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Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

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Familial Transthyretin Amyloidosis

Synonym: Familial TTR Amyloidosis. Includes: Familial Amyloid Cardiomyopathy, Familial Amyloid Polyneuropathy Type I (Portuguese-Swedish-Japanese Type), Familial Amyloid Polyneuropathy Type II (Indiana/Swiss or Maryland/German Type), Leptomeningeal Amyloidosis, Familial Oculoleptomeningeal Amyloidosis (FOLMA)

, MD, PhD, , MD, PhD, , MD, PhD, and , MD, PhD.

Author Information
, MD, PhD
Division of Clinical and Molecular Genetics
Shinshu University Hospital
Matsumoto, Japan
, MD, PhD
Department of Medicine (Neurology & Rheumatology)
Shinshu University Hospital
Matsumoto, Japan
, MD, PhD
Department of Neurology
Kyoto Prefectural University Hospital
Kyoto, Japan
, MD, PhD
Department of Medicine (Neurology & Rheumatology)
Shinshu University Hospital
Matsumoto, Japan

Initial Posting: ; Last Update: January 26, 2012.

Summary

Disease characteristics. Familial transthyretin (TTR) amyloidosis is characterized by a slowly progressive peripheral sensorimotor neuropathy and autonomic neuropathy as well as non-neuropathic changes of cardiomyopathy, nephropathy, vitreous opacities, and CNS amyloidosis. The disease usually begins in the third to fifth decade in persons from endemic foci in Portugal and Japan; onset is later in persons from other areas. Typically, sensory neuropathy starts in the lower extremities with paresthesias and hypesthesias of the feet, followed within a few years by motor neuropathy. In some persons, particularly those with early onset disease, autonomic neuropathy is the first manifestation of the condition; findings can include: orthostatic hypotension, constipation alternating with diarrhea, attacks of nausea and vomiting, delayed gastric emptying, sexual impotence, anhidrosis, and urinary retention or incontinence. Cardiac amyloidosis is mainly characterized by progressive cardiomyopathy. Individuals with leptomeningeal amyloidosis may have the following CNS findings: dementia, psychosis, visual impairment, headache, seizures, motor paresis, ataxia, myelopathy, hydrocephalus, or intracranial hemorrhage.

Diagnosis/testing. In addition to clinical symptoms, proven amyloid deposition in biopsy specimens and identification of a disease-causing mutation in TTR are necessary to establish the diagnosis. TTR amyloid deposition in tissue is demonstrated using Congo red staining and, ideally, immunohistochemical study. Although mass spectrometry can demonstrate a mass difference between wild-type and TTR protein variants in serum, it does not specify the site and kind of amino acid substitution in a number of disease-related TTR mutations; thus, DNA sequencing is usually required. Sequence analysis of TTR, the only gene in which mutations are known to cause TTR amyloidosis, detects more than 99% of disease-causing mutations.

Management. Treatment of manifestations: Orthotopic liver transplantation (OTLX) halts the progression of peripheral and/or autonomic neuropathy; OTLX is recommended in individuals younger than age 60 years with: (1) disease duration less than five years, (2) polyneuropathy restricted to the lower extremities or with autonomic neuropathy alone, and (3) no significant cardiac or renal dysfunction. Surgery is indicated for carpal tunnel syndrome and vitrectomy for vitreous involvement. In those with sick sinus syndrome or second-degree or third-degree AV block, a cardiac pacemaker may be indicated.

Surveillance: Serial nerve conduction studies to monitor polyneuropathy; serial electrocardiogram, echocardiography, and serum B-type natriuretic peptide (BNP) level to monitor cardiomyopathy; modified body mass index (mBMI) to monitor nutritional status.

Agents/circumstances to avoid: Local heating appliances, such as hot-water bottles, which can cause low-temperature burn injury in those with decreased temperature and pain perception.

Evaluation of relatives at risk: If the family-specific mutation is known, molecular genetic testing ensures early diagnosis and treatment. If the disease-causing mutation is not known, clinical evaluations ensure early diagnosis and treatment.

Genetic counseling. Familial TTR amyloidosis is inherited in an autosomal dominant manner. Each child of an affected individual (who is heterozygous for one TTR mutation) has a 50% chance of inheriting the TTR mutation. For affected individuals homozygous for TTR mutations:

  • Each sib is at a 50% risk of inheriting one TTR mutation and a 25% risk of inheriting two TTR mutations;
  • All offspring will inherit a mutation.

Prenatal testing for pregnancies at increased risk is possible if the disease-causing mutation has been identified in the family. Requests for prenatal testing for adult-onset conditions which (like familial TTR amyloidosis) do not affect intellect and have some treatment available are not common.

Diagnosis

Clinical Diagnosis

The diagnosis of familial transthyretin (TTR) amyloidosis is suspected in adults with the following:

  • Slowly progressive sensorimotor and/or autonomic neuropathy that is frequently accompanied by:
    • Cardiac conduction blocks
    • Cardiomyopathy
    • Nephropathy

      AND/OR
    • Vitreous opacities
  • Family history consistent with autosomal dominant inheritance supports the diagnosis; however, absence of other affected individuals in the family does not preclude the diagnosis of familial TTR amyloidosis especially in persons over age 50 years.

Testing

Tissue biopsy. To confirm amyloidosis, including familial TTR amyloidosis, the demonstration of amyloid deposition on biopsied tissues is essential. Deposition of amyloid in tissue can be demonstrated by Congo red staining of biopsy materials. With Congo red staining, amyloid deposits show a characteristic yellow-green birefringence under polarized light. Tissues suitable for biopsy include: subcutaneous fatty tissue of the abdominal wall, skin, gastric or rectal mucosa, sural nerve, and peritendinous fat from specimens obtained at carpal tunnel surgery. Sensitivity of endoscopic biopsy of gastrointestinal mucosa is around 85%; biopsy of the sural nerve is less sensitive because amyloid deposition is often patchy [Hund et al 2001, Koike et al 2004, Vital et al 2004].

It is ideal to show that these amyloid deposits are specifically immunolabeled by anti-TTR antibodies.

Serum variant TTR protein. TTR protein normally circulates in serum or plasma as a soluble protein having a tetrameric structure [Kelly 1998, Rochet & Lansbury 2000]. Normal plasma TTR concentration is 20-40 mg/dL (0.20-0.40 mg/mL).

Pathogenic mutations in TTR cause conformational change in the TTR protein molecule, disrupting the stability of the TTR tetramer, which is then more easily dissociated into pro-amyloidogenic monomers [Sekijima et al 2005]. Small amounts of TTR monomer (0.28-0.56 µg/mL) can be detected in the plasma of individuals with familial TTR amyloidosis and normal controls [Sekijima et al 2001].

After immunoprecipitation with anti-TTR antibody, serum variant TTR protein can be detected by mass spectrometry [Tachibana et al 1999]. Approximately 90% of TTR variants so far identified are confirmed by this method. Mass shift associated with each variant TTR protein is indicated [Connors et al 2003].

