Keywords: Amyloidosis - amyloid neuropathies, familial - polyneuropathy
Palavras-chave: Amiloidose - neuropatias amiloides familiares - polineuropatias
Transthyretin amyloidosis (ATTR) belongs to a group of severe systemic conditions
characterized by deposit of wild-type or mutant proteins in tissues and organs[1 ],[2 ].
More specifically, hereditary ATTR is caused by mutations in the gene encoding transthyretin
(TTR), a plasma protein, mainly synthesized and excreted by the liver, which circulates
in soluble form in the peripheral blood and cerebrospinal fluid and is involved in
the transport of thyroxin and retinol. Pathogenic mutations decrease the stability
of TTR tetramers and enhance their dissociation into monomers. These monomers are
susceptible to misfolding and self-aggregate into insoluble amyloid fibrils capable
of systemic extracellular deposition[1 ],[3 ].
Clinical manifestations vary according to the mutation, age of onset and geographical
location, and can be predominantly neuropathic (known as familial amyloid polyneuropathy
[ATTR-FAP]), predominantly cardiac (or TTR cardiac amyloidosis), or mixed[1 ],[2 ]. In the peripheral nervous system, amyloid deposits are in the interstitium, scattered
in the endoneurium and/or around blood vessels[1 ]. Familial amyloid polyneuropathy is a slowly-progressive disease in most patients
and has been divided into three stages following the length-dependent progression
of sensorimotor polyneuropathy. Sensory symptoms are the most frequent initial complaint.
They include distal paresthesias, numbness sometimes associated with pain, and burning
or tingling sensations, without walking impairment (stage 1 of Coutinho). At a later
stage, patients experience more generalized sensorimotor neuropathy, affecting the
upper limbs, and require assistance for walking (stage 2 of Coutinho). Ultimately,
there is a flaccid paralysis in all four limbs and the patient is confined to a wheelchair
or is bedridden (stage 3 of Coutinho)[4 ].
In an average of 10 years, the disease is fatal, usually due to infections, cachexia
or bed sores[1 ],[5 ]. In addition, autonomic neuropathy is almost constant during the course of disease,
causing a major impact on patient disability, with organ dysfunction directly related
to amyloid deposits; cardiovascular (orthostatic hypotension that can cause fatigue,
blurred vision, dizziness, faintness or repeated postural syncope); gastrointestinal
(early satiety, slow digestion, nausea, anorexia, recurrent postprandial vomiting
[later stage], dehydration and progressive weight loss); and genitourinary (erectile
dysfunction, dysuria, urinary retention). The disease also directly affects other
organs such as: ocular (vitreous opacity, keratoconjunctivitis, glaucoma), heart (conduction
abnormalities and cardiac failure), and kidney (early proteinuria progressing to kidney
failure)[1 ],[6 ].
Transthyretin familial amyloid polyneuropathy is distributed worldwide, but precise
epidemiological data are scarce. Its low incidence (< 1/200) makes it a rare disease.
Portugal, Sweden and Japan remain the largest focus of the disease, but it is likely
that the disease remains largely underdiagnosed in some areas[1 ],[6 ]. In Brazil, the population of ATTR-FAP cases is estimated to be around 5,000 patients[7 ],[8 ]. In order to characterize the natural history of ATTR, an international noninterventional
registry has been implemented - the Transthyretin Amyloidosis Outcomes Survey (THAOS)[9 ].
This study aimed to describe the characteristics of patients suffering from ATTR in
Brazil, based on data collected in THAOS.
METHODS
The THAOS is an ongoing, international, noninterventional, longitudinal, observational,
web-based registry designed to characterize ATTR (ClinicalTrials.gov
NCT00628745). It is open to all patients with ATTR (familial and wild-type) and individuals
with TTR gene mutations without a diagnosis of hereditary ATTR (asymptomatic)[2 ],[9 ],[10 ]. Prior to inclusion, the site was required to obtain all local regulatory approvals,
and participating patients had to provide their written informed consent.
The analysis was conducted on data from patients enrolled in the only Brazilian site
contributing to the registry (CEPARM - National Brazilian Amyloidosis referral center
located at the Federal University of Rio de Janeiro) from November 13, 2008 to January
14, 2016.
The outcome measures included demographics (age at symptom onset, gender, time from
onset of symptoms to diagnosis, family history), genotype, and clinical characteristics
(presence of amyloid deposit, frequency of misdiagnosis, presenting symptomatology)[11 ].
