Prof. Renzo Galanello Pediatric Clinic 2° University of Cagliari...

Thalassemia majorclinical aspects and management

Prof Renzo GalanelloPediatric Clinic 2deg University of CagliariOspedale Regionale Microcitemie-ASL8

Clinical characteristics ofβ talassemia major

severe early-onset hypochromicmicrocytic anemialiver and spleen enlargementfailure to thrivesevere skeletal manifestationregular transfusions required

(transfusion dependent)

DIAGNOSIS OF HOMOZYGOUS BETA THALASSEMIA


cbc

Hb electrophoresisHPLC

DNA globin gene analysis

globin chain synthesis

cbc




cellulose acteate electrophoresis (pH 86)cellulose acteate electrophoresis (pH 86)

origin

HbXHbFHbA

HbA2

-

+

Peripheral blood smear in β-thalassemia major (A) intermedia (B) and in heterozygous β-thalassemia (C)


AA

BB

CC

Figure 7

7

Management of Thalassemia Majorbull Conventional

ndash RBC transfusionsndash Iron chelationndash (Splenectomy)

bull Bone marrow transplantationbull Prospectives

ndash gene therapyndash Hb F induction

8

AIMS OF TRANSFUSION TREATMENTbull Normal growth and physical activitybull darr Chronic hypoxemiabull darr Compensatory marrow hyperplasia

ndash darr hypervolemiandash darr bone changes ndash darr extramedullary erythropoiesis

bull darr Splenomegaly and hypersplenismbull darr Gastro-intestinal iron absorption

Improvementof cardiacfunction

9

Guidelines For RBC TransfusionIn Thalassemia Major

lt10 mlkghRate

2-4 weeksInterval

lt20 mlKgVolume

lt140 gdLPost-transfusional hemoglobin

95-105 gdLPre-transfusional hemoglobin

10

0

50

100

150

200

250

300

350

400

0 20 40 60 80 100PATIENT WEIGHT kg

Hct 80

Hct 60

Hct 75

Hct 50

ml

AMOUNT OF BLOOD REQUIRED TO RAISE AMOUNT OF BLOOD REQUIRED TO RAISE PATIENTPATIENTrsquorsquoS HAEMOGLOBIN BY 1 gdlS HAEMOGLOBIN BY 1 gdl

TIF 2000

11

Transfusional Indices (Annual)

bull Mean hemoglobin bull Pure red cell consumptionbull Iron inputbull Mean transfusional interval

12

bull Row data fromndash transfusionndash chelationndash tests

bull Complicationsbull Therapies

Transfusional indexesIron balanceAppointmentsPrint-outsGraphsCentres Cooperation

A THALASSEMIA-ORIENTED COMPUTERIZED CLINICAL RECORDWEBTHAL

13

Transfusion - Dependent Complications

bull Iron overload

bull Infections

bull Immunization (allergic reactions alloimmunization)

1 ml pure RBC = 116 mg Fe

1 blood unit = 200 mg Fe

To maintain mean Hb = 12 g dl

100-200 mlkgy of pure RBC

Mean iron imput = 03-06 mgkgday

Includes iron absorbed by the GI tract (1 to 4 mg day)

Complications in thalassemia major

Associated with iron overloadbull Cardiopathybull Liver diseasebull EndocrinopathiesOthersbull Gallbladderbull Osteoporosisbull Hypersplenismbull Nephrolithiasisbull Thrombosisbull Pulmonary hypertension


LiverLiver biopsybiopsy

SQUIDSQUID--magneticmagneticsusceptometrysusceptometry((liverspleenliverspleen))

Serum Serum ferritinferritin

UrinaryUrinary Iron Iron ExcretionExcretion(UIE)(UIE)

MagneticMagnetic ResonanceResonanceImagingImaging ((liverheartotherliverheartotherorgansorgans) )

FreeFree ironironNTBILPI LIPNTBILPI LIP

Quantitative Quantitative phlebotomyphlebotomy

BODYIRON STORES

DETERMINATIONDirect Indirect

Royal Bromptonamp Harefield

NHLIImperial College

5ms 6ms 7ms 8ms 9ms 11ms 13ms 15ms 17ms

Deriving Myocardial T2Deriving Myocardial T2Deriving Myocardial T2

020406080

100

0 4 8 12 16 20

TE

Sign

al

Signal = Ke-

TET2

Anderson LJ Eur Heart J 2001 22 2171-9

T2 - Cardiac Risk Ranging

High Intermediate Low

Anderson et al 2002

Iron balance in thalassemia

input excretion4transfusions

05 mgKgd

4 absorption

1 - 3 mgd

4chelators

urine stool

4 loss 1 mgd

OBJECTIVES OF CHELATIONOBJECTIVES OF CHELATION

Reduceprevent iron overload

Detoxify iron

Organ targeting

Reduceprevent iron overload Reduceprevent iron overload

Detoxify ironDetoxify iron

Organ targetingOrgan targeting

Labile Labile IronIron PoolPoolFeFe2+2+ + H+ H22OO22 rarrrarr FeFe3+3+ + + OHOHmacr + OH+ OH

excessexcess ironiron

Available iron chelators

Deferoxamine

Deferiprone

Deferasirox

Possible Chelation Treatments

Monotherapy

Alternate therapy

Combination therapy simultaneoussequential

bullSafety is the issue ofmajor concern for a drugthat patients take longlife

YESYESYESYESRareRareGI GI symptomssymptomsrarerareYESYESRareRareNeutropenia Neutropenia

YESYESnonoHigh High dosesdosesRenalRenal changeschanges

RareRarenonononoLensLens opacityopacityYESYESnonononoSkinSkin rashesrashes

nonoYESYESnonoAgranulocytosisAgranulocytosis

nonoYESYESnonoWeightWeight gaingainYESYESYESYESnonoLiverLiver enzymesenzymes changeschanges

nono

YESYES

nono

nono

nono

nono

nono

no no

DEFERIPRONEDEFERIPRONE

RareRareRareRare

YESYESYESYESYESYESYESYESYESYESYESYESYESYESDEFEROXAMINEDEFEROXAMINE ICL670ICL670

nonoLensLens opacityopacity

nonoArthropathyArthropathy

nonoOsteoporosisOsteoporosisRareRareHearingHearing lossloss

nonoRetinalRetinal toxicitytoxicity

nonoYersiniaYersinia infectionsinfections

nonoBoneBone changeschanges

nonoGrowthGrowth arrestarrest

nonoLocalLocal side side effecteffect

SIDE EFFECTS FROM IRON CHELATORSSIDE EFFECTS FROM IRON CHELATORS

Consequences of improved conventionaltreatment

Prolonged life expectancyImproved endocrine functionBetter clinical conditionBetter quality of lifeImproved psychosocial status

THALASSEMIA MAJOR

Bone marrow transplantation

Gene therapy

HbF induction

Non conventional treatment

1

2

3

Thalassemia comprehensive control program


ndash Preventionraquo community educationraquo population screeningraquo genetic counselingraquo prenatal diagnosisraquo program evaluation


MCV flMCV fl

MCH pgMCH pg

Hb patternHb pattern

gt 78

gt 27

A + A2 lt 32

lt 78

lt 27

A + F (01-7) + A2 gt 36

lt 78

lt 27

A + A2 lt 36

ZnPP or iron studies

NORMAL β-THALcarrier uarr ZnPP

darr ironNormal ZnPP

IRON DEFICIENCY

Globin chainsynthesis or

α-globin gene analysis

α-THALcarrier

δ and β genesanalysis

δ + β THAL

γδβ THAL

NORMAL HbA2 β THAL

le 78

le 27

A + F (3-16) + A2 lt 32

HbF quantitαβ ratio

DNA analysis

δ β THAL

HPFH

A + abnormalband + A2

Sickling test

Negative Positive

Furtherinvestigation

HbS

Screening for common mutations by

DNA analysis

Characterization of undefined mutationsby DGGE and direct

sequencing

or

or

or

Flow chart for thalassemia screeningFlow chart for thalassemia screening

0

20

40

60

80

100

120

75 77 79 81 83 85 87 89 91 93 95 97 99 01 03 05 07

Year

Ndeg

of p

atie

nts

RefusalRefusal of of prenatalprenatal diagnosisdiagnosisor or refusalrefusal of of pregnancypregnancy interruptioninterruption

