251. Thalassemia

Question 1

What is thalassemia?

• epi
• genetics

Answer 1

T: mutations in globin (usually beta chain) resulting in inability to make globin = anemia

• 5-7% world are carriers, common in Africa, Mediterranean, India
• Beta globin locus on Ch 11: all mutations possible, do not predict phenotype (defined operationally by >8 or <8 transfusions needed per year)

Modifying genes

• inability to produce HbF (more severe)
• alpha-globin thalassemia: reduce imbalance, less hemolysis
• extra alpha globin genes: more imbalance = more severe
• genets encoding globin chaperones or protecting against hemolysis

Question 2

Hemoglobin E

• epidemiology
• cause
• CP: homozygous vs coinheritance

Answer 2

30-45% SE Asian populations are carriers
Cause: single AA substitution (point mutation) in beta globin activates cryptic mRNA splice site

Homozygous: benign microcytosis, no anemia, slightly less stable under oxidative stress

Coinheritance HbE with beta-thalassemia: similar to beta-thalassemia major in severity (SERIOUS)

Question 3

Alpha Thalassemia

• types of mutations
• effect of genotype
• HbH disease
• Hb Constant Spring disease

Answer 3

Mutations: a+ (still some alpha globin produced), a0 (large deletions with no alpha production)
Genotype: normal = 4 functional genes (2 on each Ch)
silent alpha-T = 3 functional genes
alpha-T TRAIT: homozygous a+ (“trans” one knockout on each Ch) vs heterozygous a0 (“cis” two knockout on one Ch) = 2 functional genes
Hb Bart’s Hydrops Fetalis (lethal) = no functional alpha genes (only occurs when both parents are cis heterozygotes)

HbH disease

• mutation in 3 of 4 alpha genes
• epi: SE asia, Mid E, Mediterranean
• deletional mutations mostly (nondeletional: a+ mutation causes defective alpha globins = more severe)

Hb Constant Spring

• nondeletional mutation in alpha2 gene
• high freq in SE Asia
• causes unstable elongation of mRNA
• homozygous HbCS similar to homozygous HbH

HbH/HbCS coinheritance: more severe condition

Question 4

Beta Thalassemia

- Pathophys (2 key features)

Answer 4

1. Ineffective Erythropoiesis = hypercellular marrow, elevated EPO (some EPO resistance), extramedullary hematopoiesis, bony deformities, hemochromatosis
2. Chronic Hemolysis (defective Hb) = splenomegaly, hemochromatosis, profound anemia

Question 5

What are 4 ways to dx beta thalassemia?

Answer 5

1. High performance liquid chromatography: separates normal and abnormal globin variants (USED IN NEWBORN SCREEN) - SCREENING test
2. Hb Electrophoresis: separates normal and abnormal globins (Qualitative NOT quantitative) - used to CONFIRM test for beta globin
   Note: neonatal blood will have only HbF (no HbA); post-neonatal blood will have HbF and increased HbA2
3. Peripheral blood smear/CBC: microcytic, hypochromic anemia, marked anisopoikilocytosis, Hb precipitants in supravital stain for alpha-thalassemia
4. DNA analysis

Question 6

Clinical features of beta-thalassemia and alpha-thalassemia

Answer 6

Beta

• poor growth, jaundice, hepatosplenomegaly, bony deformity, high fracture risk
• secondary hemochromatosis from blood transfusion tx (Fe overload)
• “Thal” or chipmunk facies
• crewcut skull deformity

Alpha
- fetal demise, neurocognitive deficits, limb abnormalities, hepatomegaly

Question 7

Tx for thalassemia (4)

Answer 7

1. Chronic Transfusions
   - only if consistently low anemia, growth issues, bony changes
   - risk of Fe overload: track serum ferritin (imprecise) or liver iron content (better but requires liver biopsy)
2. Iron Chelation (prevent Fe Overload from transfusions)
   - DFO (deferoxamine) - SC/IV route
   - Deferiprone, Deferasirox
3. Splenectomy
4. Bone Marrow/SC transplant (may be CURATIVE)
   - HLA matched sibling donors, best survival with younger age and higher liver fx

Room for gene therapy (engineered viral vectors), genome editing (modifying host stem cells with CRISPR/Cas9), base editing (direct conversion of base pairs from one to another without dsDNA breaks)