Hereditary ATTR Amyloidosis

Hereditary ATTR amyloidosis is a progressively fatal genetic disease cause by accumulation of transthyretin in the liver and several other organs. Both autosomal dominant and wild-type patterns are recognized and the clinical presentation depends on the subtype. The diagnosis is made by biopsy and supportive imaging studies. Liver transplantation is currently the mainstay of therapy. Novel treatment strategies are being developed, but the disease carries a poor prognosis despite all efforts.


Although mutations are present from birth, symptoms do not appear until adulthood, primarily because various degrees of penetrance are observed from one individual to another [17]. FAP patients frequently report peripheral neuropathy of sensory nerves, usually in the lower limbs and sensations such as pain and temperature are affected [7]. Wasting and weakness are also accompanying features, whereas autonomic system dysfunction is manifested by diarrhea, constipation, urinary incontinence, orthostatic hypotension and sexual impotence [7]. Apart from symptoms regarding the nervous system, both cardiac and renal dysfunction may be observed [7], particularly in patients with cardiomyopathy forms. Microalbuminuria, heavy proteinuria and progressive renal failure that leads to insufficiency is seen in patients with kidney deposits, but also anemia, since EPO production may be impaired [12] [13]. In some patients, a leptomeningeal form that include ataxia, spastic paralysis, seizures, dementia and visual disturbances as most important symptoms may be seen [1] [7]. Keratoconjuctivitis sicca, glaucoma, reduced vitreous opacity are most frequent ocular complaints [7].


Cardiac ultrasonography should be performed in all elderly patients with heart-related symptoms and an unexplained increase in thickness of the left ventricular wall should rise suspicion toward SCA [8]. In fact, a growing number of studies have emphasized the need of cardiologists to include amyloidosis into the differential diagnosis in such patients [14]. To make a definite diagnosis, tissue biopsy demonstrating amyloid deposits is a necessary procedure [10]., which can be confirmed by immunohistochemistry. If the target tissue is sensitive for biopsy, abdominal fat may serve as a valid source for confirmation of deposits [15]. Determination of the specific subtype of amyloid deposit is of great importance, as is the underlying genetic mutation, primarily for determining the therapeutic strategy [12].


Liver transplantation may be indicated in the setting of familial amyloidotic polyneuropathy, but because of limited availability and significant morbidity, this procedure must be cautiously performed [1]. More importantly, this procedure may ameliorate liver and nervous system-related symptoms, but ocular or cardiac complaints will still persist because extra-hepatic production of TTR will persist [9]. In the recent years, the approval of novel therapies, such as tafamidis, a stabilizer of TTR tetramer and drugs that interfere with RNA signalling, is promising [1]. Tafamidis binds to the unoccupied thyroxine-binding sites on the TTR tetramer and is able to stabilize the dissociation rate of TTR, thus it reduces amyloid deposition [6]. Additionally, two nanoparticle agents, ALN-TTR01 and ALN-TTR02 have been developed and are able to neutralize mutated TTR by disrupting gene expression and function of the mRNA, causing reduced TTR production [1]. Although a superior effect compared to transplantation is observed [1], liver transplant recipients in whom an early diagnosis was made showed prolonged survival rates [18].


The prognosis is poor, as fatal outcomes are expected within 10 years from the onset of the disease [6]. One of the most important factors in providing a chance for therapy is an early diagnosis, which is not the case for many patients due to a lack of clinical suspicion [14]. Despite liver transplantation that inexorably removes the primary source of TTR production, its deposition in numerous organs after the procedure has been documented, thus confirming the presence of an extra-hepatic source of TTR synthesis [19].


The cause of amyloidogenic TTR amyloidosis stems from mutations of genes that code of TTR and so far, more than 100 mutations have been discovered [2]. Two modes have been described so far - autosomal dominant type, divided into familial amyloidotic polyneuropathy (FAP) and familial amyloidotic cardiomyopathy, in which two TTR mutations, V30M (substitution of valine for methionine at position 30) [11], and V122I are responsible for the disease, respectively [6]; Wild-type TTR amyloid depositions, on the other hand, are discovered in patients suffering from senile cardiac amyloidosis (SCA), in whom various types of TTR mutations are described [2].


