Inherited Methemoglobinemia

1
Inherited Methemoglobinemia
The Condition of Feeling Blue
By Ming Chen, Laura Alison Dickson and Nasim
Daraeifar
2
Methemoglobinemia

• Is a disorder characterized by the presence of a
  higher than normal amount of methemoglobin in the
  blood
• With a higher level of methemoglobin, the ability
  to carry oxygen is decreased

3
Hemoglobin

• Hemoglobin exists as a tetramer (4 subunits),
  there are two alpha globin chain and two beta
  globin chains
• Each subunit has a heme molecule with a ferrous
  iron (Fe2)?
• Fe2 can bind to oxygen and transports oxygen
  throughout our body for our tissues to use

http//fig.cox.miami.edu/cmallery/150/chemistry/h
emoglobin.jpg
http//goldbamboo.com/images/content/5530-hemoglob
in-t-r-state-ani-hemoglobin.gif
4
Hemoglobin to Methemoglobin

• oxidative stress in the RBC causes the oxidation
  of the ferrous state (Fe2) to the ferric state
  (Fe3)?
• when the irons on hemoglobin are oxidized to the
  ferric state this is known as methemoglobin
• in most people the ferric state is reduced
  quickly back to the ferrous state and the
  concentration of methemoglobin at any time is
  kept at less than 1

http//www.emedicine.com/emerg/images/756148-81561
3-1004.JPG
5
Methemoglobinemia

• However in patients with methemoglobinemia the
  concentration of methemoglobin exceeds 1
• Methemoglobin cannot carry molecular oxygen (as
  the Fe3 cannot bind to oxygen)?
• Partial oxidation of the subunits of hemoglobin
  is possible and allosteric interactions cause the
  non-oxidized portions of these hybrids to form a
  higher affinity for oxygen
• This causes a left-shift in the oxygen
  disassociation curve causing less oxygen to be
  released into the tissue

http//www.clt.astate.edu/wwilliam/unit_2.jpg
6
Types of Methemoglobinemia

• Acquired methemoglobinemia
• Toxin induced, acidosis, dietary
• These all increase the oxidative stress and
  overwhelm the system

http//www.accessmedicine.com/

• Congenital methemoglobinemia
• There are three major types

http//www.mushroomvillage.com/sitepics/20192clg.j
pg
7
Congenital Methemoglobinemia Type 1

• Autosomal recessive mutation
• Due to genetic missense mutation of NADH
  cytochrome b5 reductase (methemoglobin
  reductase), which is responsible for reducing
  methemoglobin to hemoglobin
• The deficiency of the reductase is limited to
  RBCs
• This increases methemoglobin levels
• Type 1 has few symptoms other than visible
  cyanosis (blue skin), there are occasional
  complaints of headache, fatigue and trouble
  breathing upon exertion (if methemoglobin level
  is above 25)?

8
http//d.yimg.com/origin1.lifestyles.yahoo.com/ls/
he/healthwise/h9991037.gif
http//members.cox.net/amgough/Mutation_missense-0
1_03_03a.jpg
9
Congenital Methemoglobinemia Type 2
http//members.cox.net/amgough/Mutation_deletion.g
if

• Autosomal recessive mutation
• Due to genetic deletion or premature stop codon
  mutation of NADH cytochrome b5 reductase
• Unlike Type 1, this type of methemoglobinemia
  effects the membrane bound as well as the RBC
  enzyme
• Causes alteration in lipid metabolism effecting
  lots of tissues, specifically the CNS leading to
  problems such as mental retardation and seizures
• Usually causes death within the first few years
  of life

10
Hemoglobin M

• Autosomal dominant mutation
• Mutation of either alpha or beta globin chain in
  specific areas of hemoglobin (in or near the heme
  pocket)?
• This mutated form is called Hemoglobin M
• Leads to an accelerated rate of oxidation of Fe2
  to Fe3 within heme
• This mutation stabilizes Methemoglobin (Fe3)?
• Has few symptoms other than visible cyanosis and
  some breakdown of red blood cells
• At present, only type that cannot be treated

11
http//www.muscular-dystrophy.org/images/adi.jpg
http//rbc.gs-im3.fr/DATA/The20HW_CD/HbsM.jpg
12
Diagnosis of Methemoglobinemia

• Hard to diagnose, two tests that are commonly
  used are
• Co-oximetry test
• -measures absorbance of light. A wavelength of
  630nm characterizes methemoglobin
• Hemoglobin electrophoresis
• -identifies if you have hemoglobin M

http//www.masimo.com/Livewire/2006-01/Rad57_Red_C
O.jpg
http//www.mun.ca/biology/scarr/MGA2_14-10.jpg
13
Treatment of Methemoglobinemia
http//genchem.rutgers.edu/MK-MB.gif

