Received: 17 April 2018 | Revised: 9 July 2018 | Accepted: 4 September 2018

DOI: 10.1111/ane.13035

REVIEW ARTICLE

Hereditary transthyretin‐related amyloidosis

Josef Finsterer1 | Stephan Iglseder2 | Julia Wanschitz3 | Raffi Topakian4 |

Wolfgang N. Löscher3 | Wolfgang Grisold5

1
Krankenanstalt Rudolfstiftung, Vienna,
Austria Hereditary transthyretin(TTR)‐related amyloidosis (ATTRm amyloidosis) is an en‐
2
Konventhospital Barmherzige Brüder, Linz, demic/non‐endemic, autosomal‐dominant, early‐ and late‐onset, rare, progressive
Austria disorder, predominantly manifesting as length‐dependent, small fiber dominant, ax‐
3
Department of Neurology, Medical
onal polyneuropathy and frequently associated with cardiac disorders and other mul‐
University Innsbruck, Innsbruck, Austria
4
Department of Neurology, Klinikum Wels‐
tisystem diseases. ATTRm amyloidosis is due to variants in the TTR gene, with the
Grieskirchen, Wels, Austria substitution Val30Met as the most frequent mutation. TTR mutations lead to desta‐
5
Ludwig Boltzmann Institute for bilization and dissociation of TTR tetramers into variant TTR monomers, and forma‐
Experimental und Clinical Traumatology,
Vienna, Austria tion of amyloid fibrils, which are consecutively deposited extracellularly in various
tissues, such as nerves, heart, brain, eyes, intestines, kidneys, or the skin. Neuropathy
Correspondence
Josef Finsterer, Krankenanstalt may not only include large nerve fibers but also small fibers, and not only sensory and
Rudolfstiftung, Vienna, Austria. motor fibers but also autonomic fibers. Types of TTR variants, age at onset, pene‐
Email: fifigs1@yahoo.de
trance, and clinical presentation vary between geographical areas. Suggestive of a
ATTRm amyloidosis are a sensorimotor polyneuropathy, positive family history, auto‐
nomic dysfunction, cardiomyopathy, carpal tunnel syndrome, unexplained weight
loss, and resistance to immunotherapy. If only sensory A‐delta or C fibers are af‐
fected, small fiber neuropathy ensues. Diagnostic tests for small fiber neuropathy
include determination of intraepidermal nerve fiber density, laser‐evoked potentials,
heat‐ and cold‐detection thresholds, and measurement of the electrochemical skin
conductance. Therapy currently relies on liver transplantation and TTR‐stabilizers
(tafamidis, diflunisal).

KEYWORDS
amyloid, neuropathy, small fiber, tafamidis, transplantation, transthyretin

1 | I NTRO D U C TI O N Deposition of wild‐type (wt) TTR (ATTRwt) leads to senile, non‐he‐

Amyloidosis is a multisystem, gain‐of‐toxic function disease due to
relentless deposition of aggregates of an abnormal protein in var‐
ious tissues.1 More than 30 different abnormal proteins involved
in the generation of amyloidosis have been reported thus far.1
Amyloidogenic proteins may have a genetic origin or a non‐genetic
origin. One of the >30 proteins degenerating to amyloid is transthyre‐
tin (TTR). Extracellular deposition of mutated (variant) TTR (ATTRm)
leads to hereditary TTR‐related amyloidosis (ATTRm amyloidosis). 2
Alll authors contributed equally to this study.
reditary amyloidosis,1 with the onset typically >50 years of age. The
occurrence of ATTRwt amyloidosis is regarded as an aging‐related
phenomenon, like Aβ deposition in the brain.1
ATTRm amyloidosis is a rare, hereditary, autosomal‐domi‐
nant, adult‐onset, multisystem disease (OMIM #105210) due to
deposition of TTR‐amyloid in various organs or tissues. 3 Tissues
predominantly affected in ATTRm amyloidosis are the peripheral
nerves, leading to ATTRm‐related polyneuropathy, the meninges
(leptomeningeal amyloidosis) and cerebral arteries (amyloid angi‐
opathy), and the heart, leading to TTR‐related familial amyloid car‐
diomyopathy (TTR‐CA). 3 Other organs variably affected are the

