Biology



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The Blue People of Troublesome Creek

Adapted from an article in Science 82, Nov. 1982 by Cathy Trost

Six generations after a French orphan named Martin Fugate settled on the banks of eastern Kentucky’s Troublesome Creek with his redheaded American bride, his great-great-great-great grandson was born in a modern hospital not far from where the creek still runs. The boy inherited his father’s lankiness and his mother’s slightly nasal way of speaking. What he got from Martin Fugate was dark blue skin. “It was almost purple,” his father recalls.

Doctors were so amazed by the color of Benjy Stacy’s skin that they rushed him to a medical clinic for two days of testing. There was no explanation for skin that was the color of a bruised plum. Then Benjy’s grandmother spoke up. “Have you ever heard of the blue Fugates of Troublesome Creek?” she asked the doctors.

“My grandmother Luna on my father’s side was a blue Fugate. It was real bad in her,” Alva Stacy, the boy’s father, explained. “The doctors finally came to the conclusion that Benjy’s color was due to blood inherited from generations back.”

Benjy lost his blue tint within a few weeks, and now he is a normal-looking seven-year-old boy. His lips and fingernails still turn a shade of purple-blue when he gets cold or angry – a quirk that had medical students crowd around him as a baby and try to make him cry. “Benjy was a pretty big item in the hospital,” his mother Hilda says with a grin.

In the 1960s, Madison Cawein, a doctor at the University of Kentucky, began hearing rumors about the blue people and “tromped around the hills looking for blue people” without any success. Finally, one day when the frustrated doctor was idling inside a clinic, Patrick and Rachel Ritchie walked in.

“They were bluer’n hell,” Cawein says. “Well, as you can imagine, I really examined them. After concluding that there was no evidence of heart disease, I said ‘Aha!’ I started asking them questions: ‘Do you have any relatives who are blue?’ then I sat down and we began to chart the family.” Cawein remembers the pain that showed on the Ritchie brother’s and sister’s faces. “They were really embarrassed about being blue. Patrick was all hunched down in the hall. Rachel was leaning against the wall. They wouldn’t come into the waiting room. You could tell how much it bothered them to be blue.”

After ruling out various illnesses, the doctor suspected methemoglobinemia, a rare hereditary blood disorder that results from too much methemoglobin in the blood. Methemoglobin, which is blue, is a form of the red hemoglobin that carries oxygen. It is the color of oxygen-depleted blood that is seen in blue veins just below the skin. If the blue people did have methemoglobinemia, the next step was to find out the cause. After many blood tests and long hours of research, Cawein could not figure out the cause of the Fugates’ blue skin. Finally, he came across an article by another doctor that suggested that the blueness was caused by the absence of the enzyme diaphorase in red blood cells. Without diaphorase, blue methemoglobin cannot be converted back to red hemoglobin. Again Cawein tested the blood of as many Fugates as he could find. “So I brought back the new blood and set up my enzyme assay,” Cawein said. “And by God, they didn’t have the enzyme diaphorase. I looked at other enzymes and nothing was wrong with them. So I knew we had the defect defined.”

The blood of the Fugates had accumulated so much of the blue molecule methemoglobin that it overwhelmed the red of normal hemoglobin that shows through as pink in the skin of most Caucasians. Once he had the enzyme deficiency isolated, Cawein thought of methylene blue as the “perfectly obvious” solution. Some of the blue people thought the doctor was crazy for suggesting that a blue dye could turn them less blue. But Cawein knew from earlier studies that methylene blue had been used successfully, safely, and quickly in other cases.

Cawein packed up his black bag and visited Patrick and Rachel Ritchie’s house and injected each of them with 100 milligrams of methylene blue. “Within a few minutes, the blue color was gone from their skin,” the doctor said. “For the first time in their lives, they were pink. They were delighted.” The doctor gave each blue family a supply of methylene blue tablets to take as a daily pill. The drug’s effects are temporary, as methylene blue is normally excreted in the urine. Before Cawein ended his study of the blue people, he returned to the mountains to patch together the long and twisted journey of Martin Fugate’s recessive allele.

Martin Fugate was an orphan who immigrated to Kentucky in 1920. He married redheaded, pale-skinned Elizabeth Smith who, as luck would have it, carried the same recessive allele. They had seven children, four of whom were reported to be blue. The clan kept multiplying. Fugates married other Fugates. Sometime they married first cousins. And they married the people who lived closest to them, the Combses, Smiths, Ritchies, and Stacys. All lived in isolation from the world, bunched up in cabins up and down the hollows, and so it was only natural that a boy married the girl next door, even if she had the same last name.

One of Elizabeth and Martin’s blue boys, Zachariah, married Elizabeth’s sister and had children. One of the boys, Levy Fugate, married Mahala Ritchie. They had eight children, including one girl named Luna. Luna was Benjy Stacy’s great grandmother. A nurse who works at the rural medical center nearby remembers, “The bluest Fugates I ever saw was Luna and her kin. Luna was bluish all over. Her lips were as dark as a bruise. She was as blue a woman as I ever saw.” Luna Fugate married John Stacy, who still lives near Troublesome Creek. They had 13 children, none of whom were blue.

