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Population genetics
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)
Polycystic kidney disease
Familial adenomatous polyposis
Familial hypercholesterolemia
Hereditary spherocytosis
Huntington disease
Li-Fraumeni syndrome
Marfan syndrome
Multiple endocrine neoplasia
Myotonic dystrophy
Tuberous sclerosis
von Hippel-Lindau disease
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
Mucopolysaccharide storage disease type 1 (Hurler syndrome) (NORD)
Krabbe disease
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)
Wilson disease
Fragile X syndrome
Alport syndrome
X-linked agammaglobulinemia
Fabry disease (NORD)
Glucose-6-phosphate dehydrogenase (G6PD) deficiency
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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High Yield Notes
6 pages


9 flashcards

USMLE® Step 1 style questions USMLE

1 questions

USMLE® Step 2 style questions USMLE

1 questions

A 32-year-old African American woman comes to the clinic because of fatigue which she has noticed over the last 6 months. She works full time running her own business. She does not identify any other new symptoms and has regular menstrual cycles.

Examination is unremarkable. Urine bHCG is negative. Laboratory studies show:

Hemoglobin 10.9 g/dL
Mean corpuscular volume 73 μm3/fL
Mean corpuscular hemoglobin 22.6 pg/cell
Ferritin 130ng/mL
Serum iron 93 μg/dL

Which of the following is the most likely cause of her fatigue?


Content Reviewers:

Viviana Popa, MD

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 to 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 RBCs 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 RBC membrane, resulting in intramedullary hemolysis, or RBC breakdown in the bone marrow; or extravascular hemolysis, when RBCs 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 RBCs.

This may cause bones containing bone marrow, as well as the liver and spleen, to enlarge.

Finally, if all four alpha genes are deleted, it results in Hb Bart’s hydrops fetalis.

The problem here begins during fetal life, where gamma chains form tetramers in the absence of alpha chains, called Hb Bart’s (γ4).

  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"  (2009)
  4. "Alpha Thalassemia"  (2021)
  5. "The α-Thalassemias" New England Journal of Medicine (2014)
  6. "Alpha thalassemia"  (2017)