Secondary Logo

Journal Logo

Sixty years of transthyretin familial amyloid polyneuropathy (TTR-FAP) in Europe

where are we now? A European network approach to defining the epidemiology and management patterns for TTR-FAP

Parman, Yesima; Adams, Davidb; Obici, Laurac; Galán, Lucíad; Guergueltcheva, Velinae; Suhr, Ole B.f; Coelho, Teresag from the European Network for TTR-FAP (ATTReuNET)

doi: 10.1097/WCO.0000000000000288
SUPPLEMENT ARTICLE
Open
SDC

Purpose of review Transthyretin familial amyloid polyneuropathy (TTR-FAP) is a highly disabling, life-threatening disease characterized by progressive sensorimotor and autonomic neuropathy. The profile of the disease across Europe is inadequately understood at present.

Recent findings The incidence and clinical presentation of TTR-FAP varies widely within Europe, with early and late-onset disease subtypes. In those regions in which the disease is endemic (Portugal, Sweden, Cyprus, and Majorca), a Val30Met substitution in the TTR gene is the predominant genetic cause, whereas in the rest of Europe, cases of TTR-FAP are mainly sporadic with genetic heterogeneity. Current management strategies lack cohesion and patients can experience years of misdiagnosis and suboptimal treatment.

Summary The article aims to disseminate the findings and recommendations from two recent meetings of the European Network for TTR-FAP (ATTReuNET), a panel comprising representatives from 10 European countries (Bulgaria, Cyprus, France, Germany, Italy, the Netherlands, Portugal, Spain, Sweden, and Turkey) with expertise in the diagnosis and management of TTR-FAP. We explore the epidemiology and genetic mark of TTR-FAP across Europe and assess current management strategies, with a view to developing an alternative framework – a networked approach to disease management with an emphasis on collaboration and sharing of best practice.

aDepartment of Neurology, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey

bCHU Bicêtre, Université Paris-Sud, Paris, France

cAmyloidosis Research and Treatment Center, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy

dServicio de Neurología, Hospital Clínico San Carlos, Madrid, Spain

eUniversity Hospital Sofiamed, Sofia, Bulgaria

fDepartment of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden

gHospital Santo António, Centro Hospitalar do Porto, Porto, Portugal

Correspondence to Yesim Parman, Department of Neurology, Istanbul Medical Faculty, Istanbul University, Millet Cad., Capa, 34390 Istanbul, Turkey. Tel: +90 212 414 2477; e-mail: parmany@istanbul.edu.tr

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (www.co-neurology.com).

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc-nd/4.0

Back to Top | Article Outline

INTRODUCTION

Amyloid neuropathies are severe and life-threatening illnesses characterized by endoneurial amyloid deposits [1,2]. As a rare disease, the European prevalence of amyloidosis (including secondary amyloidosis) was estimated at 47/100 000 in 2014 [3]. Transthyretin familial amyloid polyneuropathy (TTR-FAP), also known as transthyretin (TTR) amyloidosis, is the most common form of amyloid neuropathy [1]. It is characterized by the extracellular deposition of amyloid fibrils composed of TTR, a 127 amino acid plasma transport protein for thyroxine and vitamin A that is produced predominantly by the liver [4,5].

Clinically, TTR-FAP manifests as progressive and irreversible sensorimotor and autonomic neuropathy [6], starting typically with sensory disturbances in the toes and moving rapidly upward to more proximal parts of the legs. By the time the knees are reached, the hands have usually become involved [6]. The natural course of TTR-FAP can be classified into three stages: I (sensory polyneuropathy), II (progressive walking disability), and III (wheelchair bound or bedridden) [7], with a life expectancy ranging from 7.3 to 11 years from onset [8,9].

The European Commission recommends that all European Union (EU) member countries have strategic plans in place for responding to rare diseases. This European Project for Rare Diseases National Plans Development (EUROPLAN) initiative acknowledges the importance of access to high-quality care for patients with rare diseases, and recognizes shortcomings in the existing management frameworks of many European countries [10]. The implementation of rare disease plans for TTR-FAP is not yet available across all of Europe. With this in mind, we established the European Network for TTR-FAP (ATTReuNET), comprising 15 experts for TTR-FAP from 10 European countries (Bulgaria, Cyprus, France, Germany, Italy, the Netherlands, Portugal, Spain, Sweden, and Turkey), including nine National Reference Centres (NRCs: highly specialized hospital and university teams distributed throughout the country). The panel met in November 2012 and March 2014 to share their collective experience regarding the current epidemiology, diagnosis, and management of TTR-FAP. Data were collected through the use of a semistructured questionnaire and the major findings were assimilated into the current supplement (see Table S1 within Supplementary Materials for full questionnaire, http://links.lww.com/CONR/A37).

The article discusses pan-European differences in the epidemiology and clinical presentation of TTR-FAP and highlights shortcomings of current management approaches. By proposing a framework for the development of clinical networks across European healthcare systems, we hope to facilitate communication, foster collaboration, and, ultimately, offer patients with TTR-FAP, regardless of nationality, a standardized and effective management strategy.

Box 1

Box 1

Back to Top | Article Outline

METHODOLOGY

This article is based on data derived from two sources: a systematic literature review, and outcomes from roundtable meetings of the ATTReuNET that took place in November 2012 and March 2014. The aim of the current article, together with the other two within this series, is to disseminate the major findings from the meetings and to align these with data available from the published literature base.

