Transthyretin-Related Amyloidosis 

The amyloidoses are a wide range of diseases of secondary protein structure, in which a normally soluble protein forms insoluble extracellular fibril deposits, causing organ dysfunction. All types of amyloid contain a major fibril protein that defines the type of amyloid, plus minor components. Over 20 different fibril proteins have been described in human amyloidosis, each with a different clinical picture (see Amyloidosis, Overview). One such protein that forms human amyloid fibrils is transthyretin (TTR).

TTR acts as a transport protein for thyroxine in plasma. TRR also transports retinol (vitamin A) through its association with the retinol-binding protein. It circulates as a tetramer of 4 identical subunits of 127 amino acids each. TTR was once called prealbumin because it migrates anodally to albumin on serum protein electrophoresis, but this name was misleading, as TTR is not a precursor of albumin. The TTR monomer contains 8 antiparallel beta pleated sheet domains. TTR can be found in plasma and in cerebrospinal fluid and is synthesized primarily by the liver and the choroid plexus of the brain and, to a lesser degree, by the retina. Its gene is located on the long arm of chromosome 18 and contains 4 exons and 3 introns.^[1]

The systemic amyloidoses are designated by a capital A (for amyloid) followed by the abbreviation for the chemical identity of the fibril protein. Thus, for example, TTR amyloidosis is abbreviated ATTR, and amyloidosis of the immunoglobulin light chain type is abbreviated AL.

Both normal-sequence TTR and variant-sequence TTR form amyloidosis. Normal-sequence TTR forms cardiac amyloidosis in elderly people, termed senile cardiac amyloidosis (SCA). When it was recognized that SCA is often accompanied by microscopic deposits in many other organs, the alternative name senile systemic amyloidosis (SSA) was proposed. Both terms are now used.^[1]

TTR mutations accelerate the process of TTR amyloid formation and are the most important risk factor for the development of clinically significant ATTR. More than 85 amyloidogenic TTR variants cause systemic familial amyloidosis. The age at symptom onset, pattern of organ involvement, and disease course vary, but most mutations are associated with cardiac and/or nerve involvement. The gastrointestinal tract, vitreous, lungs, and carpal ligament are also frequently affected.^[1]

Amyloidogenic TTR mutations destabilize TTR monomers or tetramers, allowing the molecule to more easily attain an amyloidogenic intermediate conformation. Other unknown factors also play a role in TTR amyloid formation, as the clinical manifestations of the disease vary widely among people carrying the same TTR variant.

When the peripheral nerves are prominently affected, the disease is termed familial amyloidotic polyneuropathy (FAP). When the heart is involved heavily but the nerves are not, the disease is called familial amyloid cardiomyopathy (FAC). Regardless of which organ is primarily targeted, the general term is simply amyloidosis-transthyretin type, abbreviated ATTR.

Most variants that cause familial ATTR are rare, but a few are common in certain populations. TTR variants are written, according to convention, by the normal amino acid found at a position in the mature protein, followed by the number of the amino acid from the amino terminal end, and the variant amino acid found, using either the 3-letter or single-letter amino acid code. The most widely recognized TTR variants are as follows:

• TTR V30M: This was the first TTR variant discovered. The role of TTR in amyloidosis was first established when TTR was found in the fibrils in several kindreds with autosomal dominant amyloidosis affecting the peripheral nerves, heart, and other organs. This syndrome was first described in Portugal in the 1950s and later in Japan and Sweden.^[2] The fibrils in patients in all 3 endemic areas were found to contain TTR that carried a substitution of methionine for valine at position 30, arising from a point mutation. This variant has now been found worldwide, is the most widely studied TTR variant, and has served as a prototype for variant-sequence ATTR. The disease in the TTR V30M kindreds was termed FAP because early symptoms arose from peripheral neuropathy, but these patients actually have systemic amyloidosis, with widespread deposits often involving the heart, gastrointestinal tract, eye, and other organs.^[3]
• TTR V122I: This variant, carried by 3.9% of African Americans and over 5% of the population in some areas of West Africa, increases the risk of late-onset (after age 60 years) cardiac amyloidosis. It appears to be the most common amyloid-associated TTR variant worldwide. Affected patients usually do not have peripheral neuropathy.^[4]
• TTR T60A: This variant causes late-onset systemic amyloidosis with cardiac, and sometimes neuropathic, involvement. This variant originated in northwest Ireland and is found in Irish and Irish American patients.^[5]
• TTR L58H: Typically affecting the carpal ligament and nerves of the upper extremities, this variant originated in Germany. It has spread throughout the United States but is most common in the mid-Atlantic region.^[5]
• TTR G6S: This is the most common TTR variant, but it appears to be a neutral polymorphism not associated with amyloidosis. It is carried by about 10% of people of white European descent.^[5]

Currently, about 100 TTR variants are known, with varying geographic distributions, degrees of amyloidogenicity, and organ predisposition. Currently known TTR variants are listed in the table below.^[1] For organ involvement, the following abbreviations are used: PN = peripheral nerves, AN = autonomic nervous system, H = heart, L = liver, LM = leptomeninges, K = kidney, S = skin, E = eye, GI = gastrointestinal tract, CL = carpal ligament, and CNS = central nervous system.