ReductionReduction of of homozygoushomozygous ββ--thalassaemiathalassaemia newbornsnewbornsin in SardiniaSardinia

β-thal alleles (47)β-thal alleles (47)-α(37) initiation cd ACCATGrarr - - CATGα2 ATGrarrACGα1 ATGrarrGTGα2 cd 29 TrarrC (Agrinio)α2 IVS1 (-5nt)α2α1 cd 110 CrarrA (Petah Tikva)α2 cd 142 TrarrA (Icaria)α2 polyA ATAArarrATGA

α-thal alleles (18)α-thal alleles (18) δ-thal allelesδ-thal alleles-65 ArarrG-55 TrarrCcd 4 CrarrTcd 27 GrarrTCorfugrave ndash72 Kb

Hb LeporeHb Lepore

δβ-thal allelesδβ-thal allelesSicilianSpanishTurkishMacedonian

HPFHHPFH

Common structuralvariants


HbSHbCHbD PunjabHbO-Arab

HETEROGENEITY OF HEMOGLOBINOPATHIES IN MEDITERRANEAN HETEROGENEITY OF HEMOGLOBINOPATHIES IN MEDITERRANEAN

-α37

-α42

-α37 Hb Hasharon-(α)205

--MED-I--MED-II-(α)52

--(MA)--(CL)--(CAL)

HPFH ndash4HPFH ndash5

-196 Aγ C rarrT-117 Aγ G rarrA

Sardinian

5 - CT89 + G30 C1-1 A1-2 A1-2 G1-5 C1-5 T1-110 A1-116 G1-130 C39 T37 A44-C54-T59-A7-C2-705 C2-745 G2-843 G2-844 A2-850-G2-850 C

-90 T-88 A-88 T-87 G-87 T-87 A-86 A-31 C-30 A-30 C6 - A8 - AA27 T1-5 A1-6 C2-1 AAACAAAAATGAAA

-101 T-92 TUTR +10-T+ 33 G2-844 GAATAAG

31

Severity ofclinical picture

Diseasecomplications

Genetic Factors Affecting The Severity Of β-thalassemia Phenotype

bull Primary Modifiersndash Variability at globin gene loci

bull Secondary Modifiersndash Variability in other genes

32

a globin

β + γglobin

Mild Phenotype

α thalassemia Mildsilent β allelesIncreased γ

Severe Phenotype

a globin

β + γglobin

Mechanisms Of β-Thalassemia Intermedia

33

ComplicationsComplications of betaof beta--thalassemia and thalassemia and geneticgenetic modifiersmodifiers

ComplicationComplication

Hyperbilirubinemia and Hyperbilirubinemia and

gallstonesgallstones

IronIron loadingloading

OsteoporosisOsteoporosisosteopeniaosteopenia

CardiacCardiac diseasedisease

ThrombosisThrombosis

HepatitisHepatitis and and liverliver cirrhosiscirrhosis

Modifier gene(s)

UGT1A1

HFE

ERGVDR Col1A1 TGFβ1

APOE4 HLAGSTM1

Factor V Leiden Prothrombin

HLA

PREVALENCE OF CHOLELITHIASIS IN BETA THALASSEMIA

5712035THALASSEMIA INTERMEDIA

20353261THALASSEMIA MAJOR

PREVALENCE

CHOLELITHIASISTOTAL

PATIENTS

Galanello Galanello etet alBJH 2001alBJH 2001

5rsquo 3rsquo

A(TA)nTAA

- 53 - 39

TATA box

Exon 1 2 3 4 5

Normal subjects A(TA)6TAA

Subjects with Gilbert syndrome A(TA)7TAA

Normal enzyme activity

Enzyme activity 30 reduction

Mutation of UGT1A1 gene promoter

36

0102030405060708090

(TA)6(TA)6 (TA)6(TA)7 (TA)7(TA)7

UGT1-A1 promoter genotype

o

f pat

ient

s w

ith

chol

elith

iasi

sMajorIntermedia

Plt005Plt005

Galanello et al BJH 2001

Prevalence of Cholelithiasis And UGT1-A1 Promoter Genotype In Thalassemia Major

And Intermedia

Clinical characteristics ofβ talassemia major

severe early-onset hypochromicmicrocytic anemialiver and spleen enlargementfailure to thrivesevere skeletal manifestationregular transfusions required

(transfusion dependent)



cbc




cbc





origin

HbXHbFHbA

HbA2

-

+



AA

BB

CC

Figure 7

7





8





9


lt10 mlkghRate

2-4 weeksInterval

lt20 mlKgVolume



10

0

50

100

150

200

250

300

350

400


Hct 80

Hct 60

Hct 75

Hct 50

ml


TIF 2000

11



12





13


bull Iron overload

bull Infections


















BODYIRON STORES






020406080

100

0 4 8 12 16 20

TE

Sign

al

Signal = Ke-

TET2




Anderson et al 2002



05 mgKgd

4 absorption

1 - 3 mgd

4chelators

urine stool

4 loss 1 mgd



Detoxify iron

Organ targeting







Deferoxamine

Deferiprone

Deferasirox


Monotherapy

Alternate therapy








nono

YESYES

nono

nono

nono

nono

nono

no no


RareRareRareRare













THALASSEMIA MAJOR


Gene therapy

HbF induction


1

2

3





MCV flMCV fl

MCH pgMCH pg


gt 78

gt 27

A + A2 lt 32

lt 78

lt 27

A + F (01-7) + A2 gt 36

lt 78

lt 27

A + A2 lt 36




IRON DEFICIENCY



α-THALcarrier


δ + β THAL

γδβ THAL

NORMAL HbA2 β THAL

le 78

le 27

A + F (3-16) + A2 lt 32


DNA analysis

δ β THAL

HPFH


Sickling test

Negative Positive


HbS


DNA analysis


sequencing

or

or

or


0

20

40

60

80

100

120

75 77 79 81 83 85 87 89 91 93 95 97 99 01 03 05 07

Year

Ndeg

of p

atie

nts





Hb LeporeHb Lepore


HPFHHPFH





-α37

-α42



--(MA)--(CL)--(CAL)



Sardinian



-101 T-92 TUTR +10-T+ 33 G2-844 GAATAAG

31






32

a globin

β + γglobin

Mild Phenotype


Severe Phenotype

a globin

β + γglobin


33










Modifier gene(s)

