Knowledge on rare diseases and orphan drugs

Although PNH has been described worldwide, exact prevalence data are not available. It is estimated at 1/80,000 in France. An incidence estimate of about 1/770,000/year has been reported with a predicted prevalence of approximately 1/62,500 in Great Britain. Higher frequency is suggested in Southeast Asia and in the Far East. Men and women are equally affected.

The disease may occur at any age but it preferentially affects young adults. The variable clinical manifestations include hemolytic anemia, medium and large vessel thrombosis (mainly involving the hepatic, abdominal, cerebral, and dermal veins), and moderate to severe hematopoietic deficiency that may lead to pancytopenia. Pallor, fatigue and stress dyspnea with activity are the usual manifestations. Hemoglobinuria results in the production of classically dark urine during the night and in the morning (about 25 % of patients), and patients may present with renal insufficiency. Jaundice may be present. Depending on their localization, thromboses (which affect 30-40 % of untreated patients) may manifest as abdominal pain, hepatomegaly, ascites and headaches. PNH is a chronic disease with hemolytic crises that may be triggered by several factors such as common infection, vaccination, surgery or certain antibiotics. Bone marrow failure may occur prior, along, or as a late complication of the disease (40-50 % of cases).

PNH is caused by somatic mutations in the PIGA gene (Xp22.1), encoding a protein involved in the biosynthesis of the glycosylphosphatidylinositol (GPI) anchor. The mutation occurs in one or several hematopoietic stem cell(s) and leads to a lack (total or partial) of all GPI-anchored cell membrane proteins (the most important being CD55 and CD59, involved in the regulation of hemolysis due to complement).

Diagnosis is based on the clinical features and presence of hemolytic anemia, especially since it is associated with thrombosis and/or peripheral blood cytopenia. Diagnosis is confirmed by flow cytometry to detect GPI-linked antigen deficiency in red cells, monocytes and granulocytes. Molecular analysis is unreliable for diagnosis as the causative mutations are non-homogenous and non-repetitive.

Differential diagnoses include all the other forms of anemia (in particular autoimmune hemolytic anemia) and other causes of deep vein thromboses, according to their clinical presentation.

Until 2007, treatment was primarily symptomatic: transfusions, use of anticoagulants and treatment of an associated aplasia. In June 2007, the monoclonal antibody Eculizumab received an orphan drug designation in Europe for the treatment of PNH. It reduces significantly the hemolysis, the need of transfusions, fatigue, the occurrence of thrombosis, the risk of renal failure, and improves the patients' survival. Bone marrow transplantation can cure PNH but is only indicated in case of severe associated medullar aplasia, due to the severe complications of this technique in this context.

The 6-year survival of patients treated since 2005 is 92 %, and median survival has increased significantly due to the use of Eculizumab and improvements in both supportive measures and management of disease complications.

Last update: October 2017 - Expert reviewer(s): Pr Régis PEFFAULT DE LA TOUR - Dr Flore SICRE DE FONTBRUNE - Pr Gérard SOCIE