Prior to the meeting in March 2014, 15 members representing 10 European countries from the ATTReuNET completed a semistructured questionnaire. The responses were used to guide the live discussion, with a focus on five main areas: epidemiology and local structure of care; diagnosis; management and funding; follow-up care of both patients and asymptomatic carriers; and the overall patient experience. The overarching objective of the meetings was to achieve a first consensus regarding the current epidemiology and genetic basis of TTR-FAP, to identify the limitations of existing diagnostic and treatment approaches and to propose alternative management strategies.

Electronic database searches (NCBI PubMed) formed the basis of the literature search within the time frame (1952 to December 2014). Key search terms included ‘transthyretin familial amyloid polyneuropathy,’ ‘familial amyloid polyneuropathy,’ ‘transthyretin amyloidosis,’ ‘TTR-FAP,’ ‘TTR-FAP and Europe,’ and ‘TTR-FAP and Bulgaria/Cyprus/France/Germany/Italy/the Netherlands/Portugal/Spain/Sweden/Turkey’.

Back to Top | Article Outline

The history of transthyretin familial amyloid polyneuropathy within Europe

The first cases of familial amyloid polyneuropathy (FAP) were described in northern Portugal in 1952 [11▪], and by 1994, 1233 cases had been diagnosed at the Centro de Estudos de Paramiloidose in Porto [12]; Sweden recorded its first case of TTR-FAP in 1965 [13].

Figure 1 shows the timeline of important milestones in the European history of TTR-FAP [9,11▪,13–29]. Europe can be regarded as a pioneer in the field, given that as a continent it is credited with the introduction of genetic screening for TTR-FAP and the approval of the first oral treatment for the disease in 2011 [29]. Furthermore, the first NRC for FAP was established in France in 2005 [22].

FIGURE 1

FIGURE 1

Back to Top | Article Outline

The prevalence and genetic basis of transthyretin familial amyloid polyneuropathy in Europe

Within Europe, the incidence of TTR-FAP is highly variable. There are large areas in Portugal and Sweden in which the disease is endemic, that is, localized to one small area, with a traceable family history with a single genetic mutation [2,30▪▪]. Smaller endemic foci have been identified in Cyprus and Majorca [31,32]. In the rest of Europe, cases of TTR-FAP are mainly sporadic or scattered, with no common genetic cause [22,26,33]. However, recently, an increasing number of TTR-FAP cases have been reported in Germany, Bulgaria, and Turkey.

Back to Top | Article Outline

Prevalence

In particular regions of Portugal and Sweden where TTR-FAP is endemic, disease prevalence ranges from 1 in 1000 to 1 in 10 000 people [34,35]. In 2003, the prevalence of FAP in Cyprus was 3.72/100 000 people, while the incidence was estimated at 0.69/100 000/year [32]. Using data derived from the ATTReuNET questionnaire, we observed that Portugal has the highest number of diagnosed, symptomatic cases (∼2000) and more than 500 diagnosed asymptomatic carriers of the disease (Table 1). The gene carrier frequency for methionine-for-valine substitution at position 30 (Val30Met) in the northern parts of Sweden has been recently estimated at 2% in the endemic areas of Västerbotten (i.e. ∼700 carrier individuals) [38]. However, the low penetrance of the trait and the often late onset of symptoms lead to a lower prevalence of the disease [39].

Table 1

Table 1

Beyond these endemic regions, the incidence of TTR-FAP is much lower, and there are no published estimates for prevalence rates across Europe. Of the nonendemic regions, France, Italy, and Germany have the most confirmed cases of TTR-FAP. A prevalence of 8.8/1 000 000 has been reported in Sicily [40].

Back to Top | Article Outline

Genetics

FAP is transmitted as an autosomal dominant trait arising from mutations of the TTR gene [4,5,30▪▪]. TTR-FAP has both genotypic and phenotypic heterogeneity [2,4], with more than 100 different mutations identified [41▪]. The nature of the mutation impacts greatly on patient outcomes, with different mutations ascribed varying patterns of clinical presentation, age of onset, and disease progression.

The most common mutation, first identified in the 1980s, is a Val30Met in the amyloid fibril protein [42]. The Val30Met point mutation accounts for 50% of TTR-FAP mutations worldwide [30▪▪]. Within Europe, the mutation is believed to have arisen independently in Portugal and Sweden [4,43] (where it is responsible for most, but not all, cases), as well as Italy [44]. Furthermore, Val30Met is the only mutation so far identified in endemic regions of Cyprus and Majorca [31,32].

In nonendemic countries, such as France, Italy, and Germany, there is genetic heterogeneity. In France alone, more than 29 mutations of the TTR gene have been identified up to 2012; TTR Val30Met mutation is the most common, occurring in 62% of cases [22]. This may relate to a large immigration from Portugal to France in the early 1970s [45]. Point mutations at TTR residue Ser77 (Tyr77 and Phe77) account for the remaining 11.8 and 6.2% of French cases, respectively [22]. Figure 2 shows the geographical localization of TTR genotypes in France, Germany, Italy, Portugal, and Sweden, and Figure 3 uses data gathered from our survey to depict the three most common point mutations observed in each of the participating countries. The most common mutation in Europe, with the exception of Bulgaria, is Val30Met, but there is heterogeneity around the second-most prevalent mutation (Figure 3).