UGT1A1

HFE


APOE4 HLAGSTM1


HLA




PREVALENCE

CHOLELITHIASISTOTAL

PATIENTS


5rsquo 3rsquo

A(TA)nTAA

- 53 - 39

TATA box

Exon 1 2 3 4 5






36

0102030405060708090

(TA)6(TA)6 (TA)6(TA)7 (TA)7(TA)7


o

f pat

ient

s w

ith

chol

elith

iasi

sMajorIntermedia

Plt005Plt005



And Intermedia



cbc




cbc





origin

HbXHbFHbA

HbA2

-

+



AA

BB

CC

Figure 7

7





8





9


lt10 mlkghRate

2-4 weeksInterval

lt20 mlKgVolume



10

0

50

100

150

200

250

300

350

400


Hct 80

Hct 60

Hct 75

Hct 50

ml


TIF 2000

11



12





13


bull Iron overload

bull Infections


















BODYIRON STORES






020406080

100

0 4 8 12 16 20

TE

Sign

al

Signal = Ke-

TET2




Anderson et al 2002



05 mgKgd

4 absorption

1 - 3 mgd

4chelators

urine stool

4 loss 1 mgd



Detoxify iron

Organ targeting







Deferoxamine

Deferiprone

Deferasirox


Monotherapy

Alternate therapy








nono

YESYES

nono

nono

nono

nono

nono

no no


RareRareRareRare













THALASSEMIA MAJOR


Gene therapy

HbF induction


1

2

3





MCV flMCV fl

MCH pgMCH pg


gt 78

gt 27

A + A2 lt 32

lt 78

lt 27

A + F (01-7) + A2 gt 36

lt 78

lt 27

A + A2 lt 36




IRON DEFICIENCY



α-THALcarrier


δ + β THAL

γδβ THAL

NORMAL HbA2 β THAL

le 78

le 27

A + F (3-16) + A2 lt 32


DNA analysis

δ β THAL

HPFH


Sickling test

Negative Positive


HbS


DNA analysis


sequencing

or

or

or


0

20

40

60

80

100

120

75 77 79 81 83 85 87 89 91 93 95 97 99 01 03 05 07

Year

Ndeg

of p

atie

nts





Hb LeporeHb Lepore


HPFHHPFH





-α37

-α42



--(MA)--(CL)--(CAL)



Sardinian



-101 T-92 TUTR +10-T+ 33 G2-844 GAATAAG

31






32

a globin

β + γglobin

Mild Phenotype


Severe Phenotype

a globin

β + γglobin


33










Modifier gene(s)

UGT1A1

HFE


APOE4 HLAGSTM1


HLA




PREVALENCE

CHOLELITHIASISTOTAL

PATIENTS


5rsquo 3rsquo

A(TA)nTAA

- 53 - 39

TATA box

Exon 1 2 3 4 5






36

0102030405060708090

(TA)6(TA)6 (TA)6(TA)7 (TA)7(TA)7


o

f pat

ient

s w

ith

chol

elith

iasi

sMajorIntermedia

Plt005Plt005



And Intermedia


origin

HbXHbFHbA

HbA2

-

+



AA

BB

CC

Figure 7

7





8





9


lt10 mlkghRate

2-4 weeksInterval

lt20 mlKgVolume



10

0

50

100

150

200

250

300

350

400


Hct 80

Hct 60

Hct 75

Hct 50

ml


TIF 2000

11



12





13


bull Iron overload

bull Infections


















BODYIRON STORES






020406080

100

0 4 8 12 16 20

TE

Sign

al

Signal = Ke-

TET2




Anderson et al 2002



05 mgKgd

4 absorption

1 - 3 mgd

4chelators

urine stool

4 loss 1 mgd



Detoxify iron

Organ targeting







Deferoxamine

Deferiprone

Deferasirox


Monotherapy

Alternate therapy








nono

YESYES

nono

nono

nono

nono

nono

no no


RareRareRareRare













THALASSEMIA MAJOR


Gene therapy

HbF induction


1

2

3





MCV flMCV fl

MCH pgMCH pg


gt 78

gt 27

A + A2 lt 32

lt 78

lt 27

A + F (01-7) + A2 gt 36

lt 78

lt 27

A + A2 lt 36




IRON DEFICIENCY



α-THALcarrier


δ + β THAL

γδβ THAL

NORMAL HbA2 β THAL

le 78

le 27

A + F (3-16) + A2 lt 32


DNA analysis

δ β THAL

HPFH


Sickling test

Negative Positive


HbS


DNA analysis


sequencing

or

or

or


0

20

40

60

80

100

120

75 77 79 81 83 85 87 89 91 93 95 97 99 01 03 05 07

Year

Ndeg

of p

atie

nts





Hb LeporeHb Lepore


HPFHHPFH





-α37

-α42



--(MA)--(CL)--(CAL)



Sardinian



-101 T-92 TUTR +10-T+ 33 G2-844 GAATAAG

31






32

a globin

β + γglobin

Mild Phenotype


Severe Phenotype

a globin

β + γglobin


33










Modifier gene(s)

UGT1A1

HFE


APOE4 HLAGSTM1


HLA




PREVALENCE

CHOLELITHIASISTOTAL

PATIENTS


5rsquo 3rsquo

A(TA)nTAA

- 53 - 39

TATA box

Exon 1 2 3 4 5






36

0102030405060708090

(TA)6(TA)6 (TA)6(TA)7 (TA)7(TA)7


o

f pat

ient

s w

ith

chol

elith

iasi

sMajorIntermedia

Plt005Plt005



And Intermedia



AA

BB

CC

Figure 7

7





8





9


lt10 mlkghRate

2-4 weeksInterval

lt20 mlKgVolume



10

0

50

100

150

200

250

300

350

400


Hct 80

Hct 60

Hct 75

Hct 50

ml


TIF 2000

11



12





13


bull Iron overload

bull Infections


















BODYIRON STORES






020406080

100

0 4 8 12 16 20

TE

Sign

al

Signal = Ke-

TET2




Anderson et al 2002



05 mgKgd

4 absorption

1 - 3 mgd

4chelators

urine stool

4 loss 1 mgd



Detoxify iron

Organ targeting







Deferoxamine

Deferiprone

Deferasirox


Monotherapy

Alternate therapy








nono

YESYES

nono

nono

nono

nono

nono

no no


RareRareRareRare













THALASSEMIA MAJOR


Gene therapy

HbF induction


1

2

3





MCV flMCV fl

MCH pgMCH pg


gt 78

gt 27

A + A2 lt 32

lt 78

lt 27

A + F (01-7) + A2 gt 36

lt 78

lt 27

A + A2 lt 36




IRON DEFICIENCY



α-THALcarrier


δ + β THAL

γδβ THAL

NORMAL HbA2 β THAL

le 78

le 27

A + F (3-16) + A2 lt 32


DNA analysis

δ β THAL

HPFH


Sickling test

Negative Positive


HbS


DNA analysis


sequencing

or

or

or


0

20

40

60

80

100

120

75 77 79 81 83 85 87 89 91 93 95 97 99 01 03 05 07

Year

Ndeg

of p

atie

nts





Hb LeporeHb Lepore


HPFHHPFH





-α37

-α42



--(MA)--(CL)--(CAL)



Sardinian



-101 T-92 TUTR +10-T+ 33 G2-844 GAATAAG

31






32

a globin

β + γglobin

Mild Phenotype


Severe Phenotype

a globin

β + γglobin


33










Modifier gene(s)

UGT1A1

HFE


APOE4 HLAGSTM1


HLA




PREVALENCE

CHOLELITHIASISTOTAL

PATIENTS


5rsquo 3rsquo

A(TA)nTAA

- 53 - 39

TATA box

Exon 1 2 3 4 5






36

0102030405060708090

(TA)6(TA)6 (TA)6(TA)7 (TA)7(TA)7


o

f pat

ient

s w

ith

chol

elith

iasi

sMajorIntermedia

Plt005Plt005



And Intermedia

7





8





9


lt10 mlkghRate

2-4 weeksInterval

lt20 mlKgVolume



10

0

50

100

150

200

250

300

350

400


Hct 80

Hct 60

Hct 75

Hct 50

ml


TIF 2000

11



12





13


bull Iron overload

bull Infections


















BODYIRON STORES






020406080

100

0 4 8 12 16 20

TE

Sign

al

Signal = Ke-

TET2




Anderson et al 2002



05 mgKgd

4 absorption

1 - 3 mgd

4chelators

urine stool

4 loss 1 mgd



Detoxify iron

Organ targeting







Deferoxamine

Deferiprone

Deferasirox


Monotherapy

Alternate therapy








nono

YESYES

nono

nono

nono

nono

nono

no no


RareRareRareRare













THALASSEMIA MAJOR


Gene therapy

HbF induction


1

2

3





MCV flMCV fl

MCH pgMCH pg


gt 78

gt 27

A + A2 lt 32

lt 78

lt 27

A + F (01-7) + A2 gt 36

lt 78

lt 27

A + A2 lt 36




IRON DEFICIENCY



α-THALcarrier


δ + β THAL

γδβ THAL

NORMAL HbA2 β THAL

le 78

le 27

A + F (3-16) + A2 lt 32


DNA analysis

δ β THAL

HPFH


Sickling test

Negative Positive


HbS


DNA analysis


sequencing

or

or

or


0

20

40

60

80

100

120

75 77 79 81 83 85 87 89 91 93 95 97 99 01 03 05 07

Year

Ndeg

of p

atie

nts





Hb LeporeHb Lepore


HPFHHPFH





-α37

-α42



--(MA)--(CL)--(CAL)



