The “Blue” People of Kentucky

A Genetics Investigation

Compiled by: Matt Dean

Adapted from an article in Science 82, November 1982 by Cathy Trost, the website http://www.people.virginia.edu/~rjh9u/fugate.html by Robert J. Huskey, and the website http://www.its.caltech.edu/~bi1/psets/Bi-1-2003-PS6.pdf

It all started over 6 generations ago after a French orphan named Martin Fugate claimed a land grant in 1820 and settled on the banks of eastern Kentucky's Troublesome Creek, with his red-headed American bride, the former Elizabeth Smith, whose skin was as pale as the mountain laurel that blooms every spring around the creek hollows. The Fugates had seven children, four were reported to be blue. The clan kept multiplying. Fugates married other Fugates. Sometimes 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 in log 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.

"When they settled this country back then, there was no roads. It was hard to get out, so they intermarried," says Dennis Stacy who counts Fugate blood in his own veins.

Martin and Elizabeth Fugate's blue children multiplied in this natural isolation tank. The marriage of one of their blue boys, Zachariah, to his mother's sister triggered the line of succession that would result in the birth, more than 100 years later of Benjy Stacy. When Benjy was born with purple skin, his relatives told the perplexed doctors about his great grandmother Luna Fugate. One relative described her as "blue all over" and another calls Luna "the bluest woman I ever saw". Luna's father, Levy Fugate, was one of Zachariah Fugate's sons. Levy married a Ritchie girl and bought 200 acres of rolling land along Ball Creek. The couple had 8 children, including Luna. A fellow by the name of John Stacy spotted Luna at Sunday services of the Old Regular Baptist Church before the turn of the century. Stacy courted her, married her, and moved from Troublesome Creek to make a living in timber on her daddy's land. John Stacy still lives on Lick Branch of Ball Creek. Stacy recalls that his father-in-law, Levy Fugate, was "part of the family that showed blue. All them old fellers way back then was blue. One of em - I remember seeing him when I was just a boy - Blue Anze, they called him. Most of them old people we knew by that name - the blue Fugates. It run in that generation who lived up and down Ball Creek".

"They looked like anybody else, cept they had the blue color," Stacy said.

"The bluest Fugates I ever saw was Luna and her kin," said Carrie Lee Kilburn, a nurse at the rural medical center called Homeplace Center. "Luna was bluish all over. Her lips were as dark as a bruise. She was as blue a woman as I ever saw."

Luna Stacy possessed the good health common to the blue people bearing at least 13 children before she died at 84. The clinic rarely saw her and never for anything serious.

Benjy Stacy was born in a modern hospital near Hazard, Kentucky, not far from Troublesome Creek. He inherited his father's lankiness and his mother's red hair but what he got from his great, great, great grandfather was dark blue skin! The doctors were astonished, not so the parents, but the boy was rushed off to a medical clinic in Lexington (University of Kentucky Medical School). Two days of tests showed no cause for Benjy's blue skin.

Benjy's grandmother Stacy asked the doctor's if they had heard of the blue Fugates of Troublesome Creek. Put on that track, they concluded that Benjy's condition was inherited. Benjy lost his blue tint within a few weeks and now he is about as normal a 7-year old boy as you might imagine. His lips and fingernails still turn a purplish blue when he gets cold or angry and that trait was exploited by the medical students back when Benjy was an infant.

What causes People to Be Blue?

After ruling out heart and lung diseases, the doctor suspected methemoglobinemia, a rare hereditary blood disorder that results from excess levels of methemoglobin in the blood. Methemoglobin which is blue, is a nonfunctional form of the red hemoglobin that carries oxygen. It is the color of oxygen-depleted blood seen in the blue veins just below the skin.

If the blue people did have methemoglobinemia, the next step was to find out the cause. It can be brought on by several things: abnormal hemoglobin formation, an enzyme deficiency, and taking too much of certain drugs, including vitamin K, which is essential for blood clotting and is abundant in pork liver and vegetable oil.

Cawein drew "lots of blood" from the Ritchies and hurried back to his lab. He tested first for abnormal hemoglobin, but the results were negative.

