Editing Hemoglobinopathy (section)

== Classification of hemoglobinopathies ==

=== A)  Qualitative ===

==== Structural abnormalities ====
Hemoglobin structural variants manifest a change in the structure of the Hb molecule. The majority of hemoglobin variants do not cause disease and are most commonly discovered either incidentally or through newborn screening. Hb variants can usually be detected by protein-based [[assay]] methods such as [[Hemoglobin electrophoresis|electrophoresis]],<ref>{{Cite web |title=Hemoglobin Electrophoresis: MedlinePlus Medical Test |url=https://medlineplus.gov/lab-tests/hemoglobin-electrophoresis/ |access-date=2024-11-20 |website=medlineplus.gov |language=en}}</ref> [[isoelectric focusing]],<ref>{{Citation |last=Garfin |first=David E. |title=[35] Isoelectric focusing |date=1990 |journal=Methods in Enzymology |volume=182 |pages=459–477 |editor-last=Deutscher |editor-first=Murray P. |url=https://linkinghub.elsevier.com/retrieve/pii/0076687990820373 |access-date=2024-11-20 |series=Guide to Protein Purification |publisher=Academic Press |doi=10.1016/0076-6879(90)82037-3 |isbn=978-0-12-182083-1 |pmid=2314254}}</ref> or [[high-performance liquid chromatography]].<ref name="Arishi-2021">{{Cite journal |last1=Arishi |first1=Wjdan A. |last2=Alhadrami |first2=Hani A. |last3=Zourob |first3=Mohammed |date=2021-05-05 |title=Techniques for the Detection of Sickle Cell Disease: A Review |journal=Micromachines |language=en |volume=12 |issue=5 |pages=519 |doi=10.3390/mi12050519 |pmc=8148117 |pmid=34063111 |doi-access=free}}</ref> Diagnosis is commonly confirmed by [[DNA sequencing]].<ref name="Arishi-20212">{{Cite journal |last1=Arishi |first1=Wjdan A. |last2=Alhadrami |first2=Hani A. |last3=Zourob |first3=Mohammed |date=2021-05-05 |title=Techniques for the Detection of Sickle Cell Disease: A Review |journal=Micromachines |language=en |volume=12 |issue=5 |pages=519 |doi=10.3390/mi12050519 |pmc=8148117 |pmid=34063111 |doi-access=free}}</ref>

The hemoglobin structural variants can be broadly classified as follows:<ref>{{Cite journal |last=Forget |first=Bernard G. |last2=Bunn |first2=H. Franklin |date=2013-02-01 |title=Classification of the Disorders of Hemoglobin |url=https://perspectivesinmedicine.cshlp.org/content/3/2/a011684 |journal=Cold Spring Harbor Perspectives in Medicine |language=en |volume=3 |issue=2 |pages=a011684 |doi=10.1101/cshperspect.a011684 |issn=2157-1422 |pmc=3552344 |pmid=23378597}}</ref>
* '''[[Sickle cell disease|Sickle cell disorders]]''', which are the most prevalent form of hemoglobinopathy. Sickle hemoglobin (HbS) is prone to [[polymerizes|polymerize]] when deoxygenated, precipitating within the red blood cell. This damages the RBC membrane resulting in its premature destruction and consequent anemia.<ref>{{Cite journal | doi=10.1016/S0065-3233(08)60287-9| pmid=2195851| isbn=9780120342402| title=Sickle Cell Hemoglobin Polymerization | journal=Advances in Protein Chemistry| year=1990| last1=Eaton| first1=William A.| last2=Hofrichter| first2=James| volume=40| pages=63–279}}</ref>
* '''Unstable hemoglobin variants''' are mutations that cause the hemoglobin molecule to [[precipitate]], spontaneously or upon [[oxidative stress]], resulting in [[hemolytic anemia]]. Precipitated, [[Denaturation (biochemistry)|denatured]] hemoglobin can attach to the inner layer of the [[plasma membrane]] of the red blood cell (RBC) forming [[Heinz bodies]], leading to premature destruction of the RBC and anemia.<ref>{{cite journal | pmid = 7655024 | year = 1995 | last1 = Srivastava | first1 = P. | last2 = Kaeda | first2 = J. S. | last3 = Roper | first3 = D. | last4 = Vulliamy | first4 = T. J. | last5 = Buckley | first5 = M. | last6 = Luzzatto | first6 = L. | title = Severe hemolytic anemia associated with the homozygous state for an unstable hemoglobin variant (Hb Bushwick) | journal = Blood | volume = 86 | issue = 5 | pages = 1977–1982 | doi = 10.1182/blood.V86.5.1977.bloodjournal8651977 | doi-access = free }}</ref>
* '''Change in oxygen affinity.''' High or low oxygen affinity hemoglobin molecules are more likely than normal to adopt the relaxed (R, oxy) state or the tense (T, deoxy) state, respectively. High oxygen affinity variants (R state) cause [[Polycythemia vera|polycythemia]] (e.g., Hb Chesapeake, Hb Montefiore). Low oxygen affinity variants can cause [[cyanosis]] (e.g., Hb Kansas, Hb Beth Israel).<ref name="auto">{{cite journal | pmid = 19734427 | year = 2009 | last1 = Percy | first1 = M. J. | last2 = Butt | first2 = N. N. | last3 = Crotty | first3 = G. M. | last4 = Drummond | first4 = M. W. | last5 = Harrison | first5 = C. | last6 = Jones | first6 = G. L. | last7 = Turner | first7 = M. | last8 = Wallis | first8 = J. | last9 = McMullin | first9 = M. F. | title = Identification of high oxygen affinity hemoglobin variants in the investigation of patients with erythrocytosis | journal = Haematologica | volume = 94 | issue = 9 | pages = 1321–1322 | doi = 10.3324/haematol.2009.008037 | pmc = 2738729 }}</ref>

