Hemoglobin M disease

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Hemoglobin M disease
Cyanosis-adult fingertips.PNG
Bluish fingertips in a cyanotic patient
Symptoms Cyanosis and dark brown blood
CausesHemoglobin M variants
Diagnostic method Hemoglobin electrophoresis, UV spectroscopy, DNA sequencing, etc.
TreatmentNo treatment is required

Hemoglobin M disease is a rare form of hemoglobinopathy, characterized by the presence of hemoglobin M (HbM) and elevated methemoglobin (metHb) level in blood. [1] HbM is an altered form of hemoglobin (Hb) due to point mutation occurring in globin-encoding genes, mostly involving tyrosine substitution for proximal (F8) or distal (E7) histidine residues. [2] HbM variants are inherited as autosomal dominant disorders and have altered oxygen affinity. [3] The pathophysiology of hemoglobin M disease involves heme iron autoxidation promoted by heme pocket structural alteration. [4]

Contents

There exists at least 13 HbM variants, such as Boston, Osaka, Saskatoon, etc., named according to their geographical locations of discovery. Different HbM variants may give different signs and symptoms. Major signs include cyanosis and dark brown blood. Patients may be asymptomatic or experience dizziness, headache, mild dyspnea, etc. [2] [5] Diagnosis is usually suspected based on cyanosis. Biochemical testing, hemoglobin electrophoresis, ultraviolet-visible wavelength light spectroscopy, and DNA-based globin gene analysis can be used for diagnosis. [2] [5] [6] [7] [8] [9] [10] Hemoglobin M disease is often not life-threatening and there is no known effective treatment. [3] [5] [10] [11] [12] [13]

Hemoglobin M disease is a congenital subtype of methemoglobinemia. [2] For other congenital subtypes of methemoglobinemia, cytochrome b5 reductase (CYB5R) deficiency is the major cause, rendering defective conversion of metHb to normal Hb. CYB5R deficiency is an autosomal recessive condition. [14]

Pedigree chart of the patient's maternal family showing autosomal dominant inheritance Lifelong cyanosis and skin color and arterial blood color in the patient's family (cropped A).jpg
Pedigree chart of the patient's maternal family showing autosomal dominant inheritance

Signs and Symptoms

Cyanotic extremities and lip discoloration Cyanotic extremities and cyanotic lip discoloration.jpg
Cyanotic extremities and lip discoloration

Cyanosis is the most common sign of hemoglobin M disease, which can be observed in all kinds of hemoglobin M diseases. It is mostly presented in the patient's lips and fingertips. [15] Cyanosis in hemoglobin M disease results from elevated levels of metHb and sulfhemoglobin (sulfHb). [16] Dark brown blood is another major sign of hemoglobin M disease. Hemoglobin M diseases caused by different HbM variants may have slight variations in their signs and symptoms, some include signs such as hemolytic anemia, decreased HbA1c, and abnormal co-oximetry. [13] [17] [18] Onset of cyanosis varies among alpha-, beta- and gamma-chain variants. Infants with alpha- or gamma-chain variants manifest cyanosis since birth but transient neonatal cyanosis caused by gamma-chain variants resolves soon after the disappearance of fetal Hb. Infants with beta-globin variants become cyanotic around 6 months after birth with the completion of the fetal-to-adult Hb switch. [19]

Hemoglobin M disease is usually asymptomatic. However, it may show symptoms such as confusion, headache, tachycardia, and mild dyspnea at metHb level ranging from 10% to 30%. Other possible moderate signs and symptoms (metHb level above 30%) include dizziness, syncope, chest pain, palpitations, and fatigue. More severe signs (metHb level above 50%) include tachypnea, metabolic acidosis, dysrhythmia, seizure, delirium, coma, and death (metHb level above 70%). [5]

Pathophysiology

HbM is a rare methemoglobin group inherited in an autosomal dominant manner, resulting from missense mutations in genes encoding alpha (HBA1, HBA2), beta (HBB), or gamma (HBG1, HBG2) globin chains. In most HbM variants, the proximal (F8) or distal (E7) histidine residue is replaced by tyrosine. [2] [3] Proximal histidine (F8) is designated as position 87 in the alpha chain and 92 in the beta chain. Distal histidine (E7) is designated as position 58 in the alpha chain and position 63 in the beta chain. [5]