FIGURE 2

FIGURE 2

FIGURE 3

FIGURE 3

Back to Top | Article Outline

Penetrance

Penetrance refers to the probability that a genetic trait will be expressed in people who carry the gene mutation. If penetrance is less than 100%, or incomplete, carriers of the gene may remain asymptomatic, yet their children can be affected clinically [4]. The management of asymptomatic carriers of mutated TTR is covered in more detail in the third article in this series [46].

In Piteå and Skelleftå, areas of northern Sweden in which TTR-FAP is endemic, the frequency of the Val30Met mutation is 2% [38]; however, penetrance is relatively low (1.7% at 30 years, 22% at 60 years) and far from complete (69%) by age 90 years [39]. Yet the penetrance is significantly higher with a risk of earlier onset when the mutation is inherited from the mother rather than from the father [39,47▪▪]. Penetrance can also vary geographically, with the Portuguese population showing much higher penetrance of the Val30Met mutation during middle age (80% at 50 years) compared with the French population (18% at 50 years) [48]. The impact of penetrance on age at onset of TTR-FAP and the clinical presentation of the disease have important implications in terms of patient management.

Back to Top | Article Outline

Clinical presentation of transthyretin familial amyloid polyneuropathy

The clinical presentation of TTR-FAP is governed by an interplay between a number of factors, including genotype and geographical origin of the patient, regional variation, penetrance of the gene mutation, and age at onset of symptoms. Consequently, there is a wide spectrum of phenotypes associated with TTR-FAP [2,8,49,50].

Back to Top | Article Outline

Age at onset of disease-related symptoms

The phenotype of TTR-FAP is associated with sex and age of onset, whereby male patients with a late onset (age >50 years) have increased risk of developing cardiomyopathy and heart failure [51▪,52,53]. Figure S1, http://links.lww.com/CONR/A35 shows how the mean age at onset of TTR-FAP-related symptoms varies among European countries. The average age of onset of disease observed in Portugal is 33.5 years, with 87% of patients developing symptoms before age 40 years (n = 1233) [35]. Within the same patient cohort, women were found to have a significantly later onset than men (33.7 vs 29.0 years; P < 0.001) [35]. The age at disease onset tends to be later in Sweden (56–57 years) [54,55], a trend mirrored in other countries of nonendemic TTR-FAP, including Germany and Italy [56,57]. In a small cohort from the Netherlands (n = 7), age at first symptom appearance ranged from 33 to 69 years [58].

Our survey has shown that in the countries represented by the ATTReuNET, the age range of patients with TTR-FAP is broad and varies from the second to the ninth decades of life (Table 1), except Bulgaria and Turkey, which estimate an older and comparatively narrower window (44–63 years and 21–66 years, respectively). Onset of symptoms can be described as bimodal, with one peak in the third to fourth decade of life (early onset) and another distinct peak in the sixth decade of life (late onset) [6].

Back to Top | Article Outline

Clinical features of transthyretin familial amyloid polyneuropathy

Within most of the regions in which it is endemic (Portugal, Cyprus, and Majorca), TTR-FAP often occurs before age 40 years (early onset), with progressive sensory-motor and autonomic neuropathy, leading to cachexia and eventually death within, on average, 10.8 years of disease onset [7,48,59]. Length-dependent small-fibre sensory-motor polyneuropathy with life-threatening autonomic dysfunction is a distinguishing feature of TTR-FAP in these regions, but frequently, there is also cardiac (conduction disturbance), renal, and ocular involvement [60▪▪].

In nonendemic areas, and in endemic regions of Sweden, the onset of disease-related symptoms tends to be later in life, from age 50 years onward [54,55], and a male predominance for the late-onset TTR-FAP has been observed [55,61]. Neuropathy tends to affect all fibres and may closely resemble chronic inflammatory demyelinating polyneuropathy [61,62]. Upper limb onset [63], motor neuropathy [64], and ataxic polyneuropathy [56] are all possible presentations of late-onset disease. Typically, sensory and motor neuropathy symptoms of upper and lower extremities occur, associated with mild autonomic symptoms [61].

The wider variation in genotype among patients with late-onset disease (∼40 variants) confers a broader spectrum of clinical features, which continues to evolve the phenotypic profile of the disease. For example, the TTR Gly47Glu mutation has been associated with mild peripheral neuropathy and cardiac involvement [58]. Compared with the TTR Val30Met mutation, TTR Glu89Gln is associated with higher left ventricular mass index, lower left ventricular ejection fraction, shorter E-wave deceleration time, more severe cardiomyopathy, and higher risk of major cardiovascular events [65]. Among TTR Val30Met patients, the occurrence of cardiomyopathy is generally age-related, presenting predominantly in late-onset male patients [51▪,52].

The high variability in age at symptom onset may serve to complicate the diagnostic process, but the importance of early diagnosis in TTR-FAP patients cannot be overemphasized, particularly as late-onset TTR-FAP often has a more severe course [60▪▪].

Back to Top | Article Outline

Existing structures and resources

The ATTReuNET panel acknowledge that while the management of patients differs widely across Europe, there are certain similarities in the overall patient experience, or journey. Overall, our findings indicate a clear need for the consolidation and coordination of expertise.