• Type 1 and 2
• Methylene Blue For severe methemoglobinemia

-NADPH methemoglobin reductase turns Methylene
blue into leukomethylene blue using
NADPH -Leukomethylene blue non-enzymatically
reduces methemoglobin to hemoglobin
http//www.thieme-connect.com/bilder/endoscopy/200
209/943en1
14
Ascorbic Acid -Directly reduces methemoglobin
to hemoglobin -Rate of reaction is too slow
alone, therefore, administered with methylene blue
http//www.fao.org/DOCREP/004/Y2809E/y2809e0o.gif
15
Case example Meet the Fugates
http//www.kirchersociety.org/blog/wp-content/uplo
ads/2006/07/bluepeople.jpg
16

• Troublesome Creek, Kentucky (Mid-1700s)?
• Martin Fugate married Elizabeth Smith who had the
  same recessive gene
• 4 of their children were blue
• Inbreeding was far from the exception due to
  their isolated location
• - Zachariah Fugate married his maternal
  aunt
• - Some married their first cousins
• - Some married the other only families
  nearby The Combses, Smiths, Stacys, Ritchies
• Those affected were varying shades of blue, the
  double recessive being all blue and others,
  mostly around their mouth and fingernails.
• In the 1960s, a hemotologist by the name of
  Madison Cawein came to solve this blue case.
• He ruled out heart and lung diseases and with the
  help of E.M. Scotts report in the Journal of
  Clinical Investigation, he was able to conclude
  that they had congenital methemoglobinemia.
• He gave them metheylene blue in tablet form as
  treatment
• ''Within a few minutes. the blue color was gone
  from their skin,"the doctor said. "For the first
  time in their lives, they were pink.They were
  delighted."
• Although most lived up to 80s without major
  complications, many did feel ashamed of their
  colour throughout their lives.

www.cse.emory.edu/sciencenet/evolution/teacher20p
rojects/The20Blue20People20of20Appalach.ppt
17
Summary

• Methemoglobinemia is a disorder characterized by
  the presence of a higher than normal (normallt1)
  amount of methemoglobin in the blood. With a
  higher level of methemoglobin the ability to
  carry oxygen is decreased
• methemoglobin is when the ferrous iron Fe(2) in
  heme is oxidized to ferric iron (fe3), this
  happens due to normal oxidative stress.
• Methemoglobin (where all 4 subunits are carrying
  ferric iron) cannot carry molecular oxygen (as
  the Fe3 cannot bind to oxygen)?. If not all the
  irons carried on the hemoglobin are oxidized
  allosteric interactions cause the non-oxidized
  portions of these hybrids to form a higher
  affinity for oxygen causing a left-shift in the
  disassociation curve causing less oxygen to be
  released into the tissue.
• methemoglobinemia can be acquired (toxin induced,
  dietary) or congenital (inherited)?
• congenital methemoglobin type 1 is a autosomal
  recessive disease caused by a missense mutation
  of NADH cytochrome b5 reductase (methemoglobin
  reductase), which is responsible for reducing
  methemoglobin to hemoglobin, this increases
  methemoglobin levels to 25 or more.The defective
  enzyme is restricted to just red blood cells and
  type 1 has few symptoms other than visible
  cyanosis (blue skin), there are occasional
  complaints of headache, fatigue and trouble
  breathing upon exertion
• congenital methoglobinemia type 2 is also an
  autosomal recessive disease caused by a genetic
  deletion or premature stop codon mutation of NADH
  cytochrome b5 reductase.Unlike Type 1, this type
  of methemoglobinemia effects the membrane bound
  as well as the RBC enzyme which makes this type
  deadly. There is alteration in lipid metabolism
  affecting lots of tissues, specifically the CNS
  leading to problems such as mental retardation
  and there is usually death within the first few
  years of life.
• Hemoglobin M is an autosomal dominant mutation
  there is a mutation of either alpha or beta
  globin chain in specific areas of hemoglobin.This
  mutated form is called Hemoglobin M. the mutation
  leads to an accelerated rate of oxidation of Fe2
  to Fe3 and it stabilizes the Fe3 form. At
  present this type cannot be treated.
• Treatment of type 1 and type 2 congenital
  methemoglobinemia is targetted at using other
  enzymes or molecules to reduce the ferric iron to
  ferrous iron. Both methylene blue and ascorbic
  acid are used to do this.

18
Bibliography

• Hunt, K. 1997. Traits and Fates, Insight in
  Biology (Teacher Guide). Education Development
  Center, Inc., 4-8.
• Umbreit, J. 2007. Methemoglobin-Its Not Just
  Blue A Concise Review. American Journal of
  Hematology. 82134-144.
• Da-Silva S, Sajan I, Underwood J. Congenital
  Methemoglobinemia A Rare Cause of Cyanosis in
  the Newborn-A Case Report. Pediatrics. 112
  158-161.
• Wright R, Lewander W, Woolf A. Methemoglobinemia
  Etiology, Pharmacology, and Clinical Management.
  Annals of Emergency Medicine. 34 (5) 646-656.
• The Blue Fugates. http//www.geocities.com/luvacuz
  n6/BlueFugates.html