AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

The amyloidoses are 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. Twenty different fibril proteins have been described in human amyloidosis, each with a different clinical picture (see Amyloidosis, Overview). One of the 20 proteins that form human amyloid fibrils is transthyretin (TTR).

TTR is a serum protein that transports thyroxine and retinol-binding protein. It circulates as a tetramer of 4 identical subunits of 127 amino acids each. TTR formerly was called prealbumin because it migrates anodally to albumin on serum protein electrophoresis, but this name was misleading because TTR is not a precursor of albumin. The TTR monomer contains 8 antiparallel beta pleated sheet domains. TTR is synthesized primarily in the liver, as well as in the choroid plexus and retina. Its gene is located on chromosome 18 and contains 4 exons.

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.

Pathophysiology

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

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 and nerve involvement. The gastrointestinal tract, vitreous, and carpal ligament are also frequently affected.

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 because the clinical picture of disease varies widely among people carrying the same TTR variant.

When the peripheral nerves are affected prominently, 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 involved most heavily, the general term is simply amyloidosis-transthyretin type, abbreviated ATTR.

Most variants causing 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. The fibrils in patients in all 3 endemic areas were found to contain TTR with a position-30 Val-to-Met substitution 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.
• TTR V122I: This variant, carried by 3.9% of African Americans and over 5.0% of the population in some areas of West Africa, increases the risk of late-onset (after age 60 y) cardiac amyloidosis. It appears to be the most common amyloid-associated TTR variant worldwide. Patients who are affected usually do not have peripheral neuropathy.
• 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.
• 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.
• 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.

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. 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 fromConnors et al)

Genetic aspects of transthyretin-related amyloidosis

Familial ATTR traditionally is 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: In Portugal, Brazil, and Japan, the average age of disease onset for TTR V30M gene carriers is 32 years, but, in Sweden, the average age of disease onset for the same variant is 56 years.
• Disease penetrance: In Portugal and Japan, more than 90% of TTR V30M gene carriers develop symptoms by middle age, but, in Sweden, disease penetrance is only 2%, and some V30M homozygous people remain asymptomatic.
• Some atypical Portuguese and Japanese kindred follow the late-onset, low-penetrance Swedish pattern.
• 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.
• Age of symptom onset is progressively earlier in successive generations (anticipation). Anticipation in some neurologic disorders is caused by expansion of trinucleotide repeats, but, in ATTR, this mechanism seems not to apply.

The explanation for the above observations is not understood. Other genetic and/or environmental variables must play roles. Anticipation, incomplete penetrance, and clinically sporadic cases in kindreds with unaffected allele carriers also have been observed with other TTR variants.

Normal-sequence transthyretin-related amyloidosis

In contrast to variant ATTR, normal-sequence cardiac ATTR always has late onset (usually after 75-80 y) and sometimes is 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 stimulus or stimuli leading to normal-sequence ATTR are not understood. The clinical picture of patients with severe SCA is similar to that 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 - Found most commonly in Maryland but also found 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 can be found at autopsy in about 15% of people older than 80 years, with a progressive increase in prevalence in people older than 80 years. In this setting, the deposited TTR usually is 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.
• 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.

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

Mortality/Morbidity

Morbidity and mortality from ATTR depends upon 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 always are 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.

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.

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.
• Other variants are documented to have originated in people of European, Japanese, and Chinese ancestry. TTR variants probably have originated in all races.

Sex

All TTR variants encoded on chromosome 18 are inherited equally 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.

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.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Patients often present with nonspecific symptoms such as weakness and weight loss. The presenting symptoms depend on the TTR variant present and the organ(s) involved. Amyloid deposition in a particular organ leads to similar clinical consequences, and therefore similar complaints, regardless of the type of amyloid deposited. For example, cardiac ATTR and cardiac AL cause similar symptoms. The most common sites of deposition are the following:

• Cardiovascular involvement
• • Patients with cardiac deposition often present with symptoms suggesting congestive heart failure (ie, dyspnea on exertion, peripheral edema) and/or arrhythmias (ie, palpitations, lightheadedness, syncope).
  • Deposition in the subendothelium of the peripheral vasculature can lead to severe postural hypotension.
• Neuropathic involvement
• • Peripheral nerve problems are the presenting symptomatology in most cases.
  • Patients with peripheral nerve deposits note sensorimotor impairment. Some TTR variants present with lower limb neuropathy (eg, TTR V30M), while other variants present with primarily upper limb neuropathy (eg, TTR I84S, TTR L58H).
  • Patients also experience hyperalgesia and altered temperature sensation.
  • Neuropathy in patients with ATTR V30M often presents as lower extremity weakness, pain, and/or impaired sensation. Autonomic dysfunction, often manifested as sexual or urinary dysfunction, is common.
• Gastrointestinal involvement
• • Patients with gastrointestinal deposits present with diarrhea and/or constipation.
  • Nausea and vomiting also occur.
• Carpal tunnel syndrome
• • Weakness and paresthesias of one or both hands, suggesting carpal ligament involvement, is often the presenting symptom in patients with the variant TTR L58H, and it also can be observed in patients with other variants. It sometimes precedes other clinical manifestations by as much as 20 years.
  • Patients with normal-sequence TTR also may develop localized symptomatic carpal ligament deposition.

Physical

As with the history, the physical findings depend on the organ involved, which is affected by the presence and identity of a TTR variant.

Common physical findings include cachexia, peripheral edema, hepatomegaly, purpura, orthostatic hypotension, impaired sensation and/or strength in the upper and/or lower extremities, and carpal tunnel syndrome.

• Cardiac involvement
• • Cardiac amyloidosis typically causes diastolic dysfunction; congestive heart failure; and arrhythmias, including heart block, premature ventricular contractions, and various tachyarrhythmias.
  • The physical findings observed are not specific for cardiac amyloidosis. Also, even in patients with amyloidosis, the findings are not specific for ATTR; they are similar to findings in patients with cardiac amyloidosis of the AL (immunoglobulin-related) type (see Amyloidosis, Overview and Amyloidosis, Immunoglobulin-Related).
• Neuropathy
• • Deposition in the peripheral nerves causes sensorimotor peripheral neuropathy, which is a prominent finding in many patients with TTR V30M and other variants but not normal-sequence ATTR.
  • Typical findings include symmetric sensory impairment and weakness, sometimes accompanied by painless ulcers, similar to the picture in diabetic neuropathy.
  • Cranial neuropathy occasionally is observed.
  • Autonomic neuropathy may cause severe orthostatic hypotension, diarrhea, and/or impotence.
  • Deep tendon reflexes often are diminished or absent, particularly late in disease.
• Central nervous system findings
• • Patients with rare TTR variants that cause CNS disease develop a wide range of abnormalities observed upon mental status and neurologic examination.
  • Objective findings may include nystagmus and pyramidal signs, with spastic paraparesis.
  • Patients with leptomeningeal and cerebrovascular deposits can have seizures, subarachnoid hemorrhages, and dementia.
• Eye findings
• • Amyloid deposits can be found in the corpus vitreum.
  • This finding may be the most specific for hereditary transthyretin amyloidosis (as opposed to other systemic amyloidoses).
• Cutaneous findings: Purpura results from the vascular fragility produced by amyloid deposition in the subendothelium of the small blood vessels.

