Genetics Sources: Thompson & Thompson Genetics

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!