Statistical analysis
Descriptive summary statistics are presented with categorical data shown as frequency
and distribution, and continuous data as mean, median, minimum, maximum.
RESULTS
In total, 160 participants (52.5% male) were included in the analysis. The majority
of participants (90.6%) reported a known family history of symptomatic ATTR. Amyloid
deposit was found in 80.8% of the biopsies performed in symptomatic participants (the
most common tissue type tested was salivary gland followed by nerve). Genetic evaluation
showed Val30Met (n = 147, 91.9%) and non-Val30Met (n = 13, 8.1%) mutations. Among
the non-Val30Met mutations identified were: Ile07Val, Val122Ile, Ala19Asp and Glu109Lys.
The overall median age at symptom onset was 32.5 years and median time from symptom
onset to diagnosis for men and women was 2.6 years and 5.0 years, respectively.
Misdiagnosis was observed in 26.6% of the symptomatic patients, with chronic inflammatory
demyelinating polyneuropathy (CIDP) being the most common diagnosis. Over one-third
(35.3%) of the patients experienced a delay of more than one year before receiving
a correct diagnosis ([Table ]).
Table
Misdiagnoses in symptomatic subjects.
% (n/N)
Val30Met
Non-Val30Met
Overall
Misdiagnosed participants who experienced a delay > 1 year before receiving correct
diagnosis
35.5% (11/31)
33.3% (1/3)
35.3% (12/34)
Misdiagnoses attributed to Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)
15.8% (6/38)
25.0% (1/4)
16.7% (7/42)
Of the 128 symptomatic patients at enrollment, 79.7% presented with motor symptoms
(80.7% Val30Met and 66.7% non-Val30Met); 87.5% presented with sensory symptoms (88.2%
Val30Met and 77.8% non-Val30Met); 93.8% presented with autonomic symptoms (94.1% Val30Met
and 88.9% non-Val-30Met); and 82.8% presented with gastrointestinal complaints (84.0%
Val30Met and 66.7% non-Val30Met). Unintentional weight loss was noted in 50.8% of
the patients. Cardiac involvement was present in 35.2% of symptomatic participants
(32.8% Val30Met and 66.7% non-Val30Met) ([Figure ]).
Figure Frequency of disease-related symptoms per genetic variation.
When considering the age of onset, 82.0% of early-onset patients (< 50 years old)
and 74.1% of late-onset patients (≥ 50 years old) presented with motor symptoms. Corresponding
values for sensory symptoms were 90.0% (early-onset) and 81.5% (late-onset), and for
autonomic symptoms were 95.0% (early-onset) and 88.9% (late-onset).
DISCUSSION
Transthyretin familial amyloid polyneuropathy was described in 1952 by Corino de Andrade[12 ] and was originally considered to be an endemic condition in some areas of Portugal,
Japan and Sweden. Over the past decades, about 120 different mutations related to
hereditary ATTR have been reported; this genetic variation results in a condition
with many different forms, with considerable phenotypic variation across individuals
and geographic location[13 ]. Therefore, there are several unanswered questions in terms of natural history and
response to therapy. For this purpose, the coordination of an international registry
will provide relevant information about the condition and its management.
This is a report based on data collected from Brazilian patients. The majority of
patients (> 90%) had Val30Met mutation. Val30Met is the mutation linked to ATTR-FAP,
and is endemically reported in Portugal, Japan and Sweden. Of note, the Brazilian
population has a strong Portuguese influence but is also a very mixed population with
other ethnic influences such as African, Italian, German and Japanese. No study has
been performed to confirm the impact of such influences on the profile of the clinical
presentation of this disease in Brazil.
Recently, Lavigne-Moreira et al.[14 ] reported the genetic heterogeneity of 128 Brazilian patients with mutations in the
TTR gene. Val30Met was the most common mutation identified (90.6%). The four non-Val30Met
mutations were Ile107Val (n = 2), Asp38Tyr (n = 2), Val122Ile (n = 1) and Val71Ala
(n = 1). Two nonpathogenic mutations Gly6Ser (n = 5) and Thr119Thr (n = 1) were also
identified[14 ]. This study was conducted in the city of Ribeirao Preto (São Paulo state), which
is in the southeast region of Brazil, the same region where our center is located.
Taken together, our findings and those of Lavigne-Moreira et al. raise the possibility
that the southeast region of Brazil is an endemic region of ATTR-FAP.