Causes

The most important risk factor for ATTR is the presence of an amyloid-associated TTR variant. Among people carrying the same TTR variant, the clinical picture varies widely. Apparently, other unknown environmental and/or genetic factors also play a major role in influencing the course of disease.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Nonspecific findings found in different types of amyloidosis include normochromic normocytic anemia, electrolyte abnormalities secondary to heart failure or malabsorption, and evidence of varying degrees of proteinuria and diminished glomerular filtration rate in patients with renal deposition.
• Biopsy with Congo red staining and with immunostaining
• • Amyloidosis (of all types) is diagnosed definitively based on demonstration of Congo red binding material in a biopsy specimen. For many years, rectal biopsy was the favored procedure when systemic amyloidosis was suspected. Now, the capillaries in subcutaneous fat are known to be involved often in ATTR and in some other types of systemic amyloidosis; therefore, subcutaneous fat aspiration often provides sufficient tissue for diagnosing amyloid, as well as for further studies such as immunostaining. On the other hand, biopsy of an organ with impaired function, such as the heart or gastrointestinal tract, has the advantage of definitively establishing a cause-and-effect relationship between organ dysfunction and amyloid deposition.
  • ATTR deposition in the peripheral nerves leads to axonal degeneration of the small nerve fibers, causing polyneuropathy. Diagnosis often can be made with sural nerve biopsy, although the deposits may be proximal to the sural nerve and therefore not found in biopsied material.
  • Other potential biopsy sites include the myocardium, stomach, rectum, or other organ suspected of heavy involvement.
  • Amyloid should not be assumed to be of the TTR type based solely on the Congo red staining and clinical picture. After Congo red staining establishes a diagnosis of amyloidosis, the specific type of amyloidosis must be determined with immunostaining of a biopsy specimen using commercially available antiserum against TTR. Control antisera against other types of amyloid precursors, including immunoglobulin light chains and amyloid A protein, should also be performed to confirm staining specificity. Even patients known to carry a TTR variant should ideally have the diagnosis confirmed with immunostaining to rule out the possibility of a different type of amyloidosis.
  • Distinguishing between ATTR and AL cardiac amyloidosis on clinical grounds alone is particularly difficult. Without immunologic identification of the deposited protein, an incorrect diagnosis of ATTR in a patient with AL, or the reverse, could lead to ineffective or harmful treatment.

Imaging Studies

• Radiolabeled P-component scanning
• • This test is available in only a few European centers as of 2001. Where it is available, radiolabeled P-component scanning is a very useful means of evaluating the total body burden of amyloid and is a sensitive noninvasive means of diagnosing amyloid in most organs. Serial studies are useful for monitoring the response to therapy in many settings.
  • One drawback is that P-component scanning is not useful for diagnosing or monitoring cardiac amyloid because the concentration of label in the intracardiac blood pool obscures the weaker signal from the labeled molecule bound to myocardial amyloid.
• Cardiac imaging
• • Cardiac deposition is, in many patients, the most serious complication of ATTR; thus, cardiac involvement usually should be assessed and monitored by imaging studies.
  • No noninvasive test is sufficiently sensitive or specific to make a definitive diagnosis of cardiac amyloidosis, although 2-dimensional echocardiography and electrocardiography, particularly when combined, can strongly suggest cardiac amyloidosis (of any type).
  • Echocardiography: The most useful noninvasive diagnostic test for cardiac amyloidosis is echocardiography, which enables visualization of increased ventricular wall thickness, increased septal thickness, and an appearance of granular "sparkling." This finding is neither sensitive nor specific enough to be diagnostic but is highly suggestive when present. Amyloid deposits in the heart occur in the ventricular interstitium, leading to thickening of the ventricular walls and interventricular septum without an increase in the intracardiac volume. Evaluation of diastolic function by Doppler echocardiography reveals impaired ventricular relaxation early in the course of disease, which progresses to short deceleration. The ejection fraction is preserved until late in disease. Other echocardiographic findings include valvular thickening, valvular insufficiency, and atrial enlargement. The combined use of electrocardiography plus echocardiography appears to be of the most diagnostic value.
• Other cardiac imaging studies: Computerized tomography scan and nuclear scintigraphy generally are not helpful.

Other Tests

• Electrocardiography: The classic finding on electrocardiography is a low-voltage QRS complex in the limb leads, resulting from replacement of normal cardiac tissue by nonconducting amyloid material. In some cases, loss of anterior forces suggests anteroseptal infarction that is not confirmed at autopsy. Various arrhythmias are observed and can be life threatening.
• Nerve conduction studies: In patients with amyloid neuropathy, serial nerve conduction studies can be useful for objectively monitoring the course of disease and for assessing response to treatment such as liver transplantation.
• Genetic studies
• • Genetic studies to look for a TTR variant can be helpful in many patients with ATTR, particularly in younger patients not known to belong to a kindred carrying a defined TTR variant. These studies generally are not available through routine clinical laboratories.
  • One approach is to perform DNA-based testing, using the polymerase chain reaction (PCR), to look for known, common TTR variants. This approach is most useful if the likely TTR variant can be surmised based on the clinical history and genetic background of the patient. These studies are performed by PCR amplifying regions of the TTR gene followed by digestion with restriction enzymes.
  • If a TTR variant is suspected, but initial screening results for a few common known variants are negative, more comprehensive analysis for a TTR variant can be performed. Either the protein can be isolated from the serum and studied using methods such as electrospray ionization mass spectrometry (ESIMS) or the gene can be studied by PCR and such methods as single-strand conformation polymorphism analysis and/or direct sequencing.
  • Determination of whether a TTR variant is present is important because the treatment options for variant-sequence ATTR differ from those for normal-sequence ATTR. Information about a TTR variant also can be of use to other family members at risk.

