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Introduction to TTR Amyloidosis (1)
Transthyretin (TTR) is a 127 amino acid, transport protein primarily synthesized in the liver. The protein is a carrier of thyroxine and retinol (vitamin A)-retinol binding protein complex. It is the tertiary carrier of thyroxine in plasma, carrying less T4 than thyroxine-binding globulin (TBG) and albumin. In its native state TTR is a tetramer, i.e. four single chain TTR monomers form a tetrameric complex.
Transthyretin amyloidosis is caused by deposition of TTR amyloid fibrils in various tissues.
The hereditary form of transthyretin amyloidosis is caused by autosomal dominant mutations in the TTR gene. The prevailing theory for amyloid formation associated with the amyloidogenic mutations is based on the observations that changes of amino acids are associated with destabilization and dissociation of the TTR tetramer, leading to abnormally folded monomers that ultimately self-assemble to amyloid fibrils (Fig. 1). These TTR amyloid fibrils are then deposited extracellularly in various tissues. There are more than 100 reported TTR single point mutations that have been associated with hereditary transthyretin amyloidosis.
References:
- Benson, M.D., Kincaid, J.C., Muscle and Nerve. 2007; 36: 411-423.
TTR Amyloidosis with Polyneuropathy
Familial Amyloid Polyneuropathy (FAP) occurs when amyloid predominately affects the peripheral and autonomic nerves (1). It is also known as Transthyretin Familial Amyloid Polyneuropathy (TTR-FAP). V30M (substitution of methionine for valine at position 30) is the most common mutation associated with the disease.(2,3) The age of onset is typically in the third or fourth decade of life or later, depending on the mutation and the patient’s ethnic background (1,4,5,6). The main feature of TTR-FAP is progressive sensorimotor and autonomic neuropathy (1,2). Although penetrance varies greatly among geographic and ethnic foci, the outcome of TTR-FAP is variably progressive and fatal (6). The only current therapy for TTR-FAP is orthotopic liver transplantation (7).
References:
- Benson, M.D., Kincaid, J.C., Muscle and Nerve. 2007; 36: 411-423.
- Herlenius, G., Wilczek, H. E., Larsson, M., Transplantation. 2004; 77: 64-71.
- Saraiva, M.J., Hum Mutat. 2001; 17: 493-503.
- Coelho, T., Sousa, A., Lourenco, E., Ramalheira, J., J Med Genet. 1994; 31: 293-299.
- Miller, S. R., Sekijima, Y., Kelly, J. W., Laboratory Investigation. 2004; 84: 545-552.
- Coutinho, P, Martins da Silva, A., Lopes-Lima, J., et al., Amsterdam: Excerpta Medica. 1980: 88-98.
- Holmgren, G., Ericzon, B. G., Groth, C.G., Steen, L., Suhr, O., Andersen, O. et al., Lancet. 1993; 341: 1113-1116.
TTR Amyloidosis with Cardiomyopathy
TTR amyloid cardiomyopathy (TTR-CM) occurs when the heart is predominantly affected (1). In this disease, which is also known as familial amyloid cardiomyopathy (FAC), TTR amyloid fibrils infiltrate the myocardium, leading to diastolic dysfunction progressing to restrictive cardiomyopathy and heart failure (2,3). Several single point mutations in TTR have been primarily associated with TTR-CM: V20I, P24S, A45T, Gly47Val, Glu51Gly, I68L, Gln92Lys, L111M and V122I (4). One common mutation, V122I (substitution of isoleucine for valine at position 122), occurs with high frequency (prevalence of approximately 3.5%) in African-Americans.
The onset of TTR-CM related to the V122I mutation or wild-type TTR is typically occurs > 60 (5). Patients may present with carpal tunnel syndrome, which has been reported in >40% of patients with TTR-CM(7). Cardiac involvement can present with conduction system disease (sinus node or atrioventricular node dysfunction) or congestive heart failure including shortness of breath, peripheral edema, syncope, exertional dyspnea, generalized fatigue or with heart blocks. The echocardiographic findings are indistinguishable from those seen in AL (primary immunoglobulin light chain) amyloidosis and include thickened ventricular walls (concentric hypertrophy, both right and left) with a normal to small left ventricular cavity, increased myocardial echogenicity, normal or mildly reduced ejection fraction, often with evidence of diastolic dysfunction and severe impairment of contraction along the longitudinal axis, and bi-atrial dilation with impaired atrial contraction (2,3).
Unlike in AL amyloidosis, the voltage on the ECG is often normal, although low voltage may be seen despite the increased wall thickness on echocardiography. Marked axis deviation, bundle branch block and AV block is common, as is atrial fibrillation (7).
Currently there is no effective therapy available. Available treatment is aimed at symptomatic relief and includes diuretics, pacemaker placement and anti-arrhythmics (3,7,8).
References:
- Ikeda S. Cardiac amyloidosis: heterogeneous pathogenic backgrounds. Intern Med. 2004; 43:1107–14.
- O'Hara CJ, Falk RH. The diagnosis and typing of cardiac amyloidosis. Amyloid. 2003 Jun; 10(2):127-9.
- Falk RH. Diagnosis and management of the cardiac amyloidoses.Circulation. 2005 Sep 27; 112(13):2047-60. Review.
- Benson MD, Wallace MR, Tejada E, Baumann H, Page B. Hereditary amyloidosis: description of a new American kindred with late onset cardiomyopathy, Appalachian amyloid. Arthritis Rheum. 1987 Feb; 30(2):195-200.
- Jacobson DR, Pastore R, Pool S, Malendowicz S, Kane I, Shivji A, Embury SH, Ballas SK, Buxbaum JN. Revised transthyretin Ile 122 allele frequency in African-Americans. Hum Genet. 1996; 98:236–8.
- Jacobson DR, Pastore RD, Yaghoubian R, Kane I, Gallo G, Buck FS, Buxbaum JN. Variant-sequence transthyretin (isoleucine 122) in late-onset cardiac amyloidosis in black Americans. N Engl J Med. 1997; 336:466–73.
- Ng B, Connors LH, Davidoff R, Skinner M, Falk RH. Senile systemic amyloidosis presenting with heart failure: a comparison with light chain-associated amyloidosis. Arch Intern Med. 2005; 165:1425–9.
- Hesse A, Altland K, Linke RP, Almeida MR, Saraiva MJ, Steinmetz A, Maisch B. Cardiac amyloidosis: a review and report of a new transthyretin (prealbumin) variant. Br Heart J. 1993 Aug; 70(2):111-5. Review.
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THAOS - Transthyretin Amyloidosis Outcomes Survey
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