Different HbM Variants

At least 13 HbM variants involving alpha- or beta- or gamma-chains have been reported. Six variants, namely HbM Boston, HbM Iwate, HbM Saskatoon, HbM Hyde Park, HbFM Osaka and HbFM Fort Ripley, manifest proximal (F8) or distal (E7) histidine substitution by tyrosine at position alpha-58, alpha-87, beta-63, beta-92, gamma-63 and gamma-92 respectively. HbM Milwaukee-1 involves valine (E11) substitution by glutamate residue at position beta-67. [10]

Alterations in Oxygen Affinity

Normal hemoglobin structure 1904 Hemoglobin.jpg
Normal hemoglobin structure

Under normal circumstances, the heme iron in ferrous state (Fe2+) is covalently bound to imidazole nitrogen of the proximal histidine (F8), and is able to bind to an oxygen molecule. [5]

Tyrosine substitution renders structural alteration of the heme pocket and promotes spontaneous oxidation of heme iron from its ferrous state to ferric state (Fe3+) through discharge of a superoxide ion. Tyrosine can form an iron-phenolate complex with ferric iron which prevents reduction back to divalent ferrous iron. [5] [20] Stable covalent bond between tyrosine and Fe3+ hinders interaction between ferric iron and oxygen. Inability of ferric heme iron in binding oxygen alters oxygen affinity of ferrous heme iron in the remaining normal subunits, impeding oxygen delivery to body tissues. [8] [21] [22]

Stabilization of ferric iron is done through various abnormal coordination mechanisms between mutant side chains and ferric iron. [22]

Mechanisms of Different Hemoglobin M Diseases

Deoxygenated T (Tensed) state (low-affinity Hb quaternary structure) [23] is stabilized in alpha-chain variants due to constraints between subunits. Ferric iron in alpha-chain variants show exceptional resistance to enzymatic reduction by metHb reductases or chemical reduction. In HbM Boston (alpha-58 [E7] His→Tyr), new Tyr (E7) coordination alters the heme plane to disrupt the normal interaction between proximal His (F8) and heme iron. In HbM Iwate (alpha-87 [F8] His→Tyr), tyrosine coordination distorts the heme position. This increases the separation between heme group and helix F within the altered alpha subunits for ferric iron stabilization. [22] [24]

Oxygenated R (Relaxed) state (high-affinity Hb quaternary structure) [23] is stabilized in beta-globin variants due to relaxed constraints between subunits. In HbM Saskatoon (beta-63 [E7] His→Tyr), substitution of a larger Tyr (E7) renders close proximity with heme ferric iron hence forming a hexacoordinate iron site where transient protonation of Tyr (E7) prompts enzymatic reduction by metHb reductase. [13] [22] [24] In HbM Hyde Park (beta-92 [F8] His→Tyr), heme loss and instability with nearby residue reconstruction contribute to its pathophysiology. [22] [24] [25]

Physiological properties of non-mutant subunits within the mutant Hb tetramer differ. Normal alpha subunits in beta-chain variants (HbM Saskatoon and HbM Hyde Park) exhibit significant cooperativity and Bohr effect, displaying an increased oxygen affinity. Normal beta subunits in alpha-chain variants (HbM Boston and HbM Iwate) exhibit reduced cooperativity and Bohr effect, displaying a decreased oxygen affinity. Hence, lower circulating oxidized Hb is observed in beta-chain variants than that in alpha-chain variants. [22] [24] [25]

For HbM Milwaukee-1 (beta-67 [E11] Val→Glu), proximity of anionic glutamate to the heme iron favors the autoxidation of ferrous iron and stabilization of ferric iron by direct coordination to its sixth coordinate position. This decreases oxygen affinity. [22] [26]

Diagnosis

Cyanosis caused by hemoglobin M disease is often mistaken as cardiac or pulmonary defects. Correct diagnosis is important to prevent unnecessary invasive procedures such as cardiac catheterization and mechanical ventilation. [5] [22]

Biochemical Testing

Exposure of venous blood samples to pure oxygen can be used to differentiate cyanosis caused by metHb from cardiopulmonary cyanosis or other cyanosis caused by low-O2 affinity Hbs. Cyanotic patients with methemoglobinemia display brownish blood while purple deoxyhemoglobin becomes bright red oxyhemoglobin in other cases. [10] Addition of potassium cyanide (KCN) can be used to further distinguish hemoglobin M disease from other subtypes of methemoglobinemia and sulfhemoglobinemia. For sulfhemoglobinemia, sulfHb is inert to cyanide and shows no colour change. Hemolysates containing metHb with wild-type globin chains turn red immediately. The color change in hemolysates containing metHb with mutated globin chains is slower and the conversion rate for different HbM variants may vary. [22]