Familial amyloidotic polyneuropathy was initially discovered in areas of Portugal and Sweden, with established prevalence rates of 1 per 1,000 individuals, implying a strong familial component [12]. Brazil and Japan are other countries that have reported clusters of patients [16]. Crude general prevalence rates, however, are estimated at 1 per 100,000 [12]. On the other hand, senile cardiac amyloidosis (SCA), which may include TTR mutations in its pathogenesis as well, affects approximately 25% of adults over 80 years [5]. Moreover, a strong predilection toward African Americans was determined in autopsy studies compared to Caucasians and Hispanic and a four-fold increased risk for SCA was established [4]. Isolated studies report that the onset of symptoms in familial amyloidotic polyneuropathy is quite wide, but almost 90% of patients develop symptoms before the age of 40 [3]. Not all individual carrying TTR mutations develop the same disease severity, i.e. a variable degree of penetrance is observed, indicating that some other factors (genetic, epigenetic or environmental) are responsible for its occurrence [12].

Sex distribution
Age distribution


Under physiological conditions, TTR is produced in the liver, the choroid plexus and several other sites, after which it is distributed throughout the circulation and the CSF. It's presumed primary role is to bind thyroxine and transport it to the CNS, but it also binds retinol in the endoplasmic reticulum of hepatocytes and transports it throughout the circulation without loss of retinol-binding protein molecules through kidney filtration [12]. This means that it is an important mediator of vitamin A transport and utilization [2] [7]. Since TTR passes through the blood-brain barrier in minimal concentrations, it was subsequently determined that another source of its production must exist in the CNS, with the most prominent candidate so far being the choroid plexus [7]. In the setting of genetic mutations, destabilization of the TTR tetrameric structure and subsequent degradation to dimers and monomers is thought to be the main pathophysiological mechanism, resulting in accumulation of fibrils in numerous tissues, including the heart, kidneys, eyes and the liver [2] [6]. In kidneys, it was discovered that the deposits directly inhibit the production of erythropoietin in the distal nephron, a phenomenon that presumably explains the appearance of anemia in these patients [13]. The basis of TTR binding and deposition in these tissues remains to be discovered, but presumably involves binding to glycosaminoglycans (GAGs) that are present on the cell membrane. Unstable monomers are confirmed neurotoxic substances, but their exact mechanism of damage is not understood [6] [7].


Genetic counselling of families in whom TTR mutations have been identified may be considered as a valid preventive strategy [9], but despite the fact that mutations responsible for this disease have been discovered, it is not possible to prevent their development, as the cause remains unknown.