Molecular Genetic Testing

Gene. TTR is the only gene in which mutations are known to cause familial TTR amyloidosis.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in Familial Transthyretin Amyloidosis

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
TTRTargeted mutation analysisc.148G>A (Val30Met4, 5100% of the targeted mutation
Sequence analysis 6Sequence variants>99% 7
Deletion/duplication analysis 8Exonic or whole-gene deletionsUnknown; none reported

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Identified in many individuals of different ethnic backgrounds; found in large clusters in Portugal, Sweden, and Japan

5. Targeted mutation panel may vary by laboratory.

6. Sequence analysis detects variants that are benign, likely benign, of unknown significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

7. The gene has four exons; and all the hitherto-identified mutations are in exons 2, 3, or 4.

8. Testing that identifies exonic or whole-gene deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

Testing Strategy

To confirm/establish the diagnosis in a proband

  • Tissue biopsy to document the presence of amyloid using Congo red staining and immunohistohemical study with anti-TTR antibodies
  • Note: Mass spectrometry to detect serum TTR protein variants may also be useful for screening.
  • Molecular genetic testing of TTR by sequence analysis (may be preceded by targeted mutation analysis)
  • Deletion/duplication testing:
    • No exonic or whole-gene deletions or duplications involving TTR have been reported to cause familial transthyretin amyloidosis.
    • However, with new deletion/duplication testing methods, it is theoretically possible that such mutations may be identified in affected individuals in whom prior testing by sequence analysis of the entire coding region was negative.

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

Clinical features of familial transthyretin (TTR) amyloidosis can include peripheral sensorimotor neuropathy and autonomic neuropathy, as well as non-neuropathic changes (cardiomyopathy, nephropathy, vitreous opacities, and CNS amyloidosis) (see Table 2).

Table 2. Phenotypes Associated with Familial Transthyretin Amyloidosis

PhenotypeRepresentative Genotype
Type Features
TTR amyloid neuropathy
(formerly familial amyloid
polyneuropathy type I
[Portuguese-Swedish-
Japanese type])
Early
Sensorimotor polyneuropathy of the legs
Carpal tunnel syndrome
Autonomic dysfunction
Constipation/ diarrhea
Impotence

Late
Cardiomyopathy
Vitreous opacities
Nephropathy
Val30Met
TTR amyloid neuropathy
(formerly familial amyloid
polyneuropathy type II
[Indiana/Swiss; Maryland/German type])
Early
Carpal tunnel syndrome

Late
Sensorimotor polyneuropathy of extremities
Autonomic dysfunction
Constipation / diarrhea
Impotence
Cardiomyopathy
Vitreous opacities
Nephropathy
Ile84Ser
TTR cardiac amyloidosis
(familial amyloid cardiomyopathy)
Cardiomegaly
Conduction block
Arrhythmia
Anginal pain
Congestive heart failure
Sudden death
Val122Ile
TTR leptomeningeal/
CNS amyloidosis
Dementia
Ataxia
Spasticity
Seizures
Hemorrhage (intracerebral and/or subarachnoid)
Psychosis
Hydrocephalus
Asp18Gly

Neuropathy. The cardinal feature of TTR-familial amyloid polyneuropathy type I is slowly progressive sensorimotor and autonomic neuropathy [Benson 2001, Hund et al 2001, Ando et al 2005]. Typically, sensory neuropathy starts in the lower extremities and is followed by motor neuropathy within a few years. The initial signs of this sensory neuropathy are paresthesias (sense of burning, shooting pain) and hypesthesias of the feet. Temperature and pain sensation are impaired earlier than vibration and position sensation. By the time sensory neuropathy progresses to the level of the knees, the hands have usually become affected. In the full-blown stage of the disease, sensory loss, muscle atrophy, and weakness of the extremities show a glove and stocking distribution. Foot drop, wrist drop, and disability of the hands and fingers are common symptoms of motor neuropathy.

Autonomic neuropathy may occur as the first clinical symptom of the disease (Table 3). The symptoms of autonomic dysfunction include: orthostatic hypotension [Vita et al 2005], constipation alternating with diarrhea, attacks of nausea and vomiting, delayed gastric emptying, sexual impotence, anhidrosis, and urinary retention or incontinence. Because of sensory loss and autonomic dysfunction, trophic ulcers on the lower extremities are common. Frequently, the autonomic neuropathy produces the most significant morbidity of the disorder.

Table 3. Symptoms at Presentation of Familial Amyloid Polyneuropathy

Symptoms% of Individuals
From Coelho et al [1994]From Ikeda et al [1987]
Sensory
(lower limbs)
Most commonly paresthesias80%49%
AutonomicVomiting3%
Constipation21%18%
Constipation alternating with diarrhea12%---
Diarrhea17%4%
Impotence24%9%
Orthostatic fainting---7%
MotorWeakness7%7%

The disease usually begins in the third, fourth, or fifth decade in persons from endemic foci in Portugal and Japan; onset is later in persons from other areas. The following findings indicate that age at onset varies greatly even within ethnically identical populations with the same TTR mutation:

  • For persons of Japanese ancestry with the Val30Met mutation who are related to two large endemic foci (Ogawa village and Arao city), the mean age at onset is 40.1±12.8 years (range 22-74 years) [Nakazato 1998].
  • For persons of Japanese ancestry with Val30Met who are unrelated to two large endemic foci, the mean age at onset is much later (62.7±6.6 years) (range 52-80 years) [Misu et al 1999, Ikeda et al 2002].
  • For persons of Portuguese ancestry with the Val30Met mutation, the mean age at onset is 33.5 ±9.4 years (range 17-78 years).
  • For persons of Swedish, French, or British ancestry, the mean age at onset is much later than that in individuals of Japanese or Portuguese ancestry [Planté-Bordeneuve et al 1998].

Sensorimotor neuropathy and autonomic neuropathy progress over ten to 20 years. Various types of cardiac conduction block frequently appear. Cachexia is a common feature at the late stage of the disease. Affected individuals usually die of cardiac failure, renal failure, or infection.

TTR-familial amyloid polyneuropathy type II (or the Indiana/Swiss or Maryland/German type) starts in the upper extremities as carpal tunnel syndrome in association with specific TTR mutations (e.g., Leu58His, Leu58Arg, Lys70Asn, Ile84Ser, Tyr114His (see Table 5) [Nakazato 1998, Connors et al 2000, Benson 2001, Hund et al 2001, Connors et al 2003]. Sensorimotor neuropathy and autonomic neuropathy are accompanied by visceral involvement. Cardiomyopathy and/or nephropathy are frequently seen in the advanced stage of the disease.

Non-neuropathic amyloidosis. Individuals with familial TTR amyloidosis do not necessarily present with polyneuropathy. Cardiac amyloidosis and leptomeningeal amyloidosis are well-known non-neuropathic forms of familial TTR amyloidosis that are associated with specific TTR mutations. In these types of familial TTR amyloidosis, polyneuropathy is absent or, if present, less evident.

Approximately one third of the TTR protein variants are accompanied by vitreous opacities.

Cardiac amyloidosis. Cardiac amyloidosis, mainly characterized by progressive cardiomyopathy, has been reported with more than two thirds of TTR mutations (see Table 5) [Nakazato 1998, Benson 2001, Saraiva 2001, Connors et al 2003, Hattori et al 2003, Benson & Kincaid 2007]. In some families with specific TTR mutations, such as Asp18Asn, Val20Ile, Pro24Ser, Ala45Thr, Ala45Ser, His56Arg, Gly57Arg, Ile68Leu, Ala81Thr, Ala81Val, His88Arg, Glu92Lys, Arg103Ser, Leu111Met, or Val122Ile (see Table 5), cardiomyopathy without peripheral neuropathy is a main feature of the disease.