Hemoglobin Electrophoresis

Differences in skin colors and arterial blood colors between a normal individual and patients Lifelong cyanosis and skin color and arterial blood color in the patient's family (cropped BC).jpg
Differences in skin colors and arterial blood colors between a normal individual and patients

It provides qualitative analysis by identification of abnormal Hb variants. Addition of KCN before electrophoresis converts all Hb types into metHb to prevent result misinterpretation due to iron state differences. Normal and abnormal Hb variants are separated by electric current, and the observed differences in migration indicate the substitution of the amino acid. [22] For clear separation, hemoglobin electrophoresis should be performed on agar gel at pH 7.1. Under alkaline conditions, HbM migrates slightly slower than HbA. [3] Further confirmatory testing can be performed by high-performance liquid chromatography (HPLC) to provide quantification of the Hb fractions. [6] [7] [8]

Ultraviolet-Visible Wavelength Light Spectroscopy

Spectral absorption of the hemolysate at various wavelengths can be used for diagnosis. [3] Compared with normal blood, a unique absorption range of HbM variants can be seen. HbM exhibits a specific light absorption pattern, shown by visible peaks at 510 and 630 nm. This explains the formation of chocolate-brown blood. [6] CO-oximetry using multiple wavelengths is preferred over pulse oximetry in metHb detection. Pulse oximetry only uses two distinct wavelengths of 660 and 940 nm which can be misleading. [12] [13]

DNA-Based Globin Gene Analysis

Automated fluorescence-based DNA sequence analysis is applied in the routine diagnosis of hemoglobinopathies as it provides a rapid and reliable result for the identification of specific globin gene mutations. [9] It is used as a further confirmatory test. [8] [22]

Treatment

Hemoglobin M disease is often not life-threatening and treatment is not necessary. There is no existing effective treatment, including methylene blue (MB) and ascorbic acid used in treating acquired methemoglobinemia. [12] MB is an oxidant and it is not used to treat hemoglobin M disease. They are prone to develop symptomatic methemoglobinemia given further exposure to oxidants. [13]

Related Research Articles

<span class="mw-page-title-main">Hemoglobin</span> Metalloprotein that binds with oxygen

Hemoglobin is a protein containing iron that facilitates the transport of oxygen in red blood cells. Almost all vertebrates contain hemoglobin, with the exception of the fish family Channichthyidae and the tissues of some invertebrate animals. Hemoglobin in the blood carries oxygen from the respiratory organs to the other tissues of the body, where it releases the oxygen to enable aerobic respiration which powers the animal's metabolism. A healthy human has 12 to 20 grams of hemoglobin in every 100 mL of blood. Hemoglobin is a metalloprotein, a chromoprotein, and globulin.

<span class="mw-page-title-main">Hemoglobinopathy</span> Any of various genetic disorders of blood

Hemoglobinopathy is the medical term for a group of inherited blood disorders and diseases that primarily affect red blood cells. They are single-gene disorders and, in most cases, they are inherited as autosomal co-dominant traits.

<span class="mw-page-title-main">Globin</span> Superfamily of oxygen-transporting globular proteins

The globins are a superfamily of heme-containing globular proteins, involved in binding and/or transporting oxygen. These proteins all incorporate the globin fold, a series of eight alpha helical segments. Two prominent members include myoglobin and hemoglobin. Both of these proteins reversibly bind oxygen via a heme prosthetic group. They are widely distributed in many organisms.

<span class="mw-page-title-main">Methemoglobinemia</span> Condition of elevated methemoglobin in the blood

Methemoglobinemia, or methaemoglobinaemia, is a condition of elevated methemoglobin in the blood. Symptoms may include headache, dizziness, shortness of breath, nausea, poor muscle coordination, and blue-colored skin (cyanosis). Complications may include seizures and heart arrhythmias.

<span class="mw-page-title-main">Thalassemia</span> Medical condition

Thalassemias are inherited blood disorders that result in abnormal hemoglobin. Symptoms depend on the type of thalassemia and can vary from none to severe. Often there is mild to severe anemia as thalassemia can affect the production of red blood cells and also affect how long the red blood cells live. Symptoms of anemia include feeling tired and having pale skin. Other symptoms of thalassemia include bone problems, an enlarged spleen, yellowish skin, pulmonary hypertension, and dark urine. Slow growth may occur in children. Symptoms and presentations of thalassemia can change over time.

