By: Taylor Eisenstein
The catch? Some of their children were—literally—blue.
Decades later, in the 20th century, some of Fugate’s descendants still possessed the characteristic dark blue skin of their ancestors, and by then, the “blue Fugates” had become a well-known phenomenon in local circles. In the 1960s, hematologist Madison Cawein and nurse Ruth Pendergrass investigated the condition exhibited by the family, determined to find the root of its cause. They eventually found that the blue taint of the Fugates’ skin could be attributed to an autosomal recessive blood disorder: methemoglobinemia.
Individuals with this condition produce methemoglobin, a form of a globular protein called hemoglobin, in excess. Ordinarily, red blood cells use hemoglobin to carry oxygen to the rest of the body. Hemoglobin’s ability to carry oxygen is facilitated by a cofactor called heme; heme contains an Fe2+ ion, or ferrous ion, which binds oxygen molecules. The ferrous form of iron in hemoglobin is often oxidized to its Fe3+–-otherwise known as ferric—form, which results in methemoglobin.
In individuals with excess methemoglobin, the normal mechanism of oxygen transport is impaired. The ferric form of iron prevents the typical binding, transport, and subsequent release of oxygen via the red blood cells to tissues throughout the body; thus, the methemoglobin form of hemoglobin ultimately prevents an effective release of oxygen to body tissues. As a result, those afflicted with methemoglobinemia tend to have arterial blood that is a chocolate brown color, resulting in their bluish hue.
Individuals like the Fugates who experience congenital methemoglobinemia usually have a gene that confers a defective form of the enzyme cytochrome b5 reductase. This enzyme helps to maintain the active form of hemoglobin by reducing methemoglobin. Deficiencies in this enzyme ultimately result in an abnormal amount of methemoglobin, precipitating the methemoglobinemia condition exhibited by the Fugates.
It is significant to note that methemoglobinemia is not solely an inherited disorder; it can be acquired as well. In acquired methemoglobinemia, the ferrous form of oxygen is similarly oxidized to its ferric form, reducing oxygen-carrying ability. However, this oxidation is usually caused by exposure to oxidant drugs and toxins. In particular, exposure to nitrobenzene, nitrites, some antibiotics, and local anesthetics, such as benzocaine, can cause acquired methemoglobinemia. For instance, dapsone, an antibiotic commonly used to treat leprosy, has been shown to cause methemoglobinemia. Some foods, such as beets and carrots, even contain high levels of naturally occurring nitrates that may contribute to methemoglobinemia risk.
To cure the Fugates’ condition, Cawein and Pendergrass employed the use of methylene blue. Methylene blue interacts with enzymes in red blood cells to form an electron donor. The electron donor, called leukomethylene blue, can reduce the ferric Fe3+ form of hemoglobin—the methemoglobin—back to its ferrous Fe2+ form, therefore restoring normal oxygen-carrying ability. Alternatively, ascorbic acid can serve as another form of treatment for methemoglobinemia.
Eventually, the Fugates and their relatives moved farther and farther apart, reproducing with new individuals, interacting with a wider gene pool, and expanding their genetic diversity. These interactions reduced the probability of passing down the recessive disorder to more offspring.
Today, while the descendants of the Fugates are no longer blue, their legacy lives on, especially as they are consistently referenced in popular culture and in biology classes across the globe.
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