Back to Top | Article Outline

Barriers to optimal management of transthyretin familial amyloid polyneuropathy

One robust theme to emerge from panel discussions was delay in diagnosis, with the majority of patients tending to see between three and four physicians before they receive an accurate diagnosis of TTR-FAP (Table S2, http://links.lww.com/CONR/A37). Only representatives from Portugal, Sweden, and Cyprus reported that patients generally consulted fewer than two physicians before diagnosis. Delay in diagnosis is most pronounced in areas where TTR-FAP is not endemic and when there is no positive family history, including in endemic areas [2,2,12]. Questionnaire data show that diagnosis was generally quicker in patients with a positive family history (∼2 years), but could be up to 5 years in the general patient cohort (Table S2, http://links.lww.com/CONR/A37).

The availability of TTR gene testing further facilitates the speed of diagnosis, particularly in endemic regions. However, in areas where there is greater genotypic variation, the diagnostic process can become confused by similarities with other types of neuropathy and incomplete sensitivity of biopsies used to identify amyloid deposits. It may also be the case that biopsy and genetic testing facilities are not widely accessible in all countries. Genetic testing for Val30Met may have limited diagnostic impact and reliability when applied with populations with low-penetrance variants and high gene frequency, such as northern Sweden [38,39].

The ability to recognize phenotypic variations of TTR-FAP is an important skill that requires appropriate training. Questionnaire data presented in Figure S2, http://links.lww.com/CONR/A36 describe the ambulatory status of patients at diagnosis and show that in most countries, the majority of patients have no mobility difficulties when they first present to the physician.

Even after diagnosis, a lack of standardized treatment strategies may negatively impact patient outcomes. Treatment approaches and the availability of oral therapeutic agents may vary even within regions of the same country. Many funding bodies do not provide financial coverage for diagnosis and management of TTR-FAP while the patient is still able-bodied. The next article in this series presents the expert group consensus on diagnosis, treatment, and management of TTR-FAP [66].

Back to Top | Article Outline

A network approach for transthyretin familial amyloid polyneuropathy

NRCs are a means to ensure equity of access to early and appropriate diagnosis, treatment, and care, and to eliminate regional disparities in treatment approaches. Most of the 10 countries involved with the ATTReuNET have at least one defined NRC (Table S3, http://links.lww.com/CONR/A37). The establishment of NRCs can encourage collaboration and the sharing of experience between different centres and motivate the teams working within them. A defined network also lends credibility and weight to the disease in proposals to public authorities for disease funding, such as coordinated research programmes. A multifaceted disease such as TTR-FAP lends itself well to this approach and serves to benefit patients. Existing initiatives include clinical guideline recommendations for diagnosis and management [4], as well as an international patient database to gather outcome information for a fuller clinical picture of the disease [67▪]. Moving forward, the panel recognizes the importance of drawing upon the experiences of similar networks for other rare inherited diseases (e.g. Charcot–Marie–Tooth disease and Duchenne muscular dystrophy).

A network has many benefits, including the potential for an increase in the number of newly diagnosed cases at the national level, and increased satisfaction among specialists in regional centres (e.g. education and independence) and from patients and their families. In addition, patients who are cared for by a multidisciplinary team at their regional centre will benefit from access to the best available recommended therapies.

Back to Top | Article Outline

The French model (the national plan for rare diseases)

The French National Network for TTR-FAP has been pivotal in improving the diagnosis of new cases and raising the quality of care for patients with the disease at the national level. The panel agreed that the system represents a good working example on which to base future initiatives in other countries. The National Plan for Rare Diseases in France was first established in 2004 with 131 NRCs certified by the French Health Ministry to ensure equity of access to diagnosis, treatment, and care; one of them concerned FAP [68,69]. These centres were selected because of the characteristics of the disease, including severe chronic pain, motor problems, sensory deficit, disturbance of autonomic function, and life-threatening disease.

The mission statements of the national plan included the facilitation of diagnosis and strategy for therapeutic, psychological, and social support; the definition and differentiation of protocols for care; the coordination of research; and the provision of training to healthcare professionals, patients, and their families, to direct and coordinate networks of healthcare professionals (medical and social) [68]. Networked treatment centres are both multicentric and multidisciplinary, bringing together all aspects of patient care; including, for example, neurology, cardiology, liver transplant, nephrology, ophthalmology, physiotherapy, and pain management. The referral process in France, under the network approach, is summarized in Figure 4. As well as fostering collaboration between medical experts and thereby guiding public health policy, the French network also liaises with the Association Française Contre L’Amylose, a TTR-FAP patient support group.

FIGURE 4

FIGURE 4

The development of a French network for TTR-FAP was facilitated by the labelling of 10 centres for neuromuscular diseases in the same way as the national plan for rare diseases (2005–2008). These centres are distributed throughout the country and include specialists for rare peripheral neuropathies who are considered as regional referents and correspondents for FAP. The network approach allows for the education of physicians about FAP, to update their knowledge and ensure they have the support of other necessary specialists (e.g. cardiologists and geneticists).

To meet the specifications of the French Health Ministry, the French NRC for FAP (NNERF) organized the first conference for TTR-FAP in 2009, inviting professionals, patients, and families to discuss and debate issues surrounding the disease and management options. In 2010, the NNERF launched a website (http://www.nnerf.org), and in 2012, the characteristics of French patients recruited with the help of the network were published [22].

