From the Guidelines
The blue people of Kentucky suffered from an autosomal recessive condition called methemoglobinemia, caused by a recessive mutation in the CYB5R3 gene, as stated in the most recent and highest quality study 1. This genetic disorder resulted from a deficiency in the enzyme methemoglobin reductase, which normally converts methemoglobin back to normal hemoglobin. Without sufficient enzyme activity, methemoglobin accumulated in the blood, giving the skin a bluish appearance. Some key points to consider in the diagnosis and treatment of methemoglobinemia include:
- The condition can result from either inherited or acquired processes, with acquired forms being the most common, mainly due to exposure to substances that cause oxidation of the Hb both directly or indirectly 1.
- Inherited forms are due either to autosomal recessive variants in the CYB5R3 gene or to autosomal dominant variants in the globin genes, collectively known as HbM disease 1.
- The diagnosis of methemoglobinemia should be suspected in case of unexplained cyanosis and hypoxemia, with clinical presentation varying from mildly symptomatic to severe cases 1.
- The severity of the presentation depends on the percentage of MetHb, the rate of increase in MetHb levels, the intrinsic ability of the patient to clear it, and the patient's underlying functional status 1. The famous Fugate family of Troublesome Creek, Kentucky, carried this genetic trait, which became concentrated in their isolated community due to intermarriage. The condition was effectively treated with methylene blue, which could temporarily restore normal hemoglobin function, as supported by the highest quality study available 1.
From the Research
Methemoglobinemia Inheritance Pattern
- The blue people of Kentucky suffered from methemoglobinemia, which can be caused by various factors, including genetic mutations 2.
- The study of a 26-year-old Hispanic pregnant female diagnosed with methemoglobinemia due to homozygous cytochrome b5 reductase deficiency suggests that this condition can be inherited in an autosomal recessive pattern 2.
- Autosomal recessive inheritance means that a person must inherit two copies of the mutated gene (one from each parent) to express the condition.
- There is no direct evidence in the provided studies to suggest that the blue people of Kentucky had an autosomal dominant form of methemoglobinemia.
Genetic Basis of Methemoglobinemia
- Methemoglobinemia can be caused by mutations in genes involved in the production of enzymes that reduce methemoglobin to normal hemoglobin, such as cytochrome b5 reductase 2.
- The genetic basis of methemoglobinemia in the blue people of Kentucky is not explicitly stated in the provided studies, but it is likely that they had a genetic mutation that affected the production or function of one of these enzymes.