Cardiac amyloidosis is usually late onset. Most individuals develop cardiac symptoms after age 50 years; cardiac amyloidosis generally presents with restrictive cardiomyopathy. The typical electrocardiogram shows a pseudoinfarction pattern with prominent Q wave in leads II, III, aVF, and V1-V3, presumably resulting from dense amyloid deposition in the anterobasal or anteroseptal wall of the left ventricle. The echocardiogram reveals left ventricular hypertrophy with preserved systolic function. The thickened walls present "a granular sparkling appearance."

Among the mutations responsible for cardiac amyloidosis, Val122Ile is notable for its prevalence in African Americans. Approximately 3.0%-3.9% of African Americans are heterozygous for Val122Ile [Yamashita et al 2005]. The high frequency of Val122Ile partly explains the observation that in individuals in the US older than age 60 years, cardiac amyloidosis is four times more common among blacks than whites [Jacobson et al 1997].

Leptomeningeal (oculoleptomeningeal) amyloidosis. Amyloid deposition is seen in the pial and arachnoid membrane, as well as in the walls of vessels in the subarachnoid space associated with TTR mutations including Leu12Pro, Asp18Gly, Ala25Thr, Val30Gly, Ala36Pro, Gly53Glu, Gly53Ala, Phe64Ser, Tyr69His, or Tyr114Cys (see Table 5) [Petersen et al 1997, Nakazato 1998, Brett et al 1999, Mascalchi et al 1999, Uemichi et al 1999, Connors et al 2000, Benson 2001, Ellie et al 2001, Saraiva 2001, Ikeda et al 2002, Blevins et al 2003, Connors et al 2003, Hammarström et al 2003, Sekijima et al 2003]. Amyloid in the blood vessels disappears as the vessels penetrate the brain parenchyma.

Individuals with leptomeningeal amyloidosis show CNS signs and symptoms including: dementia, psychosis, visual impairment, headache, seizures, motor paresis, ataxia, myelopathy, hydrocephalus, or intracranial hemorrhage.

When associated with vitreous amyloid deposits, leptomeningeal amyloidosis is known as familial oculoleptomeningeal amyloidosis (FOLMA) [Petersen et al 1997, Jin et al 2004].

In leptomeningeal amyloidosis protein concentration in the cerebrospinal fluid is usually high, and gadolinium-enhanced MRI typically shows extensive enhancement of the surface of the brain, ventricles, and spinal cord [Brett et al 1999].

Although meningeal biopsy is necessary to confirm amyloid deposition in the meninges, characteristic MRI findings and TTR mutations strongly suggest this pathology [Mitsuhashi et al 2004].

Other. Vitreous opacification has been reported in approximately 20% of families with various TTR mutations, including Val30Met [Benson 2001, Connors et al 2003, Kawaji et al 2004, Benson & Kincaid 2007]. Four out of 43 individuals with the Val30Met mutation developed vitreous amyloidosis as the first manifestation of familial TTR amyloidosis [Kawaji et al 2004]. In one case report, vitreous opacification was the only evidence of amyloid deposit caused by the Trp41Leu mutation [Yazaki et al 2002].

The kidney is consistently involved with marked deposition of amyloid demonstrated at postmortem examination. Mild to severe renal involvement is usually seen in the advanced stage [Haagsma et al 2004, Lobato et al 2004].

Amyloid deposition on the gastrointestinal tract wall, especially with involvement of the gastrointestinal autonomic nerves, is common [Ikeda et al 1982, Ikeda et al 1983].

Nodular cutaneous amyloidosis has been reported in an individual with the Thr114His mutation [Mochizuki et al 2001].

Shortness of breath induced by diffuse pulmonary amyloid deposition has been reported in two individuals with the Asp38Ala mutation [Yazak et al 2000].

Anemia with low erythropoietin has been reported in 25% of cases [Beirao et al 2004].

Genotype-Phenotype Correlations

Heterozygotes. With expanding lists of mutations in TTR (Table 5), genotype-phenotype correlations have been intensively investigated; however, they remain largely undetected.

In subsets of families with the Val30Met mutation, considerable variation in phenotypic manifestations and age of onset is observed. It is hypothesized that genetic modifiers and non-genetic factors contribute to the pathogenesis and progression of familial TTR amyloidosis [Holmgren et al 1997, Misu et al 1999, Munar-Qués et al 1999, Sobue et al 2003, Soares et al 2005].

It has been clinically and experimentally demonstrated that the benign allelic variant c.416C>T (Thr119Met) has a protective effect on amyloidogenesis in individuals who have the Val30Met mutation [Alves et al 1997, Hammarström et al 2001, Sebastião et al 2001].

Most of the more than 90 mutations in TTR result in classic peripheral and autonomic neuropathy; but some mutations are considered to be associated with unique phenotypes of familial TTR amyloidosis, in which peripheral or autonomic neuropathy is clinically absent or less prominent:

Homozygotes. The vast majority of individuals with familial TTR amyloidosis are heterozygous for a TTR mutation; however, homozygotes have been reported:

Homozygotes present with a slightly more severe clinical course (higher incidence rate and earlier onset) than heterozygotes within the same family [Tojo et al 2008]; amyloid deposition is more widespread in homozygotes than in heterozygotes [Yoshinaga et al 2004]. Most homozygotes are members of families characterized by incomplete penetrance of familial TTR amyloidosis.

Penetrance

Because the penetrance for familial TTR amyloidosis is not 100%, an individual with a TTR mutation may be symptom free until late adulthood. The penetrance may vary by mutation, geographical region, or ethnic group.

It is generally accepted that the penetrance is much higher in individuals in endemic foci than outside of endemic foci [Misu et al 1999]. In Portugal, cumulative disease risk in individuals with the Val30Met mutation is estimated at 80% by age 50 and 91% by age 70 years, whereas the risk in French heterozygotes is 14% by age 50 and 50% by age 70 years [Planté-Bordeneuve et al 2003]. In Sweden, the penetrance is much lower: 1.7% by age 30, 5% by age 40, 11% by age 50, 22% by age 60, 36% by age 70, 52% by age 80, and 69% by age 90, respectively [Hellman et al 2008].

Some Val30Met homozygotes remain asymptomatic.

Anticipation

Genetic anticipation is observed in families with TTR amyloid polyneuropathy from endemic areas [Yamamoto et al 1998, Soares et al 1999, Misu et al 2000]. In Japanese families with the Val30Met mutation, which originated from one of two endemic foci, it was reported that affected children with maternal transmission showed more profound anticipation than those with paternal transmission, especially when the children were male [Yamamoto et al 1998].

However, because not all asymptomatic individuals in these studies underwent molecular genetic testing, some asymptomatic individuals with the Val30Met mutation may not have been identified, in which case the occurrence of anticipation would be overestimated. Furthermore, male gender is known to be a genetic risk factor for TTR amyloidosis [Misu et al 1999, Koike et al 2002, Hellman et al 2008, Sekijima et al 2011], which may explain why affected male children developed TTR amyloidosis at an earlier age than their mothers.

