Alpha genes can be lost through deletion or inactivated by point mutations. If insufficient alpha chains are produced, the condition is known as alpha thalassaemia. This condition is very frequent in Asia (from India to China, including Southeast Asia). The disease also occurs in Africa. Since 4 genes code for alpha chains, there are a number of possibilities:
- All 4 alpha genes functional: normal. Genetic a
a
/a
a
.
- Only 3 alpha genes functional: silent carrier with no symptoms or signs (thalassaemia minima). Genetic a
-/a
a
.
Only 2 alpha genes functional: silent carrier, often microcytosis (alpha thalassaemia minor or alpha thalassaemia trait). Genetic a
a
/-- (= a
° thalassaemia) or a
-/a
- (= a
+ thalassaemia). The two genes can either occur on the same chromosome (cis-type) or on each of the pair (trans-type). Cis-type a
° thalassemia trait tends to be found in individuals of Asian descent, while trans-type a
+ tends to run in individuals of African descent. Expert laboratory tests help to distinguish between these two conditions, which is important. If a mother is a carrier of a
° thalassaemia, her pregnancy is at risk for Bart's hydrops foetalis syndrome (worst case scenario), while the worst possible outcome of a pregnancy of a mother with a
+ thalassaemia is a much milder condition, haemoglobin H disease.
- Only 1 alpha gene functional: excess of beta globin chains. Genetic a
-/--. The excess beta chains form tetramers and are deposited: β4 (haemoglobin H). Haemoglobin H is not stable and thermally labile. It contains two reactive –SH groups per beta chain. The beta chains in Hb A have only one –SH group. This may explain the susceptibility of Hb H to oxidation. The red blood cell inclusions (Heinz bodies) can be seen readily with brilliant cresyl blue staining (the same dye as for reticulocytes). The patient is anaemic and there is splenomegaly.
No alpha genes functional: the excess of gamma chains leads to the depositing of tetramers composed of four gamma chains: g
4 (Bart’s haemoglobin). Without the alpha globin chains, there can be no foetal or adult haemoglobin which means the red blood cells cannot carry oxygen efficiently throughout the body. Hydrops foetalis with stillbirth is the result. There is an increased risk of toxaemia of pregnancy and of post-partum haemorrhage (hypertrophy of the placenta). The only haemoglobins found in these infants are: Hb Portland (d2g2), Hb H (b4), and Hb Bart's (g4), and no Hb A or Hb A2. Electrophoresis of foetal haemoglobins shows about 80% Bart’s haemoglobin and about 20% Portland haemoglobin or Gower haemoglobin 1 (normally only present in the embryo in the first trimester).
Haemoglobin Constant Spring mutation. An unusual case of the silent carrier state is the individual who carries the Haemoglobin Constant Spring mutation. This is an abnormal elongated alpha globin due to a termination codon mutation. Individuals who have this mutation have normal red blood cell indices, but can have children who have Hb H-Constant Spring disease if the other parent has alpha thalassemia trait (--/aa). Generally, children with Hb H-Constant Spring are more affected clinically than children who have classic Hgb H disease. Two Constant Spring carriers can also pass on their genes to have a child with homozygous Constant Spring, a condition that has similar clinical implications as Haemoglobin H disease. Children with Haemoglobin H-Constant Spring (--/acsa) have a more severe course than children who have Hb H. They have a more severe anemia, with haemoglobin ranging between 7 and 8 g%. They frequently have splenomegaly and severe anemia with febrile illnesses and viral infections, often requiring transfusion. If anemia is chronically severe and the child has splenomegaly, a splenectomy may have to be performed. Care must be taken to avoid post-surgical thrombotic complications.
*
Note: Alpha thalassaemia and mental retardation.
is sometimes seen along with mental retardation (ATR syndrome). The genetics are different here: ATR-16 is the result of a deletion of the tip of chromosome 16 and ATR-X is caused by a mutation of a gene (XH2) on the long arm of chromosome X. This latter chromosome is involved in regulating various other genes, including alpha globin chains. Besides mental retardation there are also defects of the genitalia and facial deformities. All patients with ATR-X are male and have haemoglobin H disease.