Sardinian



-101 T-92 TUTR +10-T+ 33 G2-844 GAATAAG

31






32

a globin

β + γglobin

Mild Phenotype


Severe Phenotype

a globin

β + γglobin


33










Modifier gene(s)

UGT1A1

HFE


APOE4 HLAGSTM1


HLA




PREVALENCE

CHOLELITHIASISTOTAL

PATIENTS


5rsquo 3rsquo

A(TA)nTAA

- 53 - 39

TATA box

Exon 1 2 3 4 5






36

0102030405060708090

(TA)6(TA)6 (TA)6(TA)7 (TA)7(TA)7


o

f pat

ient

s w

ith

chol

elith

iasi

sMajorIntermedia

Plt005Plt005



And Intermedia

8





9


lt10 mlkghRate

2-4 weeksInterval

lt20 mlKgVolume



10

0

50

100

150

200

250

300

350

400


Hct 80

Hct 60

Hct 75

Hct 50

ml


TIF 2000

11



12





13


bull Iron overload

bull Infections


















BODYIRON STORES






020406080

100

0 4 8 12 16 20

TE

Sign

al

Signal = Ke-

TET2




Anderson et al 2002



05 mgKgd

4 absorption

1 - 3 mgd

4chelators

urine stool

4 loss 1 mgd



Detoxify iron

Organ targeting







Deferoxamine

Deferiprone

Deferasirox


Monotherapy

Alternate therapy








nono

YESYES

nono

nono

nono

nono

nono

no no


RareRareRareRare













THALASSEMIA MAJOR


Gene therapy

HbF induction


1

2

3





MCV flMCV fl

MCH pgMCH pg


gt 78

gt 27

A + A2 lt 32

lt 78

lt 27

A + F (01-7) + A2 gt 36

lt 78

lt 27

A + A2 lt 36




IRON DEFICIENCY



α-THALcarrier


δ + β THAL

γδβ THAL

NORMAL HbA2 β THAL

le 78

le 27

A + F (3-16) + A2 lt 32


DNA analysis

δ β THAL

HPFH


Sickling test

Negative Positive


HbS


DNA analysis


sequencing

or

or

or


0

20

40

60

80

100

120

75 77 79 81 83 85 87 89 91 93 95 97 99 01 03 05 07

Year

Ndeg

of p

atie

nts





Hb LeporeHb Lepore


HPFHHPFH





-α37

-α42



--(MA)--(CL)--(CAL)



Sardinian



-101 T-92 TUTR +10-T+ 33 G2-844 GAATAAG

31






32

a globin

β + γglobin

Mild Phenotype


Severe Phenotype

a globin

β + γglobin


33










Modifier gene(s)

UGT1A1

HFE


APOE4 HLAGSTM1


HLA




PREVALENCE

CHOLELITHIASISTOTAL

PATIENTS


5rsquo 3rsquo

A(TA)nTAA

- 53 - 39

TATA box

Exon 1 2 3 4 5






36

0102030405060708090

(TA)6(TA)6 (TA)6(TA)7 (TA)7(TA)7


o

f pat

ient

s w

ith

chol

elith

iasi

sMajorIntermedia

Plt005Plt005



And Intermedia

9


lt10 mlkghRate

2-4 weeksInterval

lt20 mlKgVolume



10

0

50

100

150

200

250

300

350

400


Hct 80

Hct 60

Hct 75

Hct 50

ml


TIF 2000

11



12





13


bull Iron overload

bull Infections


















BODYIRON STORES






020406080

100

0 4 8 12 16 20

TE

Sign

al

Signal = Ke-

TET2




Anderson et al 2002



05 mgKgd

4 absorption

1 - 3 mgd

4chelators

urine stool

4 loss 1 mgd



Detoxify iron

Organ targeting







Deferoxamine

Deferiprone

Deferasirox


Monotherapy

Alternate therapy








nono

YESYES

nono

nono

nono

nono

nono

no no


RareRareRareRare













THALASSEMIA MAJOR


Gene therapy

HbF induction


1

2

3





MCV flMCV fl

MCH pgMCH pg


gt 78

gt 27

A + A2 lt 32

lt 78

lt 27

A + F (01-7) + A2 gt 36

lt 78

lt 27

A + A2 lt 36




IRON DEFICIENCY



α-THALcarrier


δ + β THAL

γδβ THAL

NORMAL HbA2 β THAL

le 78

le 27

A + F (3-16) + A2 lt 32


DNA analysis

δ β THAL

HPFH


Sickling test

Negative Positive


HbS


DNA analysis


sequencing

or

or

or


0

20

40

60

80

100

120

75 77 79 81 83 85 87 89 91 93 95 97 99 01 03 05 07

Year

Ndeg

of p

atie

nts





Hb LeporeHb Lepore


HPFHHPFH





-α37

-α42



--(MA)--(CL)--(CAL)



Sardinian



-101 T-92 TUTR +10-T+ 33 G2-844 GAATAAG

31






32

a globin

β + γglobin

Mild Phenotype


Severe Phenotype

a globin

β + γglobin


33










Modifier gene(s)

UGT1A1

HFE


APOE4 HLAGSTM1


HLA




PREVALENCE

CHOLELITHIASISTOTAL

PATIENTS


5rsquo 3rsquo

A(TA)nTAA

- 53 - 39

TATA box

Exon 1 2 3 4 5






36

0102030405060708090

(TA)6(TA)6 (TA)6(TA)7 (TA)7(TA)7


o

f pat

ient

s w

ith

chol

elith

iasi

sMajorIntermedia

Plt005Plt005



And Intermedia

10

0

50

100

150

200

250

300

350

400


Hct 80

Hct 60

Hct 75

Hct 50

ml


TIF 2000

11



12





13


bull Iron overload

bull Infections


















BODYIRON STORES






020406080

100

0 4 8 12 16 20

TE

Sign

al

Signal = Ke-

TET2




Anderson et al 2002



05 mgKgd

4 absorption

1 - 3 mgd

4chelators

urine stool

4 loss 1 mgd



Detoxify iron

Organ targeting







Deferoxamine

Deferiprone

Deferasirox


Monotherapy

Alternate therapy








nono

YESYES

nono

nono

nono

nono

nono

no no


RareRareRareRare













THALASSEMIA MAJOR


Gene therapy

HbF induction


1

2

3





MCV flMCV fl

MCH pgMCH pg


gt 78

gt 27

A + A2 lt 32

lt 78

lt 27

A + F (01-7) + A2 gt 36

lt 78

lt 27

A + A2 lt 36




IRON DEFICIENCY



α-THALcarrier


δ + β THAL

γδβ THAL

NORMAL HbA2 β THAL

le 78

le 27

A + F (3-16) + A2 lt 32


DNA analysis

δ β THAL

HPFH


Sickling test

Negative Positive


HbS


DNA analysis


sequencing

or

or

or


0

20

40

60

80

100

120

75 77 79 81 83 85 87 89 91 93 95 97 99 01 03 05 07

Year

Ndeg

of p

atie

nts





Hb LeporeHb Lepore


HPFHHPFH





-α37

-α42



--(MA)--(CL)--(CAL)