Nomenclature

The neuropathy associated with TTR mutations, now called familial TTR amyloidosis, was formerly referred to as one of the following:

  • Familial amyloid polyneuropathy type I (or the Portuguese-Swedish-Japanese type)
  • Familial amyloid polyneuropathy type II (or the Indiana/Swiss or Maryland/German type)

Prevalence

The Val30Met mutation, found worldwide, is the most widely studied TTR variant and is responsible for the well-known large foci of individuals with TTR amyloid polyneuropathy in Portugal, Sweden, and Japan. Numerous families with various non-Val30Met mutations have also been identified worldwide (Table 5).

The frequency of familial TTR amyloidosis caused by the mutation Val30Met is estimated to be one in 538 in northern Portugal (Povoa do Varzim and Vila do Conde), the largest cluster worldwide of individuals with familial TTR amyloidosis.

In individuals of northern European origin in the US, the frequency of Val30Met-related familial TTR amyloidosis is estimated to be one in 100,000 [Benson 2001].

The frequency of Val30Met heterozygotes is 1.5% in the northern part of Sweden [Holmgren et al 1994]; however, the penetrance is very low in this area [Hellman et al 2008] (see Penetrance).

The frequency of Val122Ile in the African American population is 3.0%-3.9%; most heterozygous individuals develop late-onset cardiac amyloidosis. Over 5.0% of the population in some areas of West Africa is heterozygous for this mutation. In the US, the frequency of Val122Ile in the white and Hispanic populations is 0.44% and 0.0%, respectively [Jacobson et al 1997, Yamashita et al 2005].

Differential Diagnosis

A total of 20 amyloidogenic proteins including transthyretin (TTR) have been identified in human amyloidoses [Buxbaum & Tagoe 2000]. Among the hereditary amyloidoses, familial TTR amyloidosis is the most prevalent. Other hereditary amyloidoses are summarized in Table 4 [Benson 2001, Hund et al 2001, Benson 2005].

Table 4. Other Hereditary Amyloidoses

TypeDisease NamePhenotypeProtein Name
NeuropathicApo AI amyloidosis (formerly familial amyloid polyneuropathy-III [Iowa type])Early
Nephropathy
Gastric ulcers
Polyneuropathy
Apolipoprotein A-I
Gelsolin amyloidosis (formerly familial amyloid polyneuropathy-IV [Finnish-Danish type])Cranial neuropathy
Corneal lattice dystrophy
Polyneuropathy
Carpal tunnel syndrome
Gelsolin
Non-neuropathicFibrinogen A α-associated amyloidosisNephropathy
Petechiae
Fibrinogen A α
Lysozyme-associated amyloidosisNephropathyLysozyme
Familial Mediterranean feverNephropathy
Peritonitis
Periodic fever
Pyrin (marenostrin)
Apo AII amyloidosisNephropathy
Gastrointestinal hemorrhage
Apolipoprotein A-II
CerebralAlzheimer disease type 3DementiaPresenilin 1
Alzheimer disease type 4Presenilin 2
Alzheimer disease type 1 (Swedish, London, Florida, Flemish, Arctic, Iowa type)Amyloid precursor protein
Hereditary cerebral hemorrhage with amyloid (Dutch type)Cerebral hemorrhageAmyloid precursor protein
Cystatin C amyloidosis (Icelandic type)Cerebral hemorrhageCystatin C
Familial British dementiaDementia
Ataxia
Spastic palsy
Cataract
Hearing loss
BRI
Familial Danish dementia

Non-hereditary systemic amyloidoses include senile systemic amyloidosis (SSA), immunoglobulin (AL) amyloidosis, reactive (secondary, AA) amyloidosis, and ß2-microglobulin (dialysis-associated) amyloidosis. Approximately one third of individuals with AL amyloidosis have neuropathic symptoms such as polyneuropathy, autonomic neuropathy,or carpal tunnel syndrome. Therefore, it is sometimes difficult to clinically distinguish familial TTR amyloidosis from AL amyloidosis. Immunohistochemical study of biopsied tissue is necessary for the diagnosis of both types of amyloidosis.

Other acquired and familial causes of neuropathy need to be considered (see Charcot-Marie-Tooth Hereditary Neuropathy Overview). Non-hereditary, non-amyloidotic causes of neuropathy such as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), Crow-Fukase syndrome (also known as POEMS [plasma cell neoplasia with polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes]), diabetic neuropathy, or Shy-Drager syndrome should be considered, particularly when family history is negative and when the disease is in the early stage. CIDP is the most common diagnostic error; 18/90 patients with familial TTR amyloidosis without a family history were mistakenly diagnosed with CIDP [Planté-Bordeneuve et al 2007].

If cardiomyopathy or CNS manifestations (rather than sensorimotor or autonomic neuropathy) are prominent, a wide variety of diseases should be considered. Cardiac amyloidosis should be differentiated from HFE-associated hereditary hemochromatosis, glycogen storage diseases (e.g., Pompe disease), Fabry disease, cardiac sarcoidosis, and mitochondrial cytopathy (MELAS), all of which may present with restrictive cardiomyopathy.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with familial transthyretin (TTR) amyloidosis, the following evaluations are recommended:

  • Complete neurologic assessment including baseline nerve conduction studies
  • Evaluation of the heart:
    • Echocardiogram, the most useful noninvasive test for cardiac amyloidosis, for visualization of ventricular wall thickness, ventricular septal thickness, and hyperrefractile myocardial echoes (so called "granular sparkling appearance")
    • Electrocardiogram (ECG) to evaluate for characteristic findings of cardiac amyloidosis including low voltage in the standard limb leads and QS pattern in the right precordial leads with or without conduction blocks
    • Myocardial technetium-99m-pyrophosphate scintigraphy to visualize amyloid deposition in heart [Ikeda 2004]
  • Gadolinium-enhanced MRI of the brain and spinal cord to evaluate CNS amyloidosis [Mitsuhashi et al 2004]
  • Ophthalmologic evaluation
  • Evaluation of renal function
  • Genetics consultation

Treatment of Manifestations

The following are appropriate:

  • Carpal tunnel release surgery for carpal tunnel syndrome
  • Vitrectomy for vitreous involvement
  • Cardiac pacemaker implantation for second-degree or third-degree AV block and sick sinus syndrome.

Prevention of Primary Manifestations

Orthotopic liver transplantation (OLTX). The only effective therapy for the neuropathy of familial TTR amyloidosis is orthotopic liver transplantation (OLTX), which removes the main production site of the amyloidogenic protein. Successful OLTX results in rapid disappearance of variant TTR protein from the serum and thus halts the progression of peripheral and/or autonomic neuropathy. It has been shown by pre- and postoperative sural nerve biopsy that myelinated nerve fibers regenerate after OLTX [Ikeda et al 1997].

Recommended clinical criteria for OLTX in individuals with TTR amyloid polyneuropathy [Takei et al 1999, Adams et al 2000] include the following:

  • Age younger than 60 years
  • Disease duration less than five years
  • Either polyneuropathy that is restricted to the lower extremities or autonomic neuropathy alone
  • No significant cardiac or renal dysfunction

As of the end of June 2010, 1913 individuals with familial TTR amyloidosis, approximately 90% of whom were heterozygous for the Val30Met mutation, had undergone liver transplantation (www.fapwtr.org/ram_fap.htm) [Ericzon et al 2000, Ikeda et al 2003, Herlenius et al 2004, Stangou & Hawkins 2004]. The five-year survival rate was significantly higher in individuals with the Val30Met mutation than in those with other mutations (80% vs 57%, p=0.001) [Ericzon et al 2000, Ikeda et al 2003]. The most common causes of postoperative death were cardiovascular events (29%) and septicemia (26%) [Ikeda et al 2003].

