Mutations which are present in the TTR core structure reduce the stability of the protein. As a result, the TTR tetramer could separate into dimeric and monomeric forms, and these monomers coalesce by forming amyloid TTR (ATTR) aggregates (
Figure 3)
[18]. This aggregation, called amyloidogenesis, progresses to plaque formation, later depositing into tissues and neurons and inducing cytotoxicity. The different amyloidogenic diseases that present as a result were initially termed as the following: senile systemic amyloidosis (SSA), familial amyloid cardiomyopathy (FAC), and familial amyloid polyneuropathy (FAP)
[18][19]. SSA, FAC, and FAP were reported to share the same accumulation of ATTR, but the types of ATTR found were different for each disease. In the case of SSA, aggregated constituents were composed mainly of large quantities of deposited wild-type ATTR (ATTRwt) in myocardia
[20][21]. Updates in nomenclature were recently recommended by the International Society of Amyloidosis (ISA) to modify the terms SSA, FAC, and FAP to more exact definitions due to overlap in clinical presentation
[22]. SSA was renamed as wild-type amyloid TTR amyloidosis (ATTRwt amyloidosis). It usually occurs in 25% of the elderly population over 80 with higher frequency in males at 25~50: 1 ratio
[23][24]. Large amyloid deposits in the myocardia could cause congestive heart failure
[25] and ventricular hypertrophy when echocardiography showed thickened ventricular walls along with low QRS voltages from electrocardiography (ECG)
[26]. Common observable symptoms are fatigue, edema, shortness of breath, chest pain, and angina, and the severity of symptoms from these diseases may vary depending on the degree of ATTRwt deposits
[27][28][29].
FAC/FAP belong to the same pathological spectrum and differ from ATTRwt amyloidosis mainly due to ATTR mutations. In this case, ATTRv (amyloid TTR variant) refers to the mutant form of ATTR, and FAC/FAP was renamed to ATTR appended with the specific mutation that caused it (i.e., ATTRV30M) and the accompanying symptom (i.e. ATTR with cardiomyopathy)
[22]. Depending on the mutations, the hydrophobic interaction of dimer–dimer formation would vary, resulting in the instability and breakdown of the tetramers. As a result, the tendency to produce the amyloid form is enhanced and favors the development of the disease
[30]. FAP was formerly categorized into four types: FAP-I, FAP-II, FAP-III and FAP-IV, and the pathogenicity of FAP and FAC could overlap
[31][32][33]. FAP-I has since been renamed as ATTRV30M amyloidosis and is also known as the Portuguese–Swedish–Japanese type, and haplotype comparison among foci suggested common Portuguese origins among Japanese, Spanish, and Brazilian patients, while Swedish patients had entirely different haplotypic origins
[34][35]. ATTRV30M amyloidosis resulted in a wide range of symptoms such as sensory-autonomic, gastrointestinal and cardiac disturbances, impotence, and cardiomyopathy; as well as renal insufficiency in later stages of the disease
[36][37]. A study on 15 Swedish families with ATTRV30M determined through Western blot showed the type of amyloid fibril composition remained the same despite the differences of the disease age of onset. Only one family showed different types of amyloid fibril composition on two brothers with similar ages of disease onset
[38]. Despite the endemicity of the early onset form of ATTRV30M in some Portuguese, Japanese, and Swedish populations, the late onset form was shown to be more prevalent in non-endemic areas of Japan and Cyprus than previously thought, and much is still not known about its causative factors
[39][40]. Symptoms of ATTRI84S amyloidosis were similar to ATTRV30M amyloidosis, but additional sensorimotor polyneuropathy could appear late in the disease
[41]. In addition, amyloid deposits could be found in the eye, thyroid, adrenal glands, and blood vessels, leading to additional side effects from both diseases
[42][43][44][45]. Even though ATTRv amyloidosis was like ATTRwt amyloidosis in terms of disease pathomechanism, the expression of ATTRv outside cardiac tissue may lead to amyloidosis resulting in hereditary ATTR cardiomyopathy (ATTR-CM). This was described in a Danish family carrying ATTRMet
111 expressed in plasma that led to hereditary ATTR-CM (previously known as familial amyloid cardiomyopathy or FAC), whereas unafflicted members were seronegative
[46]. Patients beyond the age of 60 were reported to have hereditary ATTR-CM, and ATTRV122I and ATTRT60A could be responsible. ATTRV122I was most commonly found in 4% of African-Americans, followed by ATTRT60A in patients from United Kingdom and Ireland
[47][48][49]. The role of the non-coding variation of ATTRV122I was assessed in 4,361 unrelated African-Americans. The study showed that this allele increased 6.8-fold the risk of having ten or more outpatient surgeries. Additionally, men had a 15.2-fold higher risk of having ten or more outpatient surgeries. This non-coding variation seemed to accelerate the negative consequences associated with ATTRV122I amyloidosis
[50]. Amyloid deposits in cardiac tissues may cause a thickening of cardiac walls leading to congestive heart failure and atrial arrhythmias, and result in cardiac arrest and death
[45][51]. Carpal tunnel syndrome may manifest in the early phase of ATTRv amyloidosis and may require a great deal of attention and not simply dismissed as an unrelated symptom
[52]. More than 140 ATTRv mutations have been identified
[53] along with non-amyloidogenic mutations (
Figure 4), which may not produce amyloid, but were reported to cause functional abnormalities
in vivo [54][55]. Among non-amyloidogenic mutations, few were revealed to have a high affinity for thyroxine
[54], and rarely, alanine mutations, particularly A109T and A109V, which were described in a family with dominantly-inherited euthyroid hyperthyroxinemia
[56].