Sardinian



-101 T-92 TUTR +10-T+ 33 G2-844 GAATAAG

31






32

a globin

β + γglobin

Mild Phenotype


Severe Phenotype

a globin

β + γglobin


33










Modifier gene(s)

UGT1A1

HFE


APOE4 HLAGSTM1


HLA




PREVALENCE

CHOLELITHIASISTOTAL

PATIENTS


5rsquo 3rsquo

A(TA)nTAA

- 53 - 39

TATA box

Exon 1 2 3 4 5






36

0102030405060708090

(TA)6(TA)6 (TA)6(TA)7 (TA)7(TA)7


o

f pat

ient

s w

ith

chol

elith

iasi

sMajorIntermedia

Plt005Plt005



And Intermedia

11



12





13


bull Iron overload

bull Infections


















BODYIRON STORES






020406080

100

0 4 8 12 16 20

TE

Sign

al

Signal = Ke-

TET2




Anderson et al 2002



05 mgKgd

4 absorption

1 - 3 mgd

4chelators

urine stool

4 loss 1 mgd



Detoxify iron

Organ targeting







Deferoxamine

Deferiprone

Deferasirox


Monotherapy

Alternate therapy








nono

YESYES

nono

nono

nono

nono

nono

no no


RareRareRareRare













THALASSEMIA MAJOR


Gene therapy

HbF induction


1

2

3





MCV flMCV fl

MCH pgMCH pg


gt 78

gt 27

A + A2 lt 32

lt 78

lt 27

A + F (01-7) + A2 gt 36

lt 78

lt 27

A + A2 lt 36




IRON DEFICIENCY



α-THALcarrier


δ + β THAL

γδβ THAL

NORMAL HbA2 β THAL

le 78

le 27

A + F (3-16) + A2 lt 32


DNA analysis

δ β THAL

HPFH


Sickling test

Negative Positive


HbS


DNA analysis


sequencing

or

or

or


0

20

40

60

80

100

120

75 77 79 81 83 85 87 89 91 93 95 97 99 01 03 05 07

Year

Ndeg

of p

atie

nts





Hb LeporeHb Lepore


HPFHHPFH





-α37

-α42



--(MA)--(CL)--(CAL)



Sardinian



-101 T-92 TUTR +10-T+ 33 G2-844 GAATAAG

31






32

a globin

β + γglobin

Mild Phenotype


Severe Phenotype

a globin

β + γglobin


33










Modifier gene(s)

UGT1A1

HFE


APOE4 HLAGSTM1


HLA




PREVALENCE

CHOLELITHIASISTOTAL

PATIENTS


5rsquo 3rsquo

A(TA)nTAA

- 53 - 39

TATA box

Exon 1 2 3 4 5






36

0102030405060708090

(TA)6(TA)6 (TA)6(TA)7 (TA)7(TA)7


o

f pat

ient

s w

ith

chol

elith

iasi

sMajorIntermedia

Plt005Plt005



And Intermedia

12





13


bull Iron overload

bull Infections


















BODYIRON STORES






020406080

100

0 4 8 12 16 20

TE

Sign

al

Signal = Ke-

TET2




Anderson et al 2002



05 mgKgd

4 absorption

1 - 3 mgd

4chelators

urine stool

4 loss 1 mgd



Detoxify iron

Organ targeting







Deferoxamine

Deferiprone

Deferasirox


Monotherapy

Alternate therapy








nono

YESYES

nono

nono

nono

nono

nono

no no


RareRareRareRare













THALASSEMIA MAJOR


Gene therapy

HbF induction


1

2

3





MCV flMCV fl

MCH pgMCH pg


gt 78

gt 27

A + A2 lt 32

lt 78

lt 27

A + F (01-7) + A2 gt 36

lt 78

lt 27

A + A2 lt 36




IRON DEFICIENCY



α-THALcarrier


δ + β THAL

γδβ THAL

NORMAL HbA2 β THAL

le 78

le 27

A + F (3-16) + A2 lt 32


DNA analysis

δ β THAL

HPFH


Sickling test

Negative Positive


HbS


DNA analysis


sequencing

or

or

or


0

20

40

60

80

100

120

75 77 79 81 83 85 87 89 91 93 95 97 99 01 03 05 07

Year

Ndeg

of p

atie

nts





Hb LeporeHb Lepore


HPFHHPFH





-α37

-α42



--(MA)--(CL)--(CAL)



Sardinian



-101 T-92 TUTR +10-T+ 33 G2-844 GAATAAG

31






32

a globin

β + γglobin

Mild Phenotype


Severe Phenotype

a globin

β + γglobin


33










Modifier gene(s)

UGT1A1

HFE


APOE4 HLAGSTM1


HLA




PREVALENCE

CHOLELITHIASISTOTAL

PATIENTS


5rsquo 3rsquo

A(TA)nTAA

- 53 - 39

TATA box

Exon 1 2 3 4 5






36

0102030405060708090

(TA)6(TA)6 (TA)6(TA)7 (TA)7(TA)7


o

f pat

ient

s w

ith

chol

elith

iasi

sMajorIntermedia

Plt005Plt005



And Intermedia

13


bull Iron overload

bull Infections


















BODYIRON STORES






020406080

100

0 4 8 12 16 20

TE

Sign

al

Signal = Ke-

TET2




Anderson et al 2002



05 mgKgd

4 absorption

1 - 3 mgd

4chelators

urine stool

4 loss 1 mgd



Detoxify iron

Organ targeting







Deferoxamine

Deferiprone

Deferasirox


Monotherapy

Alternate therapy








nono

YESYES

nono

nono

nono

nono

nono

no no


RareRareRareRare













THALASSEMIA MAJOR


Gene therapy

HbF induction


1

2

3





MCV flMCV fl

MCH pgMCH pg


gt 78

gt 27

A + A2 lt 32

lt 78

lt 27

A + F (01-7) + A2 gt 36

lt 78

lt 27

A + A2 lt 36




IRON DEFICIENCY



α-THALcarrier


δ + β THAL

γδβ THAL

NORMAL HbA2 β THAL

le 78

le 27

A + F (3-16) + A2 lt 32


DNA analysis

δ β THAL

HPFH


Sickling test

Negative Positive


HbS


DNA analysis


sequencing

or

or

or


0

20

40

60

80

100

120

75 77 79 81 83 85 87 89 91 93 95 97 99 01 03 05 07

Year

Ndeg

of p

atie

nts





Hb LeporeHb Lepore


HPFHHPFH





-α37

-α42



--(MA)--(CL)--(CAL)



Sardinian



-101 T-92 TUTR +10-T+ 33 G2-844 GAATAAG

31






32

a globin

β + γglobin

Mild Phenotype


Severe Phenotype

a globin

β + γglobin


33










Modifier gene(s)

