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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
Familial transthyretin amyloidosis (ATTR)Familial transthyretin amyloidosis (ATTR)Familial transthyretin amyloidosis (ATTR)Familial transthyretin amyloidosis (ATTR)
Conformational change into fibrillary protein matrix
T4RBP RBPRBP RBP
Helix -sheet(instable monomer)
FamilialFamilial transthyretintransthyretin amyloidosisamyloidosis (ATTR)(ATTR)Familial Familial transthyretintransthyretin amyloidosisamyloidosis (ATTR)(ATTR)
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!!
Familial transthyretin amyloidosis (ATTR)Familial transthyretin amyloidosis (ATTR)Familial transthyretin amyloidosis (ATTR)Familial transthyretin amyloidosis (ATTR)
Diagnostics:
• biopsy with:- Congo red staining- immune histochemistry
• TTR electrophoresis
• molecular genetics
FamilialFamilial transthyretintransthyretin amyloidosisamyloidosis (ATTR)(ATTR)Familial Familial transthyretintransthyretin amyloidosisamyloidosis (ATTR)(ATTR)
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!
FamilialFamilial transthyretintransthyretin amyloidosisamyloidosis (ATTR)(ATTR)Familial Familial transthyretintransthyretin amyloidosisamyloidosis (ATTR)(ATTR)
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!
FamilialFamilial transthyretintransthyretin amyloidosisamyloidosis (ATTR)(ATTR)Familial Familial transthyretintransthyretin amyloidosisamyloidosis (ATTR)(ATTR)
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
FamilialFamilial transthyretintransthyretin amyloidosisamyloidosis (ATTR)(ATTR)Familial Familial transthyretintransthyretin amyloidosisamyloidosis (ATTR)(ATTR)
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
FamilialFamilial transthyretintransthyretin amyloidosisamyloidosis (ATTR)(ATTR)Familial Familial transthyretintransthyretin amyloidosisamyloidosis (ATTR)(ATTR)
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
FamilialFamilial transthyretintransthyretin amyloidosisamyloidosis (ATTR)(ATTR)Familial Familial transthyretintransthyretin amyloidosisamyloidosis (ATTR)(ATTR)
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
FamilialFamilial transthyretintransthyretin amyloidosisamyloidosis (ATTR)(ATTR)Familial Familial transthyretintransthyretin amyloidosisamyloidosis (ATTR)(ATTR)
Geographical distribution of hitherto identified cases:
FamilialFamilial transthyretintransthyretin amyloidosisamyloidosis (ATTR)(ATTR)Familial Familial transthyretintransthyretin amyloidosisamyloidosis (ATTR)(ATTR)
Prognosis:Prognosis:
Survival time: 5-15 yrs (P), 10-15 yrs (S)
Cause of death: Cachexia or cardiac crisis
FamilialFamilial transthyretintransthyretin amyloidosisamyloidosis (ATTR)(ATTR)Familial Familial transthyretintransthyretin amyloidosisamyloidosis (ATTR)(ATTR)
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)
FamilialFamilial transthyretintransthyretin amyloidosisamyloidosis (ATTR)(ATTR)Familial Familial transthyretintransthyretin amyloidosisamyloidosis (ATTR)(ATTR)
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
FamilialFamilial transthyretintransthyretin amyloidosisamyloidosis (ATTR)(ATTR)Familial Familial transthyretintransthyretin amyloidosisamyloidosis (ATTR)(ATTR)
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)
FamilialFamilial transthyretintransthyretin amyloidosisamyloidosis (ATTR)(ATTR)Familial Familial transthyretintransthyretin amyloidosisamyloidosis (ATTR)(ATTR)
Therapy: liver transplantation
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)
FamilialFamilial transthyretintransthyretin amyloidosisamyloidosis (ATTR)(ATTR)Familial Familial transthyretintransthyretin amyloidosisamyloidosis (ATTR)(ATTR)
Therapy: liver transplantation
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)
FamilialFamilial transthyretintransthyretin amyloidosisamyloidosis (ATTR)(ATTR)Familial Familial transthyretintransthyretin amyloidosisamyloidosis (ATTR)(ATTR)
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