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

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 been associated with fATTR [9, 10].

**93**

*Neurological Manifestations of Transthyretin-Related Amyloidosis*

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 muta-

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

FAP is the most common neurological manifestation of fATTR. It is autosomal dominant, but the penetrance is variable and dependent on the type of mutation. If untreated, patients will have progressive neuropathy and disability resulting in death 10–15 years after disease onset [18]. The Val30Met mutation is the most common mutation associated with FAP, with a variable disease phenotype. Early onset disease (age < 50), which is more common in endemic regions of Japan and Portugal has a high penetrance and presents with a progressive polyneuropathy predominantly involving the small fiber nerves, which is typically manifested by loss of distal pain and temperature sensation, and progressive autonomic dysfunction; the latter includes orthostatic hypotension, neurogenic bladder, erectile dysfunction and impaired bowel function (malabsorption, diarrhea and constipation), and the presence of cardiac conduction blocks often necessitate pacemaker placement [10, 19]. On the other hand, late onset (>50 year old) phenotype, which occurs in non-endemic regions of Portugal, Sweden and Japan and sporadic cases in other parts of the world, is characterized by a low penetrance rate, male sex predominance. Late onset cases may not have significant clinical dysautonomia, and often present with a progressive distal neuropathy involving large and small fiber modalities, presenting with motor weakness and loss of vibratory and position sense early on, often with significant neuropathic pain. Autonomic dysfunction was the initial manifestation of 48% of early onset and 10% of late onset FAP in a previous study [20]. Late onset FAP is often misdiagnosed for more common entities in that age group such as idiopathic neuropathy

*DOI: http://dx.doi.org/10.5772/intechopen.84470*

tion from north-west Ireland [17].

**3.2 Neurological manifestations**

most common manifestations of some of the mutations.

*3.2.1 Familial amyloid polyneuropathy (FAP)*

**3.1 Epidemiology**