UGT1A1

HFE


APOE4 HLAGSTM1


HLA




PREVALENCE

CHOLELITHIASISTOTAL

PATIENTS


5rsquo 3rsquo

A(TA)nTAA

- 53 - 39

TATA box

Exon 1 2 3 4 5






36

0102030405060708090

(TA)6(TA)6 (TA)6(TA)7 (TA)7(TA)7


o

f pat

ient

s w

ith

chol

elith

iasi

sMajorIntermedia

Plt005Plt005



And Intermedia

















BODYIRON STORES






020406080

100

0 4 8 12 16 20

TE

Sign

al

Signal = Ke-

TET2




Anderson et al 2002



05 mgKgd

4 absorption

1 - 3 mgd

4chelators

urine stool

4 loss 1 mgd



Detoxify iron

Organ targeting







Deferoxamine

Deferiprone

Deferasirox


Monotherapy

Alternate therapy








nono

YESYES

nono

nono

nono

nono

nono

no no


RareRareRareRare













THALASSEMIA MAJOR


Gene therapy

HbF induction


1

2

3





MCV flMCV fl

MCH pgMCH pg


gt 78

gt 27

A + A2 lt 32

lt 78

lt 27

A + F (01-7) + A2 gt 36

lt 78

lt 27

A + A2 lt 36




IRON DEFICIENCY



α-THALcarrier


δ + β THAL

γδβ THAL

NORMAL HbA2 β THAL

le 78

le 27

A + F (3-16) + A2 lt 32


DNA analysis

δ β THAL

HPFH


Sickling test

Negative Positive


HbS


DNA analysis


sequencing

or

or

or


0

20

40

60

80

100

120

75 77 79 81 83 85 87 89 91 93 95 97 99 01 03 05 07

Year

Ndeg

of p

atie

nts





Hb LeporeHb Lepore


HPFHHPFH





-α37

-α42



--(MA)--(CL)--(CAL)



Sardinian



-101 T-92 TUTR +10-T+ 33 G2-844 GAATAAG

31






32

a globin

β + γglobin

Mild Phenotype


Severe Phenotype

a globin

β + γglobin


33










Modifier gene(s)

UGT1A1

HFE


APOE4 HLAGSTM1


HLA




PREVALENCE

CHOLELITHIASISTOTAL

PATIENTS


5rsquo 3rsquo

A(TA)nTAA

- 53 - 39

TATA box

Exon 1 2 3 4 5






36

0102030405060708090

(TA)6(TA)6 (TA)6(TA)7 (TA)7(TA)7


o

f pat

ient

s w

ith

chol

elith

iasi

sMajorIntermedia

Plt005Plt005



And Intermedia





020406080

100

0 4 8 12 16 20

TE

Sign

al

Signal = Ke-

TET2




Anderson et al 2002



05 mgKgd

4 absorption

1 - 3 mgd

4chelators

urine stool

4 loss 1 mgd



Detoxify iron

Organ targeting







Deferoxamine

Deferiprone

Deferasirox


Monotherapy

Alternate therapy








nono

YESYES

nono

nono

nono

nono

nono

no no


RareRareRareRare













THALASSEMIA MAJOR


Gene therapy

HbF induction


1

2

3





MCV flMCV fl

MCH pgMCH pg


gt 78

gt 27

A + A2 lt 32

lt 78

lt 27

A + F (01-7) + A2 gt 36

lt 78

lt 27

A + A2 lt 36




IRON DEFICIENCY



α-THALcarrier


δ + β THAL

γδβ THAL

NORMAL HbA2 β THAL

le 78

le 27

A + F (3-16) + A2 lt 32


DNA analysis

δ β THAL

HPFH


Sickling test

Negative Positive


HbS


DNA analysis


sequencing

or

or

or


0

20

40

60

80

100

120

75 77 79 81 83 85 87 89 91 93 95 97 99 01 03 05 07

Year

Ndeg

of p

atie

nts





Hb LeporeHb Lepore


HPFHHPFH





-α37

-α42



--(MA)--(CL)--(CAL)



Sardinian



-101 T-92 TUTR +10-T+ 33 G2-844 GAATAAG

31






32

a globin

β + γglobin

Mild Phenotype


Severe Phenotype

a globin

β + γglobin


33










Modifier gene(s)

UGT1A1

HFE


APOE4 HLAGSTM1


HLA




PREVALENCE

CHOLELITHIASISTOTAL

PATIENTS


5rsquo 3rsquo

A(TA)nTAA

- 53 - 39

TATA box

Exon 1 2 3 4 5






36

0102030405060708090

(TA)6(TA)6 (TA)6(TA)7 (TA)7(TA)7


o

f pat

ient

s w

ith

chol

elith

iasi

sMajorIntermedia

Plt005Plt005



And Intermedia



Anderson et al 2002



05 mgKgd

4 absorption

1 - 3 mgd

4chelators

urine stool

4 loss 1 mgd



Detoxify iron

Organ targeting







Deferoxamine

Deferiprone

Deferasirox


Monotherapy

Alternate therapy








nono

YESYES

nono

nono

nono

nono

nono

no no


RareRareRareRare













THALASSEMIA MAJOR


Gene therapy

HbF induction


1

2

3





MCV flMCV fl

MCH pgMCH pg


gt 78

gt 27

A + A2 lt 32

lt 78

lt 27

A + F (01-7) + A2 gt 36

lt 78

lt 27

A + A2 lt 36




IRON DEFICIENCY



α-THALcarrier


δ + β THAL

γδβ THAL

NORMAL HbA2 β THAL

le 78

le 27

A + F (3-16) + A2 lt 32


DNA analysis

δ β THAL

HPFH


Sickling test

Negative Positive


HbS


DNA analysis


sequencing

or

or

or


0

20

40

60

80

100

120

75 77 79 81 83 85 87 89 91 93 95 97 99 01 03 05 07

Year

Ndeg

of p

atie

nts





Hb LeporeHb Lepore


HPFHHPFH





-α37

-α42



--(MA)--(CL)--(CAL)



Sardinian



-101 T-92 TUTR +10-T+ 33 G2-844 GAATAAG

31






32

a globin

β + γglobin

Mild Phenotype


Severe Phenotype

a globin

β + γglobin


33










Modifier gene(s)

UGT1A1

HFE


APOE4 HLAGSTM1


HLA




PREVALENCE

CHOLELITHIASISTOTAL

PATIENTS


5rsquo 3rsquo

A(TA)nTAA

- 53 - 39

TATA box

Exon 1 2 3 4 5






36

0102030405060708090

(TA)6(TA)6 (TA)6(TA)7 (TA)7(TA)7


o

f pat

ient

s w

ith

chol

elith

iasi

sMajorIntermedia

Plt005Plt005



And Intermedia



05 mgKgd

4 absorption

1 - 3 mgd

4chelators

urine stool

4 loss 1 mgd



Detoxify iron

Organ targeting







Deferoxamine

Deferiprone

Deferasirox


Monotherapy

Alternate therapy








nono

YESYES

nono

nono

nono

nono

nono

no no


RareRareRareRare













THALASSEMIA MAJOR


Gene therapy

HbF induction


1

2

3





MCV flMCV fl

MCH pgMCH pg


gt 78

gt 27

A + A2 lt 32

lt 78

lt 27

A + F (01-7) + A2 gt 36

lt 78

lt 27

A + A2 lt 36




IRON DEFICIENCY



α-THALcarrier


δ + β THAL

γδβ THAL

NORMAL HbA2 β THAL

le 78

le 27

A + F (3-16) + A2 lt 32


DNA analysis

δ β THAL

HPFH


Sickling test

Negative Positive


HbS


DNA analysis


sequencing

or

or

or


0

20

40

60

80

100

120

75 77 79 81 83 85 87 89 91 93 95 97 99 01 03 05 07

Year

Ndeg

of p

atie

nts





Hb LeporeHb Lepore


HPFHHPFH





-α37

-α42



--(MA)--(CL)--(CAL)



Sardinian



-101 T-92 TUTR +10-T+ 33 G2-844 GAATAAG

31






32

a globin

β + γglobin

Mild Phenotype


Severe Phenotype

a globin

β + γglobin


33










Modifier gene(s)

