Methemoglobinemia:The real cause of the Blue People of Kentucky

History

Martin Fugate, a French orphan, married Elizabeth Smith and settled along the Troublesome Creek in Kentucky.

The family had seven children, four were reported to have blue skin.

Martin was thought to be blue, and his wife a carrier for the recessive trait. The odds of this occurring in society is almost incalculable.

Fugate Family

History

Since the family lived along the mountainside, houses were few and far between and eventually led to Fugates’ marrying Fugates’.

They also married the families which lived closest to them which included: Combses, Smiths, Ritchies, and Stacys

To them it was only natural to marry the girl next door (even if it was your first cousin).

Pedigree of Fugate Family

Pedigree of Fugate Family

History

Several years later, Zachariah, a blue boy, married his mother’s sister, who must have been a carrier also.

Over one hundred years later, this line of succession led to the birth of Benjy Stacy, in 1975.

Upon birth he was reported to be completely purple but later turned to natural skin color.

Today, only his lips and fingernails remain blue in color.

Another Fugate Pedigree

Pedigree of the Fugates of Troublesome Creek

as gleaned from the Science 82 article

                                                                                                                  

                                 

Biological Aspects

This disorder results from a deficiency of NADH-cytochrome b5 reductase, which is also referred to as NADH diaphorase.

Most enzyme deficiencies are inborn errors of metabolism, and are inherited as recessive traits. Whereas structural defects, such as brachydactyly and structural anomalies of nonenzymatic proteins are usually inherited as dominant.

Biological Aspects (cont’d)

Red blood cells are deficient in NADH diaphorase activity and cannot reduce the oxidized iron in methemoglobin (metHb).

The red blood cells from the parents of a blue child contain some NADH diaphorase activity but not much.

Methemoglobinemia Pictures

Three Types of Methemoglobinemia

o There are three possible manifestations of this disorder, varying in severity.o Type I: Erythrocytic, only symptom is

cyanosis due to increased methemoglobino Type II: Enzymatic deficiency in all

tissues, results in mental retardation and other neurological defects

o Type III: Similar symptoms to type I, but decreased enzyme activity in ALL blood cells

Type I

The Blue People of Kentucky suffer from type I methemoglobinemia

This is caused by a single substitution mutation. R57Q, V105M Different mutations in the same gene

can result in varying levels of severity

NADH-cytochrome b5 reductase

This enzyme transfers two electrons from NADH to two molecules of cytochrome b5 via an enzyme bound FAD.

NADH and FAD are bound to two different branches of the enzyme

Cytochrome b5 transfers the electrons to a variety of acceptors

Structure

Pathway

Soluble v. Membrane Bound

Mutation in the soluble form of NADH-cytochrome b5 reductase is responsible for type I and type III manifestations of methemoglobinemia

Mutation in the membrane bound form of the enzyme result in the much more severe type II phenotype which is a system wide disorder

Enzyme Stability

Mutant enzyme is less stable and more susceptible to proteinase treatment than wildtype.

This increased instability and susceptibility to proteinase, resulting in degradation.

Mutant enzyme is also heat sensitive.

NADH Diaphorase Enzyme

Enzyme Activity

NADH Diaphorase is the enzyme that uses NADH as the reducing agent.

Without the use of this enzyme, the iron molecule in methemoglobin can not be reduced to hemoglobin, the state in which O2 is transported in the blood.

NADH Diaphorase activity

Binding of Fe2+ to Heme

Binding of O2 in hemoglobin or myoglobin is to an Fe2+- containing HEME group (iron-porphyrin)

Treatment of the Disorder

Methylene blue was used to turn their skin back to normal color because it can act as an electron donor and reduce the iron to Fe2+.

This is a quick acting reaction and the effects are only temporary.

Pathway