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TTR Amyloidosis with Cardiomyopathy

TTR-CM

TTR amyloidosis is short for transthyretin amyloidosis, a disease that is characterized by cardiomyopathy and/or slowly progressive peripheral sensorimotor and/or autonomic neuropathy. Other organs, such as meninges, kidneys, and eyes, may also be involved. In patients suffering from TTR amyloidosis with cardiomyopathy (ATTR-CMP), the accumulation of amyloid fibrils derived from either wild-type or variant transthyretin provokes diastolic dysfunction and heart failure, leading to death within a few years after the diagnosis. ATTR-CMP is most likely underdiagnosed.


Presentation

Late-onset restrictive cardiomyopathy is the cardinal feature of ATTR-CMP, irrespective of the underlying genotype. In patients suffering from wild-type ATTR-CMP or ATTR-CMP due to TTR variant p.V142I, restrictive cardiomyopathy may even be the only symptom [1]. It should be noted, though, that isolated ATTR-CMP is a rather rare phenotype of TTR amyloidosis. The disease is more commonly associated with polyneuropathy - and the interested reader is referred to the respective entry on this platform -, but mixed phenotypes have also been described. Patients may show symptoms and signs of ATTR-CMP and polyneuropathy, and they may have impaired renal function or suffer from vision loss [1] [2]. Patients with wild-type ATTR-CMP frequently develop carpal tunnel syndrome before showing any symptoms of cardiac disease [3].

Initial symptoms of cardiac involvement may comprise reduced tolerance to exercise, dyspnea on exertion, and progressive fatigue [4]. These symptoms are related to an increased left ventricular wall thickness, as revealed by sonography. The cardiac septum may also be thickened, and patients may erroneously be diagnosed with hypertrophic cardiomyopathy. Electrocardiography may confirm conduction blocks and arrhythmia, with ATTR-CMP-related arrhythmia often proving resistant to therapy [2] [5]. Electrocardiographic voltage seems to depend on the underlying genotype: Certain types of ATTR-CMP are related to low voltage in the limb leads, but normal or increased voltage have also been observed [2].

Advanced amyloidotic cardiomyopathy is accompanied by symptoms of congestive heart disease, including right heart failure with jugular vein distention, hepatomegaly, abdominal fullness, and peripheral edema [6]. Patients tend to lose weight and eventually succumb to their disease.