Stumped, the doctor turned to the medical literature for a clue. He found references to methemoglobinemia dating to the turn of the century, but it wasn't until he came across E. M. Scott's 1960 report in the Journal of Clinical Investigation (vol. 39, 1960) that the answer began to emerge.

Scott was a Public Health Service doctor at the Arctic Health Research Center in Anchorage who had discovered hereditary methemoglobinemia among Alaskan Eskimos and Indians. It was caused, Scott speculated, by an absence of the enzyme diaphorase from their red blood cells. In normal people hemoglobin is converted to methemoglobin at a very slow rate. If this conversion continued, all the body's hemoglobin would eventually be rendered useless. Normally diaphorase converts methemoglobin back to hemoglobin. Cawein was eventually able to determine that this same disorder, the lack of the diaphorase enzyme, affected the Blue Fugates.

Questions

Question 1: Genetics—The Blue People of Troublesome Creek

The year is 1975. You are a young physician working in a maternity ward near Hazard,

Kentucky. One night, you are called to attend a newborn boy, Ben Stacy, who is in good

health in all respects except for his dark blue skin. You have lived around Hazard long

enough to remember tales about the ‘blue Fugates’ of Troublesome Creek. You wonder

if Ben is related to the Fugates, so you interview his relatives and piece together the

following genealogy. In the early 1800’s, one of Ben’s ancestors, Zacharia ‘Ball Creek

Zack’ Fugate married Mary Smith. Ball Creek Zack and Mary had 12 children, two of

whom, John ‘John Blue’, and Lorenzo ‘Blue Anze’, were blue. Ball Creek Zack’s sister,

Hannah Fugate, married James Ritchie by whom she had a normal son and daughter.

Mary’s sister, Elizabeth Smith, married Martin Fugate, a distant cousin of Ball Creek

Zack. Elizabeth and Martin had many children (7-11); none were blue. One of their

sons, Levi Fugate married Hannah and James’ daughter Mahala Ritchie. Levi and

Mahala had 8 children, 7 were normal, but their daughter Luna was blue. Luna married

John Stacy and the couple had 13 normal children. One of Luna and John’s sons (name

unknown) fathered Alva Stacey who is not blue. Alva married Hilda Gosney (also

normal) and they had Ben (born blue).

A. Complete the pedigree diagram below by putting the number of each

listed person next to the appropriate symbol.

Fugate family pedigree

1. Zacharia ‘Ball Creek Zack’ Fugate

2. Mary Smith

3. Hannah Fugate

4. James Ritchie

5. Elizabeth Smith

6. Martin Fugate

7. John ‘John Blue’ Fugate

8. Lorenzo ‘Blue Anze’ Fugate

9. Levi Fugate

10. Mahala Ritchie

11. Luna Ritchie

12. John Stacy

13. Luna and John’s son

14. Alva Stacey

15. Hilda Gosney

16. Ben Stacey

B. Color in the symbol (circle or square) for affected (blue) people.

After two days of testing, you determined that Ben Stacey’s blue skin color is

caused by methemoglobinemia. This condition results from the persistence of oxidized

iron in hemoglobin. There are several genetic disorders that lead to methemoglobinemia.

Before Alva and Hilda took Ben back home to a remote area of Hazard county, you tried

to help them understand the genetic basis for their son’s blue skin.

C. Based on the pedigree above, do you tell the Stacey’s that their son’s mutation is

1. dominant or recessive? Why?

2. X-linked or autosomal? Why?

D. Which of the listed people (please use number) must be a carrier (heterozygote)?

A few weeks after Ben Stacey returned home, his parents called to tell you that

he had lost his blue skin tone and appeared normal except that his lips and fingernails

turn blue when he is cold or angry. Family stories report that Ben’s blue ancestors were

blue throughout their lives. Over the course of the next few years, you research many

case histories of blue people and you discover that people heterozygous for mutations

that cause some forms of methomoglobinemia are blue only during their first few weeks

of life. People homozygous for the same mutations are blue throughout their lives.

E. Does this change your answer to C? If so, in what way?