92 | © 2018 John Wiley & Sons A/S. wileyonlinelibrary.com/journal/ane Acta Neurol Scand. 2019;139:92–105.
Published by John Wiley & Sons Ltd
FINSTERER et al.
eyes, the gastrointestinal tract, the kidneys, and the skin. ATTRm
amyloidosis is resistant to immunotherapy. Though ATTRm‐re‐
lated polyneuropathy or TTR‐CA may occur without affection of
another tissue, a variable combination of organ affection (multi‐
organ involvement) is the most frequent phenotype. This review
aims at summarizing and discussing previous and recent findings
concerning the clinical presentation, genetic background, patho‐
genesis, diagnosis, treatment, and outcome of ATTRm‐related
polyneuropathy.
2 | M E TH O DS
Data for this review were identified by searches of MEDLINE for
references of relevant articles. Search terms applied were “tran‐
sthyretin,” “gene,” “TTR‐FAP,” or “mutation,” combined with “neu‐
ropathy,” “hereditary,” “autonomic,” “small fiber neuropathy,” and
“polyneuropathy.” Results of the search were screened for poten‐
tially relevant studies by application of inclusion and exclusion
criteria for the full texts of the relevant studies. Included were
randomized controlled trials (RCTs), observational studies with
controls, case series, and case reports. Only original articles about
humans, and published between 1966 and 2018 were included.
Reviews, editorials, and letters were not considered. Reference
lists of retrieved studies were checked for reports of additional
studies. Websites checked for additional, particularly genetic in‐
formation and for assessing the pathogenicity of TTR mutations
were the following:
Neuromuscular disease center, Washington University, St. Louis,
https://neuromuscular.wustl.edu/nother/amyloid.htm#transthyretin.
Genetics Home Reference. Transthyretin amyloidosis. https://
ghr.nlm.nih.gov/condition/transthyretin-amyloidosis.
3 | R E S U LT S
3.1 | Classification
ATTRm amyloidosis may be classified as endemic/non‐endemic,
as hereditary/non‐hereditary, early‐onset/late‐onset, or as mono‐
system/multisystem (focal/generalized) disease. ATTRm amyloido‐
sis can be endemic (localized, traceable family history, early onset)
or non‐endemic (scattered, frequently negative family history,
4
late onset). Concerning the terminology, there is some confusion
about the optimal designation of the various entities. Some authors
use ATTR‐FA synonymously with ATTRm‐related polyneuropathy.
Other authors use ATTRm synonymously with ATTRm‐related pol‐
yneuropathy. In the present review, we use the term ATTRm amy‐
loidosis for hereditary TTR‐amyloidosis. If patients with ATTRm
amyloidosis manifest with polyneuropathy or cardiomyopathy,
we additionally use the terms ATTRm‐related polyneuropathy
and TTR‐CA. The term ATTRm is reserved for describing the vari‐
ant TTR protein, as recommended by the International Society of
Amyloidosis. 5
| 93
3.2 | Clinical presentation
ATTRm amyloidosis is most frequently dominated by ATTRm‐re‐
lated polyneuropathy including autonomic involvement. In most
patients, cardiac (TTR‐CA), gastrointestinal, central nervous sys‐
tem, renal, connective tissue, or ocular involvement additionally
develop (Table 1).6 Only rarely may ATTRm amyloidosis present
exclusively as rapidly progressive polyneuropathy without involve‐
ment of other organs.7 Generally, the phenotype can be extremely
heterogeneous between geographical areas and even among fam‐
ily members carrying the same mutation. 8 In non‐endemic areas,
the natural history of ATTRm amyloidosis is more severe than in
endemic areas. 3 Bilateral CTS is reported frequently many years
before the onset of other symptoms of ATTRm amyloidosis. The
phenotype is not only determined by genetic but also epigenetic
and environmental factors. Generally, three stages of ATTRm
amyloidosis are differentiated: In stage‐I, the patient is ambula‐
tory with one cane; in stage‐II, the patient is ambulatory with two
canes; and in stage‐III, the patient is confined to a wheelchair or is
bedridden.9
3.2.1 | ATTRm‐related polyneuropathy
ATTRm‐related polyneuropathy is a hallmark of ATTRm amyloidosis
in the early‐onset and late‐onset type and presents as progressive
(distal to proximal), symmetric, axonal, sensory, autonomic, or motor
neuropathy.4
Motor and sensory fibers
Large non‐myelinated as well as small myelinated fibers are affected.
Small fiber neuropathy (SFN) predominates and mainly affects Aδ
and C fibers of sensory nerves.3 TTR‐FAP typically starts by the loss
of temperature and pain sensations in the feet associated with au‐
tonomic dysfunction, whereas proprioception and light touch sen‐
sation are initially preserved.10 Burning feet over years due to SFN
is often the initial manifestation. After years, sensory disturbances
spread from the foot soles to the insteps, ankles, lower legs, knees,
and thighs in a length‐dependent manner. Light touch becomes ad‐
ditionally impaired in the distal lower limbs but remains dissociated
in the thighs.9 With further progression, motor deficits develop in
the feet and progress in a proximal direction also in a length‐depend‐
ent manner.9 In the upper limbs, glove‐type sensory disturbances
may develop.10 Rarely, also the cranial nerves (eg, hypoglossus)
may be affected leading to tongue atrophy.11 ATTRm‐related poly‐
neuropathy is the most disabling among the late‐onset hereditary
neuropathies.3 With recognition of ATTRm‐related polyneuropathy
worldwide, classifications according to regional phenotypic variabil‐
ity12 become irrelevant.
Autonomic dysfunction
Autonomic functions can be concomitantly impaired from onset of
ATTRm‐related polyneuropathy resulting in cardiocirculatory, geni‐
tourinary, or gastrointestinal dysfunction, such as gastroparesis with
94 | FINSTERER et al.

TA B L E 1 Genotype‐phenotype correlation of TTR mutations (modified according to Sekijima 2018)

Mutation PNP CTS SFN CI CNS OI GI Other Reference

4
Ala25Ser y n n n n n n n
4
Val30Leu y n n y n n n n
4
Phe33Val y n n n n n n n
4
Asp38Ala y n n y n n n n
4
Glu42Glya y n n n n n n n
4
Phe44Ser y n n n n n n n
4
Gly47Arg y n n n n n n n
4
Gly47Val y n n n n n n n
4
Thr49Ile y n n n n n n n
4
Thr49Ala y n n n n n n n
4
Ser50Arg y n n y n n n n
4
Glu54Lys y n n n n n n n
4
Leu55Pro y n n n n n n n
4
Glu61Lys y n n n n n n n
4
Val71Ala y n n n n n n n
4
Ser77Tyr y n n n n n n n
4
Ala97Gly y n n n n n n n
4
Ala109Ser y n n n n n n n
4
Val28Ser y n n n n n n n
4
Val28Met y n n n n n n n
4
Ala36Pro y n n n n n n n
4
Ile84Asn y n n n n n n n
4
His88Arg y n n n n n n n
4
Ala120Ser y y n n n n n n
4
Leu58Arg n y n n n n n n
4
Tyr69Ile n y n n n n n n
4
Ile107Val n y n n n n n n
4
Tyr 114His n y n n n n n n
4
Ala120Thr n y n n n n n n
1
Leu58His n y n n n n n n
1
Ile84Ser n y n n n n n n
4
Asp18Glu n n n y n n n n
4
Ala36Asp n n n y n n n n
4
Ala45Asp n n n y n n n n
4
Ser50Ile n n n y n n n n
4
Thr59Arg n n n y n n n n
4,30
Thr60Ala y n n y n n n n
4
Glu89Lys n n n y n n n n
4
Gln92Lys n n n y n n n n
4
Val94Gly n n n y n n n n
4
Val122Ile n n n y n n n n
4
Glu89Gln n n n y n n n n
4
Pro24Ser n n n y n n n n
4
Ala25Thr n n n n y n n n
4
Gly53Glu n n n n y n n n

(Continues)
FINSTERER et al. | 95

TA B L E 1 (Continued)

Mutation PNP CTS SFN CI CNS OI GI Other Reference

4
Tyr114Cys n n n n y n n n
4
Asp18Gly n n n n y n n n
4
Tyr69His n n n n y n n n
92
Ala97Ser y n n y n y n n

CI, cardiac involvement; CNS, central nervous system involvement; CTS, carpal tunnel syndrome; GI, gastrointestinal involvement; OI, ocular involve‐
ment; PNP, polyneuropathy; SFN, small fiber neuropathy.

nausea, followed by vomiting, pos‐tprandial diarrhea, and constipa‐

tion, cardiac conduction defects, orthostatic hypotension, dysuria,
urinary retention with recurrent urinary infections, sweating abnor‐
malities (sudomotor dysfunction), and sexual dysfunctions (eg, erec‐
tile dysfunction).9