Weakness
  • Symptoms Symptoms may include: peripheral neuropathy: limb weakness and pain, loss of sensation autonomic neuropathy: disturbances of bowel, bladder and blood pressure and sexual dysfunction heart failure – symptoms result from stiffening of the heart[ttramyloidosis.uk]
  • Buildup of amyloid in the heart muscle can cause weakness and lead to heart failure and death. In some cases, people may also experience nerve pain. Symptoms usually begin at 50 or 60 years of age. It exists in hereditary and non-hereditary forms.[gethealthystayhealthy.com]
  • Degeneration progresses to larger nerve fibers resulting in muscle atrophy, weakness and difficulty walking.[thaos.net]
  • , pain, and/or impaired sensation; autonomic dysfunction, often manifesting as sexual or urinary dysfunction [2] Carpal ligament deposits: Weakness and paresthesias of one or both hands (eg, variant TTR L58H, normal-sequence TTR); localized symptomatic[emedicine.medscape.com]
Asymptomatic
  • , MYH7, MYPN, NEBL, NEXN, NKX2-5, PLN, PRDM16, RAF1, RBM20, RYR2, SCN5A, SGCD, TAZ, TBX20, TCAP, TMPO, TNNC1, TNNI3, TNNT2, TPM1, TTN, TTR, TXNRD2, VCL Clinical Utility: Confirmation of a clinical diagnosis in symptomatic patients Risk assessment of asymptomatic[genedx.com]
  • Hereditary ATTR-CMP is generally considered an autosomal dominant disorder, but asymptomatic carriers of amyloidogenic TTR variants have occasionally been described.[symptoma.com]
  • In inherited cardiac TTR-cardiomyopathy, the typical clinical picture of cardiovascular involvement ranges from asymptomatic atrioventricular and bundle branch block to severe and rapidly progressive heart failure owing to the significant restrictive[thaos.net]
  • […] of amyloidosis and asymptomatic relatives with the variant gene carry the V30M variant.[emedicine.medscape.com]
Fatigue
  • In early stages of the disease, patients may claim reduced tolerance to exercise, premature fatigue, and dyspnea. Advanced ATTR-CMP is associated with abdominal fullness, leg edema, and jugular vein distention.[symptoma.com]
  • Patients usually exhibit symptoms of congestive heart failure, including: Shortness of breath Labored breathing during exercise Peripheral swelling ( edema caused by a buildup of fluid in the lower limbs) Fainting ( syncope ) Generalized fatigue The mutation[pfizer.com]
  • They may include: shortness of breath, sometimes just after mild exertion palpitations and abnormal heart rhythms, most frequently atrial fibrillation or atrial flutter leg swelling (oedema) weight loss nausea fatigue dizziness and collapse (syncope or[ttramyloidosis.uk]
  • These unstable, misfolded proteins building up in the myocardium can lead to cardiomyopathy and symptoms of heart failure, including dyspnea, fatigue, orthostatic hypotension, and syncope.[tctmd.com]
  • […] involvement is often identified with the presence of conduction system disease ( sinus node or atrioventricular node dysfunction) and/or congestive heart failure , including shortness of breath, peripheral edema , syncope , exertional dyspnea , generalized fatigue[en.wikipedia.org]
Medication Noncompliance
  • She had previous multiple admissions for hypertensive crisis attributed to medication noncompliance. On admission, she was hypoxic and in hypertensive crisis with a blood pressure of 290/112 mmHg.[pubs.sciepub.com]
Leg Edema
  • Advanced ATTR-CMP is associated with abdominal fullness, leg edema, and jugular vein distention. Affected individuals may also suffer from arrhythmia. Within years, ATTR-CMP causes congestive heart failure and leads to death.[symptoma.com]
  • Support stockings may be recommended for patients with leg edema (swelling).[ttrstudy.com]
Dyspnea
  • In early stages of the disease, patients may claim reduced tolerance to exercise, premature fatigue, and dyspnea. Advanced ATTR-CMP is associated with abdominal fullness, leg edema, and jugular vein distention.[symptoma.com]
  • These unstable, misfolded proteins building up in the myocardium can lead to cardiomyopathy and symptoms of heart failure, including dyspnea, fatigue, orthostatic hypotension, and syncope.[tctmd.com]
  • Cardiac involvement is often identified with the presence of conduction system disease ( sinus node or atrioventricular node dysfunction) and/or congestive heart failure , including shortness of breath, peripheral edema , syncope , exertional dyspnea[en.wikipedia.org]
  • One serious adverse event (SAE) of dyspnea deemed unrelated to study drug was observed in one actively-treated subject (3%) and SAEs of atrial fibrillation, congestive heart failure, and cellulitis were observed in two placebo-treated subjects (12%).[globenewswire.com]
  • He reported exertional dyspnea and worsening peripheral edema over the previous two months.[elsevier.pt]
Exertional Dyspnea
  • Cardiac involvement is often identified with the presence of conduction system disease ( sinus node or atrioventricular node dysfunction) and/or congestive heart failure , including shortness of breath, peripheral edema , syncope , exertional dyspnea[en.wikipedia.org]
  • He reported exertional dyspnea and worsening peripheral edema over the previous two months.[elsevier.pt]
Exertional Dyspnea