UGT1A1

HFE


APOE4 HLAGSTM1


HLA




PREVALENCE

CHOLELITHIASISTOTAL

PATIENTS


5rsquo 3rsquo

A(TA)nTAA

- 53 - 39

TATA box

Exon 1 2 3 4 5






36

0102030405060708090

(TA)6(TA)6 (TA)6(TA)7 (TA)7(TA)7


o

f pat

ient

s w

ith

chol

elith

iasi

sMajorIntermedia

Plt005Plt005



And Intermedia



Detoxify iron

Organ targeting







Deferoxamine

Deferiprone

Deferasirox


Monotherapy

Alternate therapy








nono

YESYES

nono

nono

nono

nono

nono

no no


RareRareRareRare













THALASSEMIA MAJOR


Gene therapy

HbF induction


1

2

3





MCV flMCV fl

MCH pgMCH pg


gt 78

gt 27

A + A2 lt 32

lt 78

lt 27

A + F (01-7) + A2 gt 36

lt 78

lt 27

A + A2 lt 36




IRON DEFICIENCY



α-THALcarrier


δ + β THAL

γδβ THAL

NORMAL HbA2 β THAL

le 78

le 27

A + F (3-16) + A2 lt 32


DNA analysis

δ β THAL

HPFH


Sickling test

Negative Positive


HbS


DNA analysis


sequencing

or

or

or


0

20

40

60

80

100

120

75 77 79 81 83 85 87 89 91 93 95 97 99 01 03 05 07

Year

Ndeg

of p

atie

nts





Hb LeporeHb Lepore


HPFHHPFH





-α37

-α42



--(MA)--(CL)--(CAL)



Sardinian



-101 T-92 TUTR +10-T+ 33 G2-844 GAATAAG

31






32

a globin

β + γglobin

Mild Phenotype


Severe Phenotype

a globin

β + γglobin


33










Modifier gene(s)

UGT1A1

HFE


APOE4 HLAGSTM1


HLA




PREVALENCE

CHOLELITHIASISTOTAL

PATIENTS


5rsquo 3rsquo

A(TA)nTAA

- 53 - 39

TATA box

Exon 1 2 3 4 5






36

0102030405060708090

(TA)6(TA)6 (TA)6(TA)7 (TA)7(TA)7


o

f pat

ient

s w

ith

chol

elith

iasi

sMajorIntermedia

Plt005Plt005



And Intermedia


Deferoxamine

Deferiprone

Deferasirox


Monotherapy

Alternate therapy








nono

YESYES

nono

nono

nono

nono

nono

no no


RareRareRareRare













THALASSEMIA MAJOR


Gene therapy

HbF induction


1

2

3





MCV flMCV fl

MCH pgMCH pg


gt 78

gt 27

A + A2 lt 32

lt 78

lt 27

A + F (01-7) + A2 gt 36

lt 78

lt 27

A + A2 lt 36




IRON DEFICIENCY



α-THALcarrier


δ + β THAL

γδβ THAL

NORMAL HbA2 β THAL

le 78

le 27

A + F (3-16) + A2 lt 32


DNA analysis

δ β THAL

HPFH


Sickling test

Negative Positive


HbS


DNA analysis


sequencing

or

or

or


0

20

40

60

80

100

120

75 77 79 81 83 85 87 89 91 93 95 97 99 01 03 05 07

Year

Ndeg

of p

atie

nts





Hb LeporeHb Lepore


HPFHHPFH





-α37

-α42



--(MA)--(CL)--(CAL)



Sardinian



-101 T-92 TUTR +10-T+ 33 G2-844 GAATAAG

31






32

a globin

β + γglobin

Mild Phenotype


Severe Phenotype

a globin

β + γglobin


33










Modifier gene(s)

UGT1A1

HFE


APOE4 HLAGSTM1


HLA




PREVALENCE

CHOLELITHIASISTOTAL

PATIENTS


5rsquo 3rsquo

A(TA)nTAA

- 53 - 39

TATA box

Exon 1 2 3 4 5






36

0102030405060708090

(TA)6(TA)6 (TA)6(TA)7 (TA)7(TA)7


o

f pat

ient

s w

ith

chol

elith

iasi

sMajorIntermedia

Plt005Plt005



And Intermedia


Monotherapy

Alternate therapy








nono

YESYES

nono

nono

nono

nono

nono

no no


RareRareRareRare













THALASSEMIA MAJOR


Gene therapy

HbF induction


1

2

3





MCV flMCV fl

MCH pgMCH pg


gt 78

gt 27

A + A2 lt 32

lt 78

lt 27

A + F (01-7) + A2 gt 36

lt 78

lt 27

A + A2 lt 36




IRON DEFICIENCY



α-THALcarrier


δ + β THAL

γδβ THAL

NORMAL HbA2 β THAL

le 78

le 27

A + F (3-16) + A2 lt 32


DNA analysis

δ β THAL

HPFH


Sickling test

Negative Positive


HbS


DNA analysis


sequencing

or

or

or


0

20

40

60

80

100

120

75 77 79 81 83 85 87 89 91 93 95 97 99 01 03 05 07

Year

Ndeg

of p

atie

nts





Hb LeporeHb Lepore


HPFHHPFH





-α37

-α42



--(MA)--(CL)--(CAL)



Sardinian



-101 T-92 TUTR +10-T+ 33 G2-844 GAATAAG

31






32

a globin

β + γglobin

Mild Phenotype


Severe Phenotype

a globin

β + γglobin


33










Modifier gene(s)

UGT1A1

HFE


APOE4 HLAGSTM1


HLA




PREVALENCE

CHOLELITHIASISTOTAL

PATIENTS


5rsquo 3rsquo

A(TA)nTAA

- 53 - 39

TATA box

Exon 1 2 3 4 5






36

0102030405060708090

(TA)6(TA)6 (TA)6(TA)7 (TA)7(TA)7


o

f pat

ient

s w

ith

chol

elith

iasi

sMajorIntermedia

Plt005Plt005



And Intermedia







nono

YESYES

nono

nono

nono

nono

nono

no no


RareRareRareRare













THALASSEMIA MAJOR


Gene therapy

HbF induction


1

2

3





MCV flMCV fl

MCH pgMCH pg


gt 78

gt 27

A + A2 lt 32

lt 78

lt 27

A + F (01-7) + A2 gt 36

lt 78

lt 27

A + A2 lt 36




IRON DEFICIENCY



α-THALcarrier


δ + β THAL

γδβ THAL

NORMAL HbA2 β THAL

le 78

le 27

A + F (3-16) + A2 lt 32


DNA analysis

δ β THAL

HPFH


Sickling test

Negative Positive


HbS


DNA analysis


sequencing

or

or

or


0

20

40

60

80

100

120

75 77 79 81 83 85 87 89 91 93 95 97 99 01 03 05 07

Year

Ndeg

of p

atie

nts





Hb LeporeHb Lepore


HPFHHPFH





-α37

-α42



--(MA)--(CL)--(CAL)



Sardinian



-101 T-92 TUTR +10-T+ 33 G2-844 GAATAAG

31






32

a globin

β + γglobin

Mild Phenotype


Severe Phenotype

a globin

β + γglobin


33










Modifier gene(s)

UGT1A1

HFE


APOE4 HLAGSTM1


HLA




PREVALENCE

CHOLELITHIASISTOTAL

PATIENTS


5rsquo 3rsquo

A(TA)nTAA

- 53 - 39

TATA box

Exon 1 2 3 4 5






36

0102030405060708090

(TA)6(TA)6 (TA)6(TA)7 (TA)7(TA)7


o

f pat

ient

s w

ith

chol

elith

iasi

sMajorIntermedia

Plt005Plt005



And Intermedia



THALASSEMIA MAJOR


Gene therapy

HbF induction


1

2

3





MCV flMCV fl

MCH pgMCH pg


gt 78

gt 27

A + A2 lt 32

lt 78

lt 27

A + F (01-7) + A2 gt 36

lt 78

lt 27

A + A2 lt 36




IRON DEFICIENCY



α-THALcarrier


δ + β THAL

γδβ THAL

NORMAL HbA2 β THAL

le 78

le 27

A + F (3-16) + A2 lt 32


DNA analysis

δ β THAL

HPFH


Sickling test

Negative Positive


HbS


DNA analysis


sequencing

or

or

or


0

20

40

60

80

100

120

75 77 79 81 83 85 87 89 91 93 95 97 99 01 03 05 07

Year

Ndeg

of p

atie

nts





Hb LeporeHb Lepore


HPFHHPFH





-α37

-α42



--(MA)--(CL)--(CAL)