3.2.2 | Cardiac involvement in ATTRm amyloidosis

(TTR‐CA)
TTR‐CA develops in about half of the patients with ATTRm amyloi‐
dosis. 8 TTR‐CA is already present at the time of the first positive
biopsy in 51% of the patients.13 TTR‐CA most frequently manifests
clinically as heart failure with normal systolic function, conduction
blocks, ventricular arrhythmias, or sudden cardiac death (SCD).14
Electrocardiographic (ECG) abnormalities typically recorded in
TTR‐CA patients are low voltage ECG, and QS‐pattern in right
precordial leads (suggesting myocardial infarction), but all other
ECG abnormalities may also variably occur, including atrial fibril‐
lation.15 Typically for TTR‐CA is that atrial fibrillation is associated
F I G U R E 1 Long‐axis 4C‐10 min showing diffuse subendocardial
without enlargement of the left atrium.15 SCD may occur in case of
enhancement in hypertrophied ventricles and atria with zebra
involvement of the cardiac conduction system. Echocardiography
stripe appearance [reprint from Kharadi et al Ann Indian Acad Sci
and cardiac MRI typically show myocardial thickening, including 2016, with permission]
the interatrial septum.1 On cardiac MRI, subendocardial late gado‐
linium enhancement (LGE), another characteristic feature can be
found (Figure 1).1 In a study of 263 patients with TTR‐CA, cardiac
MRI revealed asymmetric hypertrophy associated with hyper‐ 3.2.3 | Central nervous system (CNS) ATTRm
trophic cardiomyopathy as the commonest pattern of ventricular amyloidosis
remodeling in ATTR‐CA.16 LGE imaging was typical in all patients CNS manifestations of ATTRm amyloidosis include cerebral amy‐
with TTR‐CA.16 TTR‐CA is most frequently associated with the loid angiopathy and leptomeningeal amyloidosis. Amyloid may be
mutation Val122Ile.1 Since 3% of Afro‐Americans are heterozy‐ also deposited in veins of the subarachnoid space.4 Amyloid depo‐
gous for this mutation, TTR‐CA occurs frequently in this ethnic sition in cerebral amyloid angiopathy can be particularly found in
group. Other TTR mutations associated with TTR‐CA are Ser50Ile, the media and adventitia of medium‐ and small‐sized arteries, ar‐
Leu121Met, Asp18Glu, Ala36Asp, Ala45Asp, Thr59Arg, Thr60Ala, terioles, and veins of the cortex and the leptomeninges.1 Cerebral
Glu89Lys, Gln92Lys, Val94Gly, Glu89Gln, and Pro24Ser (Table 1).1 amyloid angiopathy may lead to ischemic stroke, intracerebral
It is well established that TTR‐CA is associated with an increased hemorrhage, focal subarachnoid bleeding resulting in hydro‐
mortality.13 TTR‐CA is the major cause of death in patients with cephalus, headache, spastic paraparesis, ataxia, seizures, amyloid
ATTRm amyloidosis in non‐endemic areas.17 The extracellular vol‐ spells, psychosis, or progressive dementia similar to Aß‐associated
ume fraction (ECV) correlated with the amyloid burden and was CAA.4,12 Leptomeningeal amyloidosis is infrequent in association
an independent prognostic factor for survival in a cohort of 263 with the mutation Val30Met.1 More frequently, leptomeningeal
16
patients with TTR‐CA. An early marker of cardiac involvement in amyloidosis is associated with the mutations Ala25Thr, Gly53Glu,
ATTRm amyloidosis and prognostic factor of poor outcome is atrial Tyr114Cys, Asp18Gly, or Tyr69His (Table 1).4,12 Leptomeningeal
affection.18 amyloidosis can be even a serious complication after liver
96 | FINSTERER et al.
transplantation (LTX) since the choroid plexus continues to pro‐
19
duce ATTRm.
3.2.4 | Ocular manifestations of ATTRm amyloidosis
Ocular involvement manifests as reduced visual acuity, dry eyes
(sicca syndrome with an abnormal Schirmer test), vitreous opacity,
pupillary abnormalities (dyscoria (abnormal pupillary shape), scal‐
loped pupils), secondary open‐angle glaucoma, abnormal conjunc‐
tival vessels, keratoconjunctivitis, abnormal tear break‐up time,
deposition of amyloid in the lens, or retinal amyloid angiopathy
(tortuous vessels). 20 The prevalence of all ocular manifestations of
ATTRm amyloidosis increases with disease duration. 21
3.2.5 | Gastrointestinal involvement
Gastrointestinal involvement may manifest as nausea, early satiety,
recurrent vomiting due to gastroparesis, severe, postprandial, wa‐
tery diarrhea, or severe constipation leading to malnutrition and un‐
intentional weight loss. In more severe cases, ileus may develop. 22
3.2.6 | Renal involvement
Renal involvement may manifest as nephrotic syndrome or progres‐
sive renal failure. Renal failure occurs in one‐third of the Portuguese
23
patients. Renal involvement is rare in Japanese patients. A compli‐
cation of renal involvement could be renal anemia due to reduced
production of erythropoietin.
3.2.7 | Involvement of other structures
Non‐specific symptoms in ATTRm amyloidosis may be hoarseness,
coldness, Charcot’s joints, or hyperthyroxinemia. Deposition of amy‐
loid in the transversal carpi ligament may lead to compression neu‐
ropathy of the median nerve (CTS).
3.3 | Age and manifestations at onset
Onset of ATTRm amyloidosis is between age 10 and age 90 years
in endemic and non‐endemic areas.8 However, in endemic areas,
early onset (age < 50 years; Portugal) or late onset (age > 50 years;
4
Sweden), or both (Japan) can be delineated. Mean age at onset
in Portugal is 33.5 years.4 On the contrary, mean age at onset in
Sweden is in the 50 s or 60 s.4 Onset in Japan is bimodal, with a peak
between ages 30 and 40 years and a second peak at age > 60 years.
Early and late onset can be also found in cohorts from the United
States, Switzerland, and Germany.12 In a study of 206 genetically
confirmed patients with ATTRm‐related polyneuropathy from the
24
United States, (Minnesota) mean age at onset was 63.3 years.
a Turkish study of 17 patients with ATTRm amyloidosis, mean age
at onset was 40.4 years and the initial manifestation was feet pares‐
thesias in 15 patients. 25 Interestingly, in two patients, ATTRm amy‐
loidosis started with dysarthria and hemiparesis. 25 Generally, age
at onset depends on the genotype and the gender of the mutation
carrier.
3.3.1 | Early‐onset phenotype
Early‐onset ATTRm amyloidosis starts between late 20 s and the
early 40 s and is characterized by progressive, axonal, length‐de‐
pendent, sensorimotor polyneuropathy with initially predominant
loss of small fiber function (nociception, thermal sensation (sensory
dissociation)), a positive family history, severe autonomic dysfunction
(orthostatic hypotension, impotence, neurogenic bladder, disturbed
bowel contractions), gastrointestinal involvement, and cardiac con‐
duction defects requiring pacemaker implantation. 26-30 There may
be myocardial thickening and arrhythmias. Vitreous opacities and
bilateral CTS can be also a feature of the early‐onset phenotype. In
patients carrying the mutations Leu58His, Ile84Ser, and Tyr114His,
neuropathy starts in the upper extremities as CTS.1 The early‐onset
phenotype is additionally characterized by high penetrance.
