Alpha Thalassemia  :Evaluation

Mark Curran M.D. F.A.C.O.G.

Alpha thalassemia is one of the most common autosomal recessive disorders in the world. Alpha thalassemia is found in most populations worldwide, but is most common in the Middle East, Southeast Asia, and certain Mediterranean countries. [1]. The high birth prevalence rate of alpha thalassemia major (ATM) reported by The California Newborn Screening Program in Vietnamese, Chinese, and Filipino mothers is a reflection of migration patterns to the area [5]

The alpha 1 and alpha 2 globin genes are located close together in a region of each chromosome 16 known as the alpha-globin locus. Alpha thalassemia is an inherited autosomal recessive disorder caused by a complete absence or decrease in the production of alpha globin peptides due to a deletion or mutation of one or more of the four alpha globin genes.

Production of inadequate amounts of hemoglobin in alpha thalassemia results in the formation of red blood cells that are small (microcytic) and pale appearing (hypochromic), properties that are reflected in the CBC indices of mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) respectively. The routine CBC is, therefore, a quick and inexpensive test that can be used as a universal screen for alpha thalassemia. An MCV of less than 80 fL or MCH less than 27 pg/cells in the absence of iron deficiency suggests the patient may be a carrier of alpha- or beta-thalassemia [1]. Additional testing includes hemoglobin electrophoresis and screening for the father of the baby’s red blood cell indices. Hemoglobin electrophoresis is typically normal in silent carriers or patients with alpha thalassemia trait [2]. DNA analysis for globin mutations is necessary for the evaluation of at-risk couples.  The table below categorizes the types of alpha thalassemia.

Alpha Thalassemia Genotype and Associated Phenotype  [2-4]

Condition	Genotype	Phenotype
No alpha thalassemia	(α α/α α)	MCV (fL) 87.6±5.5 MCH (pg ) 30.2±2.1
Silent carrier (α-thalassemia minima)	(α α/α -)	MCV 81.2±6.9 MCH 26.2±2.3  AsymptomaticHemoglobin electrophoresis normal
Thalassemia trait (α-thalassemia minor) Alpha thal 1 *Heterozygous	(α α/- -) cis	MCV 71.6±4.1  MCH 22.9±1.3  AsymptomaticPeripheral blood smear typically shows hypochromia, microcytosis, and target cellsThe hemoglobin electrophoresis is usually normal if no other hemoglobinopathy is present
Thalassemia trait (α-thalassemia minor) Alpha-thal-2 Homozygous	( α -/α -) trans
Hemoglobin H (HbH) disease (α-thalassemia intermedia) *	(α -/- -)	MCV 61±4 MCH 18.4±1.2 Moderate-to-severe hemolytic anemiaMarked phenotypic variabilityincreased risks of fetal growth restriction, preterm birth, and low birth weight
Hemoglobin Bart’s ( ATM)	(- -/- -)	Hydrops fetalis Urogenital and limb abnormalities, polyhydramnios, oligohydramnios, intrauterine preeclampsia and abruptio placenta
*If both parents are heterozygous, or one parent is Hb H and the other is heterozygous, or both parents are Hb H the probability of hemoglobin Bart’s in one of their offspring is 25% . REFERENCES  1 Chui DH, Waye JS. Hydrops fetalis caused by α-thalassemia: An emerging health care problem. Blood. 1998;91:2213–22 2. Origa R, Moi P. Alpha-Thalassemia. 2005 Nov 1 [Updated 2016 Dec 29]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1435/ 3.  Tongsong T, Srisupundit K, Luewan S. Outcomes of pregnancies affected by hemoglobin H disease. Int J Gynaecol Obstet. 2009 Mar;104(3):206–8 4.  Songdej D, Babbs C, Higgs DR; BHFS International Consortium.An international registry of survivors with Hb Bart's hydrops fetalis syndrome. Blood. 2017 Mar 9;129(10):1251-1259. 5. Feuchtbaum L, Carter J, Dowray S, Currier RJ, Lorey F. Birth prevalence of disorders detectable through newborn screening by race/ethnicity. Genet Med. 2012 Nov;14(11):937-45.