Table of Contents
What Is Thalassemia?
Thalassemia is an inherited blood disorder that causes the body to have less than normal hemoglobin or oxygen-carrying protein and RBCs (red blood cells). Clinical features of this condition include fatigue, paleness, weakness, and slow growth.
Thalassemia is mainly of two types:
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Alpha Thalassemia - In this type, a person inherits four genes (two from each parent) to form an elongated alpha-globin chain.
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Beta Thalassemia - In this type, a person inherits two beta globin genes (one from each parent).
Alpha and beta thalassemia are well-researched, while other rare variants of thalassemia may pose diagnostic challenges due to complex forms and usual mutations in the globin genes.
What Are the Other Known Rare Thalassemia Variants?
Rare thalassemia variants include:
1. Rare Thalassemia Beta Variant
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Hereditary Persistence of Fetal Hemoglobin:
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Often benign, but when co-inherited, it can ameliorate the severity of beta-thalassemia.
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It can keep the production of fetal hemoglobin active into adulthood due to mutations.
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Delta-Beta Thalassemia:
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Leads to elevated fetal hemoglobin levels.
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It can remove both beta and delta globin genes caused by deletions.
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Clinical conditions can range from asymptomatic to anemia (mild).
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Lepore Hemoglobin:
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Causes anemia (mild to moderate).
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It creates a fusion gene as it develops from unequal crossing-over between the beta and delta globin genes.
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2. Uncommon Alpha Thalassemia Variant
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Hemoglobin (Hb) Quong Sze:
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Results from point mutation and is known as another non-deletional alpha thalassemia variant.
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It is mainly present with microcytosis and mild anemia.
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Hemoglobin Constant Spring (Hb CS):
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It is a non-deletional alpha thalassemia variant that results from an alpha-globin gene mutation, further leading to elongated alpha-globin chain
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It mainly results in mild hemolytic anemia.
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Hemoglobin (Hb) Pakse:
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It leads to an elongated alpha-globin chain caused by mutation.
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It is mainly present with microcytosis and mild anemia.
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How Is Screening and Diagnosing of Rare Thalassemia Variants Done?
Rare variants of thalassemia are challenging to diagnose; however, various methods are involved in screening and diagnosing these conditions through clinical, biochemical, and hematological approaches due to the complexity and diversity in the genetics of these thalassemia variants.
These methods include:
1. Clinical Examination (History and Physical):
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Family history of thalassemia and anemia.
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Symptoms, such as pallor, fatigue, splenomegaly, and jaundice.
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Ethnic background, as this condition is more prevalent in this population group.
2. Biochemical Tests:
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High-Performance Liquid Chromatography (HPLC) - It identifies and quantifies different fractions of hemoglobin and is a more precise test than electrophoresis.
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Hemoglobin Electrophoresis - This test helps separate different types of hemoglobin based on their charge. It also identifies and quantifies HbA2 and HbF, abnormal hemoglobin variants.
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Capillary Electrophoresis - This is also a method used to separate hemoglobin variants and helps detect small variations in the composition of hemoglobin.
3. Hematological Tests:
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CBC or Complete Blood Count - It reveals microcytosis (MCV or low mean corpuscular volume) , low hemoglobin levels, and hypochromia (MCH or low mean corpuscular hemoglobin).
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Reticulocyte Count - It usually gets elevated due to hemolysis.
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Peripheral Blood Smear: It reveals the presence of hypochromic red blood cells and microcytic cells. Basophilic stippling, target cells, and anisopoikilocytosis are also detected.
4. Molecular Diagnostic Tests:
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DNA (Deoxyribonucleic Acid) Analysis
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Polymerase chain reaction (PCR) is used to identify known mutations by amplifying the DNA sequences.
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Next-generation sequencing (NGS) is a method for identifying novel and known mutations by comprehensively sequencing the globin genes.
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Another method is Sanger sequencing for detailed globin gene analysis in specific regions.
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Multiplex ligation-dependent probe amplification (MLPA) is another technique of DNA analysis that helps detect duplications and deletions in the globin genes.
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Genetic Counseling and Prenatal Diagnosis
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This method is mainly advised for couples (both partners are carriers) at risk.
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Prenatal diagnosis involves techniques such as amniocentesis and chorionic villus sampling (CVS) followed by molecular testing.
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5. Functional Studies:
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In vivo and In vitro studies are also conducted to assess hemoglobin production and stability due to the impact of specific mutations. These studies also involve expression studies and globin chain assays in cell models.
What Are the Challenges in Screening and Diagnosis of Rare Thalassemia Variants?
Challenges that may occur during the screening and diagnosis of thalassemia variants may be due to diverse clinical appearance, genetic complexity, and certain drawbacks of diagnostic tools.
These include:
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Symptoms of rare thalassemia variants often overlap with the clinical features of sickle cell anemia and common thalassemia. Also, conditions like iron deficiency anemia often exist with microcytic hypochromic anemia, thus making the differential diagnosis more complicated.
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Genetic heterogeneity due to a wide range of mutations, such as deletions, point mutations, insertions, and other complex events, makes the diagnosis more challenging.
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The limited sensitivity of standard tests, such as electrophoresis, may prevent the detection of all abnormal hemoglobin variants. Also, thalassemia variants often show a similar pattern to that of normal hemoglobin, making diagnosis very challenging due to their similar appearance.
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Population variability also affects the diagnosis, as one variant in a specific population or geographical region may not be present in another. Thus, variants common to other populations may be missed. Therefore, more tailored screening programs may need to be designed.
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Mutations obtained through the sequencing process require more functional studies to confirm their often uncertain pathogenicity. This process is very resource-intensive and time-consuming. Also, diversity in expressions may lead to varying clinical manifestations within the same group, making diagnosis complicated.
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Prenatal screening poses a risk to the fetus, and postnatal screening needs to be more specific and sensitive for early detection without giving any false positive results.
Conclusion
Thus, the screening and diagnosis of rare thalassemia variants can be done through a multidisciplinary approach, tailoring the approaches to diagnose this variant in a timely and correct manner and overcoming the challenges. This would improve patient outcomes and strategies for managing rare thalassemia variants.