3.3.2 | Late‐onset phenotype
Late‐onset ATTRm amyloidosis starts after age 50 years and mani‐
fests initially with progressive, axonal sensorimotor symptoms in
the distal lower extremities.4 Both large and small fiber functions
are already impaired initially, and there is rather loss of all sensory
modalities than sensory dissociation.4 Autonomic involvement is
rare but cardiac involvement is frequent. Cardiomyopathy may even
dominate the phenotype.12 Gastrointestinal manifestations are fre‐
quent. Some patients may develop bilateral CTS. There is a marked
male preponderance.4 The late‐onset type is characterized by low
penetrance and often has a negative family history. Carriers of the
Val30Met in non‐endemic areas and in the endemic focus in Sweden
usually present with the late‐onset phenotype.1 Phenotypes at
onset in Japanese patients differ significantly between patients from
endemic and non‐endemic areas.
3.4 | ATTRwt amyloidosis
Typically, ATTRwt amyloidosis manifests with cardiac abnormali‐
ties, such as systolic dysfunction, heart failure, atrial fibrillation, or
ventricular arrhythmias, occasionally requiring implantation of an
implantable cardioverter defibrillator (ICD). Another typical clinical
manifestation of ATTRwt amyloidosis is CTS, which may occur as the
presenting manifestation of ATTRwt amyloidosis.31 Rarely, ATTRwt
4
amyloidosis may manifest with renal dysfunction. In a Japanese
study of 51 patients with ATTRwt amyloidosis, 76% presented with
heart failure, 59% with conduction defects, 49% with renal insuffi‐
ciency, 45% with CTS, and 22% with spinal canal stenosis.32
In
3.5 | Epidemiology and gender
Previously, ATTRm‐related polyneuropathy was regarded to be a
rare disease. Today, it is well acknowledged that there are more
FINSTERER et al.
patients with ATTRm amyloidosis worldwide than previously
thought.1 ATTRm amyloidosis is currently regarded as the most
common form of hereditary amyloidosis.1 In Japan, an estimated
prevalence of 0.87‐1.1 per 1 000 000 has been reported. 33 The
global prevalence is 8000‐10000 patients. The estimated inci‐
dence is 1:100 000. ATTRwt amyloidosis is also regarded as a fre‐
quent disorder, since autopsy studies of patients >80 years have
shown that 10% of them had ATTRwt depositions.1 Of all ATTRm
amyloidosis cases, 72% are male, and of the ATTRwt amyloidosis
cases, 85%‐90% are male. Thus, there is a striking male gender
preponderance.1
3.6 | Etiology and pathogenesis
3.6.1 | Wild‐type TTR
TTR is a 55 kDa homo‐tetrameric protein composed of 127‐resi‐
due β‐rich subunits.34 TTR is synthesized in the liver (the main
source of serum TTR), choroid plexus, the retina, and the pancreas.
Interestingly, the prevalence of diabetes is not increased in ATTRm
amyloidosis. From these organs, it is secreted into blood, cerebro‐
12
spinal fluid (CSF), and the eyes. The main function of TTR is the
transport of thyroxin (T4) and of retinol‐binding protein/vitamin‐A
complex (holoRBP).34 Though the TTR tetramer contains two T4
34
binding sites, <1% of them are occupied by T4 molecules. This is
because the affinity of T4 to thyroid‐binding globulin is higher, and
the concentration of T4 in the serum is lower compared to that of
TTR. Thus, only 50% of the available TTR is bound to holoRBP.
3.6.2 | Mutated TTR
ATTRm amyloidosis is due to mutations in the TTR gene, with in‐
complete penetrance.1 More than 130 different mutations in the
TTR gene have been thus far detected (Table 1), and considerable
genotype‐phenotype relations have been established.12 Most of
the mutations are point mutations.10 In single cases, compound
heterozygous mutations and microdeletions have been reported.
Currently, two different nomenclature systems for TTR gene mu‐
tations are applied. According to the old system, which is used for
this review, amino acid changes are located at positions 20 amino
acids lower than in the new system. Thus, mutations such as V30M,
T60A, Glu89Lys are now referred as V50M, T80A, and Glu109Lys,
respectively. The most common TTR mutation is the substitution
Val30Met (c.148G>A).1,12 This mutation is predominantly associated
12
with ATTRm‐related polyneuropathy and responsible for a large
endemic focus in Portugal (Povoa do Varazim, Porto) where ATTRm
amyloidosis due to the Val30Met variant has been first described by
Andrade C in 1951 (“disorder of the small feet”).1 There are strong
indications that the mutation drifted by migration of Portuguese
fisherman to Japan and the United States. In a study of 206 patients
with ATTRm amyloidosis from the United States, the most frequent
mutation was the substitution Thr60Ala. 24 The most frequent muta‐
tions causing TTR‐CA are Val122Ile and Ile68Leu.10 A small number
| 97
of TTR mutations are non‐amyloidogenic.4 Recently, it has been
shown that polymorphisms in various different genes (eg, APCS, AR,
RBP4) may modify the phenotype since age at onset of ATTRm amy‐
loidosis was associated with the presence of polymorphisms in these
genes.35
3.6.3 | TTR amyloid fibril formation
TTR mutations cause instability of the TTR tetramer. The generation
of amyloid from normally folded TTR tetramer starts with the dis‐
sociation of the TTR tetramer into TTR monomers. Then, folded TTR
monomers are transformed into misfolded monomers inducing the
generation of oligomers by aggregation of variant TTR monomers and
lastly of amyloid fibrils. TTR mutations destabilize the native quater‐
nary and tertiary structure of TTR, thereby inducing conformational
changes leading to dissociation of tetramers and partial unfolding of
resultant monomers.11 TTR mutations also decrease the thermody‐
namic stability of TTR, thus favoring the shift to misfolded monomer
species and kinetic instability. Amyloid formation is regarded as a nu‐
cleation‐dependent process, which means that fibril growth requires
the formation of a high‐energy quaternary oligomeric structure be‐
fore addition of monomers becomes energetically favorable. These
destabilizing effects also decrease the secretion of TTR from cells. A
drug known to accelerate TTR amyloidogenesis is heparin.36
3.6.4 | Toxicity of ATTR
ATTR exhibits its toxic effect via different pathways. In ATTRm amy‐
loidosis, amyloid fibrils cause tissue damage by compression, obstruc‐
tion, or disturbance of local blood circulation.1 Deposition of amyloid
fibrils causes CTS, vitreous opacity, or glaucoma. However, there are
also indications that mature TTR amyloid fibrils are not tissue toxic
contrary to low molecular weight monomers. Today, it is assumed that
oligomers and protofibrils are the actual toxic agent in ATTRm amy‐
loidosis and ATTRwt amyloidosis. Additionally, TTR oligomers may
induce influx of calcium, which itself can be cytotoxic.37 TTR‐induced
toxicity may be also mediated by receptor for advanced glycation end
products (RAGE).38,39 Activation of RAGE leads to endoplasmatic
reticulum stress, activation of extracellular signal‐regulated kinases
