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 . The management of asymptomatic carriers of mutated TTR is covered in more detail in the third article in this series .
In Piteå and Skelleftå, areas of northern Sweden in which TTR-FAP is endemic, the frequency of the Val30Met mutation is 2% ; however, penetrance is relatively low (1.7% at 30 years, 22% at 60 years) and far from complete (69%) by age 90 years . 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) . 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.
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].
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) . 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) . 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 .
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) .
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 , motor neuropathy , and ataxic polyneuropathy  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 .
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 . 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 . 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▪▪].
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.
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 .
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 , 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.
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) . 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.
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 .
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.
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.
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).
Financial support and sponsorship
This supplement was funded by Pfizer.
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.
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amyloidosis; epidemiology; Europe; polyneuropathy; transthyretin familial amyloid polyneuropathy
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