Known TTR Variants (adapted from Connors et al)

(Open Table in a new window)

Genetic aspects of transthyretin-related amyloidosis

Familial ATTR is traditionally thought of as a group of autosomal-dominant diseases, but it is now known that disease expression is more complicated. The most abundant data pertain to TTR V30M; the following observations have been made:

• Variation in age of onset: The usual age of disease onset among TTR V30M gene carriers in Portugal, Brazil, and Japan is in the third to fourth decade of life. However, there are late-onset cases (as seen in Sweden) in which disease onset is in the fifth to sixth decade of life.
• Disease penetrance: In Portugal and Japan, more than 90% of TTR V30M gene carriers develop symptoms by middle age. However, in Sweden, disease penetrance is only 2%, and some V30M homozygous individuals remain asymptomatic.^[3]
• Some atypical Portuguese and Japanese kindred follow the late-onset, low-penetrance Swedish pattern.^[2]
• Some patients with no family history of amyloidosis and asymptomatic relatives with the variant gene carry the V30M variant.
• Disease onset is earlier in males than in females.^[6]
• Age of symptom onset is progressively earlier in successive generations. This feature is referred to as anticipation. Anticipation in some neurologic disorders is caused by expansion of trinucleotide repeats. However, in ATTR, this mechanism seems not to apply.

The explanation for the above observations is not well understood. Other genetic and/or environmental variables are thought to be at play. Anticipation, incomplete penetrance, and clinically sporadic cases in kindreds with unaffected allele carriers also have been observed with other TTR variants.^[5]

Normal-sequence transthyretin-related amyloidosis

In contrast to variant ATTR, normal-sequence cardiac ATTR is associated with aging, usually in the seventh and eighth decade of life. This is commonly of little or no clinical significance. On the other hand, other elderly patients with normal-sequence ATTR develop extensive, symptomatic, and even fatal cardiac ATTR.

The stimuli that lead to normal-sequence ATTR are not understood. The clinical manifestations of severe SCA are similar to those observed in familial ATTR and in cardiac amyloidosis of the immunoglobulin light chain type (AL).

Frequency

United States

The only TTR variant for which population-based prevalence studies have been conducted is TTR V122I; this variant has an allele prevalence of 0.02 (2%) in the African American population. Among African Americans, 3.9% of the population are heterozygous for this variant allele (about 1.3 million people). About 13,000 African Americans are homozygous for this variant. Limited data suggest that the latter group is at greater risk of developing clinical disease.

The other most common amyloidosis-associated TTR variants in the United States are as follows:

• TTR V30M - Also the most widespread variant worldwide
• TTR T60A - Most common in an area centered in West Virginia
• TTR L58H - Most commonly seen in Maryland but also throughout the United States
• TTR S77Y - Found in Europe and the United States
• TTR I84S - Found in an area centered in Indiana

Most other amyloid-associated TTR variants are rare. Many have been found in only one or a few families.

Cardiac ATTR amyloidosis has a progressive increase in prevalence in people older than 80 years and is seen in about 15% of autopsies. In this setting, the deposited TTR is usually of normal sequence.

International

A few amyloidosis-associated TTR variants are common in certain populations, although few data indicate population frequencies. The most common TTR variants include the following:

• TTR V30M is found throughout Europe, in North and South America, and Japan. It is most common in some areas of northern Sweden (where it is carried by more than 1% of the population), northern Portugal, and certain areas in Japan.^[3]
• TTR V122I originated in West Africa. It is carried by 3.9% of African Americans and 5% or more of the population in some areas of West Africa.^[4]

The other amyloid-associated TTR variants appear to be less common, although no firm data are available on population prevalences.

Mortality/Morbidity

Morbidity and mortality from ATTR depends on whether a TTR variant is present and, if so, which variant. Some variants cause clinical disease by age 40 years in all gene carriers and are always fatal within a few years of symptom onset. Other variants typically cause much milder, later onset disease, and some carriers of the variant genes remain asymptomatic until late in life.^[7]

Morbidity depends on the organ(s) involved. Neuropathy and cardiomyopathy are most common. The most common immediate cause of death is from cardiac failure or fatal arrhythmia.^[8]

Race

TTR variants occur in all races.

• The most common variant worldwide, TTR V122I, apparently originated in West Africa, has spread throughout that area and the Americas, and is carried by 3.9% of African Americans. Therefore, cardiac amyloidosis is more prevalent among African Americans than among people of other races in the United States.^[4]
• Other variants are documented to have originated in people of European, Japanese, and Chinese ancestry. TTR variants have probably originated in all races.^[5]

Sex

All TTR variants encoded on chromosome 18 are inherited with equal frequency in males and females. For unknown reasons, disease penetrance is greater and age of onset earlier in males than in females. Individual case reports and several small series suggest that normal-sequence cardiac ATTR is more common in males than in females, although the sex ratio is unknown.^[6]

Age

The age of onset varies widely, depending on the presence and identity of the TTR variant.

• Normal-sequence cardiac ATTR presents after age 60 years and usually after age 70 years.
• Variant-sequence ATTR presents in teenaged individuals and in people in their early 20s for the most aggressive variants and in people older than 50 years for many others.
• The average age of onset for ATTR V30M is 32 years in Japan and Portugal and 56 years in Sweden. The reason for this difference is not known.