(ERK1/2), involved in meiosis, mitosis, and post‐mitotic functions,
and caspase‐dependent apoptosis.38,39 Additionally, oxidized forms
of TTR can be cytotoxic to human cardiomyocytes in vitro, suggest‐
ing that age‐related oxidative modifications of TTR may contribute to
initiation of amyloid formation in late‐onset ATTRwt amyloidosis.40
3.7 | Diagnosis
3.7.1 | General considerations
The diagnosis ATTRm amyloidosis is established upon the individ‐
ual and family history, clinical neurologic examination, and instru‐
mental investigations, particularly by proof of amyloid deposition
on biopsy specimens and identification of a disease‐causing TTR
98 | FINSTERER et al.
mutation.1 ATTRm amyloidosis should be suspected in the pres‐
ence of a progressive, axonal, length‐dependent polyneuropathy,
initially affecting temperature and pain sensation in association
with one or more of the following manifestations: positive fam‐
ily history for neuropathy, autonomic dysfunction, cardiomyopa‐
thy, gastrointestinal disorder, unexplained weight loss, CTS, renal
3
impairment, or ocular impairment. These red flags are common
in early‐onset ATTRm amyloidosis but uncommon in late‐onset
cases and thus less appropriate for diagnosing ATTRm amyloido‐
sis in non‐endemic areas (Figure 2). 27,41 To establish the diagnosis
of ATTRm amyloidosis, two related symptoms and positive biopsy
3
findings for ATTRm depositions are required. The most common
combinations are ATTRm‐related polyneuropathy and autonomic
dysfunction and ATTRm‐related polyneuropathy and TTR‐CA.42
3.7.2 | Individual and family history
Patients with ATTRm amyloidosis may report a number of different
abnormalities related to polyneuropathy. These include paresthe‐
sias, dysesthesias, allodynia, neuropathic pain, hyperalgesia, exer‐
cise intolerance, muscle weakness, unexplained weight loss, and
muscle wasting. Ocular complaints may include visual field defects,
ocular pain, visual disturbances, or oversensitivity to light. In case of
autonomic involvement, patients may complain about urinary distur‐
bances, erectile dysfunction, fainting and syncopes, or orthostatic
intolerance. In case of gastrointestinal involvement, patients may
report diarrhea, or constipation, vomiting, or persisting nausea. If
the heart is affected, leg edema, exercise intolerance, or exertional
dyspnea may be reported. In a study of 141 Japanese families with
ATTRm amyloidosis, the family history was positive in 98% of the
early‐onset cohorts and in 48% of the late‐onset cohorts. 27 In non‐
endemic areas, the family history is positive in only half of the cases.
3.7.3 | Clinical neurologic examination
The neurologic examination may reveal signs of large and small fiber
dysfunction, reduced tendon reflexes, weakness, wasting, sensory
ataxic gait, orthostatic hypotension, leg edema, exertional dyspnea,
FIGURE 2 Criteria for diagnosing
TTR‐FA
or neck vein distension. The severity of polyneuropathy can be as‐
sessed by application of various polyneuropathy scores. These in‐
clude the neuropathy impairment score (NIS), the NIS‐lower limb
(LL) score, the polyneuropathy disability (PND) score, the Norfolk
QOL‐DN total score, the Kumamoto score for assessing sensory dis‐
turbances, or the modified Norris score. In case of muscle weakness,
quantification by grip strength measurement can be carried out. In a
retrospective, cross‐sectional study of 283 ATTRm amyloidosis pa‐
tients, NIS was correlated with functional scores of locomotion, with
the PND score, and with the disease stage.43 There was a negative
correlation between right‐hand grip strength and the PND score.43
3.7.4 | Blood and CSF tests
TTR circulates in the blood as a soluble tetramer. Serum levels of
TTR are reduced in ATTRm amyloidosis. Reference limits for serum
TTR are 20‐40 mg/dL. Mutant TTR may be determined in the serum
by application of mass‐spectroscopy after immunoprecipitation with
anti‐TTR antibodies and dissociation of the tetrameric structure into
proamyloidogenic monomers. Immunoprecipitation allows iden‐
tifying 90% of ATTRm variants.12 Serum TTR levels were lower at
the 1‐year and 2‐year follow‐up after starting TTR‐stabilizers in un‐
treated patients with ATTRwt amyloidosis compared to treated pa‐
tients.44 Small amounts of TTR monomers (0.28‐0.56 µg/mL) can be
detected in the serum of patients with ATTRm amyloidosis.45 Since
TTR is also produced in the choroid plexus, TTR may be also found in
the CSF.9 Frequently, the CSF protein is elevated.
3.7.5 | Electrophysiology, ultrasound, and MRI of
large peripheral nerves
Electrophysiological techniques such as nerve conduction studies
and somato‐sensory‐evoked potentials (SSEPs) should be applied to
assess the degree of affection of large sensory and motor fibers in
the disease. Ultrasound of peripheral nerves may show enlargement
at entrapment sites and in proximal nerve segments, and segmental
structural alterations with change or even loss of the physiological
fascicular structure.46 There may be also increased echogenicity
FINSTERER et al.
within the interfascicular epineurium without substantial enlarge‐
ment of the nerve.46 Injury of lower limb nerves can be detected
and quantified by high‐resolution magnetic resonance neurography
(HR‐MRN).47 Application of HR‐MRN to 13 symptomatic patients
with ATTRm amyloidosis and asymptomatic mutation carriers re‐
vealed that the number of nerve lesion voxels upon histogram‐based
normalization of nerve voxel signal intensities was higher in patients
than in asymptomatic carriers or healthy controls.47
3.7.6 | Assessment of SFN
SFN usually manifests clinically with somato‐sensory manifesta‐
tions (neuropathic pain, paresthesias) or autonomic manifesta‐
tions.48 SFN often represents a diagnostic challenge. Standard
electrophysiological evaluation is usually normal. Quantitative
sensory testing (QST) can be carried out to assess small fiber func‐
tion by determination of thresholds for cold, warm, pressure, or
pain sensation. The most accurate tool for diagnosing SFN is the
skin biopsy. Of additional help can be pain‐related evoked poten‐
tials (PREP), laser‐evoked potentials (LEP), determination of heat‐
and cold‐detection thresholds, the sympathetic skin response
(SSR), and measurement of the electrochemical skin conductance
(ESC) by means of the QSART and the SUDOSCAN. Application
of the SUDOSCAN allows testing the autonomic innervation of
the sweat glands.49 In a study of 133 ATTRm amyloidosis patients,
ESC allowed to distinguish manifesting patients with ANS involve‐
ment from patients without ANS involvement.47 In this study, the
SUDOSCAN had a sensitivity of 76’% and specificity of 85%.47
Since SFN is often the initial manifestation, it is essential to diag‐
nose SFN properly and to start therapy in time.
3.7.7 | Autonomic testing
Autonomic testing is crucial for demonstrating autonomic involve‐
