hereditary transthyretin amyloidoses (attr)

Familial Familial amyloidoticamyloidotic polyneuropathypolyneuropathy

HereditaryHereditarytransthyretin amyloidoses (ATTR)

E. Hund, Heidelberg, g

Familial transthyretin amyloidosisFamilial transthyretin amyloidosis

Etiology: genetically determined variants of physiological serum proteinsp ys o og ca se u p ote s

Variant protein Abbreviation

transthyretin (ca. 70%) ATTR

Apolipoprotein-A1 u. A2 AApoA1/A2Fibrinogen-A AFib

others:

Gelsolin AGelLysozym ALysCystatin C ACysCystatin C ACysA-precursor protein A

Familial transthyretin amyloidosis (ATTR)Familial transthyretin amyloidosis (ATTR)Familial transthyretin amyloidosis (ATTR)Familial transthyretin amyloidosis (ATTR)

History of TTR amyloidosis:

1949 Ostertag: „Familiäre Amyloidoseerkrankung“

1952 Andrade: „Peculiar form of peripheral neuropathy: Familial atypical generalized amyloidosis“ F ili l l id l th (FAP) M l d é i h “Familial amyloid polyneuropathy (FAP), „Mal dos pésinhos“

1978 Prealbumin (TTR) identified as the main component

1983 TTR-Met30 as the first identified mutation

FamilialFamilial transthyretintransthyretin amyloidosisamyloidosis (ATTR)(ATTR)Familial Familial transthyretintransthyretin amyloidosisamyloidosis (ATTR)(ATTR)

TTR: structure and genetic variants

- most frequent cause of ATTR- over 100 mutations known,- mainly point mutations,- autosomal dominant inheritance

- 8 antiparallel -chains: native protein is weakly amyloidogenic ( SCA, SSA)t bl t t bi d T4 and RBP- stable tetramer binds T4 and RBP

Main synthesis: liver (incretory)Main synthesis: liver (incretory)Additional synthesis: retina, choroid plexus


Conformational change into fibrillary protein matrix

T4RBP RBPRBP RBP

Helix -sheet(instable monomer)


Clinical manifestations: organ involvement

FAP FAC

- Peripheral nerve: polyneuropathy, CTS Only heart- Heart: Cardiomyopathy (cardiac insufficiency, rhythm disturb.)

- Gut: diarrhea, often alternating with constipation

- Eye: variousy

I t t Kid i l t l 10 % li i l d!!Important: Kidney involvement only 10 %, liver never involved!!


Diagnostics:

• biopsy with:- Congo red staining- immune histochemistry

• TTR electrophoresis

• molecular genetics


Clinical particularities: two different age peaks

Peak age in Met30 mutations:Peak age in Met30 mutations:

early onset (Portugal): 30 40 (33 5) yrsearly onset (Portugal): 30-40 (33,5) yrs

late onset (Sweden): 50-60 (56 7) yrs !late onset (Sweden): 50-60 (56,7) yrs !In single cases as late as 78 yrs!


Clinical particularities : isolated cases

• generally high proportion of „spontaneous“ cases:I F h 6 % i h i f il hi !In French pts 65% with negative family history!

l t i S di h ti t• low penetrance in Swedish patients:by age 60 yrs: 22 %by age 90 yrs: 69 %

Therefore: numerous isolated cases!


Clinics: Tree of a TTR-Val107 familyClinics: Tree of a TTR Val107 family

1 285 40

1 271 9370

3

pos

370

2

72 54 58 45206821 654 7

neg

35

pos pos pos

35


Clinics: Tree of a TTR-Val107 familyClinics: Tree of a TTR Val107 family

75 82

2123 73 6569 63 61

neg

6676

pos pos pos pos

2123 73 6569 63 616676


Clinics: Trees of singular TTR-Val107 probandsClinics: Trees of singular TTR Val107 probands

I1 238

I78

1 2

1 69II

1 2

1 64

II6364 32III

pospos

3

41III


Tree of a large family with the TTR-Met30 mutationTree of a large family with the TTR Met30 mutation

Q llQuelle:Prof. Willig

TTR mutations5

Geographical dis-t ib ti i GER

55

tribution in GER3

5

77

1 proband 5

673 b d

2 probands

p oba d

3

4 44

5 57

94 probands

3 probands

5 4

55

105 probands

36

56 and more

Quelle: K. Altland, Giessen


Geographical distribution of hitherto identified cases:


Prognosis:Prognosis:

Survival time: 5-15 yrs (P), 10-15 yrs (S)

Cause of death: Cachexia or cardiac crisis


Therapy: e apyLiver transplantation (OLT)

Rationale:

Elimination of the main production site of variant TTR

Actually 110 OLTs/yr

By now over 1500 OLTs worldwideySource: World Transplant Registry (www.fapwtr.org)


Therapy: li t l t ti (OLT)liver transplantation (OLT)

Technique:Domino-Tx, today app 80 DLTs/yrtoday app. 80 DLTs/yr

Risk:Risk:TTR amyloidosis in the recipientafter 20 - 30 yrs possible


Therapy: liver transplantation

O tOutcome: 5-year survival time with today‘s OP techniques and strategiesOP techniques and strategies excellent

Source: World Transplant Registry (www.fapwtr.org)Sou ce o d a sp a eg s y ( ap o g)



O tOutcome: dependent of- duration of symptomsduration of symptoms- i.e. with late operation prognosis is worse

Source : World Transplant Registry (www.fapwtr.org)Sou ce o d a sp a eg s y ( ap o g)



O tOutcome: dependent of- Body mass indexBody mass index- i.e. with late operation prognosisis worse

Source: World Transplant Registry (www fapwtr org)Source: World Transplant Registry (www.fapwtr.org)


Conclusions

1) Hereditary TTR amyloidoses are systemic disorders with- rapidly progressing, invalidazing motor-sens.-autonome PNPp y p g g, g- cardiac involvement limits outcome- isolated cardiac amyloidosis is typical of several mutations

2) TTR amyloidoses are characterized by two different age peaks(early vs. late onset / Portuguese vs. Swedish type)

3) Familiy history is frequently negative

4) Early liver Tx is the only available therapy

hereditary transthyretin amyloidoses (attr)

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