A 25-year-old Canadian woman of Vietnamese origin presented with mild microcytic anemia during routine prenatal care. Testing revealed she had beta-thalassemia trait due to a nonsense mutation in her beta-globin gene. Her Greek husband also carried the same mutation, giving them a 25% risk of having a child with beta-thalassemia major. Beta-thalassemia is caused by a deficiency in alpha or beta globin production and results in anemia and other symptoms. Current treatments include blood transfusions, chelation therapy, and potentially gene therapy through stem cell gene correction.

1. Thalassemia CASE 44
Presented by Dilina Aarewatte | Group 8 | Semester IV
TSMU-IFM 2/10/2020

2. The Case
▫ A 25 year old Healthy Canadian woman, presented to her
obstetrician for routine prenatal care.
▫ Results of her complete blood count showed signs of a mild
microcytic anemia
▫ Hemoglobin 98 g/L [ref.  121-151 g/L]
▫ Mean Corpuscular Volume 75 µm³ [ref.  87 ± 5]

3. History
▫ J.Z. - 25 yr, Canadian woman,
Vietnamese origin
▫ Spouse – T.Z. - Greek origin
▫ J.Z. unaware of any blood disorders
in her family, or T.Z.’s family. (No FHx)

4. Investigations
▫ Hemoglobin electrophoresis was done for J.Z.
▫ Findings:
▫ Mildly elevated Hb A2 (α2δ2) and Hb F (α2γ2)
This suggested that J.Z. had a β-thalassemia trait.
▫ Molecular testing was done for J.Z and T.Z. both.
▫ J.Z – Nonsense mutation in β-globin allele (no α globin deletions)
▫ T.Z - Nonsense mutation in β-globin allele (no α globin deletions)
The couple was advised by the physician that their risk of having a child with
β thalassemia major was 25%.

5. Etiology & Incidence
▫ Autosomal recessive disorder.
▫ Caused by the relative deficiency of α or β globin.
▫ Most common among Mediterranean, African, Middle
eastern, Indian, Chinese, and South-east Asian populations.
▫ Heterozygous advantage gives resistance to malaria.

7. Pathogenesis of Thalassemia
▫ Results from inadequate Hb
production, causing unbalanced globin
sub-unit accumulation.
▫ Hypochromia & microcytocis seen due
to inadequate production
▫ Ineffective erythropoiesis & hemolytic
anemia due to unbalanced globin
accumulation.
▫ Severity of diseases depends on the
degree of imbalance in production.

8. “▫ Although there are more than 200 different
mutations that can cause thalassemia, a few
mutations are seen in majority of the cases:
Deletion of α- globin genes – 80% of α-thalassemia
▫ 15 mutations cause 90% of β-thalassemia cases.
▫ These high frequencies are said to be due to selection.

9. Clinical Symptoms & Diagnosis
▫ In a population, the α-globin mutations are reflected by the
phenotypes observed in the population.
▫ Clinical symptoms
▫ Anemia [hypochromic
microcytic]
▫ Pallor
▫ Fatigue
▫ Hepatosplenomegaly

10. ▫ Hepatosplenomegaly
▫ Pallor

11. ▫ In β thalassemia,
▫ Growth retardation,
▫ Mild bone marrow erythroid hyperplasia is foumd.
▫ Patients with β-thalassemia major present with severe
hemolytic anemia when postnatal decrease of Hb F occurs.
▫ The anemia and ineffective erythropoiesis causes
▫ Growth retardation
▫ Jaundice
▫ Hepatosplenomegaly
▫ Patients usually present within first 2 years of life,
and if untreated, dies around 5 years of age.

12. Newborn screening
▫ Diagnosis of Thalassemia trait
maybe done through newborn
or antenatal screening.
▫ FBC or HPLC is used.
▫ HPLC is a sensitive and precise
method for the identification of
Hb A2, Hb F and abnormal
hemoglobin. It has become the
method of choice for
thalassemia screening because
of its speed and reliability.

13. Genetic methods of diagnosis
▫ Prenatal diagnosis of both α
and β thalassemia can be
done by molecular analysis of
fetal DNA, from either
chorionic villi or amniocytes.
▫ Preimplantation diagnosis is
possible if expected genetic
mutations are known
beforehand.

14. Treatment & management
▫ If increased levels of Hb A2 is found and iron deficiency
is ruled out, β thalassemia trait is confirmed. Treatment
for it includes
▫ Blood transfusions
▫ Iron chelation
▫ Prompt treatment of infection
▫ Splenectomy
▫ For Hb H disease, where hydrops fetalis may occur,
treatment is primarily supportive. Avoidance of oxidant
drugs & iron, folate supplementation are included in
therapy.

15. ▫ Splenectomy is indicated in the transfusion-dependent
patient when hypersplenism increases blood transfusion
requirement and prevents adequate control of body iron with
chelation therapy.

16. Gene Therapy of Beta Thalassemia Using a Self-inactivating
Lentiviral Vector
▫ Currently, the only cure for thalassemia is bone marrow
transplantation from a related, compatible donor, which has,
however, the significant risk of transplant related mortality, graft
versus host disease and limited source.
▫ Therefore, gene transfer, achieved by transplantation of the
patient's own stem cells that have been genetically-modified with
the corrected gene, could potentially cure thalassemia.

17. ▫ This study will use an experimental gene
transfer procedure performed in a laboratory to
insert the related gene into the participant's
autologous stem cells using a self-inactivating
lentiviral vector.
▫ The purpose of this study is to evaluate the
safety and effectiveness of the gene transfer
procedure and to determine the ability of the
gene-corrected cells at generating new,
healthy blood cells in individuals.

18. Thank you!