ment. One of the most frequently applied tests is measuring heart
rate variability (HRV) in response to deep breathing (six breaths/
min).50 In a study of 165 ATTRm amyloidosis patients carrying the
mutation Val30Met, HRV was reduced in 47%.50 HRV during physi‐
ological breathing as assessed by Fourier analysis of the ECG on
the Holter signal allows to detect sympathetic or parasympathetic
over‐ or underactivity. Another test frequently applied is the tilt
test, which is useful to assess the sympathetic innervation of the
myocardium or the precapillary sphincters and to assess orthostatic
dysfunction. Autonomic involvement can be also assessed by inves‐
tigations of urinary‐genital functions. Sympathetic innervation of
the sweat glands can be assessed by means of the SUDOSCAN and
the NEUROPAD. Autonomic denervation of the myocardium can
be best assessed by reduced tracer uptake on the meta‐iodo‐ben‐
zyl‐guanidine (MIBG)‐SPECT, which can also be used to distinguish
Parkinsonian syndromes. Quantification of sweat glands in skin
biopsy allows assessing the sympathetic innervation of the sweat
glands. Distal vasomotricity can be explored by application of the
laser Doppler flowmetry (LDF).
| 99
3.7.8 | Biopsy
Demonstration of amyloid deposition
Demonstration of amyloid on histopathology is a prerequisite for
diagnosing ATTRm amyloidosis. This is particularly the case if the
family history is negative for ATTRm amyloidosis. Deposition of
amyloid in affected tissues can be directly demonstrated by Congo
red staining of various biopsy materials. Amyloid depositions dis‐
play a characteristic apple‐green birefringence under polarized
light examination. Amyloid may be also detected upon biopsy of the
subcutaneous fat, sural nerve, the rectal mucosa, labial and other
salivary glands (sensitivity up to 92%), the kidneys, the endomyo‐
cardium, or tenosynovial tissue obtained during CTS surgery. 51,52
However, organs clinically affected and not mentioned above can
be also biopsied. Biopsy of the sural nerve is less sensitive because
amyloid deposition is often patchy.12 A common histological finding
on nerve biopsy is loss of small neurons with/without neighbor‐
ing ATTRm deposition. 53 Additionally, Schwann cell atrophy and
disruption of the blood‐nerve barrier can be found. 53 Negative bi‐
opsy findings do not rule out ATTRm amyloidosis. Immunostaining
of amyloid helps to identify amyloid subtypes, including TTR,
but is not capable to differentiate between ATTRm and ATTRwt.
Immunohistochemistry and immune‐florescence proteomic analy‐
sis are crucial for the correct specification of the amyloid sub‐
type or differentiation between ATTRm and ATTRwt. 2 If biopsy
findings are negative but ATTRm amyloidosis is still suspected, it
is recommended to perform sequencing of the TTR gene. A diag‐
nostic challenge is sporadic cases with a negative family history in
non‐endemic areas. 54-56 Genotypic and phenotypic heterogeneity
and the non‐specific nature of various symptoms often delay the
diagnosis. 57
Skin biopsy
Skin biopsy is usually carried out to diagnose SFN. It is currently the
most reliable diagnostic tool to detect SFN.48 The most valuable
parameter in this respect is the intraepidermal nerve fiber density
(IENFD).48 In a study of 32 patients with ATTRm amyloidosis, IENFD
was reduced in symptomatic Val30Met and non‐Val30Met muta‐
tion carriers. 58 The IENFD can be also reduced in asymptomatic
mutation carriers. 58 IENFD is negatively correlated with disease
duration, and positively with the Kumamoto score, heat/pain detec‐
tion thresholds, and the sensory nerve action potential (SNAP). 58
Sudomotor nerves, stained with protein gene product (PGP9.5)
or vasoactive intestinal peptide (VIP), are usually also reduced in
TTR‐SFN. 59
3.7.9 | Genetic tests
Documentation of a pathogenic TTR mutation is crucial for di‐
agnosing ATTRm amyloidosis. A targeted approach is justified if
the TTR mutation is already known in another family member. If
ATTRm amyloidosis is suspected despite a negative family history,
sequencing of the entire TTR gene is recommended. The most
100 | FINSTERER et al.
frequent mutations are heterozygous point mutations (Table 1).
Occasionally, compound heterozygous point mutations and mi‐
crodeletions have been reported.9 The mutation Val30Met is the
most common variant in Europe, except in Bulgaria (Glu89Gln) and
the UK (Thr 60Ala). 54 In sporadic cases, the entire coding regions
(ie, all four exons) should be sequenced. 42
In a recent Brazilian
study of 123 patients with ATTRm amyloidosis, 90.6% carried the
mutation Val30Met and 7 carried non‐Val30Met mutations, such
60
as Aps38Tyr, Ile107Val, Val71Ala, and Val121Ile.
3.7.10 | Other instrumental investigations
Cardiac involvement
To assess cardiac involvement, ECG, long‐term ECG, echocardiogra‐
phy, cardiac MRI with contrast medium are useful diagnostic tools.
99 m Technetium‐pyrophosphate (99mTcPYP) SPECT has become
the most relevant non‐invasive imaging tool for diagnosing cardiac
amyloidosis.61 A possibility to detect ATTRm or ATTRwt is by applica‐
tion of the 99mTcDPD SPECT, which highly sensitive for TTR‐CA.62
Autonomic denervation of the myocardium can be best assessed
by application of the MIBG‐SPECT. MIBG scintigraphy proved to
be a strong and independent prognostic marker of poor outcome
63
in ATTRm amyloidosis. If the MIBG‐SPECT is inconclusive and
the heart the only clinically affected organ, endomyocardial biopsy
should be considered.
Cerebral involvement
To assess CNS involvement, MRI with contrast medium of the brain
or the spinal cord, MRI‐angiography, CT angiography, or biopsy of
the meninges may be helpful. TTR may be reduced in the CSF.
Ocular involvement
Assessment of ocular involvement requires a complete ophthalmo‐
logic workup, including Schirmer test, disk examination, optic coher‐
ence tomography (OCT), and retinal angiography. Recently, it has
been shown that the corneal nerve fiber length (CNFL) is shortened
in ATTRm amyloidosis patients on in vivo confocal corneal micros‐
copy (IVCM). 64
In a study of 15 ATTRm amyloidosis patients, the
64
correlation between CNFL and the severity of SFN was negative.
There was a positive correlation between CNFL and the SNAP and
between CNFL and the IENFD.64
Gastrointestinal involvement
Gastrointestinal affection requires gastroscopy and colonoscopy,
and mucosal biopsy.
General investigations
To screen patients for suspected ATTRm amyloidosis non‐inva‐
sively, abdominal fat ultrasonography (AFUS) has been recently pro‐
posed.65 In a study of 19 patients with ATTRm amyloidosis, AFUS
showed increased mean echogenicity and loss of normal structure of
fat tissue layers.65 Results on AFUS were positively correlated with
the amount of ATTRm deposition in fat tissues.65
3.7.11 | ATTRwt amyloidosis
To diagnose ATTRwt amyloidosis, it is necessary to prove deposi‐
tion of ATTRwt on a biopsy specimen and to rule out a mutation in