  • Cardiac involvement is often identified with the presence of conduction system disease ( sinus node or atrioventricular node dysfunction) and/or congestive heart failure , including shortness of breath, peripheral edema , syncope , exertional dyspnea[en.wikipedia.org]
  • He reported exertional dyspnea and worsening peripheral edema over the previous two months.[elsevier.pt]
Abdominal Fullness
  • Advanced amyloidotic cardiomyopathy is accompanied by symptoms of congestive heart disease, including right heart failure with jugular vein distention, hepatomegaly, abdominal fullness, and peripheral edema.[symptoma.com]
Heart Failure
  • Additionally, patients should be provided conventional treatment for heart failure while respecting their specific needs.[symptoma.com]
  • Symptoms include the usual signs and symptoms associated with heart failure, such as shortness of breath and peripheral (e.g., ankle) edema. What are the challenges in diagnosing TTR-CM? TTR-CM is typically diagnosed by heart failure specialists.[cathlabdigest.com]
  • failure with at least one of the following: History of hospitalization for heart failure Clinical evidence of heart failure (signs or symptoms of volume overload or elevated intracardiac pressures) with past or current need for diuretic use Evidence[wikijournalclub.org]
  • In contrast to the rapid progression of heart failure in AL amyloidosis, SSA results in slowly progressive heart failure.[jamanetwork.com]
  • Therefore, we present a suspected case of ATTR amyloidosis in an African American female with heart failure and macroglossia. 2.[pubs.sciepub.com]
Heart Block
  • block. [6] [7] Unfortunately, echocardiographic findings are indistinguishable from those seen in AL amyloidosis , and include thickened ventricular walls ( concentric hypertrophy , both right and left) with a normal-to-small left ventricular cavity,[en.wikipedia.org]
  • block, as well as bundle branch block (ATTR more so than AL). 30 The valves are usually thickened, often associated with mild to moderate regurgitation.[mdedge.com]
  • Calcium-channel blockers and digoxin are potentially toxic. 6 The high incidence of progressive heart block in some amyloid subtypes suggests a relative contraindication to beta-blocker use, at least in the absence of regular ECG monitoring. 39 Chemotherapy[ecrjournal.com]
  • It is also our practice to recommend prophylactic pacemaker placement for TTR cardiac amyloidosis patients with symptoms of presyncope and a high degree of heart block (for example, first-degree AV block with right bundle and left anterior fascicular[ahajournals.org]
Heart Block
  • block. [6] [7] Unfortunately, echocardiographic findings are indistinguishable from those seen in AL amyloidosis , and include thickened ventricular walls ( concentric hypertrophy , both right and left) with a normal-to-small left ventricular cavity,[en.wikipedia.org]
  • block, as well as bundle branch block (ATTR more so than AL). 30 The valves are usually thickened, often associated with mild to moderate regurgitation.[mdedge.com]
  • Calcium-channel blockers and digoxin are potentially toxic. 6 The high incidence of progressive heart block in some amyloid subtypes suggests a relative contraindication to beta-blocker use, at least in the absence of regular ECG monitoring. 39 Chemotherapy[ecrjournal.com]
  • It is also our practice to recommend prophylactic pacemaker placement for TTR cardiac amyloidosis patients with symptoms of presyncope and a high degree of heart block (for example, first-degree AV block with right bundle and left anterior fascicular[ahajournals.org]
Jugular Venous Distention
  • Heart failure was defined as jugular venous distention with or without peripheral edema and/or the presence of radiographic features of congestive heart failure.[jamanetwork.com]
Leg Pain
  • I find having a regular leg and feet massage eases my leg pains and stiffness. Keep your legs and feet always moisturised. Carry out daily hand exercise to keep them working.[amyloidosis.org.uk]
Visual Impairment
  • Patients may not relate carpal tunnel syndrome, nephritic syndrome, or visual impairment to their heart condition, but the treating physician should be able to do so and voice a suspicion of cardiac amyloidosis.[symptoma.com]
  • Some patients also develop vitreous amyloid deposition that leads to visual impairment (oculoleptomeningeal amyloidosis).[malacards.org]
  • Leptomeningeal amyloidosis aka oculoleptomeningeal amyloidosis affects predominantly the central nervous system, sometimes combined with visual impairment.[genedx.com]
  • Individuals with leptomeningeal amyloidosis show CNS signs and symptoms including: dementia, psychosis, visual impairment, headache, seizures, motor paresis, ataxia, myelopathy, hydrocephalus, or intracranial hemorrhage.[pharmaceuticalintelligence.com]
Blurred Vision
  • vision, blindness, protein loss in the urine, kidney failure, goiter (thyroid swelling), etc.[ttrstudy.com]
Meningism
  • Other organs, such as meninges, kidneys, and eyes, may also be involved.[symptoma.com]
  • When associated with vitreous amyloid deposits, leptomeningeal amyloidosis is known as familial oculolepto-meningeal amyloidosis (FOLMA).[pharmaceuticalintelligence.com]

