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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
27 pages


21 flashcards

USMLE® Step 1 style questions USMLE

4 questions

USMLE® Step 2 style questions USMLE

2 questions

A 23-year-old woman comes to her primary care clinic because her brother was recently diagnosed with hereditary hemochromatosis and was instructed to obtain a genetic test to rule out the disease. She says that for the last three months she has been feeling relatively weak and lethargic; however, denies fever, chills, joint pain, or skin hyperpigmentation. Her temperature is 37.0°C (98.6°F), pulse is 85/min, respirations are 16/min, and blood pressure is 123/78 mm Hg. She is anicteric and does not have organomegaly. AST and ALT concentrations are normal. Which of the following gene mutations is associated with hereditary hemochromatosis?


Content Reviewers:

Rishi Desai, MD, MPH

Hemochromatosis is a metabolic disorder where the body absorbs too much iron from the food you eat.

This accumulation of iron leads to elevated iron in the blood and poisoning of tissues in the liver, pancreas, heart, pituitary gland, joints and skin.

The root -chromat- actually refers to color or the darkening of the skin that happens when iron is deposited into it.

If we take a close look at our red blood cells, we’ll notice that they’re loaded with millions of copies of the same exact protein called hemoglobin, which binds to oxygen and turns our blood cells into little oxygen transporters, and basically allow us to move oxygen to all the tissues in our body.

If we take an even closer look at those hemoglobin proteins, we’ll find that they’re made of four heme molecules, which have, right in the middle, iron.

This iron molecule is what binds to oxygen, so without iron, we probably wouldn’t fare too well, right? Right.

Normally, you actually lose a small amount of iron every day, about 1 mg, some in the sweat, some in shedded skin cells, and some in shedded cells in the gastrointestinal tract.

Most of us, through the diet, take in 10-20 mg of iron every day, and absorb about 10% of that, so 1-2 mg, which is perfect!

People with hemochromatosis, though, absorb an unusually high amount of iron, sometimes as much as 4 mg per day, even though you probably only need about 1 mg to even out your losses, right?

You’d think that absorbing more of something is good, but in this case, a net gain of about 3 mg a day comes out to about 1 g per year of excess iron in your body, leading to more than 20 g by age 40!

Most of this iron you hold on to is deposited in your organs, most notably the liver, but also in your pancreas, your heart, joints, skin, and pituitary gland.

This process of depositing iron into organs is called hemosiderosis. But hey, a little hemosiderosis over the course of a lifetime never hurt anyone, right? Wrong!

Unfortunately, all this extra iron does start doing some serious damage because iron in the body is actually pretty good at generating free radicals through the fenton reaction.

The fenton reaction is where molecules of iron 2+ are oxidized by hydrogen peroxide, producing iron 3+ and the hydroxyl radical and hydroxide ion as byproducts; now, iron 3+ can then be reduced back to iron 2+ via hydrogen peroxide again, creating a peroxide radical and a proton, and then the cycle repeats, creating this like endless loop of free radical generation.

So, over time, all these deposits of iron slowly damage the cells in the various organs by free radical generation, which can cause cell death and then lead to tissue fibrosis. Dang.

Usually, since it takes so long to accumulate and for damage to set in, it’s not diagnosed until age 50 for men and usually 10 to 20 years after menopause for women, mostly because women have one extra method of getting rid of iron, which is through bleeding as part of the menstrual cycle.

Another, really important point that we skipped over, though, is why someone might absorb more iron than normal in the first place. Well, someone could have primary or secondary hemochromatosis.

Primary hemochromatosis is also sometimes called hereditary hemochromatosis, so I’m sure you can guess that it’s caused by a gene mutation, and it is, specifically in the HFE gene, which stands for High F-E, or iron, which is located on chromosome 6; this guy usually helps regulate how much iron we absorb from food.

People with this autosomal recessive disorder have a defect or mutation, though, either the C282Y mutation or H63D mutation, the former being more common.

This mutation specifically affects the absorptive cells in your small intestine, called enterocytes. These guys are super important for absorbing all sorts of things, including iron.

One awesome thing about them though, is that they only move the iron they absorbed into the blood when there’s a need to move it into the blood. So basically they regulate how much iron goes into your blood from your intestine.

With this mutation though, these enterocytes aren’t as good at regulating the iron, so most of the iron in your diet just goes right across from the gut through to your bloodstream, overloading the blood with iron.

If hemochromatosis is brought on by some other means besides a genetic mutation,it’s called secondary hemochromatosis. An example of secondary hemochromatosis is through frequent blood transfusions.

When you get new blood through the transfusion, after about 120 days those red blood cells die off and the iron they contain gets recycled, so each new bag of blood basically adds a bag of iron to your body. So lots of transfusions means lots of iron in the blood.