the TTR gene. ATTRwt can be detected by immunocytochemical
and proteomic analysis.1 Though ATTRwt amyloidosis is most fre‐
quently diagnosed upon endomyocardial biopsy, this invasive tech‐
nique is not appealing.1 Though abnormal uptake of 99mrTcPYP
on myocardial SPECT is highly suggestive of myocardial amyloi‐
dosis and uptake of 99mTcDPD suggestive for ATTRm/ATTRwt
deposition, histopathological confirmation of the suspicion is nec‐
essary. If ATTRwt deposition is also found in tenosynovial tissue,
confirmation of ATTRwt in other tissues is necessary, since local‐
ized deposition of ATTRwt is common in elderly subjects.1
3.7.12 | Differential diagnoses
All types of axonal hereditary neuropathies should be consid‐
ered as differential diagnoses of ATTRm‐related polyneuropathy.
However, the most common misdiagnosis of ATTRm‐related poly‐
neuropathy is chronic inflammatory demyelinating polyneuropathy
(CIDP). 66 Thus, if patients with CIDP do not respond to immuno‐
globulins and if axonal lesions predominate, ATTRm‐related poly‐
neuropathy should be suspected. Even autonomic dysfunction may
occur in CIDP patients. Other differential diagnoses are lumbar spi‐
nal canal stenosis, idiopathic axonal polyneuropathy, paraneoplas‐
tic peripheral neuropathy, toxic neuropathy, vasculitic neuropathy,
and motor neuron disease. 67-69 Differential diagnoses of SFN that
need to be considered include diabetes, dysimmune syndromes
(Sjögren syndrome, sarcoidosis, monoclonal gammopathy), or ge‐
netic conditions (sodium channel disease, Fabry’s disease, neu‐
ropathy due to mutations in the prion protein). Hereditary amyloid
neuropathies other than ATTRm‐related polyneuropathy include
neuropathy due to mutations in the apolipoprotein A1, gelsolin, or
beta2‐microglobulin genes, respectively.42 Amyloid proteins other
than ATTRm associated with cardiomyopathy include amyloids
from immunoglobulin light chains (paraprotein, myeloma), serum
amyloid A, atrial natriuretic factor, or from apolipoprotein A1. 2
For the clinician, it is important to have a high index of suspicion,
when red flags are present in a patient with “idiopathic” polyneurop‐
athy. Rapid progression, ambulatory loss early on, and autonomic dis‐
turbances may serve as red flags for ATTRm‐related polyneuropathy.
However, lack of amyloid in nerve biopsies of patients with ATTRm‐re‐
lated polyneuropathy is possible, while other diagnostic pitfalls include
unspecific electrophysiological and coincident laboratory findings such
as pathologic glucose tolerance or a monoclonal gammopathy.57
3.8 | Treatment
3.8.1 | Liver transplantation (LTX)
Until 1990, ATTRm amyloidosis used to be an incurable disease.
In 1990, LTX was introduced as a causative therapy of ATTRm
FINSTERER et al.
amyloidosis. LTX can have a beneficial effect, at least on ATTRm‐
related polyneuropathy, if carried out early in the disease course
1
(<5 years disease duration) and in young patients. LTX results in
slowing of progression of ATTRm‐related polyneuropathy and of au‐
70
tonomic involvement in some patients. LTX removes the primary
source of ATTRm production, eliminates 95% of ATTRm, slows or
stops progression of the disease, and improves the disease in single
4
cases. In a study of 6 patients with ATTRm‐related polyneuropathy,
the amount of deposited ATTRm regressed during an observational
71
period of 10 years after LTX. In other cases, progression of the dis‐
ease could be stopped depending on the type of mutation and the
side effects of immunosuppressive drugs. LTX replaces the mutated
TTR gene by the wt‐gene in the liver, why serum levels of ATTRm
1
rapidly decrease after LTX. Accordingly, long‐term follow‐up biop‐
sies of patients having undergone LTX showed regression of amyloid
deposition.72 LTX usually has no benefit on TTR‐CA, leptomenin‐
geal involvement, or on ATTRwt amyloidosis.1 New, long‐term re‐
sults allow selection of best candidates for LTX based on phenotype
3
and cardiac involvement. LTX is not indicated in late stages, when
there is malabsorption, ileus, or diarrhea, requiring parenteral nutri‐
tion or if there is TTR‐CA with ventricular arrhythmias. According
to Japanese data, LTX is particularly effective in early‐onset ATTRm
amyloidosis but not in late‐onset ATTRm amyloidosis.73 Interestingly,
the outcome after LTX is better if living donor liver grafts are im‐
planted compared to implantation of grafts from deceased donors.74
The outcome of LTX may be further improved if LTX is combined in
tandem with TTR‐stabilizers. Transplantation of livers from patients
with ATTRm amyloidosis to non‐ATTRm patients with liver failure
can subsequently induce amyloidosis in some recipients.5
LTX for ATTRm amyloidosis has several limitations: (a) Organ dam‐
age present already prior to LTX is hardly reversed. (b) Outcomes are
mutation‐specific (patients carrying the Val30Met have a better out‐
come than non‐Val30Met patients). (c) Amyloid deposition continues
after LTX because ATTRwt deposits on existing amyloid. (d) ATTRm
deposition continues because of local production in the choroid
plexus or the retinal epithelium. (e) LTX carries the risk of surgery and
long‐term immunosuppression has side effects. (f) Many patients are
4
not suitable candidates for LTX, and that LTX is not widely available.
3.8.2 | TTR‐ stabilizers
TTR‐tetramer‐stabilizers currently available include tafamidis and
76
diflunisal. Long‐term randomized controlled trials have shown
that tetramer stabilizers slowed the progression of ATTRm‐related
polyneuropathy and preserve quality of life in ATTRm‐related poly‐
neuropathy patients. Early treatment with tafamidis can delay pro‐
gression of ATTRm‐related polyneuropathy over 5.5 years.77 Studies
on the long‐term effect of tafamidis showed that 40% respond as
78
reflected on the NIS‐LL score, that biochemical stabilization of
78
TTR can be achieved, that prevention of functional progression
can be achieved in up to 50% of the patients,67 and that tafamidis
may not prevent the progression of the disease.79 In the THAOS
survey, patients under tafamidis had significantly less deterioration
| 101
as assessed by the Norfolk Quality of Life scale than untreated pa‐
tients.80 Tafamidis is currently approved for ATTRm‐related poly‐
neuropathy stage‐1.11 TTR‐stabilizers are the first‐line option for
early‐onset ATTRm‐related polyneuropathy in Europe.4 Another
TTR‐stabilizer currently under investigation, but not yet approved,
is tolcapone.
TTR gene silencing drugs are subject to phase‐3 clinical trials.3
Other compounds currently under investigation include the small
interfering (si) RNA patisiran, which silences the mRNA, and the anti‐
sense oligonucleotide (AON) inotersen. In these phase‐3 trials, both
inotersen and patisiran have met their primary and secondary end‐
points for the Neuropathy Impairment Score (NIS) and for quality of
life scores. Both are currently moving forward with FDA approval and
