Knowledge on rare diseases and orphan drugs

Sickle cell anemia (SCA) is the most common form of SCD. Worldwide, it is estimated that there are over 400,000 newborns with sickle cell anemia. The birth prevalence varies according to region, with prevalence greatest in regions affected by holoendemic malaria. In Europe, the pooled birth prevalence is 1/2,300, although this varies between countries.

The disease does not manifest during fetal life or up to the first three months of life due to the presence of high levels of fetal hemoglobin. Clinical manifestations evolve with age and are extremely variable between individuals and at different times. In addition to anemia and bacterial infections, VOAs cause hyperalgic focal ischemia (and sometimes infarction) when they occur in the abdomen, chest or skeleton. Over the course of time, VOAs may compromise the integrity of tissues or organs.

SCA is due to homozygous mutations (rs334) in the beta globin gene, HBB (11p15.4); this variant is termed HbS. There are other forms of sickle cell disease are due to compound heterozygosity for the HbS gene and other hemoglobin (Hb) variants. Under deoxygenated conditions, HbS polymerizes and thereby alters the shape and function of erythrocytes, triggering a cascade of events that leads to hemolysis, vascular occlusion, reduced bioavailability of nitric oxide, and endothelial injury.

Diagnosis is based on analysis of hemoglobin using isoelectric focusing or capillary electrophoresis combined with HPLC, solubility test (Itano test) and molecular analysis. Screening of healthy carriers, by family or by population surveys, helps prevention but requires prospective genetic counseling.

Differential diagnoses include other hereditary hemolytic diseases, and those with recurrent vascular obstruction.

Following genetic counseling, prenatal genetic diagnosis is possible via chorionic villi sampling (before 14 weeks of amenorrhea) or amniotic fluid (from 17 weeks onwards).

The pattern of inheritance is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child at each pregnancy.

From birth, management should integrate prevention of infections, pain and eventual complications, with social, psycho-educational and nutritional support, within multidisciplinary centers that are equipped with intensive care (immediate access to blood transfusion). Special attention should be paid to pregnant women with SCA. Prospective research of vasculopathies is needed. An orphan drug based on hydroxycarbamide (hydroxyurea) has obtained European marketing authorization for the severe forms of the disease. Regular or occasional transfusions remain an essential therapeutic method. Bone marrow transplantation has its main indication in severe cases, particularly in cases with cerebral vasculopathy. L-glutamine, crizanlizumab and voxelotor are currently in phase III trials.

The prognosis is difficult to predict. Acute bacterial infections, malarial attacks, splenic sequestration, severe VOA or organ failure can be a cause of death.

Last update: February 2021 - Expert reviewer(s): Pr Frédéric GALACTEROS | EuroBloodNet*

* European Reference Network