Hereditary Spherocytosis: Genetics and Diagnosis Overview

Hereditary Spherocytosis: Understanding Its Genetics and Diagnosis

Hereditary spherocytosis (HS) is an inherited disorder affecting the production and function of red blood cells (RBCs). Characterized by abnormal RBCs shaped like tiny spheres, HS causes a variety of complications due to anemia, splenomegaly, jaundice, and other issues. The condition is primarily seen in individuals of Northern European descent, occurring in approximately 1 in 2,000 people.

Genetics of Hereditary Spherocytosis

HS is typically inherited in an autosomal dominant pattern, meaning a single copy of the mutated gene from either parent is sufficient to pass the condition onto offspring. Mutations in at least five genes can lead to HS because they encode proteins that play critical roles in maintaining the integrity of RBC membranes: ANC1, ANK1, EPB41L2, EPB42, SGCD, SPTB, and SLC4A1.

These proteins perform functions such as transporting molecules into and out of cells, attaching to other proteins, and maintaining cell structure. They help support the RBC's biconcave shape, which allows them to navigate through the body's circulatory system efficiently. However, in individuals with HS, changes in these proteins disrupt normal RBC functioning, leading to the characteristic spherical shape and reduced lifespan of RBCs.

Diagnosis of Hereditary Spherocytosis

Diagnosing HS involves several steps:

1. Clinical Evaluation: Look for signs of anemia, jaundice, splenomegaly, and gallstones.

2. Family History: Investigate a family history of the condition or related symptoms.

3. Blood Tests: Check for low levels of reticulocytes (Ret), low mean corpuscular volume (MCV), and increased numbers of spherocytes.

4. Osmotic Fragility Test: Detects how well RBCs resist rupturing during exposure to hypotonic solutions.

5. Direct Examination of RBCs: Visualize RBC shapes under a microscope to identify any abnormalities.

If the initial evaluation suggests HS, further tests may include:

• Genetic Testing: Confirm the presence of gene mutations responsible for HS.
• Additional Blood Tests: Assess parameters like hemoglobin (Hb) levels, mean reticulocyte volume (MRV), mean sphered cell volume (MSCV), mean corpuscular hemoglobin concentration (MCHC), and peripheral blood cell morphology.
• Serum Bilirubin Measurement: Determine whether the liver is properly processing old RBCs.

For challenging cases where the diagnosis remains uncertain despite these tests, specialized techniques such as next-generation sequencing or single-gene panel sequencing may be employed to search for potential mutations.