Workup

Patients should be queried for a possible family history of cardiac disease, death due to cardiac failure, or even diagnoses of ATTR-CMP. Certain mutations are predominantly found in high-risk kindreds, suggesting founder effects. Nevertheless, about half of ATTR-CMP patients have no family history at all of cardiac disease [2] [4]. The late onset of symptoms, limited penetrance, and a non-hereditary etiology of the disease may all contribute to an inconspicuous family anamnesis.

With regard to the patient's own medical history, particular attention should be paid to such disorders known to precede or accompany ATTR-CMP. Patients may not relate carpal tunnel syndrome, nephritic syndrome, or visual impairment to their heart condition, but the treating physician should be able to do so and voice a suspicion of cardiac amyloidosis [6].

The identification of the amyloid type is a prerequisite for treatment planning. In this context, the differentiation between light chain amyloidosis and TTR amyloidosis is particularly challenging. Neither sonography nor electrocardiography allow for the distinction of amyloid types, and patients should be referred for gadolinium-enhanced magnetic resonance imaging and/or bone scintigraphy with 99mTc-DPD. Characteristic findings are global or patchy subendocardial late gadolinium enhancement and myocardial uptake of 99mTc-DPD, respectively [5]. These imaging techniques increasingly replace the current gold standard of diagnosis, which is endomyocardial biopsy, an invasive procedure that may be difficult to carry out in the elderly [7]. Congo red staining of biopsy specimens may corroborate the presence of amyloid deposits, and positive results should entail immunohistochemical analyses with antibodies selective for transthyretin amyloid to confirm the type of amyloid protein involved in the disease [5] [6].

Both diagnostic imaging and histological analyses should be complemented by genetic studies to clarify whether amyloid deposits comprise wild-type or variant transthyretin. While homozygosity for wild-type TTR can be shown by means of gel electrophoresis, the identification of gene variants requires the TTR gene to be sequenced [6].

Right Bundle Branch Block
  • Half of the patients with SSA had right bundle branch block compared with only 1 of the 16 nonpaced patients with AL amyloidosis ( P .01).[jamanetwork.com]
Ventricular Hypertrophy
  • Clues to the diagnosis include ventricular "hypertrophy" seen on echocardiography with inappropriately low electrical voltages on electrocardiogram (ECG) (see below).[acc.org]
  • Additional Information Cardiomyopathies are generally characterized by weakening and impaired contractile function of the myocardium that leads to ventricular hypertrophy or dilation.[labcorp.com]
  • Cardiac amyloidosis usually manifests in the sixth decade of life with progressive left ventricular hypertrophy and restrictive cardiomyopathy.[genedx.com]
  • [Epub ahead of print] BACKGROUND A part from common genetic causes related to sarcomeric genes mutations, Hypertrophic cardiomyopathy (HCM) encompasses a heterogenous group of disorders that are associated with left ventricular hypertrophy, yet genetically[escardio.org]
  • Electrocardiogram demonstrated sinus tachycardia (104 bpm), left ventricular hypertrophy, and ST elevations in anterolateral leads. Chest radiograph showed bilateral consolidations and worsening pulmonary congestion.[pubs.sciepub.com]

Treatment

Transthyretin is mainly produced in the liver, and orthotopic liver transplantation eliminates more than 95% of abnormal, amyloidogenic transthyretin from the circulation of patients with hereditary TTR amyloidosis [8]. For a long time, liver transplantation has been considered the only curative treatment of TTR amyloidosis, and it has usually been carried out in patients with early-onset disease. ATTR-CMP, however, is generally diagnosed beyond the age of 70 years, and advanced cardiac involvement may require additional heart transplantation. What's more, liver transplantation has been described to provoke a paradoxical acceleration of cardiac amyloid deposition [8]. The risks of the procedure thus outweigh the potential benefits of liver transplantation in these patients, and other treatment options must be explored. Similarly, liver transplantation is not a viable approach to wild-type ATTR-CMP [5].

Recent advances in the treatment of TTR amyloidosis give some hope to those suffering from ATTR-CMP [2] [5]:

  • Small interfering RNAs like Revusiran may suppress the expression of the TTR gene. Revusiran has been shown to lower serum levels of wild-type and variant transthyretin by >85% in ATTR-CMP patients.
  • Antisense oligonucleotides like ISIS-TTRrx may be administered to inhibit the translation of transthyretin, thereby decreasing the overall amyloid load and delaying disease progression.
  • Other drugs are developed that aim at the stabilization of the tetrameric transthyretin molecule and the reduction of amyloid deposition, or the dissolution of the amyloid matrix. Tafamidis meglumine and diflunisal, as well as doxycycline plus tauroursodeoxycholic acid and the anthracycline 4'-iodo-4'-deoxy-doxorubicin shall be mentioned in this context.

These treatment strategies are currently tested in clinical trials, many of which have yielded promising results. Nevertheless, controlled trials in ATTR-CMP patients are still pending, and none of the aforementioned compounds has yet been approved for the therapy of ATTR-CMP.