Poor outcomes of transplanted individuals based on ten years' experience [Ikeda et al 2003] include:

  • Poor nutritional condition (mean body mass index <600)
  • Severe polyneuropathy (Norris score <55/81)
  • Permanent urinary incontinence
  • Marked postural hypotension
  • A fixed pulse rate

OLTX is not effective in the non-neuropathic forms of familial TTR amyloidosis (i.e., cardiac amyloidosis, leptomeningeal amyloidosis, and familial oculoleptomeningeal amyloidosis [FOLMA]).

Cardiomyopathy was reported to progress after OLTX in some individuals with specific non-Val30Met mutations (Ala36Pro, Glu42Gly, and Ser77Tyr) (see Table 5) [Dubrey et al 1997, Stangou et al 1998, Yazaki et al 2000, Hornsten et al 2004]. It is presumed that amyloid cardiomyopathy may accelerate after OLTX by progressive deposition of wild-type TTR on a template of amyloid derived from variant TTR [Yazaki et al 2000, Hornsten et al 2004]. Therefore, it is critical to assess the severity of cardiac amyloidosis when considering OLTX [Coutinho et al 2004, Juneblad et al 2004].

Individuals with leptomeningeal involvement may not be candidates for liver transplantation because amyloidogenic TTR variants that cause intracranial amyloid deposits are considered to be derived from the choroid plexus.

Vitreous opacities may also progress after OLTX, possibly as the result of de novo production of variant TTR in the retinal epithelium.

Note: Because liver involvement in familial TTR amyloidosis is minimal, the liver of an individual with familial TTR amyloidosis can be grafted into an individual with liver cancer or end-stage liver disease (so-called "domino" liver transplantation). Since 1995, more than 330 domino liver transplantations have been performed. Several individuals who had received a liver graft from heterozygotes with familial TTR amyloidosis developed symptomatic systemic TTR amyloidosis [Stangou et al 2005, Goto et al 2006, Barreiros et al 2010, Obayashi et al 2011, Lladó et al 2011, Adams et al 2011]

Prevention of Secondary Complications

Cardiac pacing for persons with familial TTR amyloidosis with conduction block helps prevent sudden death.

Surveillance

Serial nerve conduction studies can be used to objectively monitor the course of the polyneuropathy.

Serial electrocardiogram, echocardiography, and serum B-type natriuretic peptide (BNP) level can be used to monitor the course of cardiomyopathy and conduction block.

Modified body mass index (mBMI) can be used to monitor nutritional status.

Agents/Circumstances to Avoid

Since most individuals with familial TTR amyloidosis have decreased temperature and pain perception, affected individuals should not use local heating appliances, such as hot-water bottles, which can cause low-temperature burn injury.

Evaluation of Relatives at Risk

It is appropriate to offer molecular genetic testing to at-risk relatives if the disease-causing mutation is identified in an affected family member so that morbidity and mortality can be reduced by early diagnosis and treatment.

If the disease-causing mutation in the family is not known, it is appropriate to offer clinical diagnostic evaluations to identify those family members who will benefit from early treatment.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Strategies of potential molecular therapies for familial TTR amyloidosis include the following [Saraiva 2002, Ando 2003, Sekijima et al 2008]:

  • Inhibition of synthesis of variant TTR
  • Stabilization of variant TTR
  • Inhibition of aggregation of amyloidogenic intermediates
  • Disruption of insoluble amyloid fibrils

Drugs that stabilize the TTR tetramer and prevent dissociation into monomers and drugs that disrupt TTR amyloid fibrils into amorphous materials have been designed [Saraiva 2002, Miller et al 2004, Almeida et al 2005].

Phase I and II clinical trials of diflunisal showed that diflunisal increased serum TTR stability in persons with familial TTR amyloidosis beyond the level of normal controls without adverse effects. A randomized double-blind placebo-controlled multicenter/multinational clinical trial is currently underway to determine whether diflunisal will alter the progression of familial TTR amyloidosis [Sekijima et al 2006, Tojo et al 2006]. This study is currently fully enrolled; results are anticipated in December, 2012.

Recently, tafamidis(Vyndaqel®), a small molecule that binds TTR tetramer selectively and potently, has been developed as a TTR kinetic stabilizer to ameliorate familial TTR amyloidosis. In a dose escalation Phase I study in healthy volunteers, tafamidis was found to be safe and well tolerated. In addition, tafamidis showed strong TTR stabilization effects in plasma of study participants. Phase II/III studies of tafamidis showed efficacy in delaying peripheral neurologic impairment compared with individuals treated with placebo. In addition, tafamidis resulted in improved nutritional status (modified body mass index, mBMI) of the study participants.

Based on these findings, the European Commission approved tafamidis for the treatment of familial TTR amyloid polyneuropathy in adult individuals with stage 1 symptomatic polyneuropathy in November, 2011. Tafamidis will be available by prescription in Europe in early 2012.

Inhibition of variant TTR mRNA expression by small interfering RNAs (siRNA) [Love et al 2010] and antisense oligonucleotide [Benson et al 2006] is also under investigation.

In July 2010, Alnylam pharmaceuticals initiated dosing in a Phase I human clinical study with siRNA. The Phase I study was designed as a randomized, placebo-controlled, single-dose escalation study in individuals with familial TTR amyloidosis. The administration of siRNA(ALN-TTR01) resulted in statistically significant reductions in serum TTR protein levels in affected individuals. Lowering of serum TTR protein was found to be dose dependent, rapid, and durable after just a single dose.

Isis pharmaceuticals is currently evaluating oligonucleotide targeting of TTR amyloidosis (ISIS-TTRRx) in a Phase I study.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

Plasma exchange, affinity column binding with a monoclonal antibody, and use of a special column with affinity for TTR were considered as possible methods for elimination of amyloidogenic TTR from the blood circulation. Serum TTR levels decreased significantly immediately after treatment, but then returned to the same levels as before treatment because of the rapid turnover of TTR. Therefore, these methods were concluded not to be effective for familial TTR amyloidosis.

4’-iodo-4’-deoxydoxorubicin (IDOX) has been reported to bind to several types of amyloid and lead to the catabolism of amyloid in deposits. In a multicenter clinical trial, IDOX was administered to persons with AL amyloidosis; however, no obvious benefit could be detected.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Familial transthyretin (TTR) amyloidosis is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Some individuals diagnosed with familial TTR amyloidosis have an affected parent.
  • A proband with familial TTR amyloidosis may have the disorder as the result of a new gene mutation. The proportion of cases caused by de novo mutation is unknown.
  • Recommendations for the evaluation of parents of a proband with apparent de novo mutation include molecular genetic testing if the pathogenic variant in TTR has been identified in the proband.

    Note: The family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent.

