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

Abstract

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.

Box 1

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FIGURE 1

Timeline of important milestones in the European history of TTR-FAP. EMA, European Medicines Agency; TTR, transthyretin; TTR-FAP, transthyretin familial amyloid polyneuropathy.

FIGURE 2

Location of TTR genotypes in Portugal, Germany, France, Italy and Sweden. TTR, transthyretin. Portugal: Family distribution according to region of origin. Seven families are from Madeira island (nonrepresented). Courtesy of Teresa Coelho, 2015. Germany: Geographic distribution of patients seen at the Heidelberg Amyloidosis Centre. Courtesy of Ernst Hund, 2014. France: Distribution of FAP in France. TTR Met30 Port (full black circles); TTR Met30 non Port (full red circles); TTR Tyr77 (green full square); TTR Phe77 (pink full triangles); stars: non Met30 TTR-FAP (neither Tyr77, nor Phe77; in details). In red circle, enlargement of Paris and its inner suburbs is depicted. TTR Met30 Port is mainly found in Paris region, TTR Met30 non Port is more ubiquitous. TTR Tyr77 is mainly found in northern France and TTR Phe77 in south western. Other mutations are scattered across the entire territory. Adapted from Adams et al.[22]. Italy: Distribution of TTR genotypes across Italy. Courtesy of Laura Obici, 2015. Sweden: Origin and clustering areas of the three most common mutations in Sweden. In the remaining areas of Sweden, there are sporadic cases of predominantly Val30Met, with 11 additional mutations identified. Courtesy of Ole B. Suhr, 2015.

FIGURE 3

The most frequent TTR point mutations observed across Europe. TTR, transthyretin. Data compiled from clinical experience of the European Network for TTR-FAP (ATTReuNET) in March 2014.

FIGURE 4

The referral process for TTR-FAP patients in France. FAP, familial amyloid polyneuropathy; TTR-FAP, transthyretin familial amyloid polyneuropathy. Information compiled from clinical experience of the European Network for TTR-FAP (ATTReuNET) in March 2014.