Additionally, patients should be provided conventional treatment for heart failure while respecting their specific needs. Because ATTR-CMP patients tend to be hypotensive and may have impaired renal function, medication limiting the heart's ability to adjust myocardial contractility and beat rate according to activity or demand should be avoided [6]. Conditions like atrial fibrillation are accompanied by increased risks of thrombus formation and warrant the administration of anticoagulants, and arrhythmic patients may require a pacemaker [2].

Prognosis

ATTR-CMP follows a progressive course and is universally fatal, and there are little differences in the prognoses of patients diagnosed with non-hereditary or hereditary ATTR-CMP. With regard to the former, median survival times of five years have been reported, and death occurs at a median age of 81 years. For hereditary ATTR-CMP due to TTR variant p.V142I, the median survival time from diagnosis has been reported to be 33 months, with patients dying at a median age of 78 years [1].

Etiology

ATTR-CMP may refer to non-hereditary and hereditary types of TTR amyloidosis:

  • Non-hereditary ATTR-CMP has formerly been designated as senile systemic amyloidosis and is related to the deposition of native or wild-type transthyretin [2]. It is currently considered an age-related disorder whose causes remain unknown.
  • Hereditary ATTR-CMP, by contrast, is caused by mutations in the TTR gene that result in the synthesis and deposition of variant transthyretin. About 140 variants of TTR have been described, 130 of which are amyloidogenic. The underlying mutation strongly affects the phenotype of the patient: The most common phenotype associated with variant TTR is familial amyloid polyneuropathy, while isolated familial amyloid cardiomyopathy is a rare disease [1]. Still, the understanding of genotype-phenotype correlations remains incomplete, and an exhaustive list of mutations leading to ATTR-CMP cannot be provided. Variant p.V142I has been related to ATTR-CMP, as have variants p.V40I, p.E62D, and p.S43N, among others [1]. Hereditary ATTR-CMP is generally considered an autosomal dominant disorder, but asymptomatic carriers of amyloidogenic TTR variants have occasionally been described [1] [6].

Epidemiology

The majority of patients with wild-type ATTR-CMP are Caucasian males, who are most commonly diagnosed during their eighth decade of live [1]. Females may be affected, too, but only account for about 2% of the patients [2]. Even though autopsy studies confirmed the presence of wild-type transthyretin deposits in about 25% of people aged 85 years and older, this type of ATTR-CMP is rarely confirmed, supporting the hypothesis that it is highly underdiagnosed [9].

TTR variant p.V142I, presumably the most common cause of hereditary ATTR-CMP, is mostly carried by patients of African ancestry. Indeed, the prevalence of TTR variant p.V142I has been estimated at >3 % in people of African descent [10]. The patients' median age at the time of diagnosis is 76 years, although homozygosity may provoke an earlier onset of cardiac dysfunction [1].

In general, reported incidence and prevalence rates are increasing. This fact is generally attributed to improvements in the diagnosis of ATTR-CMP and does most likely not reflect any change in disease demographics.

Sex distribution
Age distribution

Pathophysiology

ATTR-CMP may or may not be related to mutations in the TTR gene and the synthesis of abnormal transthyretin. Changes in the conformational structure of the protein result in the dissociation of the native tetramer, misfolding, misassembly, and the aggregation of insoluble amyloid fibrils [5]. These amyloid fibrils are deposited extracellularly and interfere with organ function mainly due to their physical presence; they compress, obstruct, and hinder local blood circulation. However, intermediates such as protofibrils and soluble oligomers may also mediate cytotoxic effects. The latter depend on the underlying genotype and are of different severity [2].

Prevention

The causes of wild-type ATTR-CMP are poorly understood, so no recommendations can be given to prevent late-onset cardiac disease due to transthyretin depositions. With regard to hereditary ATTR-CMP, families known to harbor amyloidogenic variants of the TTR gene may benefit from genetic counseling. This particularly applies to those kindreds suffering from early-onset disease with devastating and widespread amyloidosis and reduced life expectancy, which account for a small minority of ATTR-CMP patients.

Summary

Amyloidoses are a group of disorders characterized by the aggregation and extracellular deposition of a specific protein. More than two dozen different amyloid fibril proteins have been identified in humans, and the nature of the amyloid precursor protein is pivotal for the classification of the disease. Transthyretin is one of those proteins, and its accumulation in different organ systems provokes distinct types of transthyretin amyloidosis [5].