Sibs of a proband

  • The risk to sibs depends on the genetic status of the parents.
  • Sibs of an affected individual have a 50% chance of inheriting a TTR pathogenic variant if one parent has a pathogenic variant.
  • At least 26 homozygous persons with familial TTR amyloidosis have been reported. In this circumstance, sibs of the proband have a 50% chance of inheriting one TTR mutation and a 25% chance of inheriting two TTR pathogenic variants.
  • If the pathogenic variant found in the proband cannot be detected in the DNA of either parent, the risk to sibs is low but greater than that of the general population because (although no instances have been reported to date) germline mosaicism remains a possibility.

Offspring of a proband

  • Every child of an affected individual has a 50% risk of inheriting a pathogenic variant in TTR.
  • If the proband is homozygous for a TTR mutation, all offspring will inherit the pathogenic variant.

Other family members of a proband. The risk to other family members depends on the genetic status of the proband's parents. If a parent is affected or has a pathogenic variant, his or her family members are at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Testing of at-risk asymptomatic adults. Testing of at-risk asymptomatic adults for familial TTR amyloidosis is possible using the techniques described in Molecular Genetic Testing. Such testing is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals. When testing at-risk individuals for familial TTR amyloidosis, an affected family member should be tested first to confirm the molecular diagnosis in the family.

Testing for the pathogenic variant in the absence of definite symptoms of the disease is predictive testing. At-risk symptomatic adult family members may seek testing in order to make personal decisions regarding reproduction, financial matters, and career planning. Others may have different motivations including simply the "need to know." Testing of asymptomatic at-risk adult family members usually involves pretest interviews in which the motives for requesting the test, the individual's knowledge of familial TTR amyloidosis, the possible impact of positive and negative test results, and neurologic status are assessed. Those seeking testing should be counseled regarding possible problems that they may encounter with regard to health, life, and disability insurance coverage, employment and educational discrimination, and changes in social and family interaction. Other issues to consider are implications for the at-risk status of other family members. Informed consent should be procured and records kept confidential. Individuals with a positive test result need arrangements for long-term follow-up and evaluation.

Related liver transplantation donors. In Japan, where liver transplantation from living, related donors is the generally accepted therapy of familial TTR amyloidosis, molecular genetic testing of asymptomatic adult relatives is always performed on family members volunteering to be donors.

Molecular genetic testing of asymptomatic individuals younger than age 18 years who are at risk for adult-onset disorders is not considered appropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.

Children who are symptomatic usually benefit from having a specific diagnosis established. See also the National Society of Genetic Counselors position statement on genetic testing of minors and the American Society of Human Genetics and American College of Medical Genetics points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals

Prenatal Testing

If the pathogenic variant has been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for adult-onset conditions which (like familial TTR amyloidosis) do not affect intellect and have some treatment available are not common. Differences in perspective may exist among medical professionals and in families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) has been reported [Almeida et al 2005] and may be an option for some families in which the pathogenic variant has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Amyloidosis Foundation (AF)
    7151 North Main Street
    Suite 2
    Clarkston MI 48346
    Email: info@amyloidosis.org
  • American Liver Foundation
    75 Maiden Lane
    Suite 603
    New York NY 10038
    Phone: 800-465-4837 (Toll-free HelpLine); 212-668-1000
    Fax: 212-483-8179
    Email: info@liverfoundation.org
  • Neuropathy Association, Inc.
    60 East 42nd Street
    Suite 942
    New York 10165
    Phone: 212-692-0662
    Fax: 212-692-0668
    Email: info@neuropathy.org
  • Transthyretin Amyloidosis Outcomes Survey (THAOS)
    Phone: 617-252-5500
    Fax: 617-252-5501
    Email: THAOS@foldrx.com

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Familial Transthyretin Amyloidosis: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Familial Transthyretin Amyloidosis (View All in OMIM)

105210AMYLOIDOSIS, HEREDITARY, TRANSTHYRETIN-RELATED
176300TRANSTHYRETIN; TTR

Molecular Genetic Pathogenesis

The main component of amyloid is protein fibrils. In familial transthyretin (TTR) amyloidosis, the fibrils are mainly composed of self-aggregated TTR protein. TTR protein is potentially amyloidogenic because of its extensive beta-sheet structure. The key factor in amyloidogenesis in familial TTR amyloidosis is the stability of the TTR protein [Kelly 1998, Rochet & Lansbury 2000, Sekijima et al 2005]. The TTR protein normally circulates in plasma as a soluble protein having a tetrameric structure. The amyloidogenic process is understood to comprise two steps: soluble TTR tetramers dissociate into pro-amyloidogenic monomers that, in turn, polymerize into amyloid fibrils in certain tissues [Kelly 1998, Rochet & Lansbury 2000]. Pathogenic mutations in TTR cause significant conformational change in TTR protein molecules, in turn disrupting the stability of the TTR tetramer. In other words, a tetramer containing variant TTR monomers is more easily dissociated into pro-amyloidogenic monomers than is a normal TTR tetramer [Sekijima et al 2005].

It has been demonstrated that all disease-associated TTR variants are energetically (thermodynamically and kinetically) less stable than wild-type TTR. On the other hand, suppressor mutations (Thr119Met and Arg104His) are more stable than wild-type TTR. In vitro amyloidogenicity correlates very well with protein stability. However, extremely destabilized (highly amyloidogenic in vitro) TTR variants do not induce severe systemic amyloidosis because serum concentrations of these TTR variants are very low. The low serum concentration of highly destabilized TTR variants is a result of degradation by endoplasmic reticulum (ER) quality control system (ERAD) of the hepatic cells. The most pathogenic TTR variant (Leu55Pro) exhibiting the earliest disease onset is the most destabilized variant that can be secreted at levels comparable to the wild-type, barely avoiding ERAD. TTR variants that predominantly induce CNS amyloidosis are the least stable variants. The choroid plexus secretes highly destabilized TTR variants more efficiently than hepatic cells, thus, it is thought, accounting for CNS selective amyloid deposition (leptomeningeal amyloidosis) [Hammarström et al 2003, Sekijima et al 2003, Mitsuhashi et al 2005, Sekijima et al 2005].

Gene structure. Human TTR contains four exons and spans approximately 7 kb. All exons but exon 1 consist of fewer than 200 base pairs. Exon 1 encodes a signal peptide and the first three amino acids of the mature protein. Normal allelic variants have been described in individuals of various ethnic backgrounds (Table 5) [Nakazato 1998, Benson 2001, Saraiva 2001, Connors et al 2003]. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. To date, more than 90 point mutations and one in-frame microdeletion have been identified in exons 2-4 in TTR in individuals with familial TTR amyloidosis [Connors et al 2000, Benson 2001, Saraiva 2001, Connors et al 2003, Benson & Kincaid 2007]. No mutation has been described in exon 1, which encodes amino acids 1 through 3.

The Val30Met pathogenic variant, found worldwide, is the most widely studied TTR variant and is responsible for the well-known large foci of individuals with TTR amyloid polyneuropathy in Portugal, Sweden, and Japan. Several haplotypes are associated with Val30Met in different ethnic groups, suggesting that multiple founders spontaneously occurred in each group.

Val122Ile, present in 3.0%-3.9% of African Americans and more than 5.0% of the population in some areas of West Africa, is the most common amyloid-associated TTR variant worldwide [Jacobson et al 1997, Yamashita et al 2005].

