There are a lot of blues connected to Kentucky: bluegrass music, “Blue Moon over Kentucky”, and even the blue people of Kentucky. You heard that right, Kentucky has its own population of smurf-like humans (Roos, 2023)!
In the 1820s, Martin Fugate immigrated from France to Kentucky, settling along the banks of Troublesome Creek (Phillips, Vatanchi and Glick, 2017). He married a local named Elizabeth Smith, and they started a family, having seven children. Shockingly, it is reported that Fugate and four of his children had skin that exhibited a peculiar blue colouration (Figure 1). Since they resided in a geographically isolated region of Kentucky, the Fugates resorted to consanguineous marital practices, with many marrying their close relatives. Over generations, many Fugate relatives displayed a similar blue hue to Martin Fugate. From there, the “blue people of Kentucky” were born.
It was not until the 1960s that Fugate descendants learned what caused their unusual appearances. Hematologist Madison Cawein and nurse Ruth Pendergass travelled to rural Kentucky to study the Fugates (Phillips, Vatanchi and Glick, 2017). They took blood samples, hoping to determine the reason for the Fugates’ blue skin, and concluded that they had methemoglobinemia, a blood disorder. This disorder results in cyanosis, a bluish colour in body tissue stemming from a lack of oxygen in the blood.
Methemoglobinemia is a condition involving increased levels of methemoglobin in the blood (Ludlow, Wilkerson and Nappe, 2023). Methemoglobin, a form of hemoglobin, contains iron in at least one of its heme groups that is in the oxidized ferric (Fe3+) state, as opposed to the regular reduced ferrous (Fe2+) state (Figure 2). Ferric iron cannot bind to oxygen; thus, it fails to deliver oxygen to the tissues of the body.
Cytochrome b5 reductase (cb5r) is an oxidoreductase enzyme that reduces methemoglobin to hemoglobin and regulates methemoglobin concentrations (Elahian, et al., 2014) (Figure 3). Cb5r deficiency, a recessively inherited trait, causes recessive congenital methemoglobinemia (RCM) (Percy and Lappin, 2008). RCM can be divided into type I and type II, with type II being more severe. Type I RCM is benign, its only symptom is well-tolerated cyanosis and its deficiency is limited to red blood cells. On the other hand, type II RCM results in cyanosis and neurological impairment, and is due to the loss of cb5r function throughout the body. It was type I RCM that the Fugate clan passed down over generations of inbreeding. Luckily, most family members suffered solely from cyanosis and lived well into their 80s and 90s (Phillips, Vatanchi and Glick, 2017).
Once Doctor Cawein identified what was ailing the Fugates, he treated them with methylene blue, fading their skin from blue to pink within a few minutes (Phillips, Vatanchi and Glick, 2017). Methylthioninium chloride, commonly known as methylene blue, is a basic thiazine dye with medicinal purposes, mainly remedying methemoglobinemia (Pushparajah Mak and Liebelt, 2021). When methylene blue is in the presence of nicotinamide adenine dinucleotide phosphate (NADPH) it becomes leukomethylene blue (Figure 3). Leukomethylene blue possesses the ability to reduce methemoglobin to hemoglobin, effectively reducing methemoglobin concentrations within red blood cells.
As for the Fugate family, once the Appalachians became more accessible, many members moved elsewhere and married others, decreasing the frequency of cb5r deficiency. While it is unlikely that RCM will reappear in Kentucky, there is no telling if other blue families will arise in the future.
References
Elahian, F., Sepehrizadeh, Z., Moghimi, B. and Mirzaei, S.A., 2014. Human cytochrome b5 reductase: structure, function, and potential applications. Critical Reviews in Biotechnology, 34(2), pp.134–143. https://doi.org/10.3109/07388551.2012.732031.
Ludlow, J.T., Wilkerson, R.G. and Nappe, T.M., 2023. Methemoglobinemia. In: StatPearls. [online] Treasure Island (FL): StatPearls Publishing. Available at: <http://www.ncbi.nlm.nih.gov/books/NBK537317/> [Accessed 29 October 2023].
Percy, M.J. and Lappin, T.R., 2008. Recessive congenital methaemoglobinaemia: Cytochrome b5 reductase deficiency. British Journal of Haematology, 141(3), pp.298–308. https://doi.org/10.1111/j.1365-2141.2008.07017.x.
Phillips, G.S., Vatanchi, M. and Glick, S.A., 2017. The Fugates of Troublesome Creek. JAMA Dermatology, 153(6), p.513. https://doi.org/10.1001/jamadermatol.2017.1038.
Pineda, H., 2021. Methemoglobinemia. [online] The Intern at Work. Available at: <https://www.theinternatwork.com/infographics-2/2021/10/31/methemoglobinemia> [Accessed 29 October 2023].
Pushparajah Mak, R.S. and Liebelt, E.L., 2021. Methylene blue: An antidote for methemoglobinemia and beyond. Pediatric Emergency Care, 37(9), p.474. https://doi.org/10.1097/PEC.0000000000002526.
Roos, D., 2023. The True Story of the Blue People of Kentucky | HowStuffWorks. [online] Available at: <https://health.howstuffworks.com/human-body/systems/circulatory/blue-people-kentucky.htm> [Accessed 29 October 2023].
Whipple, M., 2023. Blue Fugates: The True Story of Kentucky’s Blue People. [online] TheCollector. Available at: <https://www.thecollector.com/blue-fugates-kentucky/> [Accessed 29 October 2023].