Sardinian



-101 T-92 TUTR +10-T+ 33 G2-844 GAATAAG

31






32

a globin

β + γglobin

Mild Phenotype


Severe Phenotype

a globin

β + γglobin


33










Modifier gene(s)

UGT1A1

HFE


APOE4 HLAGSTM1


HLA




PREVALENCE

CHOLELITHIASISTOTAL

PATIENTS


5rsquo 3rsquo

A(TA)nTAA

- 53 - 39

TATA box

Exon 1 2 3 4 5






36

0102030405060708090

(TA)6(TA)6 (TA)6(TA)7 (TA)7(TA)7


o

f pat

ient

s w

ith

chol

elith

iasi

sMajorIntermedia

Plt005Plt005



And Intermedia





MCV flMCV fl

MCH pgMCH pg


gt 78

gt 27

A + A2 lt 32

lt 78

lt 27

A + F (01-7) + A2 gt 36

lt 78

lt 27

A + A2 lt 36




IRON DEFICIENCY



α-THALcarrier


δ + β THAL

γδβ THAL

NORMAL HbA2 β THAL

le 78

le 27

A + F (3-16) + A2 lt 32


DNA analysis

δ β THAL

HPFH


Sickling test

Negative Positive


HbS


DNA analysis


sequencing

or

or

or


0

20

40

60

80

100

120

75 77 79 81 83 85 87 89 91 93 95 97 99 01 03 05 07

Year

Ndeg

of p

atie

nts





Hb LeporeHb Lepore


HPFHHPFH





-α37

-α42



--(MA)--(CL)--(CAL)



Sardinian



-101 T-92 TUTR +10-T+ 33 G2-844 GAATAAG

31






32

a globin

β + γglobin

Mild Phenotype


Severe Phenotype

a globin

β + γglobin


33










Modifier gene(s)

UGT1A1

HFE


APOE4 HLAGSTM1


HLA




PREVALENCE

CHOLELITHIASISTOTAL

PATIENTS


5rsquo 3rsquo

A(TA)nTAA

- 53 - 39

TATA box

Exon 1 2 3 4 5






36

0102030405060708090

(TA)6(TA)6 (TA)6(TA)7 (TA)7(TA)7


o

f pat

ient

s w

ith

chol

elith

iasi

sMajorIntermedia

Plt005Plt005



And Intermedia

0

20

40

60

80

100

120

75 77 79 81 83 85 87 89 91 93 95 97 99 01 03 05 07

Year

Ndeg

of p

atie

nts





Hb LeporeHb Lepore


HPFHHPFH





-α37

-α42



--(MA)--(CL)--(CAL)



Sardinian



-101 T-92 TUTR +10-T+ 33 G2-844 GAATAAG

31






32

a globin

β + γglobin

Mild Phenotype


Severe Phenotype

a globin

β + γglobin


33










Modifier gene(s)

UGT1A1

HFE


APOE4 HLAGSTM1


HLA




PREVALENCE

CHOLELITHIASISTOTAL

PATIENTS


5rsquo 3rsquo

A(TA)nTAA

- 53 - 39

TATA box

Exon 1 2 3 4 5






36

0102030405060708090

(TA)6(TA)6 (TA)6(TA)7 (TA)7(TA)7


o

f pat

ient

s w

ith

chol

elith

iasi

sMajorIntermedia

Plt005Plt005



And Intermedia



Hb LeporeHb Lepore


HPFHHPFH





-α37

-α42



--(MA)--(CL)--(CAL)



Sardinian



-101 T-92 TUTR +10-T+ 33 G2-844 GAATAAG

31






32

a globin

β + γglobin

Mild Phenotype


Severe Phenotype

a globin

β + γglobin


33










Modifier gene(s)

UGT1A1

HFE


APOE4 HLAGSTM1


HLA




PREVALENCE

CHOLELITHIASISTOTAL

PATIENTS


5rsquo 3rsquo

A(TA)nTAA

- 53 - 39

TATA box

Exon 1 2 3 4 5






36

0102030405060708090

(TA)6(TA)6 (TA)6(TA)7 (TA)7(TA)7


o

f pat

ient

s w

ith

chol

elith

iasi

sMajorIntermedia

Plt005Plt005



And Intermedia

31






32

a globin

β + γglobin

Mild Phenotype


Severe Phenotype

a globin

β + γglobin


33










Modifier gene(s)

UGT1A1

HFE


APOE4 HLAGSTM1


HLA




PREVALENCE

CHOLELITHIASISTOTAL

PATIENTS


5rsquo 3rsquo

A(TA)nTAA

- 53 - 39

TATA box

Exon 1 2 3 4 5






36

0102030405060708090

(TA)6(TA)6 (TA)6(TA)7 (TA)7(TA)7


o

f pat

ient

s w

ith

chol

elith

iasi

sMajorIntermedia

Plt005Plt005



And Intermedia

32

a globin

β + γglobin

Mild Phenotype


Severe Phenotype

a globin

β + γglobin


33










Modifier gene(s)

UGT1A1

HFE


APOE4 HLAGSTM1


HLA




PREVALENCE

CHOLELITHIASISTOTAL

PATIENTS


5rsquo 3rsquo

A(TA)nTAA

- 53 - 39

TATA box

Exon 1 2 3 4 5






36

0102030405060708090

(TA)6(TA)6 (TA)6(TA)7 (TA)7(TA)7


o

f pat

ient

s w

ith

chol

elith

iasi

sMajorIntermedia

Plt005Plt005



And Intermedia

33










Modifier gene(s)

UGT1A1

HFE


APOE4 HLAGSTM1


HLA




PREVALENCE

CHOLELITHIASISTOTAL

PATIENTS


5rsquo 3rsquo

A(TA)nTAA

- 53 - 39

TATA box

Exon 1 2 3 4 5






36

0102030405060708090

(TA)6(TA)6 (TA)6(TA)7 (TA)7(TA)7


o

f pat

ient

s w

ith

chol

elith

iasi

sMajorIntermedia

Plt005Plt005



And Intermedia




PREVALENCE

CHOLELITHIASISTOTAL

PATIENTS


5rsquo 3rsquo

A(TA)nTAA

- 53 - 39

TATA box

Exon 1 2 3 4 5






36

0102030405060708090

(TA)6(TA)6 (TA)6(TA)7 (TA)7(TA)7


o

f pat

ient

s w

ith

chol

elith

iasi

sMajorIntermedia

Plt005Plt005



And Intermedia

5rsquo 3rsquo

A(TA)nTAA

- 53 - 39

TATA box

Exon 1 2 3 4 5






36

0102030405060708090

(TA)6(TA)6 (TA)6(TA)7 (TA)7(TA)7


o

f pat

ient

s w

ith

chol

elith

iasi

sMajorIntermedia

Plt005Plt005



And Intermedia

36

0102030405060708090

(TA)6(TA)6 (TA)6(TA)7 (TA)7(TA)7


o

f pat

ient

s w

ith

chol

elith

iasi

sMajorIntermedia

Plt005Plt005



And Intermedia

Prof. Renzo Galanello Pediatric Clinic 2° University of Cagliari...

Documents

Transcript of Prof. Renzo Galanello Pediatric Clinic 2° University of Cagliari...