Back to Top | Article Outline

Benefits associated with a European network

The existing network among Italian NRCs has also contributed significantly to improved diagnosis and awareness of TTR-FAP. The initiative has also enabled gathering of information on the natural history of the disease in nonendemic areas and promoted participation in clinical trials. In Spain, a consensus group is currently working to establish common, national guidelines for the care and treatment of TTR-FAP. Sweden is also in the process of developing a national network. Portugal has two multidisciplinary centres, in Lisbon and Porto, that are recognized by patients, families, and healthcare personnel as being the most appropriate places of assistance for these patients. In 2012, the Portuguese Ministry of Health designated them as the only prescribers of oral medication fully reimbursed by the Portuguese National Health System. The development of formally recognized NRCs is now occurring and should be in place before the end of the year. These two centres have been recently formally recognized as the NRCs for FAP in Portugal.

Through the hosting of two national advisory board meetings of neurologists specializing in TTR-FAP, progress has been made in Turkey, a country currently lacking a multidisciplinary approach to treatment. Increased disease awareness and diagnosis of new patients has been a key consequence of these meetings. The use of global patient registries is essential to chart the natural history of rare diseases like TTR-FAP, and to this end, the THAOS (Transthyretin Amyloidosis Outcomes Survey) registry has recently been established [67▪].

The benefits associated with a network approach to TTR-FAP management are summarized in Table 2. It is anticipated that raising awareness of TTR-FAP, not just among healthcare professionals but among patients and their families as well, will lead to increased rates of screening and improved rates of detection. Earlier diagnosis is the key to the more effective management of patients.

Table 2

Table 2

Back to Top | Article Outline

CONCLUSION

TTR-FAP is a rare, yet devastating, systemic disorder with predominant neurologic involvement that persists throughout Europe, with high genotypic variability. Fibre length-dependent sensory-motor and autonomic neuropathy are neurological hallmarks of TTR-FAP, although additional neuropathic, gastrointestinal, cardiovascular, renal, and ocular symptoms all contribute to the phenotypic heterogeneity of the disease. Given these differences, it follows that patient management strategies lack standardization at the regional, national, and international level. The formation of the ATTReuNET is the first step in an ongoing transformative process seeking to standardize disease management across Europe. A collaborative, fully networked approach to TTR-FAP management will permit the sharing of resources and expertise and will ultimately allow all patients access to the highest standards of clinical care. The immediate 5-year aim is to network existing NRCs from the countries represented in the current panel, with a view to then expanding into other countries through the creation of new NRCs. In 10 years, it is hoped that the network will serve all European countries affected by TTR-FAP. The group may also consider application for EU funding for epidemiological and genetic studies, and to support advocacy group development for empowerment of patients and families.

Back to Top | Article Outline

Acknowledgements

The authors would like to acknowledge Anna Palmer of PAREXEL for provision of writing assistance during the development of this article, with funding provided by Pfizer. Members of the ATTReuNET who provided country-specific information for this article were David Adams [CHU Bicêtre (APHP), Université Paris-Sud, Paris, France]; Juan Buades (Servicio de Medicina Interna, Hospital Son Llatzer, Palma de Mallorca, Spain); Josep M. Campistol (Instituto Clínico de Nefrología y Urología ICNU, Barcelona, Spain); Teresa Coelho (Hospital Santo António, Centro Hospitalar do Porto, Porto, Portugal); Lucía Galán (Servicio de Neurología, Hospital Clínico San Carlos, Madrid, Spain); Ivailo Tournev (Department of Neurology, Medical University – Sofia, and Department of Cognitive Science and Psychology, New Bulgarian University, Sofia, Bulgaria); Velina Guergueltcheva (University Hospital Sofiamed, Sofia, Bulgaria); Bouke P. Hazenberg (University Medical Center Groningen, University of Groningen, Groningen, the Netherlands); Ernst Hund (Universität Heidelberg, Heidelberg, Germany), Jan B. Kuks (Department of Neurology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands); Theodore Kyriakides (Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus); Laura Obici (Amyloidosis Research and Treatment Center, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy); Yesim Parman (Istanbul University, Istanbul, Turkey); Michel S. Slama (Hôpital Antoine Beclere, Université Paris-Sud, Clamart, France); and Ole B. Suhr (Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden).

Back to Top | Article Outline

Financial support and sponsorship

This supplement was funded by Pfizer.

Back to Top | Article Outline

Conflicts of interest

Medical writing support was provided by PAREXEL and funded by Pfizer. The interpretation, discussion, and publication by the authors are independent of the funding organization, which sought no control over the content of the subsequent publications. Authors did not receive payment for any article within this supplement. Y.P. participates in a clinical study financed by Alnylam Pharmaceuticals, has received payment honoraria for lecturing by Pfizer and has received financial support from Pfizer to attend scientific meetings. D.A. received honoraria from Pfizer for organizing and participating in symposia and master classes, received funding from Alnylam for participating in scientific congresses, and is the principal investigator in clinical trials sponsored by Alnylam and Isis Pharmaceuticals. L.O. received financial support from Alnylam to attend scientific meetings, received honoraria from Pfizer for lectures, and is the principal investigator in a clinical trial sponsored by Alnylam. L.G. has received honoraria from Pfizer as a consultant and for several lectures. V.G. participates in a clinical study financed by Alnylam Pharmaceuticals; has received payment honoraria for lecturing by Pfizer, Sanofi-Genzyme, and Aquachim JSCo; and has served as expert for Pfizer and Sanofi-Genzyme. O.B.S.'s department received honoraria from Pfizer for his contributions to educational activities and his services as clinical investigator in clinical trials; he is a member of the THAOS registry sponsored by Pfizer, and he participates as clinical investigator in clinical trials sponsored by Alnylam. T.C. received financial support to attend scientific meetings from Pfizer, Alnylam, and Isis Pharmaceuticals, and received honoraria from Pfizer for work on a speaker's bureau.