<span class="mw-page-title-main">Cyanosis</span> Decreased oxygen in the blood

Cyanosis is the change of body tissue color to a bluish-purple hue, as a result of decrease in the amount of oxygen bound to the hemoglobin in the red blood cells of the capillary bed. Cyanosis is apparent usually in the body tissues covered with thin skin, including the mucous membranes, lips, nail beds, and ear lobes. Some medications may cause discoloration such as medications containing amiodarone or silver. Furthermore, mongolian spots, large birthmarks, and the consumption of food products with blue or purple dyes can also result in the bluish skin tissue discoloration and may be mistaken for cyanosis. Appropriate physical examination and history taking is a crucial part to diagnose cyanosis. Management of cyanosis involves treating the main cause, as cyanosis isn’t a disease, it is a symptom.

<span class="mw-page-title-main">Fetal hemoglobin</span> Oxygen carrier protein in the human fetus

Fetal hemoglobin, or foetal haemoglobin is the main oxygen carrier protein in the human fetus. Hemoglobin F is found in fetal red blood cells, and is involved in transporting oxygen from the mother's bloodstream to organs and tissues in the fetus. It is produced at around 6 weeks of pregnancy and the levels remain high after birth until the baby is roughly 2–4 months old. Hemoglobin F has a different composition than adult forms of hemoglobin, allowing it to bind oxygen more strongly; this in turn enables the developing fetus to retrieve oxygen from the mother's bloodstream, which occurs through the placenta found in the mother's uterus.

<span class="mw-page-title-main">Methemoglobin</span> Type of hemoglobin

Methemoglobin (British: methaemoglobin, shortened MetHb) (pronounced "met-hemoglobin") is a hemoglobin in the form of metalloprotein, in which the iron in the heme group is in the Fe3+ (ferric) state, not the Fe2+ (ferrous) of normal hemoglobin. Sometimes, it is also referred to as ferrihemoglobin. Methemoglobin cannot bind oxygen, which means it cannot carry oxygen to tissues. It is bluish chocolate-brown in color. In human blood a trace amount of methemoglobin is normally produced spontaneously, but when present in excess the blood becomes abnormally dark bluish brown. The NADH-dependent enzyme methemoglobin reductase (a type of diaphorase) is responsible for converting methemoglobin back to hemoglobin.

A respiratory pigment is a metalloprotein that serves a variety of important functions, its main being O2 transport. Other functions performed include O2 storage, CO2 transport, and transportation of substances other than respiratory gases. There are four major classifications of respiratory pigment: hemoglobin, hemocyanin, erythrocruorin–chlorocruorin, and hemerythrin. The heme-containing globin is the most commonly-occurring respiratory pigment, occurring in at least 9 different phyla of animals.

<span class="mw-page-title-main">Hemoglobin A</span> 4f CC w I/ pop m onf

Hemoglobin A (HbA), also known as adult hemoglobin, hemoglobin A1 or α2β2, is the most common human hemoglobin tetramer, accounting for over 97% of the total red blood cell hemoglobin. Hemoglobin is an oxygen-binding protein, found in erythrocytes, which transports oxygen from the lungs to the tissues. Hemoglobin A is the most common adult form of hemoglobin and exists as a tetramer containing two alpha subunits and two beta subunits (α2β2). Hemoglobin A2 (HbA2) is a less common adult form of hemoglobin and is composed of two alpha and two delta-globin subunits. This hemoglobin makes up 1-3% of hemoglobin in adults.

Hemoglobin A2 (HbA2) is a normal variant of hemoglobin A that consists of two alpha and two delta chains (α2δ2) and is found at low levels in normal human blood. Hemoglobin A2 may be increased in beta thalassemia or in people who are heterozygous for the beta thalassemia gene.

<span class="mw-page-title-main">Alpha-thalassemia</span> Thalassemia involving the genes HBA1and HBA2 hemoglobin genes

Alpha-thalassemia is a form of thalassemia involving the genes HBA1 and HBA2. Thalassemias are a group of inherited blood conditions which result in the impaired production of hemoglobin, the molecule that carries oxygen in the blood. Normal hemoglobin consists of two alpha chains and two beta chains; in alpha-thalassemia, there is a quantitative decrease in the amount of alpha chains, resulting in fewer normal hemoglobin molecules. Furthermore, alpha-thalassemia leads to the production of unstable beta globin molecules which cause increased red blood cell destruction. The degree of impairment is based on which clinical phenotype is present.