Table 5. TTR Variants and Their Phenotypes

LocationProtein Amino Acid Change
(Standard Nomenclature) 1, 2
(DNA Nucleotide Change – Standard Nomenclature) 1, 2PhenotypeGeographic Focus
Exon 2Gly6Ser
(p.Gly26Ser)
(c.76G>A) 3Non-amyloid, FEH 4Northern European origin
Cys10Arg
(p.Cys30Arg)
(c.88T>C)Heart, eye, PN USA
Leu12Pro
(p.Leu32Pro)
(c.95T>C)LM, liver UK
Met13Ile
(p.Met33Ile)
(c.99G>C) 3Non-amyloidGermany
Asp18Glu
(p.Asp38Glu)
(c.114T>A)PN South America, USA
Asp18Gly
(p.Asp38Gly)
(c.113A>G)LM Hungary
Asp18Asn
(p.Asp38Asn)
(c.112G>A)Heart USA
Val20lle
(p.Val40Ile)
(c.118G>A)Heart, CTS Germany, USA
Ser23Asn
(p.Ser43Asn)
(c.128G>A)Heart, PN, eye USA
Pro24Ser
(p.Pro44Ser)
(c.130C>T)Heart, CTS, PN USA
Ala25Ser
(p.Ala45Ser)
(c.133G>T)Heart, CTS, PN USA
Ala25Thr
(p.Ala45Thr)
(c.133G>A)LM, PN Japan
Val28Met
(p.Val48Met)
(c.142G>A)PN, AN Portugal
Val30Met
(p.Val50Met)
(c.148G>A)PN, AN, eye, LM Portugal, Japan, Sweden, USA
Val30Ala
(p.Val50Ala)
(c.149T>C)Heart, AN USA
Val30Leu
(p.Val50Leu)
(c.148G>C)PN, heart Japan
Val30Gly
(p.Val50Gly)
(c.149T>G)LM, eye USA
Val32Ala
(p.Val52Ala)
(c.155T>C)PN Israel
Phe33Ile
(p.Phe53Ile)
(c.157T>A)PN, eye Israel
Phe33Leu
(p.Phe53Leu)
(c.157T>C)PN, heart USA
Phe33Val
(p.Phe53Val)
(c.157T>G)PN , eyeUK, Japan, China
Phe33Cys
(p.Phe53Cys)
(c.158T>G)CTS, heart, eye, kidney USA
Arg34Thr
(p.Arg54Thr)
(c.161G>C)PN, heart Italy
Arg34Gly
(p.Arg54Gly)
(c.160A>G)Eye UK
Lys35Asn
(p.Lys55Asn)
(c.165G>C)PN, AN, heart France
Lys35Thr
(p.Lys55Thr)
(c.164A>C)Eye USA
Ala36Pro
(p.Ala56Pro)
(c.166G>C)Eye, CTS USA
Asp38Ala
(p.Asp58Ala)
(c.173A>C)PN, heart, lungJapan
Trp41Leu
(p.Trp61Leu)
(c.182G>T)Eye, PN USA
Glu42Gly
(p.Glu62Gly)
(c.185A>G)PN, AN, heart Japan, USA, Russia
Glu42Asp
(p.Glu62Asp)
(c.186G>T)Heart France
Phe44Ser
(p.Phe64Ser)
(c.191T>C)PN, AN, heart USA
Ala45Thr
(p.Ala65Thr)
(c.193G>A)Heart USA
Ala45Asp
(p.Ala65Asp)
(c.194C>A)Heart, PN USA
Ala45Ser
(p.Ala65Ser)
(c.193G>T)Heart Sweden
Gly47Arg
(p.Gly67Arg)
(c.199G>A)PN, AN Japan
Gly47Ala
(p.Gly67Ala)
(c.200G>C)Heart, AN Italy, France
Gly47Val
(p.Gly67Val)
(c.200G>T)CTS, PN, AN, heart Sri Lanka
Gly47Glu
(p.Gly67Glu)
(c.200G>A)Heart, PN, AN Turkey, USA, Germany
Exon 3Thr49Ala
(p.Thr69Ala)
(c.205A>G)Heart, CTS France, Italy
Thr49Ile
(p.Thr69Ile)
(c.206C>T)PN, heart Japan, Spain
Thr49Pro
(p.Thr69Pro)
(c.205A>C)Heart, PN USA
Ser50Arg
(p.Ser70Arg)
(c.210T>C)AN, PN Japan, France/Italy, USA
Ser50Ile
(p.Ser70Ile)
(c.209G>T)Heart, PN, AN Japan
Glu51Gly
(p.Glu71Gly)
(c.212A>G)Heart USA
Ser52Pro
(p.Ser72Pro)
(c.214T>C)PN, AN, heart, kidneyUK
Gly53Glu
(p.Gly73Glu)
(c.218G>A)LM, heart Basque, Sweden
Gly53Ala
(p.Gly73Ala)
(c.218G>C)LM, heart UK
Glu54Gly
(p.Glu74Gly)
(c.221A>G)PN, AN, eye UK
Glu54Lys
(p.Glu74Lys)
(c.220G>A)PN, AN, heart, eye Japan
Glu54Leu
(p.Glu74Leu)
(c.220_221delGAinsCT) Not describedUK
Leu55Pro
(p.Leu75Pro)
(c.224T>C)Heart, AN, eye USA, Taiwan
Leu55Arg
(p.Leu75Arg)
(c.224T>G)LM Germany
Leu55Gln
(p.Leu75Gln)
(c.224T>A)Eye, PN USA
His56Arg
(p.His76Arg)
(c.227A>G)Heart USA
Gly57Arg
(p.Gly77Arg)
(c.229G>A)Heart Sweden
Leu58His
(p.Leu78His)
(c.233T>G)CTS, heart USA (MD)
Leu58Arg
(p.Leu78Arg)
(c.233T>G)CTS, AN, eye Japan
Thr59Lys
(p.Thr79Lys)
(c.236C>A)Heart, PN, AN Italy, USA (Chinese)
Thr60Ala
(p.Thr80Ala)
(c.238A>G)Heart, CTS USA (Appalachian)
Glu61Lys
(p.Glu81Lys)
(c.241G>A)PN Japan
Glu61Gly
(p.Glu81Gly)
(c.242A>G)Heart, PN USA
Phe64Leu
(p.Phe84Leu)
(c.250T>C)PN, CTS, heart USA, Italy
Phe64Ser
(p.Phe84Ser)
(c.251T>C)LM, PN, eye Canada, UK
Ile68Leu
(p.Ile88Leu)
(c.262A>T)Heart, PN Germany
Tyr69His
(p.Tyr89His)
(c.265T>C)Eye, LM Canada, USA
Tyr69Ile
(p.Tyr89Ile)
(c.265_266delTAinsAT)Heart, CTS, AN Japan
Lys70Asn
(p.Lys90Asn)
(c.270A>C)Eye, CTS, PN USA
Val71Ala
(p.Val91Ala)
(c.272T>C)PN, Eye, CTS France, Spain
Ile73Val
(p.Ile93Val)
(c.277A>G)PN, AN Bangladesh
Asp74His
(p.Asp94His)
(c.280G>C) 3Non-amyloid, Germany
Ser77Tyr
(p.Ser97Tyr)
(c.290C>A)Heart, kidney, PNUSA (IL, TX), France
Ser77Phe
(p.Ser97Phe)
(c.290C>T)PN, AN, heart France
Tyr78Phe
(p.Tyr98Phe)
(c.293A>T)PN, CTS, skin France
Ala81Thr
(p.Ala101Thr)
(c.301G>A)Heart USA
Ala81Val
(p.Ala101Val)
(c.302C>T)Heart UK
Ile84Ser
(p.Ile104Ser)
(c.311T>G)Heart, CTS, eye USA (IN), Hungary
Ile84Asn
(p.Ile104Asn)
(c.311T>A)Heart, eye USA
Ile84Thr
(p.Ile104Thr)
(c.311T>C)Heart, PN Germany, UK
His88Arg
(p.His108Arg)
(c.323A>G)Heart Sweden
Glu89Gln
(p.Glu109Gln)
(c.325G>C)PN, heart Italy
Glu89Lys
(p.Glu109Lys)
(c.325G>A)PN, heart USA
His90Asn
(p.His110Asn)
(c.328C>A) 3Non-amyloidGermany, Portugal
His90Asp
(p.His110Asp)
(c.328C>G)Heart UK
Ala91Ser
(p.Ala111Ser)
(c.331G>T)PN, CTS, heart France
Glu92Lys
(p.Gln112Lys)
(c.334G>A)Heart Japan
Val94Ala
(p.Val114Ala)
(c.341T>C)Heart, PN, AN, kidney Germany, USA
Exon 4Ala97Gly
(p.Ala117Gly)
(c.350C>G)Heart, PN Japan
Ala97Ser
(p.Ala117Ser)
(c.349G>T)PN, heart Taiwan, USA
Asp99Asn
(p.Asp119Asn)
(c.355G>A)Non-amyloidDenmark
Gly101Ser
(p.Gly121Ser)
(c.361G>A) 3Non-amyloidJapan
Pro102Arg
(p.Pro122Arg)
(c.365C>G) 3Non-amyloidGermany
Arg103Ser
(p.Arg123Ser)
(c.367C>A)HeartUSA
Arg104Cys
(p.Arg124Cys)
(c.370C>T) 3Non-amyloidUSA
Arg104His
(p.Arg124His)
(c.371G>A) 3Non-amyloid, FEHJapan, USA (Chinese)
Ile107Val
(p.Ile127Val)
(c.379A>G)Heart, CTS, PN USA
Ile107Met
(p.Ile127Met)
(c.381T>C)PN, heart Germany
Ile107Phe
(p.Ile127Phe)
(c.379A>T)PN, AN UK
Ala109Thr
(p.Ala129Thr)
(c.385G>A) 3Non-amyloid, FEHPortugal
Ala109Val
(p.Ala129Val)
(c.385G>A) 3Non-amyloid, FEH 4USA
Ala109Ser
(p.Ala129Ser)
(c.386C>T)PN, AN Japan
Leu111Met
(p.Leu131Met)
(c.391C>A)Heart Denmark
Ser112Ile
(p.Ser132Ile)
(c.395G>T)PN, heart Italy
Tyr114Cys
(p.Tyr134Cys)
(c.401A>G)PN, AN, eye, LM Japan, USA
Tyr114His
(p.Tyr134His)
(c.400T>C)CTS, skin Japan
Tyr116Ser
(p.Tyr136Ser)
(c.407A>C)PN, CTS, AN France
Thr119Met
(p.Thr139Met)
(c.416C>T) 3Non-amyloid, FEH 4Portugal, USA
Ala120Ser
(p.Ala140Ser)
(c.418G>T)AN, heart, PN Afro-Caribbean
Val122Ile
(p.Val142Ile)
(c.424G>A)Heart USA
delVal122
(p.Val142del)
(c.424_426delGTC)Heart, PN USA, Ecuador, Spain
Val122Ala
(p.Val142Ala)
(c.425T>CHeart, eye, PN USA
Pro125Ser
(p.Pro145Ser)
(c.433C>T) 3Non-amyloidogenicItaly