Back to Top | Article Outline

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest
Back to Top | Article Outline

REFERENCES

1. Adams D. Hereditary and acquired amyloid neuropathies. J Neurol 2001; 248:647–657.
2. Adams D, Lozeron P, Lacroix C. Amyloid neuropathies. Curr Opin Neurol 2012; 25:564–572.
3. Orphanet Report Series – Rare Disease Collection. Prevalence of rare diseases: bibliographic data. Orphanet. http://www.orpha.net/orphacom/cahiers/docs/GB/Prevalence_of_rare_diseases_by_alphabetical_list.pdf. [Accessed 11 November 2014]
4. Ando Y, Coelho T, Berk JL, et al. Guideline of transthyretin-related hereditary amyloidosis for clinicians. Orphanet J Rare Dis 2013; 8:31.
5. Barreiros AP, Galle PR, Otto G. Familial amyloid polyneuropathy. Dig Dis 2013; 31:170–174.
6. Hund E. Familial amyloidotic polyneuropathy: current and emerging treatment options for transthyretin-mediated amyloidosis. Appl Clin Genet 2012; 5:37–41.
7. Coutinho P, da Silva AM, Lima JL, Barbosa AR. Glenner GG, e Costa PP, de Freitas AF. Forty years of experience with type 1 amyloid neuropathy: review of 483 cases. Amyloid and amyloidosis. Amsterdam: Excerpta Medica; 1980. 88–98.
8. Koike H, Tanaka F, Hashimoto R, et al. Natural history of transthyretin Val30Met familial amyloid polyneuropathy: analysis of late-onset cases from nonendemic areas. J Neurol Neurosurg Psychiatry 2012; 83:152–158.
9. Adams D. Recent advances in the treatment of familial amyloid polyneuropathy. Ther Adv Neurol Disord 2013; 6:129–139.
10. European Commission. The European Project for Rare Diseases National Plans Development (EUROPLAN). EUROPLAN website. http://www.europlanproject.eu/. [Accessed 1 January 2015]
11▪. Andrade C. A peculiar form of peripheral neuropathy; familiar atypical generalized amyloidosis with special involvement of the peripheral nerves. Brain 1952; 75:408–427.

Historical paper including the first description of FAP.

12. Coelho T, Sousa A, Lourenco E, Ramalheira J. A study of 159 Portuguese patients with familial amyloidotic polyneuropathy (FAP) whose parents were both unaffected. J Med Genet 1994; 31:293–299.
13. Andersson R. Familial amyloidosis with polyneuropathy. A clinical study based on patients living in northern Sweden. Acta Med Scand Suppl 1976; 590:1–64.
14. De Bruyn RS, Stern RO. A case of the progressive hypertrophic polyneuritis of Dejeerine and Sottas, with pathological examination. Brain 1929; 52:84–107.
15. Munar-Ques M, Costa PP, Saraiva MJ, et al. [Familial type I (Portuguese form) amyloidotic polyneuropathy in Majorca. Study using the TTR (Met30) genetic marker]. Med Clin (Barc) 1988; 91:441–444.
16. Benson MD, Cohen AS. Generalized amyloid in a family of Swedish origin. A study of 426 family members in seven generations of a new kinship with neuropathy, nephropathy, and central nervous system involvement. Ann Intern Med 1977; 86:419–424.
17. Saraiva MJ, Birken S, Costa PP, Goodman DS. Family studies of the genetic abnormality in transthyretin (prealbumin) in Portuguese patients with familial amyloidotic polyneuropathy. Ann N Y Acad Sci 1984; 435:86–100.
18. Salvi F, Montagna P, Plasmati R, et al. Restless legs syndrome and nocturnal myoclonus: initial clinical manifestation of familial amyloid polyneuropathy. J Neurol Neurosurg Psychiatry 1990; 53:522–525.
19. Skare J, Yazici H, Erken E, et al. Homozygosity for the met30 transthyretin gene in a Turkish kindred with familial amyloidotic polyneuropathy. Hum Genet 1990; 86:89–90.
20. Sarafov S. Transthyretin familial amyloid polyneuropathy in Bulgaria. International Symposium on Liver Transplantation in Familial Amyloidotic Polyneuropathy. Rio de Janerio, Brazil.
21. Schonenberger M, Schultze HE, Schwick G. [A prealbumin of human serum]. Biochem Z 1956; 328:267–284.
22. Adams D, Lozeron P, Theaudin M, et al. Regional difference and similarity of familial amyloidosis with polyneuropathy in France. Amyloid 2012; 19 (Suppl 1):61–64.
23. Said G, Ropert A, Faux N. Length-dependent degeneration of fibers in Portuguese amyloid polyneuropathy: a clinicopathologic study. Neurology 1984; 34:1025–1032.
24. Costa PP, Figueira AS, Bravo FR. Amyloid fibril protein related to prealbumin in familial amyloidotic polyneuropathy. Proc Natl Acad Sci U S A 1978; 75:4499–4503.
25. Saraiva MJ, Sherman W, Goodman DS. Presence of a plasma transthyretin (prealbumin) variant in familial amyloidotic polyneuropathy in a kindred of Greek origin. J Lab Clin Med 1986; 108:17–22.
26. Adams D, Reilly M, Harding AE, Said G. [Demonstration of genetic mutation in most of the amyloid neuropathies with sporadic occurrence]. Rev Neurol (Paris) 1992; 148:736–741.
27. Holmgren G, Ericzon BG, Groth CG, et al. Clinical improvement and amyloid regression after liver transplantation in hereditary transthyretin amyloidosis. Lancet 1993; 341:1113–1116.
28. Lopez Andreu FR, Munar-Ques M, Parrilla P, et al. [Liver transplantation for the treatment of type I familial amyloidotic polyneuropathy]. Med Clin (Barc) 1993; 101:581–583.
29. Business Wire. Pfizer's Vyndaqel® (tafamidis) first therapy approved in the European Union for the rare and fatal neurodegenerative disease transthyretin familial amyloid polyneuropathy (TTR-FAP). Business Wire. http://www.businesswire.com/news/home/20111117005505/en/Pfizer%E2%80%99s-Vyndaqel%C2%AE-tafamidis-Therapy-Approved-European-Union#.VNnde-aUeSo. [Accessed 1 January 2015]
30▪▪. Plante-Bordeneuve V, Said G. Familial amyloid polyneuropathy. Lancet Neurol 2011; 10:1086–1097.