====Chemical abnormalities====
[[Methemoglobinemia]] is a condition caused by elevated levels of [[methemoglobin]] in the blood. Methaemoglobin is a form of hemoglobin that contains the [[ferric]] [Fe<sup>3+</sup>] form of iron, instead of the [[ferrous]] [Fe<sup>2+</sup>] form . Methemoglobin cannot bind [[oxygen]], which means it cannot carry oxygen to tissues. In human [[blood]] a trace amount of methemoglobin is normally produced spontaneously; the enzyme [[methemoglobin reductase]] is responsible for converting methemoglobin back to [[hemoglobin]].<ref name="Ludlow_2019">{{Cite book |title=StatPearls [Internet]. |vauthors=Ludlow JT, Wilkerson RG, Nappe TM |date=January 2019 |publisher=StatPearls Publishing |location=Treasure Island (FL) |chapter=Methemoglobinemia |pmid=30726002}}</ref><ref>{{cite journal |vauthors=Elahian F, Sepehrizadeh Z, Moghimi B, Mirzaei SA |date=June 2014 |title=Human cytochrome b5 reductase: structure, function, and potential applications |journal=Critical Reviews in Biotechnology |volume=34 |issue=2 |pages=134–143 |doi=10.3109/07388551.2012.732031 |pmid=23113554}}</ref> Methemoglobinemia can be hereditary but more commonly occurs as a side effect of certain medications or by abuse of [[Recreational drug use|recreational drugs]].<ref>{{Cite web |title=Methemoglobinemia (MetHb): Symptoms, Causes & Treatment |url=https://my.clevelandclinic.org/health/diseases/24115-methemoglobinemia |archive-url=http://web.archive.org/web/20241229080906/https://my.clevelandclinic.org/health/diseases/24115-methemoglobinemia |archive-date=2024-12-29 |access-date=2025-01-01 |website=Cleveland Clinic |language=en}}</ref>

===B)  Quantitative===

==== Production abnormalities ====
[[File:B-Thal.jpg|Red blood cells from a person with beta thalassemia|right|thumb]][[Thalassemia|Thalassemias]] are quantitative defects that lead to reduced levels of one type of globin chain, creating an imbalance in the ratio of alpha-like chains to beta-like chains. This ratio is normally tightly regulated to prevent excess globin chains of one type from accumulating. The excess chains that fail to incorporate into normal hemoglobin can form non-functional aggregates that precipitate. This can lead to premature RBC destruction in the bone marrow and/or in the peripheral blood. Thalassemia subtypes of clinical significance are [[alpha-thalassemia|alpha thalassemia]] and [[beta thalassemia]]. A third subtype, [[delta-thalassemia|delta thalassemia]], affects production of HBA2 and is generally asymptomatic.<ref>{{Citation |last=Dasgupta |first=Amitava |title=Chapter 21 - Hemoglobinopathy |date=2014-01-01 |work=Clinical Chemistry, Immunology and Laboratory Quality Control |pages=363–390 |editor-last= |editor-first= |url=https://linkinghub.elsevier.com/retrieve/pii/B9780124078215000218 |access-date=2025-01-01 |place=San Diego |publisher=Elsevier |doi=10.1016/b978-0-12-407821-5.00021-8 |isbn=978-0-12-407821-5 |last2= |first2= |editor2-last= |editor2-first=}}</ref>

The severity of alpha thalassemia depends on how many of the four genes that code for [[Hemoglobin subunit alpha|alpha globin]] are faulty. In the fetus, a deficiency of alpha globin results in the production of [[Hemoglobin Barts]] - a dysfunctional [[hemoglobin]] that consists of four [[Globin|gamma globins]]. In this situation, a fetus will develop [[hydrops fetalis]] and normally die before or shortly after birth.<ref>{{Cite web |title=Pathophysiology of alpha thalassemia |url=http://www.uptodate.com/contents/pathophysiology-of-alpha-thalassemia |access-date=2016-08-30 |website=www.uptodate.com}}</ref> In adults alpha thalassemia manifests as [[Hemoglobin H disease|HbH disease]]. In this, excess [[Hemoglobin subunit beta|beta-globin]] forms β<small>4</small>-tetramers, which accumulate and precipitate in red blood cells, damaging their membranes. Damaged RBCs are removed by the [[spleen]] resulting in moderate to severe anemia.<ref name=":12">{{Cite journal |last1=Fucharoen |first1=Suthat |last2=Viprakasit |first2=Vip |date=2009-01-01 |title=Hb H disease: clinical course and disease modifiers |journal=Hematology |volume=2009 |issue=1 |pages=26–34 |doi=10.1182/asheducation-2009.1.26 |issn=1520-4391 |pmid=20008179 |doi-access=free}}</ref>

In beta thalassemia, reduced production of beta globin, combined with a normal synthesis of alpha globin, results in an accumulation of excess unmatched alpha globin. This precipitates in the red cell precursors in the bone marrow, triggering their premature destruction. Anemia in beta thalassemia results from a combination of ineffective production of RBCs, peripheral [[hemolysis]], and an overall reduction in hemoglobin synthesis.<ref>{{Cite journal |last=Thein |first=Swee Lay |date=2005-01-01 |title=Pathophysiology of β Thalassemia—A Guide to Molecular Therapies |url=https://ashpublications.org/hematology/article/2005/1/31/19297/Pathophysiology-of-Thalassemia-A-Guide-to |journal=Hematology |volume=2005 |issue=1 |pages=31–37 |doi=10.1182/asheducation-2005.1.31 |issn=1520-4391}}</ref>