The Molecular Biology of Paroxysmal Nocturnal Hemoglobinuria (PNH)

Study Overview
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Brief Summary
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This study is designed to better understand the molecular biology of paroxysmal nocturnal hemoglobinuria (PNH) and to determine if prion protein (PrP) functions in long term hematopoietic stem cell renewal.

Detailed Description
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Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by hemolytic anemia, thrombosis, and variable cytopenia. It can be associated with significant morbidity including acute kidney failure, cerebral infarction, mesenteric infarction, Budd-Chiari syndrome, aplastic anemia, and leukemic transformation. The average survival time from diagnosis is 15 years. PNH is an acquired clonal disorder of the hematopoietic stem cell. Two distinct populations of hematopoietic cells exist in each PNH patient: one non-clonal population of normal cells, and one clonal population of PNH cells. The clonal population of PNH cells is identified by a mutation in the PIG-A gene that results in absence of the glycophosphatidylinositol (GPI) anchor of several surface proteins. Consequently, these surface proteins are unable to perform their functions on the cell surface. Deficiency of two of these surface proteins, CD55 (decay accelerating factor) and CD59 (membrane inhibitor of reactive lysis) that prevent complement mediated destruction, have been shown to underlie the clinical presentation of PNH. Identifying the mutation causing the predominant clones may help us better understand the molecular biology of PNH. When this is accomplished, new therapies to control and eventually cure the disease can be designed. In addition, we propose to determine the function of PrP in human hematopoietic stem cells. PrP is a glycoprotein attached to the cell membrane by a glycosylphosphatidylinositol (GPI) anchor. In PNH, a disorder whose pathogenesis lies in the absence of GPI anchors, PrP expression is reduced in monocytes and granulocytes from the PNH clone.

Official Title
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The Molecular Biology of Paroxysmal Nocturnal Hemoglobinuria (PNH)

Conditions
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Hemoglobinuria, Paroxysmal

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects suspected of or diagnosed with Paroxysmal Nocturnal Hemoglobinuria (PNH) Age > 7 Exclusion Criteria: 1. Those not meeting the inclusion criteria

Ages Eligible for Study
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Minimum Age: 7 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Affected Population<br>Subjects suspected of having Paroxysmal Nocturnal Hemoglobinuria (PNH) | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Identify the mutation causing the predominant clones through analysis of extracted DNA/RNA from erythroid colonies |  | After sample is obtained | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reconfirmation of PrP expression in human granulocytes, hematopoietic progenitors and stem cells |  | After sample is obtained | 
| Analysis of PrP function in human long term hematopoietic stem cells |  | After sample is obtained | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Paroxysmal Nocturnal Hemoglobinuria, PIG-A Mutation, Prion Protein, Hematopoietic stem cells, Clonal disorder