Excellent review and guide for the clinician about different aspects of FAP.

31. Buades Reines J, Ripoll Vera T, Uson Martin M, et al. Epidemiology of transthyretin-associated familial amyloid polyneuropathy in the Majorcan area: Son Llàtzer Hospital descriptive study. Orphanet J Rare Dis 2014; 9:29.
32. Dardiotis E, Koutsou P, Papanicolaou EZ, et al. Epidemiological, clinical and genetic study of familial amyloidotic polyneuropathy in Cyprus. Amyloid 2009; 16:32–37.
33. Holt IJ, Harding AE, Middleton L, et al. Molecular genetics of amyloid neuropathy in Europe. Lancet 1989; 1:524–526.
34. A rare disease with a global presence. Recognizing TTR-FAP. http://www.recognizingttr-fap.com/epidemiology. [Accessed 1 January 2015]
35. Sousa A, Coelho T, Barros J, Sequeiros J. Genetic epidemiology of familial amyloidotic polyneuropathy (FAP)-type I in Povoa do Varzim and Vila do Conde (north of Portugal). Am J Med Genet 1995; 60:512–521.
36. How the EU works. European Union Web site. http://europa.eu/about-eu/facts-figures/living/index_en.htm. [Accessed 8 September 2015]
    37. One World Nations Online: Turkey. Nations Online website. http://www.nationsonline.org/oneworld/turkey.htm. [Accessed 8 September 2015]
      38. Olsson M, Jonasson J, Cederquist K, Suhr OB. Frequency of the transthyretin Val30Met mutation in the northern Swedish population. Amyloid 2014; 21:18–20.
      39. Hellman U, Alarcon F, Lundgren HE, et al. Heterogeneity of penetrance in familial amyloid polyneuropathy, ATTR Val30Met, in the Swedish population. Amyloid 2008; 15:181–186.
      40. Mazzeo A, Russo M, Di Bella G, et al. Transthyretin-related familial amyloid polyneuropathy (TTR-FAP): a single-center experience in Sicily, an Italian endemic area. J Neuromuscul Dis 2015; 2:S39–S48.
      41▪. Benson MD, Kincaid JC. The molecular biology and clinical features of amyloid neuropathy. Muscle Nerve 2007; 36:411–423.

      Excellent review focusing on clinical aspects of the disease as well as the first perspectives on the pathomechanisms and possible treatment strategies just before the treatment era.

      42. Saraiva MJ, Birken S, Costa PP, Goodman DS. Amyloid fibril protein in familial amyloidotic polyneuropathy, Portuguese type. Definition of molecular abnormality in transthyretin (prealbumin). J Clin Invest 1984; 74:104–119.
      43. Zaros C, Genin E, Hellman U, et al. On the origin of the transthyretin Val30Met familial amyloid polyneuropathy. Ann Hum Genet 2008; 72:478–484.
      44. Iorio A, De Angelis F, Girolamo M, et al. Most recent common ancestor of TTR Val30Met mutation in Italian population and its potential role in genotype-phenotype correlation. Amyloid 2015; 22:73–78.
      45. Baganha M. Pinto AC. Portuguese emigration after World War II. Modern Portugal. Palo Alto: SPOSS; 1998. 189–205.
      46. Obici L, Kuks JB, Buades J, et al. Recommendations for presymptomatic genetic testing and management of individuals at risk for hereditary transthyretin amyloidosis. Curr Opin Neurol 2015; (In press).
      47▪▪. Lemos C, Coelho T, Alves-Ferreira M, et al. Overcoming artefact: anticipation in 284 Portuguese kindreds with familial amyloid polyneuropathy (FAP) ATTRV30 M. J Neurol Neurosurg Psychiatry 2014; 85:326–330.

      Excellent article focusing on genetic anticipation and intrafamilial correlations in a large cohort.