articles about these studies are in press in the New England Journal
of Medicine. These results further emphasize that timely recognition
and accurate diagnosis are crucial as effective treatment is available.
As ATTRm amyloidosis is a progressive disease, it may cause irrevers‐
ible tissue damage if untreated or treated too late.66,75,81
3.8.3 | Symptomatic measures
In the era prior to LTX and TTR‐stabilizers, treatment of ATTRm
amyloidosis was restricted to symptomatic measures, such as treat‐
ment of neuropathic pain, implantation of a pacemaker, or parenteral
nutrition. Today, treatment of ATTRm amyloidosis relies on three
pillars: disease‐modifying targeted therapy to prevent further pro‐
duction of ATTRm (LTX, TTR‐stabilizers), symptomatic treatment of
nerve, cardiac, ocular, cerebral, gastrointestinal, and renal involve‐
ment, and genetic counseling and supportive care. Treatment algo‐
rithms vary between countries.4 First‐line therapy in Japan is LTX,
while European countries adopted pharmacotherapeutic options as
first‐line treatment.4 In a recent Italian study, epigallocatechin‐3‐gal‐
late failed to improve survival of patients with TTR‐CA.82
3.8.4 | Gene therapy
Recently, the first investigational RNA interference therapeutic
agent has been shown highly effective in improving multiple dif‐
ferent manifestations of ATTRm amyloidosis.83 In a randomized,
controlled, phase‐3 trial, 225 patients with ATTRm amyloidosis
with polyneuropathy received 0.3 mg/kg patisiran intravenously
every three weeks over 18 months.83 The modified Neuropathy
Impairment Score+7 increased significantly over this period in the
verum group.83 In a randomized, double‐blind, placebo‐controlled,
phase‐3 trial of 112 patients with ATTRm amyloidosis, the antisense
oligonucleotide inotersen (300 mg subcutaneously every week) re‐
sulted in significant improvement of the clinical neurologic course
and the quality of life in the included patient.84
3.9 | Genetic counseling
Patients in whom ATTRm amyloidosis was diagnosed and at‐risk
family members require genetic counseling. Genetic counseling
102 | FINSTERER et al.
must be carried out by trained professionals.3 Regular monitoring of
asymptomatic carriers is warranted to detect early manifestations of
ATTRm amyloidosis.
3.10 | Prognosis and outcome
ATTRm amyloidosis is the most severe form among the hereditary
neuropathies.46 Without treatment, patients die from progressive
organ dysfunction, particularly heart failure, infection, or cachexia
8
approximately within 10 years of disease onset. Cardiac involve‐
ment is the most important prognostic factor in patients with gener‐
alized amyloidosis. 2 In a recent retrospective study of 120 patients
with TTR‐CA of whom 29 received tafamidis, application of TTR‐
stabilizers was associated with decreased rate of orthotopic heart
transplantation and death.85 Another major factor influencing the
survival rate of ATTRm amyloidosis patients is the TTR genotype. In
patients carrying the Val30Met variant, 5‐year and 10‐year survival
rates were 82% and 74%, respectively, compared with a 5‐year and
10‐year survival rate of 59% and 44% in non‐Val30Met carriers.86,87
In early‐onset ATTRm amyloidosis, prognosis in transplanted pa‐
tients is better than in non‐transplanted patients. This effect is no
longer present in patients with late‐onset ATTRm amyloidosis. It has
been also reported that the prognosis of females with early‐onset
ATTRm amyloidosis carrying the Val30Met mutation is much better
than in males carrying Val30Met with late‐onset ATTRm amyloido‐
73
sis. In a study of 206 genetically confirmed patients with ATTRm
amyloidosis, mean survival after diagnosis was 56.8 months. 24 In
this study, risk factors for death on multivariate analysis were age
at onset, presence of Thr60Ala or Val122Ile mutations, neuropathy,
24
and weight loss. The overall survival rate of patients undergoing
LTX is >80% five years after surgery.86 Progression of cardiac amy‐
loid deposition is more pronounced in non‐Val30Met carriers than
in late‐onset Val30Met liver recipients.88 The mean survival period
from the onset of heart failure is 75 months in ATTRwt amyloidosis.
A severe and rapid course with a survival of 6‐7 years after onset has
been reported in patients with late‐onset ATTRm amyloidosis carry‐
ing the mutations Val30Met, Ile107Val, or Thr60Ala.43,89
3.11 | Predictors of survival
In patients with ATTRwt amyloidosis, low serum TTR levels were
associated with short survival.44 In a 20‐year retrospective study
of 1379 patients having undergone LTX, survival was reduced with
high body mass index, early‐onset, long disease duration before
LTX, and with Val30Met vs. non‐Val30Met mutation.75 In a mono‐
centric cohort study of 215 ATTRm amyloidosis patients, predic‐
tors of death were PND score > II, orthostatic hypotension, NYHA
stage > I, QRS duration >120 ms, and thickened interventricular
septum.90 Survival was reduced if there was cardiac dysautonomia
after LTX, or on MIBG‐SPECT and no response to atropine.91 In a
study of 116 patients with ATTRwt amyloidosis, reduced serum TTR
values were associated with short survival.44 Low TTR serum levels
were an independent predictor of the outcome in these patients.44
4 | CO N C LU S I O N S
ATTRm amyloidosis is a multifaceted, fascinating disorder, which still
has a number of surprises to provide to the clinician and the scientist.
Most importantly, ATTRm amyloidosis needs to be diagnosed early
in the course to provide optimal treatment to improve outcome.
Current and future studies should thus direct toward the evaluation
and invention of new methods to recognize early manifestations at
onset. This issue not only refers to better characterization of clinical
manifestations at onset but also to instrumental investigations that
can reliably confirm the presence of ATTRm or ATTRwt depositions
in clinically affected or unaffected tissues. Currently available, mini‐
mally invasive or non‐invasive methods for early diagnosis include
skin biopsy, IVCM, HR‐MRN, and AFUS. However, future perspec‐
tives should also include the invention of new techniques for early
diagnosing ATTRm amyloidosis to prolong the survival in this still
progressive and lethal disease.
AC K N OW L E D G M E N T S
None.
C O N FL I C T O F I N T E R E S T S
There are no conflict of interests.
AU T H O R C O N T R I B U T I O N
JF designed the study, involved in literature search, and discussed
and first drafted the manuscript. WL, RT, JW, SI, and WG involved in
literature search and made critical review of the manuscript.
ORCID
Josef Finsterer http://orcid.org/0000-0003-2839-7305
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How to cite this article: Finsterer J, Iglseder S, Wanschitz J,
Topakian R, Löscher WN, Grisold W. Hereditary
transthyretin‐related amyloidosis. Acta Neurol Scand.
2019;139:92–105. https://doi.org/10.1111/ane.13035
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