Transcript Methemoglobinemia: What really is in the drinking water in

Methemoglobinemia:
The real cause of the Blue
People of Kentucky
History
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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
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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
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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
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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)
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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
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There are three possible manifestations of
this disorder, varying in severity.
o Type I: Erythrocytic, only symptom is
cyanosis due to increased
methemoglobin
o 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
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The Blue People of Kentucky suffer
from type I methemoglobinemia
This is caused by a single
substitution mutation.
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R57Q, V105M
Different mutations in the same gene
can result in varying levels of severity
NADH-cytochrome b5 reductase
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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
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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
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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
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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
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Binding of O2 in hemoglobin or
myoglobin is to an Fe2+- containing
HEME group (iron-porphyrin)
Treatment of the Disorder
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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