<span class="mw-page-title-main">Sickle cell trait</span> Medical condition

Sickle cell trait describes a condition in which a person has one abnormal allele of the hemoglobin beta gene, but does not display the severe symptoms of sickle cell disease that occur in a person who has two copies of that allele. Those who are heterozygous for the sickle cell allele produce both normal and abnormal hemoglobin.

Iron-binding proteins are carrier proteins and metalloproteins that are important in iron metabolism and the immune response. Iron is required for life.

<span class="mw-page-title-main">Hemoglobin variants</span> Forms of hemoglobin caused by variations in genetics

Hemoglobin variants are different types of hemoglobin molecules, by different combinations of its subunits and/or mutations thereof. Hemoglobin variants are a part of the normal embryonic and fetal development. They may also be pathologic mutant forms of hemoglobin in a population, caused by variations in genetics. Some well-known hemoglobin variants, such as sickle-cell anemia, are responsible for diseases and are considered hemoglobinopathies. Other variants cause no detectable pathology, and are thus considered non-pathological variants.

Hemoglobin Barts, abbreviated Hb Barts, is an abnormal type of hemoglobin that consists of four gamma globins. It is moderately insoluble, and therefore accumulates in the red blood cells. Hb Barts has an extremely high affinity for oxygen, so it cannot release oxygen to the tissue. Therefore, this makes it an inefficient oxygen carrier. As an embryo develops, it begins to produce alpha-globins at weeks 5–6 of development. When both of the HBA1 and HBA2 genes which code for alpha globins becomes dysfunctional, the affected fetuses will have difficulty in synthesizing a functional hemoglobin. As a result, gamma chains will accumulate and form four gamma globins. These gamma globins bind to form hemoglobin Barts. It is produced in the disease alpha-thalassemia and in the most severe of cases, it is the only form of hemoglobin in circulation. In this situation, a fetus will develop hydrops fetalis and normally die before or shortly after birth, unless intrauterine blood transfusion is performed.

<span class="mw-page-title-main">Hemoglobin, alpha 2</span> Mammalian protein found in Homo sapiens

Hemoglobin, alpha 2 also known as HBA2 is a gene that in humans codes for the alpha globin chain of hemoglobin.

Within the medical specialty of hematology, Hemoglobin D-Punjab, also known as hemoglobin D-Los Angeles, D-North Carolina, D-Portugal, D-Oak Ridge, and D-Chicago, is a hemoglobin variant. It originates from a point mutation in the human β-globin locus and is one of the most common hemoglobin variants worldwide. It is so named because of its higher prevalence in the Punjab region of India and Pakistan, along with northern China, and North America. It is also the most frequent hemoglobin variant in Xinjiang Uyghur Autonomous Region of China, with a 1997 study indicating that Hemoglobin D-Punjab accounts for 55.6% of the total hemoglobin variants.

Hemoglobin H (Hb H)Disease, also called alpha-thalassemia intermedia, is a disease affecting hemoglobin, the oxygen carrying molecule within red blood cells. It is a form of Alpha-thalassemia which most commonly occurs due to deletion of 3 out of 4 of the α-globin genes.

<span class="mw-page-title-main">Hemoglobin Hopkins-2</span>

Hemoglobin Hopkins-2 is a mutation of the protein hemoglobin, which is responsible for the transportation of oxygen through the blood from the lungs to the musculature of the body in vertebrates. The specific mutation in Hemoglobin Hopkins-2 results in two abnormal α chains. The mutation is the result of histidine 112 being replaced with aspartic acid in the protein's polypeptide sequence. Additionally, within one of the mutated alpha chains, there are substitutes at 114 and 118, two points on the amino acid chain. This mutation can cause sickle cell anemia.

