Lepore disease is a rare, inherited blood disorder classified as a hemoglobinopathy, affecting the structure or production of hemoglobin. Hemoglobin is the protein in red blood cells responsible for carrying oxygen. The condition involves defects in the delta and beta globin chains, components of adult hemoglobin. The defect results in an inability to produce sufficient normal hemoglobin, which significantly reduces the red blood cells’ oxygen-carrying capacity.
The Genetic Origin of Lepore Disease
The cause of Lepore disease is a specific genetic error involving the genes that code for the delta and beta globin chains. These two genes are located close to each other on chromosome 11 and share a high degree of sequence similarity. During the formation of reproductive cells, a misalignment between the two homologous chromosomes can occur.
This misalignment leads to an unequal crossover event, resulting in a single, abnormal fusion gene, referred to as Hemoglobin (Hb) Lepore. The resulting fusion chain is a hybrid, combining the beginning section of the delta-globin gene with the latter section of the beta-globin gene. This genetic defect follows an autosomal recessive inheritance pattern, meaning a person must inherit a copy of the fusion gene from both parents to develop the severe form of the disease.
The resulting delta-beta fusion chain is synthesized at a significantly slower rate than a normal beta chain. This reduced production causes an overall deficiency in the non-alpha globin chains, creating an imbalance similar to beta-thalassemia. Three main variants of the fusion gene exist, named for their discovery locations: Hb Lepore Washington-Boston, Hb Lepore Baltimore, and Hb Lepore Hollandia.
Recognizing the Clinical Symptoms
The clinical manifestations of Lepore disease vary widely, determined by whether an individual inherits one copy (heterozygous trait) or two copies (homozygous or compound heterozygous) of the defective gene. Heterozygous individuals, often called carriers, typically experience a mild or asymptomatic state. They may have mild anemia, though their red blood cells are usually smaller (microcytic) and paler (hypochromic).
The homozygous state, or the compound heterozygous state (Hb Lepore plus a beta-thalassemia gene), leads to a severe form of the disease. This severe presentation closely resembles beta-thalassemia major. Symptoms typically become apparent within the first two years of life, once the body switches from producing fetal hemoglobin to adult hemoglobin.
Patients with the severe form often present with chronic fatigue and pallor due to profound anemia. The body attempts to compensate for the lack of healthy red blood cells, leading to the enlargement of the spleen (splenomegaly) and liver (hepatomegaly). Other signs include jaundice, caused by the breakdown of red blood cells, and potential growth retardation in children.
Diagnostic Procedures and Disease Classification
Identifying Lepore disease begins with a comprehensive blood analysis, specifically a Complete Blood Count (CBC). This test typically reveals microcytic and hypochromic red blood cells, suggesting a thalassemia-like condition. Definitive diagnosis relies on techniques that separate and quantify the different types of hemoglobin present in the blood.
Specialized tests like Hemoglobin Electrophoresis or High-Performance Liquid Chromatography (HPLC) are used to detect the presence of the Hb Lepore variant. HPLC is often preferred for its ability to accurately quantify the different hemoglobin fractions. The presence of Hb Lepore, which can range from 5% to 15% in carriers, along with elevated levels of fetal hemoglobin (HbF), helps confirm the diagnosis.
The results of these tests classify the severity of the condition, dictating the necessary level of care. The severe form is confirmed by a marked increase in HbF, sometimes reaching 70–90%, and the near-total absence of normal adult hemoglobin (HbA).
Treatment and Long-Term Management
The management of Lepore disease is tailored to the individual’s clinical severity, which parallels the treatment strategies for beta-thalassemia. For individuals who are carriers (Hb Lepore trait), no specific medical treatment is typically required, and care focuses on monitoring and genetic counseling. These individuals may be advised on family planning, particularly if their partner is also a carrier for a hemoglobin disorder.
Patients presenting with the severe, symptomatic form of the disease require regular, ongoing medical intervention. A primary component of care for severe anemia is chronic blood transfusions to maintain adequate oxygen-carrying capacity. Transfusions help suppress ineffective red blood cell production in the bone marrow, improving overall quality of life and preventing complications like bone deformities.
A direct consequence of frequent blood transfusions is the buildup of excess iron in the body, which can damage organs like the heart and liver. To prevent this toxicity, iron chelation therapy is administered, using medications that bind to and remove the excess iron. Folic acid supplementation is also routinely provided to support the increased production of red blood cells.
In recent years, newer therapeutic options have emerged, such as luspatercept, a medication approved for use in adults with beta-thalassemia, including those with Hb Lepore, that reduces the need for transfusions. For some patients with severe disease, the only potential cure is a hematopoietic stem cell transplant, often referred to as a bone marrow transplant. This procedure carries significant risks but offers the possibility of complete disease resolution for eligible patients.