Histologic Findings

Biopsy of an affected organ followed by routine hematoxylin and eosin staining reveals homogeneous interstitial eosinophilic material. Amyloid material stained with Congo red and viewed under polarized light appears bright green. Specific staining with antibodies against TTR proves the diagnosis of ATTR, as opposed to other types of amyloidosis that have similar appearance after hematoxylin and eosin or Congo red staining.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

No pharmacologic therapy is available that reverses the process of TTR amyloid formation. Thus, care generally is limited to supportive measures.

Cardiac involvement

Diuretics are the mainstay of therapy for amyloid-related congestive heart failure (whether ATTR, AL, or, rarely, another type). The optimal degree of diuresis often is difficult to judge. When edema is troubling and symptomatic postural hypotension is not present, fluid can be removed with careful diuresis. On the other hand, hypotension resulting from a low ejection fraction and/or autonomic neuropathy may limit diuretic use.

Digoxin and calcium channel blockers are contraindicated in cardiac amyloidosis. Digoxin is ineffective and is associated with morbidity and mortality. Calcium channel blocking agents bind to amyloid fibrils, presumably leading to local toxic concentrations, and can worsen congestive heart failure in patients with cardiac amyloidosis.

Surgical Care

• Liver transplantation
• • An important therapeutic advance for this condition is liver transplantation, first performed for FAP in 1990. More than 700 liver transplants have been reported to the Familial Amyloid Polyneuropathy World Transplant Registry (FAPWTR). In suitable patients, this replaces the source of variant TTR with a source of normal-sequence TTR, sometimes leading to gradual fibril resorption and disease stabilization, especially of neurologic complications. Ideally, the transplant should be performed as early in the disease course as possible, before significant neurologic disability has been incurred.
  • However, patients with cardiac, leptomeningeal, gastrointestinal, or ocular involvement often progress despite transplantation.
  • The identification of TTR variants in patients who clinically could have either SCA or unrecognized familial ATTR is important because liver transplantation would not benefit patients with deposition of normal-sequence TTR. On the other hand, patients with normal-sequence ATTR could be included in experimental trials of drugs that might inhibit or reverse deposition.
• Combined heart and liver or liver and kidney transplantation has been performed in a very few patients, with variable success
• Carpal tunnel release
• • Involvement of the carpal ligament is observed not only in ATTR but also, most commonly, in Ab₂M in patients undergoing dialysis and in patients with AL (see Amyloidosis, Beta2M [Dialysis Related] and Amyloidosis, Immunoglobulin-Related). Treatment is surgical.
  • At the time of carpal tunnel release, a biopsy should be performed if a definitive diagnosis has not been established previously so that both Congo red staining and immunostaining can be performed. Why the carpal ligament, or indeed any organ, is a favored location for amyloid deposition is not known.
• Vitrectomy: Vitrectomy is useful in patients with vitreous involvement.

Diet

No diet affects ATTR. Patients with congestive heart failure arising from ATTR should receive appropriate dietary management for that condition.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Currently, no pharmacologic therapy is available for ATTR. A number of small molecules that may have the potential to inhibit or reverse TTR amyloid formation are under preclinical study. Diuretics are the mainstay of therapy for amyloid-related congestive heart failure (whether ATTR, AL, or, rarely, another type).

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Complications

• Complications reflect the organ system(s) involved. The most severe complication of systemic ATTR is extensive cardiac deposition, with consequent congestive heart failure and/or arrhythmias, and is the cause of death in many patients with ATTR.
• Severe complications include a variety of gastrointestinal disorders (malabsorption, nausea, vomiting, diarrhea, constipation). Neuropathy can lead to paresis, sexual dysfunction, and sphincter dysfunction.

