Hemoglobinopathy

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Hemoglobinopathy Main page

Overview

Classification

Epidemiology and Demographics

Diagnostic approach

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sogand Goudarzi, MD


Overview

Hemoglobinopathy is a kind of genetic defect that results in abnormal structure of one of the globin chains of the hemoglobin molecule. Most common hemoglobinopathies include sickle-cell disease and thalassemia. The clinical manifestations of the hemoglobinopathies ranges from mild hypochromic anemia to severe hematological disease.


Classification

Hemoglobinopathy be classified according to genetic and structure of hemoglobin into two main groups:[1]

 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hemoglobinopathy classification
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Quantititive disorders of globulin chain synthesis
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Qualitative disorders of globulin structure
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
α-thalassemia
 
β-thalassemia
 
De novo and acquired α-thalassemia
 
 
 
Sickle cell disorders
 
 
 
Hemoglobins with decreased stability (unstable hemoglobin variants)
 
 
 
Hemoglobins with altered oxygen affinity
 
 
 
Methemoglobin
 
 
 
Posttranslational modifications
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Deletion of α globin
• One gene: α+ athalassemia
• Two gene in cis: α0 thalassemia
• two gene in trans: homozygous α+ thalassemia (phenotype α0 thalassemia)
• Three gene: HbH disease
• Four genes: Hydrops fetalis with Hb Bart's
 
 
 
 
 
 
 
α-Thalassemia with mental retardation syndrome (ATR):
• Due to large deletions on chromosome 16 involving the α-globin genes
• Due to mutations of the ATRX transcription factor gene on chromosome X
α-Thalassemia associated with myelodysplastic
 
 
 
 
SA, sickle cell trait
 
 
 
 
Mutants causing congenital Heinz body hemolytic anemia
 
 
 
 
High/increased oxygen affinity stateso
Fetal red cells
• Decreased RBC 2,3 BPG
Carboxyhemoglobinemia, HbCO
• Structural variants
 
 
 
 
Congenital methemoglobinemia
• Structural variants
Cytochrome b5 reductase deficiency
 
 
 
 
 
Nonenzymatic glycosylation
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Low/decreased oxygen affinity states
2,3 BPG
• Structural variants
 
 
 
 
Acquired (toxic) methemoglobinemia
 
 
 
 
 
Amino-terminal acetylation
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nondeletion mutants
Hb Constnt Spring
• Other
 
 
 
 
 
 
 
α-Thalassemia associated with myelodysplastic syndromes (ATMDS)
• Due to mutations of the ATRX gene
 
 
 
 
SS, sickle cell anemia/disease
 
 
 
 
Acquired instabilityoxidant hemolysis
• Drug-induced
G6PD deficiency
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Amino-terminal carbamylation
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SC, HbSC disease
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Deamidation
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
S/β thal, sickle β-thalassemia disease
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
S with other Hb variants: D, O-Arab, other
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SF, Hb S/HPFH
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical classification
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biochemical/genetic classification
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Structural variants with β-thalassemia phenotype
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Minor/trait
 
Intermediate
 
Major
 
 
 
β0 thalassemia
 
β0 thalassemia
 
δ-thalassemia
 
 
γ-thalassemia
 
Lepore fusion gene
 
 
 
 
 
 
HbS/β-thalassemia
 
HbE/β-thalassemia
 
Other
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
δβ-thalassemia
 
εγδβ-thalassemia
 
HPFH
 
 

The range of clinical manifestations of the hemoglobinopathies are from mild hypochromic anemia to moderate hematological disease to severe.

Epidemiology and Demographics

Prevalence

  • In 2008, the prevalence of hemoglobinopathy carrier was estimated to be 700 per 100,000 (7%), worldwide.[2]
  • The most prevalence of hemoglobinopathy gene carriers in the world's are in South-East Asia (up to 70%) and Arab nations (up to 60%).[2]
  • In Russia, prevalence of hemoglobinopathy is rare.[2]
  • In recent years, prevale of hemglobinopathy is increased in Germany.[3]

Region

α-thalassemias

It occurs frequently in Africa, Arab nations, South-East Asia.[4]

β-thalassemias

It occurs frequently in Mediterranean countries, South-East Europe, Arab nations, and Asia.[5]

Diagnostic Approach

Hemoglobin testing (hemoglobin electrophoresis or chromatography), [[Red blood cell |red blood cell]] count, hemoglobin pattern, cardinal symptoms are used to reach the diagnosis of a particular hemoglobinopathy.[6]

 
 
 
 
 
 
 
 
 
 
 
 
 
 
History & clinical symptoms
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood test
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hemolysate
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diagnosis of abnormal hemoglobins
 
 
 
 
 
 
 
 
 
 
 
Diagnosis of β-thalassemia
 
 
 
 
 
 
 
Diagnosis of α-thalassemia
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alkaline electrophoresis
acid Electrophoresis
HPLC
 
 
 
 
 
 
 
 
 
 
 
Electrophoresis HPLC
HbA2,Hbf
 
 
 
 
 
 
 
Electrophoresis HPLC
DNA testing
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Evidence of abnormality,comparison of mobility with that of known abnormalities, if HBS suspected: solubility test
 
 
Separation/quantification
 
 
 
 
 
 
 
 
 
Evalution of all data and findings
 
 
 
 
 
 
 
Evalution of all data and findings
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diagnosis of β-thalassemia
 
 
 
 
 
 
 
Diagnosis of α-thalassemia
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DNA sequencing if needed
 
 
 
 
 
 
 
 
 
 
 
 
DNA sequencing if needed(thalassemia major, thalassemia intermedia
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Evaluation of all data and findings(including blood count ethnic and origin
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diagnosis of hemoglobinopathy
 
 
 
 

References

  1. Forget BG, Bunn HF (February 2013). "Classification of the disorders of hemoglobin". Cold Spring Harb Perspect Med. 3 (2): a011684. PMC 3552344Freely accessible. PMID 23378597. doi:10.1101/cshperspect.a011684. 
  2. 2.0 2.1 2.2 Kohne E (August 2011). "Hemoglobinopathies: clinical manifestations, diagnosis, and treatment". Dtsch Arztebl Int. 108 (31-32): 532–40. PMC 3163784Freely accessible. PMID 21886666. doi:10.3238/arztebl.2011.0532. 
  3. Cario H, Stahnke K, Sander S, Kohne E (January 2000). "Epidemiological situation and treatment of patients with thalassemia major in Germany: results of the German multicenter beta-thalassemia study". Ann. Hematol. 79 (1): 7–12. PMID 10663615. 
  4. Kohne E (August 2011). "Hemoglobinopathies: clinical manifestations, diagnosis, and treatment". Dtsch Arztebl Int. 108 (31-32): 532–40. PMC 3163784Freely accessible. PMID 21886666. doi:10.3238/arztebl.2011.0532. 
  5. Kohne E (August 2011). "Hemoglobinopathies: clinical manifestations, diagnosis, and treatment". Dtsch Arztebl Int. 108 (31-32): 532–40. PMC 3163784Freely accessible. PMID 21886666. doi:10.3238/arztebl.2011.0532. 
  6. Herklotz R, Risch L, Huber AR (January 2006). "[Hemoglobinopathies--clinical symptoms and diagnosis of thalassemia and abnormal hemoglobins]". Ther Umsch (in German). 63 (1): 35–46. PMID 16450733. doi:10.1024/0040-5930.63.1.35. 


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