Transthyretin-Related Familial Amyloid Polyneuropathy (TTR-FAP): A Single-Center Experience in Sicily, an Italian Endemic Area

Abstract

Background: Familial amyloid polyneuropathy related to transthyretin gene (TTR-FAP) is a life-threatening disease transmitted as an autosomal dominant trait. Val30Met mutation accounts for the majority of the patients with large endemic foci especially in Portugal, Sweden and Japan. However, more than one hundred other mutations have been described worldwide. A great phenotypic variability among patients with late- and early-onset has been reported.

Objective: To present a detailed report of TTR-FAP patients diagnosed in our tertiary neuromuscular center, in a 20-year period.

Methods: Clinical informations were gathered through the database of our center.

Results: The study involved 76 individuals carrying a TTR-FAP mutation. Three phenotypes were identified, each corresponding to a different TTR variant, homogeneous within and heterogeneous between each other: i) Glu89Gln mutation, characterised by 5th - 6th decade onset, neuropathy as presenting symptoms, early heart dysfunction, cardiomyopathy as major cause of mortality followed by dysautonomia and cachexia; ii) Phe64Leu mutation, marked by familiarity reported in one-half of cases, late onset, severe peripheral neuropathy, moderate dysautonomia and mild cardiomyopathy, death for wasting syndrome; iii) Thr49Ala mutation, distinguished by onset in the 5th decade, autonomic disturbances as inaugural symptoms which may remain isolated for many years, moderate polyneuropathy, cachexia as major cause of mortality followed by cardiomyopathy.

Conclusions: This survey highlighted a prevalence of 8.8/1,000,000 in Sicily Island. Good knowledge of the natural history of the disease according to different TTR mutations allow clinicians to optimise multiprofessional care for patients and to offer carriers a personalized follow-up to reveal first signs of the disease.

Keywords: FAP; Familial amyloid polyneuropathy; Italy; TTR; amyloidosis; cardiomyopathy; dysautonomia; epidemiology; transthyretin.

Fig.1

Geographical distribution of TTR-FAP patients families in Sicily according to different mutations.

Fig.2

Clinical findings in an asymptomatic Glu89Gln carrier, showing higher sensitivity of ^99mTc-DPD scintigraphy in detecting heart involvement. She was followed every two years with neurographic, autonomic and cardiological tests. Asterisk indicates a pathological result. At first control in 2006, at 46 years of age, Charcot-Marie-Tooth neuropathy score (CMTNS), compound autonomic dysfunction test (CADT), inter-ventricular septum thickness (IVST) and ejection fraction (EF) were normal; cardiac MRI and ^99mTc-DPD scintigraphy were also normal; the latter showed no significant cardiac uptake (score 0) and normal indexes of semiquantitative analysis (HR, WBR, H/WB ratio; see Materials and Methods). In 2008, CMTNS, CADT, IVST, EF and cardiac MRI were still normal. On the contrary, ^99mTc-DPD scan showed a mild cardiac uptake (score 1) confirmed by some pathological semiquantitative indexes. After two years, in 2010, there was a mild peripheral and autonomic nerve involvement at CMTNS and CADT, IVST was increased, cardiac MRI showed a minimal signal hyperintensity (arrow), and scintigraphy worsened to score 2.

Fig.3

Estimated penetrance curve according to mutation.