Transthyretin familial amyloid polyneuropathy is a progressive fatal disease, with
patients presenting with motor disability within five years of diagnosis and generally
being fatal within a decade without treatment[1 ]. Therefore, the need for early diagnosis is clear given that therapeutic interventions
(liver transplantation or anti-amyloidogenic therapy) are designed to reduce further
deposition, but do not address the effect of already-deposited amyloid, and appear
to be effective in early disease[1 ],[2 ],[5 ],[15 ]. The diagnosis of ATTR-FAP remains challenging in the early stages of the disease
and requires expertise, adequate diagnostic methods and a multidisciplinary approach[5 ],[13 ]. The median age at onset of disease-related symptoms was 32.5 years old, and the
median time from symptom onset to diagnosis for men and women was 2.6 years and 5.0
years, respectively, in the Brazilian database. The early erectile dysfunction encountered
in the majority of our male patients probably helped in the shorter time for diagnosis
compared to women. Our findings agree with the Portuguese and Japanese population
described with early onset (mean age of 33 years) and average time for diagnosis varying
from two to six years[4 ],[13 ]. The main reasons for this long time for diagnosis are: the absence of family history,
atypical clinical presentations (varied phenotypes), difficulties in detecting amyloid
deposits in a single tissue biopsy, and the rare use of TTR gene analysis in the screening
of idiopathic polyneuropathy[3 ].
In addition, overall, approximately 25% of symptomatic patients are misdiagnosed;
and correct diagnosis was delayed by more than a year in about one-third of them;
CIDP being the most common disease for misdiagnosis. This result is similar to the
one reported by Cortese et al.,[15 ] who conducted a review on the medical records of 150 patients in Pavia, Italy, and
found 49 misdiagnosed patients (32%), in which CIDP was the most frequent error. The
following typical findings in ATTR-FAP help in the differentiation from CIDP: small
fiber predominant sensation loss; absence of nonuniform demyelination on nerve conduction
studies (temporal dispersion and/or conduction blocks); weight loss; distal predominant
weakness and moderate to severe autonomic dysfunction. The latter seems to be one
of the most important. We found autonomic symptoms in approximately 94% of our patients,
which are usually seen in less than 25% of patients with CIDP, who have no or minimal
autonomic dysfunction[16 ]. Other differential diagnoses of ATTR-FAP are diabetic neuropathy, inherited sensory
and autonomic neuropathies, leprosy, toxic neuropathies, immunoglobulin light-chain
amyloidosis and Fabry's disease. The Brazilian consensus on ATTR-FAP recommends that
it should be strongly considered in patients with progressive polyneuropathy of unknown
etiology who have one or more of the following: family history of neuropathy; orthostatic
hypotension; erectile dysfunction; unexplained weight loss; arrhythmias and/or cardiomyopathy;
bilateral carpal tunnel syndrome; renal abnormalities; vitreous opacities; gastrointestinal
complaints (chronic diarrhea, constipation or diarrhea/constipation); rapid progression
and/or prior treatment failure[17 ].
Histological confirmation of the disease requires tissue sampling to demonstrate amyloid
deposition. The site of biopsy needs to be guided by clinical features and the expertise
of the center. Tissues like salivary glands, subcutaneous abdominal fat or rectal
mucosa should be chosen first. However, the severity of polyneuropathy often requires
a nerve biopsy[1 ]. When the presentation is cardiac, the cardiac biopsy or scintigraphy could help
in the differential diagnosis with other forms of amyloidosis and also of another
cardiomyopathy. Also, immunohistochemistry studies or mass spectrometry-based proteomics
can be done to identify the amyloid protein, and the latter can even differentiate
wild- type from mutated transthyretin[13 ].
Of note is the fact that, at the present moment, the center enrolled 220 patients
in the THAOS database, meaning an increase of 37.5% in the number of new patients
in the last two years. This reflects an increase in medical knowledge about the disease
and interest in new available therapies.
In conclusion, ATTR-FAP in Brazilian patients starts early, has a strong family history,
the majority has the Val30Met mutation and the most common presentation is of a sensorimotor
and autonomic neuropathy. A delay of more than one year before receiving a correct
diagnosis is common and approximately one-quarter of the patients were misdiagnosed,
further delaying the introduction of correct management. Awareness should be raised
among physicians about the identification and diagnostics work-up of ATTR-FAP.
