufficient for the development of PNH. Because PIGA encodes an enzyme essential for the expression of a host of surface proteins, the PIGA gene provides a highly sensitive system for the study of somatic mutations in hematopoietic cells. In a note added in proof, Araten et al. (1999) reported the finding of a tyr98-to-ter mutation (311770.0002) in a 61-year-old man being phlebotomized for hemochromatosis. This was confirmed in samples taken 8 weeks apart. This same mutation had been reported in a patient with PNH (Savoia et al., 1996). Thus, the very same PIGA mutation that caused PNH in one person did not cause PNH in another person.
Conditions favoring mutation in cases of PNH have been suggested by the coexistence of multiple clones with different mutations of the PIGA gene and the appearance of leukemic clones in patients. Horikawa et al. (2002) tested this hypothesis by examining the frequency of mutations in the HPRT gene (308000), identified by both resistance to 6-thioguanine and gene analysis. T-cell colonies resistant to 6-thioguanine formed in methylcellulose culture were found in 8 (67%) of 12 PNH patients and 3 (18%) of 17 age-matched healthy volunteers. Incidence of resistant colonies ranged from 40 to 367 [mean 149, x 10(-7)] in the 8 patients and from 1 to 16 [mean 7, x 10(-7)] in the 3 healthy donors. Unlike PNH cells, 6-thioguanine-resistant cells expressed CD59, indicating that the HPRT mutation did not occur in PNH clones. No correlation was noted between HPRT mutation frequency and content of therapy received by the patients. The authors concluded that in PNH patients, conditions exist that favor the occurrence of diverse somatic mutations in blood cells.
Hu et al. (2005) confirmed the finding that mutations of the PIGA gene are relatively common in normal hematopoiesis; however, they demonstrated that these mutations occur in differentiated progenitor cells rather than in hematopoietic stem cells.
Fujimi et al. (2002) described an elderly patient with paroxysmal nocturnal hemoglobinuria who had recurrent enterocolitis and hemolytic attacks associated with cellular immunodeficiency. Administration of granulocyte colony-simulating factor (138970) resulted in an increased T-cell count, normalization of T-cell function, increased blood levels of helper T cells (Th1 and Th2) cytokines, and improvement in the enterocolitis attacks.
In patients with PNH, Hillmen et al. (2004) tested the clinical efficacy of eculizumab, a humanized antibody that inhibits the activation of terminal complement components. They found that the drug was safe and well tolerated by the patients. This antibody against terminal complement protein C5 (120900) reduced intravascular hemolysis, hemoglobinuria, and the need for transfusion, with an associated improvement in the quality of life.
In 11 PNH patients of Japanese origin who had a poor response to treatment with eculizumab (615749), Nishimura et al. (2014) identified a heterozygous variant in the C5 gene (R885H; 120900.0006). Both the R885H variant and wildtype C5 caused classic pathway hemolysis in vitro, but only wildtype C5 bound to and was blocked by eculizumab. In vitro hemolysis due to nonmutant and mutant C5 was completely blocked with the use of N19-8, a monoclonal antibody that binds to a different site on C5 than does eculizumab. A variant affecting the same residue (R885C; 120900.0007) was found in another PNH patient of Asian descent who had a poor response to eculizumab. The findings indicated that changes at this residue disrupt the eculizumab epitope on C5.
To solicit data on pregnancies with PNH, Kelly et al. (2015) sent a questionnaire to members of the International PNH Interest Group and to physicians participating in the International PNH registry. Of the 94 questionnaires sent out, 75 were returned, for an 80% response rate. Data on 75 pregnancies in 61 women with PNH were evaluated. There were no maternal deaths and 3 fetal deaths (4%). Six miscarriages (8%) occurred during the first trimester. Requirements for transfusion of red cells increased during pregnancy from a mean of 0.14 U per month in the 6 months before pregnancy to 0.92 units per month during pregnancy. Platelet transfusions were given in 16 pregnancies. In 54% of pregnancies that progressed past the first trimester, the dose or the frequency of use of eculizumab had to increased. Low molecular weight heparin was used in 88% of the pregnancies. Ten hemorrhagic events and 2 thrombotic events were documented; both thrombotic events occurred during the postpartum period. A total of 22 births (29%) were premature. Eculizumab was detected in 7 of 20 cord blood samples tested. A total of 25 babies were breastfed, and in 10 of these cases breast milk was examined for the presence of eculizumab; the drug was not detected in any of those samples. Kelly et al. (2015) concluded that eculizumab provided benefit for women with PNH during pregnancy, as evidenced by high rate of fetal survival and a low rate of maternal complications. These results can be compared with historical data reporting a maternal mortality in PNH between 8 and 20.8%, with thromboembolism as the primary cause of death; most thrombotic events occurred during the postpartum period. Fetal mortality had been reported to be between 4 and 9%, with only half the pregnancies progressing to term in 1 study. Comparison of the historical data with pregnancies treated with eculizumab documented improved maternal and fetal outcome.
Hillmen et al. (2021) reported the results of a phase 3 open-label randomized controlled trial comparing the efficacy and safety of 16-weeks of treatment with pegcetacoplan, which targets complement C320, versus the C5 inhibitor eculizumab in 80 adults with paroxysmal nocturnal hemoglobinuria and hemoglobin levels less than 10.5 g/dl despite eculizumab therapy. The 41 patients treated with pegcetacoplan had a significantly greater increase in hemoglobin level than the 39 patients treated with eculizumab (p less than 0.001). Eighty-five percent of patients receiving pegcetacoplan no longer required transfusions, compared to 15% of those receiving eculizumab. The most common adverse events during treatment were injection site reactions, which occurred in 37% treated with pegcetacoplan versus 3% treated with eculizumab. The incidence of serious adverse events was similar in the 2 groups.
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