Alpha-thalassemia

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Alpha-thalassemia

Genetics

Population genetics

Mendelian genetics and punnett squares

Hardy-Weinberg equilibrium

Inheritance patterns

Independent assortment of genes and linkage

Evolution and natural selection

Genetic disorders

Down syndrome (Trisomy 21)

Edwards syndrome (Trisomy 18)

Patau syndrome (Trisomy 13)

Fragile X syndrome

Huntington disease

Myotonic dystrophy

Friedreich ataxia

Turner syndrome

Klinefelter syndrome

Prader-Willi syndrome

Angelman syndrome

Beckwith-Wiedemann syndrome

Cri du chat syndrome

Williams syndrome

Alagille syndrome (NORD)

Achondroplasia

Polycystic kidney disease

Familial adenomatous polyposis

Familial hypercholesterolemia

Hereditary spherocytosis

Huntington disease

Li-Fraumeni syndrome

Marfan syndrome

Multiple endocrine neoplasia

Myotonic dystrophy

Neurofibromatosis

Treacher Collins syndrome

Tuberous sclerosis

von Hippel-Lindau disease

Albinism

Polycystic kidney disease

Cystic fibrosis

Friedreich ataxia

Gaucher disease (NORD)

Glycogen storage disease type I

Glycogen storage disease type II (NORD)

Glycogen storage disease type III

Glycogen storage disease type IV

Glycogen storage disease type V

Hemochromatosis

Mucopolysaccharide storage disease type 1 (Hurler syndrome) (NORD)

Krabbe disease

Leukodystrophy

Niemann-Pick disease types A and B (NORD)

Niemann-Pick disease type C

Primary ciliary dyskinesia

Phenylketonuria (NORD)

Sickle cell disease (NORD)

Tay-Sachs disease (NORD)

Alpha-thalassemia

Beta-thalassemia

Wilson disease

Fragile X syndrome

Alport syndrome

X-linked agammaglobulinemia

Fabry disease (NORD)

Glucose-6-phosphate dehydrogenase (G6PD) deficiency

Hemophilia

Mucopolysaccharide storage disease type 2 (Hunter syndrome) (NORD)

Lesch-Nyhan syndrome

Muscular dystrophy

Ornithine transcarbamylase deficiency

Wiskott-Aldrich syndrome

Mitochondrial myopathy

Autosomal trisomies: Pathology review

Muscular dystrophies and mitochondrial myopathies: Pathology review

Miscellaneous genetic disorders: Pathology review

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Alpha-thalassemia

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Alpha-thalassemia

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A 29-year-old Chinese primigravid woman comes to the clinic at 24 weeks gestation for the first time due to decreased fetal movements. Her prenatal care has been inconsistent, but she has been taking vitamins daily. The patient’s past medical history is significant for anemia. An ultrasound is performed and shows increased placental thickness. The ultrasound also reveals fetal ascites as well as pericardial and pleural effusions. The amniotic fluid index is measured to be 26 cm. Which of the following most accurately describes the predominant form of hemoglobin found in this fetus?  

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Content Reviewers

Viviana Popa, MD

Contributors

Jahnavi Narayanan, MBBS

Jake Ryan

Marisa Pedron

Alaina Mueller

Robyn Hughes, MScBMC

Elizabeth Nixon-Shapiro, MSMI, CMI

Alpha-thalassemia is a genetic disorder where there’s a deficiency in production of the alpha globin chains of hemoglobin, which is the oxygen-carrying protein in red blood cells.

Normally, hemoglobin is made up of four globin chains, each bound to a heme group. There are four major types of globin chains- alpha (α), beta (β), gamma (γ), and delta (δ). These four globin chains combine in different ways to give rise different kinds of hemoglobin. First, there’s hemoglobin F (or HbF), where F stands for fetal hemoglobin, and it’s made up of two α-globin and two γ-globin chains. Hemoglobin A (or HbA) is the major form of adult hemoglobin, made up of two α-globin and two β-globin chains. Finally, hemoglobin A2 (or HbA2) amounts for a small fraction of adult hemoglobin in the blood, and it’s made up of two α-globin and two δ-globin chains. Alpha chain synthesis is controlled by four alpha genes, two on each copy of chromosome 16. And alpha thalassemia is caused by mutations in the alpha genes, most commonly a gene deletion. The mutations are inherited in an autosomal recessive pattern, which means that you need mutated genes from both parents to get the disease. If a person has one defective alpha gene, they’re called a silent carrier, because they don’t have symptoms, but can still pass the gene to their children. If a person has two defective alpha genes, the person has alpha thalassemia minor, which causes mild symptoms. This can either be caused by a ‘cis’ deletion, where mutated genes are on the same chromosome; or a ‘trans’ deletion when the mutated genes are on two different chromosomes. Cis-deletion variants are more prevalent in Asian populations, whereas, trans-deletion variants are more prevalent in African populations.

If there are three defective alpha genes, there’s moderate disease, called hemoglobin H, or HbH, disease. This is caused by excess beta chains, which clump together within developing red blood cells to form tetramers (β4), and give rise to a form of hemoglobin called hemoglobin H. HbH molecules cause hypoxia in two ways. First, they damage the red blood cell membrane, resulting in intramedullary hemolysis, or red blood cell breakdown in the bone marrow; or extravascular hemolysis, when red blood cells are destroyed by macrophages in the spleen. Second, HbH has very high affinity for oxygen, and doesn’t release oxygen to the tissues. And a consequence of hypoxia is that it signals the bone marrow, as well as extramedullary tissues like the liver and spleen, to increase production of red blood cells. This may cause the bones that contain bone marrow, as well as the liver and spleen, to enlarge.

Summary

Alpha-thalassemia is an inherited blood disorder in which there is insufficient production of alpha globin chains of hemoglobin. Hemoglobin is the protein in red blood cells that carries oxygen from the lungs to all parts of the body. Symptoms will vary depending on the extent of the deficiency of the globin chains. Some people with alpha-thalassemia do not have symptoms, while others experience mild to moderate anemia.

Sources

  1. "Robbins and Cotran Pathologic Basis of Disease, Professional Edition E-Book" Elsevier Health Sciences (2014)
  2. "Pathophysiology of Disease: An Introduction to Clinical Medicine 8E" McGraw-Hill Education / Medical (2018)
  3. "Alpha and beta thalassemia" undefined (2009)
  4. "Alpha Thalassemia" undefined (2021)
  5. "The α-Thalassemias" New England Journal of Medicine (2014)
  6. "Alpha thalassemia" undefined (2017)
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