Transthyretin amyloidoses may predominantly affect the heart, causing ATTR-CMP or familial amyloid cardiomyopathy, the nervous system, as observed in patients with familial amyloid polyneuropathy, or other organs. All these types of the disease are associated with diminished stability of transthyretin tetramers, which may or may not be caused by mutations in the TTR gene. Patients may carry amyloidogenic variants of the gene, or they may experience the consequences of age-related modifications of transthyretin. Accordingly, they are diagnosed with hereditary ATTR-CMP or wild-type ATTR-CMP.

Patient Information

Transthyretin is mainly produced in the liver and fulfills a variety of functions in the human body, e.g., assisting in the transport of thyroid hormones and vitamin A, which is essential for vision. Transthyretin may undergo conformational changes, either due to inherited mutations in the TTR gene or age-related modifications, and may form insoluble amyloid fibrils that accumulate in the extracellular compartment. This is a space-occupying process associated with the compression and obstruction of adjacent structures, whose function may be limited in the course of the disease. Transthyretin amyloid is preferentially deposited in the heart, nervous system, and eyes, and patients who present with cardiac disease due to transthyretin amyloidosis are diagnosed with TTR amyloidosis with cardiomyopathy (ATTR-CMP). It should be noted that multiple organ systems may be affected, and patients may develop neuropathies, such as carpal tunnel syndrome, before manifesting signs and symptoms of heart disease.

The cardinal symptom of ATTR-CMP is heart failure. In early stages of the disease, patients may claim reduced tolerance to exercise, premature fatigue, and dyspnea. Advanced ATTR-CMP is associated with abdominal fullness, leg edema, and jugular vein distention. Affected individuals may also suffer from arrhythmia. Within years, ATTR-CMP causes congestive heart failure and leads to death. Despite intense research efforts, curative treatment is not yet available. Patients are provided symptomatic treatment to maintain life quality, and, if at all possible, may be enrolled in clinical trials on drugs that limit the synthesis of transthyretin, stabilize its native conformation, or favor the dissolution of abnormal amyloid fibrils.

References

Article

  1. Rowczenio D, Quarta CC, Fontana M, et al. Analysis of the TTR gene in the investigation of amyloidosis: A 25-year single UK center experience. Hum Mutat. 2019; 40(1):90-96.
  2. Dubrey S, Ackermann E, Gillmore J. The transthyretin amyloidoses: advances in therapy. Postgrad Med J. 2015; 91(1078):439-448.
  3. Sekijima Y, Uchiyama S, Tojo K, et al. High prevalence of wild-type transthyretin deposition in patients with idiopathic carpal tunnel syndrome: a common cause of carpal tunnel syndrome in the elderly. Hum Pathol. 2011; 42(11):1785-1791.
  4. Molina OG, Judge D, Campbell W, Chahal H, Mugmon M. Transthyretin cardiac amyloidosis: an under-diagnosed cause of heart failure. J Community Hosp Intern Med Perspect. 2014; 4(5):25500.
  5. Sekijima Y. Transthyretin (ATTR) amyloidosis: clinical spectrum, molecular pathogenesis and disease-modifying treatments. J Neurol Neurosurg Psychiatry. 2015; 86(9):1036-1043.
  6. Mankad AK, Shah KB. Transthyretin Cardiac Amyloidosis. Curr Cardiol Rep. 2017; 19(10):97.
  7. Gillmore JD, Maurer MS, Falk RH, et al. Nonbiopsy Diagnosis of Cardiac Transthyretin Amyloidosis. Circulation. 2016; 133(24):2404-2412.
  8. Stangou AJ, Hawkins PN. Liver transplantation in transthyretin-related familial amyloid polyneuropathy. Curr Opin Neurol. 2004; 17(5):615-620.
  9. Tanskanen M, Peuralinna T, Polvikoski T, et al. Senile systemic amyloidosis affects 25% of the very aged and associates with genetic variation in alpha2-macroglobulin and tau: a population-based autopsy study. Ann Med. 2008; 40(3):232-239.
  10. Yamashita T, Hamidi Asl K, Yazaki M, Benson MD. A prospective evaluation of the transthyretin Ile122 allele frequency in an African-American population. Amyloid. 2005; 12(2):127-130.

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Last updated: 2019-07-11 20:02