      48. Plante-Bordeneuve V, Carayol J, Ferreira A, et al. Genetic study of transthyretin amyloid neuropathies: carrier risks among French and Portuguese families. J Med Genet 2003; 40:e120.
      49. Adams D, Theaudin M, Cauquil C, et al. FAP neuropathy and emerging treatments. Curr Neurol Neurosci Rep 2014; 14:435.
      50. Ando Y, Araki S, Ando M. Transthyretin and familial amyloidotic polyneuropathy. Intern Med 1993; 32:920–922.
      51▪. Suhr OB, Lindqvist P, Olofsson BO, et al. Myocardial hypertrophy and function are related to age at onset in familial amyloidotic polyneuropathy. Amyloid 2006; 13:154–159.

      Important study drawing attention to the fact that cardiac involvement is more prominent in late-onset cases.

      52. Hornsten R, Pennlert J, Wiklund U, et al. Heart complications in familial transthyretin amyloidosis: impact of age and gender. Amyloid 2010; 17:63–68.
      53. Rapezzi C, Riva L, Quarta CC, et al. Gender-related risk of myocardial involvement in systemic amyloidosis. Amyloid 2008; 15:40–48.
      54. Holmgren G, Costa PM, Andersson C, et al. Geographical distribution of TTR Met30 carriers in northern Sweden: discrepancy between carrier frequency and prevalence rate. J Med Genet 1994; 31:351–354.
      55. Sousa A, Andersson R, Drugge U, et al. Familial amyloidotic polyneuropathy in Sweden: geographical distribution, age of onset, and prevalence. Hum Hered 1993; 43:288–294.
      56. Dohrn MF, Rocken C, De Bleecker JL, et al. Diagnostic hallmarks and pitfalls in late-onset progressive transthyretin-related amyloid-neuropathy. J Neurol 2013; 260:3093–3108.
      57. Di Iorio G, Sanges G, Cerracchio A, et al. Familial amyloidotic polyneuropathy: description of an Italian kindred. Ital J Neurol Sci 1993; 14:303–309.
      58. Haagsma EB, Hawkins PN, Benson MD, et al. Familial amyloidotic polyneuropathy with severe renal involvement in association with transthyretin Gly47Glu in Dutch, British and American-Finnish families. Amyloid 2004; 11:44–49.
      59. Adams D, Samuel D, Goulon-Goeau C, et al. The course and prognostic factors of familial amyloid polyneuropathy after liver transplantation. Brain 2000; 123 (Pt 7):1495–1504.
      60▪▪. Adams D, Cauquil C, Theaudin M, et al. Current and future treatment of amyloid neuropathies. Expert Rev Neurother 2014; 14:1437–1451.

      Article focusing on new treatment options that have opened up a revolutionary path in treating FAP.

      61. Koike H, Misu K, Ikeda S, et al. Type I (transthyretin Met30) familial amyloid polyneuropathy in Japan: early- vs late-onset form. Arch Neurol 2002; 59:1771–1776.
      62. Mariani L, Lozeron P, Theaudin M, et al. Genotype-phenotype correlation and course of TTR familial amyloid polyneuropathies in France. Ann Neurol 2015; doi: 10.1002/ana.24519. Epub 2015 September 15.
      63. Theaudin M, Yalo B, Mincheva Z, et al. Multifocal neuropathy with upper limb onset as a frequent phenotype in familial amyloid polyneuropathy in France. Neurology 2013; 80(Meeting Abstracts 1): P05.065.
      64. Lozeron P, Lacroix C, Theaudin M, et al. An amyotrophic lateral sclerosis-like syndrome revealing an amyloid polyneuropathy associated with a novel transthyretin mutation. Amyloid 2013; 20:188–192.
      65. Rapezzi C, Perugini E, Salvi F, et al. Phenotypic and genotypic heterogeneity in transthyretin-related cardiac amyloidosis: towards tailoring of therapeutic strategies? Amyloid 2006; 13:143–153.
      66. Adams D, Suhr OB, Hund E, et al. First European consensus for diagnosis, management, and treatment of transthyretin familial amyloid polyneuropathy. Curr Opin Neurol 2015; (In press).
      67▪. Plante-Bordeneuve V, Suhr OB, Maurer MS, et al. The Transthyretin Amyloidosis Outcomes Survey (THAOS) registry: design and methodology. Curr Med Res Opin 2013; 29:77–84.

      Article describing the design and methodology of the first and unique database (THAOS), which is open to all clinicians following FAP patients and carriers.

      68. Ministry of Health and Social Protection. French National Plan for Rare Diseases 2005–2008. Orpha net. http://www.orpha.net/actor/EuropaNews/2006/doc/French_National_Plan.pdf. [Accessed 1 January 2015]
      69. Aymé S, Rodwell C. 2012 report on the state of the art of rare disease activities in Europe of the European Union Committee of Experts on Rare Diseases. 2012. http://www.eucerd.eu/wp-content/uploads/2012/09/2012ReportStateofArtRDActivitiesFR.pdf. [Accessed 8 September 2015]
      Keywords:

      amyloidosis; epidemiology; Europe; polyneuropathy; transthyretin familial amyloid polyneuropathy

      Supplemental Digital Content

      Back to Top | Article Outline
      Copyright © 2016 Wolters Kluwer Health, Inc. All rights resereved.