Prognosis

• The prognosis depends on the presence and identity of a TTR variant and organ or organs involved. Patients with early-onset of variant-sequence TTR may die within a few years of diagnosis. Older patients with slowly progressive disease can live for decades after the onset of symptoms and may never develop life-threatening disease.
• Unlike in AL, even symptomatic cardiac involvement does not necessarily portend a bleak prognosis. Median survival in cardiac AL is about 6 months, but median survival is several years in older patients with cardiac ATTR, even when a TTR variant is present.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to diagnose definitively the specific type of amyloidosis, with consequent incorrect treatment

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Adams D, Samuel D, Goulon-Goeau C, et al. The course and prognostic factors of familial amyloid polyneuropathy after liver transplantation. Brain. Jul 2000;123 (Pt 7):1495-504. [Medline].
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• Connors LH, Lim A, Prokaeva T. Tabulation of human transthyretin (TTR) variants, 2003. Amyloid. Sep 2003;10(3):160-84.
• Damas AM, Saraiva MJ. Review: TTR amyloidosis-structural features leading to protein aggregation and their implications on therapeutic strategies. J Struct Biol. Jun 2000;130(2-3):290-9. [Medline].
• Ericzon B-G, Larson M, Herlenius G, et al. Report from the Familial Amyloidotic Polyneuropathy World Transplant Registry (FAPWTR) and the Domino Liver Transplant Registry (DLTR). Amyloid. 2003;10 (suppl 1):67-76.
• Jacobson DR, Pastore RD, Yaghoubian R, et al. Variant-sequence transthyretin (isoleucine 122) in late-onset cardiac amyloidosis in black Americans. N Engl J Med. Feb 13 1997;336(7):466-73. [Medline].
• Jacobson DR, Buxbaum JN. Genetic aspects of amyloidosis. Adv Hum Genet. 1991;20:69-123, 309-11. [Medline].
• Klabunde T, Petrassi HM, Oza VB, et al. Rational design of potent human transthyretin amyloid disease inhibitors. Nat Struct Biol. Apr 2000;7(4):312-21. [Medline].
• Montagna P, Marchello L, Plasmati R, et al. Electromyographic findings in transthyretin (TTR)-related familial amyloid polyneuropathy (FAP). Electroencephalogr Clin Neurophysiol. Oct 1996;101(5):423-30. [Medline].
• Monteiro E, Freire A, Barrosa E. Familial amyloid polyneuropathy and liver transplantation. J Hepatology. 2004;41:188-194.
• Palha JA, Ballinari D, Amboldi N, et al. 4''-Iodo-4''-deoxydoxorubicin disrupts the fibrillar structure of transthyretin amyloid. Am J Pathol. Jun 2000;156(6):1919-25. [Medline].
• Peterson SA, Klabunde T, Lashuel HA, et al. Inhibiting transthyretin conformational changes that lead to amyloid fibril formation. Proc Natl Acad Sci U S A. Oct 27 1998;95(22):12956-60. [Medline].
• Plante-Bordeneuve V, Lalu T, Misrahi M, et al. Genotypic-phenotypic variations in a series of 65 patients with familial amyloid polyneuropathy. Neurology. Sep 1998;51(3):708-14. [Medline].
• Saraiva MJ, Birken S, Costa PP. Amyloid fibril protein in familial amyloidotic polyneuropathy, Portuguese type. Definition of molecular abnormality in transthyretin (prealbumin). J Clin Invest. Jul 1984;74(1):104-19. [Medline].
• Saraiva MJ. Transthyretin amyloidosis: a tale of weak interactions. FEBS Letters. 2001;498:201-203.
• Suhr OB, Herlenius G, Friman S. Liver transplantation for hereditary transthyretin amyloidosis. Liver Transpl. May 2000;6(3):263-76. [Medline].
• Suhr OB, Svendson IH, Andersson R, et al. Hereditary transthyretin amyloidosis from a Scandinavian perspective. J Int Med. 2003;254:225-235.

Article Last Updated: Sep 20, 2006