Table derived from Connors et al [2003] and Benson & Kincaid [2007]

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

AN = autonomic neuropathy

CTS = carpal tunnel syndrome

FEH = familial euthyroid hypertyroxinemia (see Genetically Related Disorders)

LM = leptomeningeal

PN = peripheral neuropathy

1. For the DNA nucleotide change the numbering begins at the Met initiation codon.

2. For the protein amino acid change, both alternate and standard (parentheses) naming conventions are given. The alternate designations are numbered according to the beginning of the mature protein, while the standard nomenclature uses numbering beginning at the Met initiation codon and includes the 20 amino-acid signal sequence. The nucleotide naming conventions follow those of Human Genome Variation Society (www​.hgvs.org).

Reference sequences for the standard nomenclature are NM_000371​.1 and NP_000362​.1.

3. Benign variant

4. See Genetically Related Disorders.

Normal gene product. The human TTR cDNA encodes a 20-amino acid signal peptide plus a 127-amino acid mature protein with molecular mass 14 kd. TTR is a normal plasma protein synthesized predominantly by the liver. TTR is secreted into plasma as a tetrameric form (Mw = 55 kd) composed of four identical monomers; its plasma half-life is approximately one to two days. TTR concentration in plasma normally ranges from 20 to 40 mg/dL.

TTR is considered to transport thyroxine and retinol-binding protein (RBP) coupled to vitamin A. TTR binds virtually all of serum RBP and approximately 15% of serum thyroxine. In the cerebrospinal fluid, TTR is required for transport of serum thyroxine across the blood-brain barrier.

The choroid plexus is the source of the cerebrospinal fluid TTR. The TTR concentration in cerebrospinal fluid ranges from 10 µg/mL to 40 µg/mL.

The other site of synthesis is the retina.

Abnormal gene product. It is speculated that amyloidogenic TTR variants reduce the stability of the physiologic TTR tetramer, and consequently produce a pro-amyloidogenic monomer more easily than normal TTR (see Molecular Genetic Pathogenesis) [Kelly 1998, Rochet & Lansbury 2000, Saraiva 2002, Sekijima et al 2005].

References

Published Guidelines/Consensus Statements

  1. American Society of Human Genetics and American College of Medical Genetics. Points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents. Available online. 1995. Accessed 3-12-14. [PMC free article: PMC1801355] [PubMed: 7485175]
  2. National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset disorders. Available online. 2012. Accessed 3-12-14.

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Suggested Reading

  1. Sekijima Y, Kelly JW, Ikeda S. Pathogenesis of and therapeutic strategies to ameliorate the transthyretin amyloidoses. Curr Pharm Des. 2008;14:3219–30. [PubMed: 19075702]
  2. Planté-Bordeneuve V, Said G. Familial amyloid polyneuropathy. Lancet Neurol. 2011;10:1086–97. [PubMed: 22094129]

Chapter Notes

Revision History

  • 26 January 2012 (me) Comprehensive update posted live
  • 15 September 2009 (me) Comprehensive update posted live
  • 15 March 2006 (me) Comprehensive update posted to live Web site
  • 2 March 2005 (cd) Revision: mutation scanning and sequencing of select exons no longer clinically available
  • 5 March 2004 (ky) Revision: molecular genetic testing
  • 9 January 2004 (me) Comprehensive update posted to live Web site
  • 5 November 2001 (me) Review posted to live Web site
  • 25 June 2001 (ky) Original submission
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Tests in GTR by Gene

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