As coal mining and the railroads brought progress to Kentucky, the blue Fugates started moving out of their communities and marrying other people. The strain of inherited blue began to disappear as the recessive gene spread to families where it was unlikely to be paired with a similar gene.

Benjy Stacy is one of the last of the blue Fugates. With Fugate blood on both his mother’s and his father’s side, the boy could have received genes for the enzyme deficiency from either direction. Because the boy was intensely blue at birth but then recovered his normal skin tones, Benjy is assume to have inherited only one allele for the condition. Such people tend to be blue only at birth, probably because newborns normally have smaller amounts of diaphorase. The enzyme eventually builds to normal levels in most children and to almost normal levels in those like Benjy, who carry one recessive allele.

Cawein and his colleagues published their research on hereditary diaphorase deficiency in 1964. He hasn’t studied the condition in years. The producers of the television show “That’s Incredible” recently approached him. They wanted to parade the blue people across the screen in their weekly display of human oddities. Cawein would have no part of it, and he related with glee that a film crew sent to Kentucky from Hollywood fled the “two mean dogs in every front yard” without any film. He cheers their bad luck, not out of malice, but out of a deep respect for the blue people of Troublesome Creek.

Now that you have read the story, “The Blue People of Troublesome Creek,” complete the pedigree below.

The Fugate Pedigree: (with phenotypes only)

Martin Elizabeth

Fugate Smith

7 children, 4 blue

Zachariah (unknown

Fugate name)

Levi Mahala

Fugate Ritchie

8 children, 1 blue

Luna John

Fugate Stacy

13 children, none blue

Unknown Unknown

Alva Hilda

Stacy Godsey

Benjy

Stacy

________________________________________________________________________________________________________

A Message from Benjamin Stacy

From: Benjamin Arnold Stacy

Subject: Fugate Pedigree

Date: Sun, 14 Mar 1999 20:43:06-0500

To Whom It May Concern:

My name is Benjamin Arnold Stacy, Ben for short. I am the “Benjy” (misspelled in the original article in Science 82) mentioned in the article. My mother’s maiden name is Hilda B. Godsey. I was surprised to see that someone had taken the time to map the genealogy of my family. I would like to thank you for taking that interest, because it was something that I had wanted to do myself. I do not know that much about methemoglobinemia and happened to come across this web site while searching. Just for your information, I am 24 years old now and am in my senior year of college at Eastern Kentucky University. The color of my lips and fingernails usually draws some attention, but mostly out of concern for my health or curiosity. I have had no major health problems related to the disorder and simply try to live an average life in spite of being “blue.” Again, thank you for your efforts.

Benjamin Arnold Stacy

The Chemistry and Genetics Behind Blue People

Extend Your Inquiry (optional)

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The Blue Families carry an ineffective allele of the gene for NADH diaphorase (ND). NADH diaphorase is an enzyme that repairs hemoglobin when it has been damaged by oxidation, leaving the iron atom in the +3 state. However, if the enzyme is inactive due to DNA sequence variation, then damaged hemoglobin cannot be repaired, and accumulates--producing blue skin color.

Dr. Cawein, of The Blue People of Troublesome Creek and Curing the Kentucky Blues, used methylene blue to repair the damaged hemoglobin. That is, methylene blue, in its reduced form, is a colorless, water-soluble molecule. When it has been oxidized, it becomes blue. The blue tint that this gives to urine accounts for the last quote in Kathy Trost's article, that "I can see that old blue running out of my skin." The use of vitamin C by Dr. Deeny in Ireland achieves the same result of repairing damaged hemoglobin. However, vitamin C is colorless, so there is no excretion of blue pigment.

[pic]

The blue trait is a good example of something that does not fit the traditional view of alleles as being dominant or recessive. A person carrying one copy of the "blue allele" of ND has more total ND enzyme than does a person carrying two copies of the"blue allele," and thus the blue characteristics are much less pronounced; the "blue allele" is recessive. But the blue characteristics are not altogether absent (note the blueness at birth, and the blueness of lips and fingernails), so this allele does not fit the typical definition of "recessive." In fact, most genetic variation reflects alleles that are neither strictly dominant nor strictly recessive; gradations, such as that we see here, are the norm.

Note: RED = reduced form; OX = oxidative form

Remember LEO-GER: An oxidation reaction loses electrons; a reduction reaction gains electrons

Source:

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This modified pedigree is only an approximation.

Complete the pedigree by:

- shading the symbols that need to be shaded

- writing the genotype of each person next to his/her name. Use the letter B to represent the allele for the gene that codes for the enzyme diaphorase.

Remember that seemingly unaffected individuals might be carriers of the allele. If you are not sure that a person is a carrier, leave the genotype as B__. Do not just randomly guess at the genotype.

Recommendation: USE A PENCIL.

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