**3.1 Epidemiology**

*Amyloid Diseases*

**2. Transthyretin (TTR)**

TTR is a 127 amino acid protein, is encoded by 7 kb of DNA spanning exons 1–4 of a single gene on chromosome 18 [4]. TTR is a carrier molecule of thyroxine and vitamin A. Serum TTR is synthesized and excreted by the liver as a tetrameric structure. Other sources of local TTR synthesis include epithelial cells of the choroid plexus and the retinal pigment epithelium. TTR is however dispensable for thyroid hormone homeostasis; TTR knockout mice are euthyroid and have a normal phenotype [5, 6]. The presence of point mutations in TTR results in destabilization of the tetramere, and dissociation into amyloidogenic monomers, which misfold and self-aggregate into insoluble amyloid fibrils (**Figure 1**). Two distinct types of amyloid fibrils have been described in TTR amyloid deposits: type A, consists of C-terminal TTR fragments and full-length TTR, and type B, which only consists of full-length TTR [7]. Type A fibrils often target the heart and type B fibrils occur predominantly with neurological symptoms [8]. Every organ of an individual patient contains the same (either type A or type B) fibrils, and the composition is unchanged over time. The presence of C-terminal TTR fragments has an impact on the affinity for various tracers used for intensity of tissue Congo red staining and of noninvasive imaging of amyloid depositions using 99 m-technetium-diphosphono-propanodicarboxylic acid scintigraphy [7].

**92**

**Figure 1.**

*[from [63], with permission].*

**3. Familial transthyretin related amyloidosis (fATTR)**

been associated with fATTR [9, 10].

fATTR is a multisystem disease involving the heart (cardiomyopathy, conduction disturbances), gastrointestinal tract, kidneys, thyroid, salivary glands, eyes, peripheral and central nervous system. More than 130 pathological mutations have

*Amyloid formation by TTR requires rate-limiting tetramer dissociation to a pair of folded dimers, which then quickly dissociate into folded monomers. Partial unfolding of the monomers yields the aggregation-prone amyloidogenic intermediate. The amyloidogenic intermediate can misassemble to form a variety of aggregate morphologies, including spherical oligomers, amorphous aggregates, and fibrils. Tafamidis binding to the TTR tetramer (upper left, see text below) dramatically slows dissociation, thereby efficiently inhibiting aggregation* 

There is a marked variation in the prevalence and age of onset of ATTR in different countries, partly as a result of variation in the type of pathogenic mutation. fATTR is endemic in northern Portugal, Sweden and Japan, but sporadically occurs everywhere in the globe, with estimated number of about 5–10,000 patients worldwide [11]. The global prevalence is estimated at 0.87–1.1 per million; prevalence in Europe and Japan are estimated at 1/100,000 and 1 per million individuals respectively [12, 13]. The age of onset has a wide range, between 10s and 90s [10]. In Japan, the age of onset is bimodal, with early (30–40 year old) and late (60s) onset peaks [10]; on the other hand, the age of onset is more likely to be early (25–35 years old) in Portugal and late in Sweden [14, 15]. The most common mutation associated with familial amyloid polyneuropathy (FAP) is Val30Met mutation (replacement of valine with methionine at position 30), with endemic spots in northern Portugal (where its prevalence is estimated at 1/538), Sweden, Japan, and Brazil. On the other hand, the most common mutation in the US metropolitan areas is Val122Ile (isoleucine is substituted for valine at position 122); this mutation almost exclusively occurs in patients of African descent and has he allele prevalence of 0.0173; i.e. 3.43% of African Americans carry at least one copy of the mutant gene [16]. Val122Ile related fATTR generally has a cardiac phenotype. In the UK population the majority of patients have the T60A missense mutation where tyrosine is replaced by adenine at position 60. This has been traced to a single founder mutation from north-west Ireland [17].

## **3.2 Neurological manifestations**

Depending on the mutation in TTR, the phenotype can be cardiologic, neurologic, or mixed. Neurological manifestations, particularly polyneuropathy are the most common manifestations of some of the mutations.
