BY: Dr. MOHD SALAH

Data from Dubai Thalassemia Centre

Chromosome 11-globin gene

Chromosome 16 -globin gene

An example of inheritance:Marriage between two carriers

Red blood cell Oxygen from

lungsOxygen released to tissue cells

Oxygen boded with hemoglobin molecules

Hemoglobin molecules

1. 1. Homozygous or compound heterozygous state for thalassemia

a) Inheritance of mild thalassemia alleles

b) Co-inheritance of thalassemiac) Increased Hb F response

Xmn1 –polymorphism promoter mutations Trans-acting HPFH genetic

determinants

2. 2. Heterozygous state for thalassemiaa) Co-inheritance of extra globin genes

()

b) Dominantly inherited thalassemia(Hyperunstable chainvariants)

3. Compound heterozygous for thalassemia and chain variants e.g. Hb E

4. Compound heterozygotes for thalassemia and HPFH .

-Thalassaemia genotypes of parents HbF values in parents Co-inheritance of thalassemia Age at presentation Level of Hb at presentation Level of Hb A

All patients had:Serial FBCsHb Electrophoresis (HPLC) &/ or IEFMolecular characterization of alphagenes ( Deletional and non-deletional) Beta genes mutations &Xmn1Clinical monitoring of any possiblecomplication

HbA: Decreased HbF: Inc(80-90 %) HbA2: Variable

HbA: Decreased(>20%) HbF: Inc(70-80 %) HbA2: N or Increased

The mean age is 11 (3-33) yrs,

Non-deletional alpha-gene mutation was normal in all our patients.

Most of pts have mild to moderate thalassemic features.

Average hemoglobin level : 8.5 g/dl.

40% of patients had infrequent hemoglobin drop needed blood transfusion.

509

420

44 45

0

100

200

300

400

500

600

Total BTM BTI BMT

No of pts

82.52%

8.64%

8.84%

44%

33%

23%

severe mutation mild mutation mixed

2515

62.5

37.5

0

10

20

30

40

50

60

70

no. of pts %

male female

9 = IVS 1 - 5 (G-C) / IVS 1 - 5 (G-C) 4 = IVS 1 - 5 (G-C) / - 25 bp del 3 = IVS 1 - 1(G-C) / IVS 1 – 1(G - C) 1 = IVS 1 - 1 (G-T) / IVS 1 - 1 (G - T) 1 = -25 bp del / -25 bp del

2= CD 26 (G-A) / Milder mutation 2= IVS 11–1 (G-C) / IVS 11 – 1 1= IVS 1-6 (T-C) / IVS 1-6 (T-C) 1= CD 27 (G-T) / CD 39 (G-T) 1= CD 26 (G-A) / IVS 1 – 130 (G-C) 2= VS 1-6 (T-C) / mild 2= IVS 1-6(T-C) / IVS II-848(C-A) 2 = Cd 8 (-AA) / Cd 8 (-AA)

2= IVS 1 - 5 (G-C) / - 88 (C-A) 3= IVS 1 - 5 (G-C) / Poly A 2= IVS 1– 5 (G-C) / CD 26 (G-A) 1= IVS 1 – 5 (G-C)/ 1= -25 bp del / CD 27 (G-T) 25 bp del / CD 27 (G-T)

14

4

6

10

6

02468

101214

No. of pts

Homozygous severe Hetero severe Homo mildHetero mild/severe Hetero mild/mild

9, 47%

4, 21%

6, 32%HomozygousWith severeWith mild

IVS 1-5(GC) =19

-Thal. Status

18 severe - mutation

8 normal - thal

4 heterozygous -thal 3.7

6 homozygous -thal 3.7

13 13

5

9

0

2

4

6

8

10

12

14

Never tx Rarely tx Freq. tx Planned tx

Total Severe mut. Mild mut.

4/20 (20%) patients received blood transfusion rarely

4/4 (100%) are homozygous positive for XmnI,

2/4 (50%) are heterozygous for –3.7 alpha-gene mutation (alpha-thalassemia trait)

Xmn1

5-P/P 2- P/ - ve

13

8

5

0

2

4

6

8

10

12

14

No of pts

total mild mutation severe mut.

2 PTS

SEVERE MUTATION N-geneDeletional & nondeletional N- Xmn1

2 PTSSEVERE MUTATION 1 a-GENE DELETION Xmn1-p/p

1-Pt a- Thal. Trait

0 0.5 1 1.5 2 2.5 3

Thal. Features

pregnancy

path. fracture

Delayed puberty

Multifactorial

Among the known factors affecting the phenotypic severity in our pts.:

Type of Beta mutation.

The presence of alpha-gene defect.

XmnI mutation (homozygous and hetero) would ameliorate the clinical course.

Two of our patients have severe mutation with normal a-thal and normal Xmn1

Further studies still needed to specify other factors.

Erol Baysal, PhD Aref Chehal, MD Maisam Bakir,MD Essam Dohair, MD Lab. Technicians Nursing Staff Abdulla Alkhayat.MD

Al Wasl Hospital, Genetic and Thalassemia Center, Dubai,

UAE.