References

  1. ↑ "Hemoglobin M disease (Concept Id: C3665425) – MedGen – NCBI". www.ncbi.nlm.nih.gov. Retrieved 2022-03-28.
  2. 1 2 3 4 5 Ludlow, John T.; Wilkerson, Richard G.; Nappe, Thomas M. (2022), "Methemoglobinemia", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID   30726002 , retrieved 2022-03-28
  3. 1 2 3 4 5 Randolph, Tim R. (2020-01-01), Keohane, Elaine M.; Otto, Catherine N.; Walenga, Jeanine M. (eds.), "24 - Hemoglobinopathies (structural defects in hemoglobin)", Rodak's Hematology (Sixth Edition), St. Louis (MO): Elsevier, pp. 394–423, ISBN   978-0-323-53045-3 , retrieved 2022-03-28
  4. ↑ Alonso-Ojembarrena, A. (2016). "Hemoglobin M Disease as a Cause of Cyanosis in a Newborn". Journal of Pediatric Hematology/Oncology. 38 (3): 173–175. doi:10.1097/MPH.0000000000000489. PMID   26694193. S2CID   26848356 – via PubMed.
  5. 1 2 3 4 5 6 7 8 Iolascon, Achille; Bianchi, Paola; Andolfo, Immacolata; Russo, Roberta; Barcellini, Wilma; Fermo, Elisa; Toldi, Gergely; Ghirardello, Stefano; Rees, Davis; Van Wijk, Richard; Kattamis, Antonis (2021-09-23). "Recommendations for diagnosis and treatment of methemoglobinemia". American Journal of Hematology. 96 (12): 1666–1678. doi:10.1002/ajh.26340. hdl: 1887/3249335 . ISSN   0361-8609. PMC   9291883 . PMID   34467556. S2CID   237377613.
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  7. 1 2 Leung, Kwok Yin; Au, Patrick; Tang, Mary (2020-01-01), Pandya, Pranav P.; Oepkes, Dick; Sebire, Neil J.; Wapner, Ronald J. (eds.), "27 - Prenatal Screening for Thalassemias", Fetal Medicine (Third Edition), London: Elsevier, pp. 263–273.e1, ISBN   978-0-7020-6956-7 , retrieved 2022-03-28
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  10. 1 2 3 4 Old, John (2013-01-01), Rimoin, David; Pyeritz, Reed; Korf, Bruce (eds.), "Chapter 71 - Hemoglobinopathies and Thalassemias", Emery and Rimoin's Principles and Practice of Medical Genetics (Sixth Edition), Oxford: Academic Press, pp. 1–44, ISBN   978-0-12-383834-6 , retrieved 2022-03-28
  11. ↑ Rehman, Habib Ur (2001). "Methemoglobinemia". Western Journal of Medicine. 175 (3): 193–196. doi:10.1136/ewjm.175.3.193. ISSN   0093-0415. PMC   1071541 . PMID   11527852.
  12. 1 2 3 Patnaik, Sibabratta; Natarajan, Manivachagan Muthappa; James, Ebor Jacob; Ebenezer, Kala (2014). "Methylene blue unresponsive methemoglobinemia". Indian Journal of Critical Care Medicine. 18 (4): 253–255. doi: 10.4103/0972-5229.130582 . ISSN   0972-5229. PMC   4033863 . PMID   24872659.
  13. 1 2 3 4 5 Göttgens, Eva-Leonne; Baks, Kristian; Harteveld, Cornelis L.; Goossens, Kristel; van Gammeren, Adriaan J. (2021). "Cyanosis, hemolysis, decreased HbA1c and abnormal co-oximetry in a patient with hemoglobin M Saskatoon [HBB:c.190C > T p.His64Tyr]". Hematology (Amsterdam, Netherlands). 26 (1): 914–918. doi: 10.1080/16078454.2021.1999048 . hdl: 1887/3249333 . ISSN   1607-8454. PMID   34789072. S2CID   244346360.
  14. ↑ Percy, Melanie J.; Lappin, Terry R. (2008). "Recessive congenital methaemoglobinaemia: cytochrome b(5) reductase deficiency". British Journal of Haematology. 141 (3): 298–308. doi: 10.1111/j.1365-2141.2008.07017.x . ISSN   1365-2141. PMID   18318771. S2CID   36408296.
  15. ↑ Özsoylu, S. (1972). "Congenital Methemoglobinemia Due to Hemoglobin M". Acta Haematologica. 47 (4): 225–232. doi:10.1159/000208528. ISSN   0001-5792. PMID   4625305.