Hereditary ATTR amyloidosis, also referred to as amlyoidogenic transthyretin amyloidosis, familial transthyretin (TTR) amyloidosis or transthyretin-related amyloidosis, is a condition resulting from transthyretin (TTR) amyloid accumulation in the liver, gastrointestinal (GI) tract, heart, kidneys and the eyes [1]. Namely, various mutations of TTR, which is coded on chromosome 18, lead to protein misfolding and abundant accumulation of amyloid fibrils in tissues. More than 100 TTR mutations have been discovered [2]. The vast majority of mutations are transferred by autosomal dominant patterns of inheritance and two forms have been recognized - Familial amyloidotic polyneuropathy (FAP) and familial amyloidotic cardiomyopathy [1]. The two most common mutations identified, V30M and V122I are responsible for the development of these two forms, respectively [6]. On the other hand, wild-type TTR mutations may be seen in patients suffering from senile cardiac amyloidosis (SCA), a condition affecting almost 25% of individuals over 80 years [5]. TTR is a thyroid-binding protein found in both plasma and cerebrospinal fluid (CSF) and it is primarily synthesized in the liver, but several extra-hepatic sites of production are identified, most likely the choroid plexus [2]. In circulation, TTR carries thyroxine (T4) and retinol and it is assumed that one of the roles are delivery of thyroxine to the central nervous system [2]. The clinical presentation may depend on the subtype. FAP is distinguished by diminished pain and temperature sensations in the lower limbs as a result of sensory polyneuropathy, together with autonomic dysfunction (inadequate sphincter control, impotence and orthostatic hypotension) and wasting [7]. Familial amyloidotic cardiomyopathy manifests as weakness, fatigue and disturbed heart conduction system, whereas proteinuria and renal insufficiency, but also anemia may be seen in all forms of the disease due to protein accumulation in the kidneys [12]. Ocular symptoms, such as glaucoma and keratoconjunctivitis are also observed [7]. An initial diagnosis can be made by obtaining a detailed patient history that might reveal familial occurrence of symptoms, but a proper physical examination and imaging studies including echocardiography or electrophysiologic studies are used for further investigation [10]. To confirm amyloidogenic transthyretin amyloidosis, a biopsy of the affected tissue with visualization of amyloid deposits is necessary. Treatment options are currently aimed at liver transplantation and management of renal disease, but novel drugs that attempt to stabilize TTR and prevent its further accumulation have been developed in recent years [6]. Despite current therapeutic options, the diagnosis carries a fatal prognosis within 10 years due to severe nervous system involvement, as well as cardiac, renal and liver failure [9]. However, appropriate therapy in early diagnosed patients carries a much better prognosis, which is why high clinical suspicion is necessary in patients suffering from undisclosed polyneuropathy or renal/cardiac disease.

Patient Information

Hereditary ATTR amyloidosis is a rare disease caused by genetic mutations that cause accumulation of transthyretin (TTR), a protein that serves as a transport molecule for thyroid hormone and constituents of vitamin A. TTR is synthesized primarily in the liver, but other sites of its production have been identified as well, including the choroid plexus (the site of cerebrospinal fluid production in the brain). In the presence of mutations on chromosome 18 that are transferred by an autosomal dominant patter of inheritance (meaning that if one parent has the disease, there is a 50% chance his/her child will have it), TTR does not fold properly and thus accumulates in various tissues. The two familial forms of this disease are known as familial amyloidotic polyneuropathy (FAP) and familial amyloidotic cardiomyopathy, but some patients may develop TTR mutations irrespective of positive family history (known as wild-type mutations), which are confirmed in senile cardiac amyloidosis (SCA). This is a condition that affects up to 25% of individuals over 80 years old. Depending on the underlying subtype, different symptoms may dominate the clinical presentation. In the setting of FAP, progressive damage of peripheral nerves responsible for pain and temperature sensation is most prominent, followed by weakness and dysfunction of the autonomic nervous system (ANS) - inadequate bowel movement, urinary incontinence and sexual impotence are the most common signs. On the other hand, familial amyloidotic cardiomyopathy may be diagnosed in patients with unexplained heart rhythm disorders. In addition, renal disease that manifesting as increased protein loss, anemia and rapidly progressive end-stage kidney failure is not uncommon for all types, while visual disturbances are also a frequent finding. The diagnosis is not made easily, as clinical finding are not that specific, but a thorough physical examination and a properly obtained patient history may reveal vital clues for further workup. Cardiac ultrasound and studies that evaluate nerve signalling should be performed. To confirm amyloidogenic transthyretin amyloidosis, a biopsy of the tissue in which TTR amyloid accumulates is necessary. Until recently, liver transplantation and management of kidney disease were the only therapeutic strategies, but novel drugs that attempt to reduce the level of TTR degradation and accumulation have been developed. Tafamidis is a drug that is able to bind to TTR and prevent its destabilization, whereas nanoparticle drugs that alter gene expression have also been synthesized. Despite available treatment strategies, the prognosis is rather poor, as the progressive nature of this disease leads to fatal outcomes within 10 years after the diagnosis. Unfortunately, many patients are undiagnosed for years due to a lack of clinical suspicion and having in mind the fact that early recognition carries a much better prognosis, physicians need to be aware of this condition in patients with unexplained nervous, cardiac and renal symptoms.



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