  16. ↑ Rangan, Aruna; Savedra, Michelle E.; Dergam-Larson, Camila; Swanson, Kenneth C.; Szuberski, Jessica; Go, Ronald S.; Porter, Tavanna R.; Brunker, Sarah E.; Shi, Min; Nguyen, Phuong L.; Hoyer, James D. (August 2021). "Interpreting sulfhemoglobin and methemoglobin in patients with cyanosis: An overview of patients with M-hemoglobin variants". International Journal of Laboratory Hematology. 43 (4): 837–844. doi:10.1111/ijlh.13581. ISSN   1751-553X. PMID   34092029. S2CID   235362094.
  17. ↑ Pisciotta, A. V.; Ebbe, S. N.; Hinz, J. E. (July 1959). "Clinical and laboratory features of two variants of methemoglobin M disease". The Journal of Laboratory and Clinical Medicine. 54 (1): 73–87. ISSN   0022-2143. PMID   13665153.
  18. ↑ Rastogi, Loveena; Langer, Sabina; Radhakrishnan, Nita; Saxena, Renu; Kotwal, Jyoti (2020-09-30). "Hb-M Hyde Park: a rare cause of cyanosis arising from a de novo mutation". Blood Research. 55 (3): 177–180. doi:10.5045/br.2020.2020084. ISSN   2287-979X. PMC   7536569 . PMID   32747614.
  19. ↑ Nelson textbook of pediatrics. Robert Kliegman, Bonita Stanton, Joseph W., III St. Geme, Nina Felice Schor, Richard E. Behrman, Waldo E. Preceded by: Nelson (Edition 21 ed.). Philadelphia, PA. 2020. ISBN   978-0-323-56888-3. OCLC   1096283151.{{cite book}}: CS1 maint: location missing publisher (link) CS1 maint: others (link)
  20. ↑ Spears, Frances; Banerjee, Arnab (June 2008). "Hemoglobin M variant and congenital methemoglobinemia: methylene blue will not be effective in the presence of hemoglobin M". Canadian Journal of Anaesthesia. 55 (6): 391–392. doi: 10.1007/BF03021499 . ISSN   0832-610X. PMID   18566207. S2CID   46308991.
  21. ↑ Vichinsky, E. P.; Lubin, B. H. (May 1980). "Unstable hemoglobins, hemoglobins with altered oxygen affinity, and m-hemoglobins". Pediatric Clinics of North America. 27 (2): 421–428. doi:10.1016/s0031-3955(16)33859-7. ISSN   0031-3955. PMID   7383714.
  22. 1 2 3 4 5 6 7 8 9 10 11 Nathan and Oski's hematology and oncology of infancy and childhood. Stuart H. Orkin, David E. Fisher, David Ginsburg, A. Thomas Look, Samuel E. Lux, David G. Nathan (8th ed.). Philadelphia, PA. 2015. ISBN   978-0-323-29177-4. OCLC   894113533.{{cite book}}: CS1 maint: location missing publisher (link) CS1 maint: others (link)
  23. 1 2 Mihailescu, Mihaela-Rita; Russu, Irina M. (2001-03-27). "A signature of the T → R transition in human hemoglobin". Proceedings of the National Academy of Sciences of the United States of America. 98 (7): 3773–3777. Bibcode:2001PNAS...98.3773M. doi: 10.1073/pnas.071493598 . ISSN   0027-8424. PMC   31128 . PMID   11259676.
  24. 1 2 3 4 Thom, Christopher S.; Dickson, Claire F.; Gell, David A.; Weiss, Mitchell J. (March 2013). "Hemoglobin Variants: Biochemical Properties and Clinical Correlates". Cold Spring Harbor Perspectives in Medicine. 3 (3): a011858. doi:10.1101/cshperspect.a011858. ISSN   2157-1422. PMC   3579210 . PMID   23388674.
  25. 1 2 Kim, Dae Sung; Baek, Hee Jo; Kim, Bo Ram; Yoon, Bo Ae; Lee, Jun Hyung; Kook, Hoon (December 2020). "The First Korean Family with Hemoglobin-M Milwaukee-2 Leading to Hereditary Methemoglobinemia". Yonsei Medical Journal. 61 (12): 1064–1067. doi:10.3349/ymj.2020.61.12.1064. ISSN   1976-2437. PMC   7700874 . PMID   33251782.
  26. ↑ Stucke, Astrid G.; Riess, Matthias L.; Connolly, Lois A. (April 2006). "Hemoglobin M (Milwaukee) affects arterial oxygen saturation and makes pulse oximetry unreliable". Anesthesiology. 104 (4): 887–888. doi: 10.1097/00000542-200604000-00036 . ISSN   0003-3022. PMID   16571987.
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