Clinical characteristics.

Hereditary transthyretin amyloidosis (ATTRv amyloidosis) is characterized by a slowly progressive peripheral sensorimotor and/or autonomic neuropathy. Amyloidosis can involve the heart, central nervous system (CNS), eyes, and kidneys. 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 paresthesia and hypesthesia 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 restrictive 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. Ocular involvement includes vitreous opacity, glaucoma, dry eye, and ocular amyloid angiopathy. Mild-to-severe kidney disease can develop.

Diagnosis/testing.

The diagnosis of ATTRv amyloidosis is established in a proband with characteristic clinical features, including imaging or histopathology findings of amyloidosis, and a heterozygous pathogenic variant in TTR identified by molecular genetic testing.

Management.

Targeted therapies: Pharmacotherapeutics (e.g., gene-silencing therapies, transthyretin tetramer stabilizers) are first-line therapy for all individuals with ATTRv amyloidosis. There is limited indication for orthotopic liver transplantation.

Treatment of manifestations: Pharmacologic treatments for neuropathic pain; surgical release for carpal tunnel syndrome; ankle-foot orthoses and physical therapy for motor neuropathy; standard treatments for autonomic dysfunction and CNS manifestations. In those with sick sinus syndrome or second- or third-degree atrioventricular block, a cardiac pacemaker may be indicated. Vitrectomy for vitreous opacification; surgical treatment for glaucoma; ocular lubrication for dry eye; erythropoietin or intravenous iron for normocytic normochromic anemia; hemodialysis as needed for end-stage kidney disease.

Surveillance: Abdominal wall fat aspiration or gastrointestinal tract biopsy annually to identify disease onset in asymptomatic individuals; systematic neurologic screening at least annually; nerve conduction studies annually; clinical assessment for manifestations of cardiac disease and serum B-type natriuretic peptide levels annually; electrocardiogram and echocardiography at least annually; ^99mTc-PYP myocardial scintigraphy every three to five years; clinical assessment for dementia, psychosis, headache, seizures, motor paresis, and ataxia annually; ophthalmology examination including assessment for glaucoma at least annually; laboratory assessment of kidney function annually; modified body mass index annually; assessment of psychological manifestations as needed.

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

Evaluation of relatives at risk: Clarify the genetic status of at-risk relatives by molecular genetic testing for the TTR pathogenic variant(s) in the family in order to identify as early as possible those who would benefit from prompt early diagnosis and treatment.

Genetic counseling.

ATTRv amyloidosis is inherited in an autosomal dominant manner. Each child of an individual who is heterozygous for a TTR pathogenic variant has a 50% risk of inheriting the TTR pathogenic variant. All offspring of an individual who has biallelic TTR pathogenic variants will inherit a pathogenic variant. Once the TTR pathogenic variant(s) has been identified in an affected family member, predictive testing for at-risk family members and prenatal/preimplantation genetic testing are possible.

Suggestive Findings

Hereditary transthyretin amyloidosis (ATTRv amyloidosis) should be suspected in adults with the following clinical, imaging, and histopathology findings and family history.

Clinical findings. Slowly progressive sensorimotor and/or autonomic neuropathy that is frequently accompanied by one or more of the following:

• Cardiac conduction blocks
• Cardiomyopathy
• Nephropathy
• Vitreous opacities
• Glaucoma

Imaging findings

• Echocardiogram may show left ventricular or biventricular thickening with speckled myocardium.
• Gadolinium contrast-guided cardiac MRI can show characteristic gadolinium distribution. Note: Gadolinium administration in those with ATTRv amyloidosis-related nephropathy can lead to nephrogenic systemic fibrosis.
• Bone scintigraphy using ^99mtechnetium-3,3-diphosphono-1-2-propanodicarboxylic acid (Tc-DPD), ^99mTc-pyrophosphate (Tc-PYP), and/or ^99mTc-hydroxymethylene-diphosphonate (Tc-HMDP) can show cardiac amyloid [Gillmore et al 2016]. Note: Bone scintigraphy is negative in young individuals with the TTR p.Val50Met pathogenic variant.
• Amyloid PET imaging using Pittsburgh compound B is useful for detecting amyloid in individuals with early-onset ATTRv amyloidosis due to the TTR p.Val50Met pathogenic variant [Takasone et al 2020].

Histopathology findings

• Tissue biopsy to identify amyloid deposits. Tissues suitable for biopsy include subcutaneous fatty tissue of the abdominal wall, skin, gastric or rectal mucosa, sural nerve, endocardium, and peritendinous fat from specimens obtained at carpal tunnel surgery. With Congo red staining, amyloid deposits show a characteristic yellow-green birefringence under polarized light.
  Note: Sensitivity of endoscopic biopsy of gastrointestinal mucosa is approximately 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].
• Immunohistochemistry of tissue biopsies with anti-transthyretin antibodies can identify amyloid deposits.

Family history is consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations). Family history can include rapidly progressive polyneuropathy of unknown cause, cardiac failure, sudden cardiac death, or cardiac arrhythmia. Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of ATTRv amyloidosis is established in a proband with suggestive findings (including imaging or histopathology findings of ATTRv amyloidosis) and a heterozygous pathogenic (or likely pathogenic) variant in TTR identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous TTR variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Clinical Description

Clinical features of hereditary transthyretin amyloidosis (ATTRv amyloidosis) can include peripheral sensorimotor neuropathy and autonomic neuropathy, as well as non-neuropathic changes. Cardiac amyloidosis (e.g., restrictive cardiomyopathy, arrhythmia), leptomeningeal amyloidosis (e.g., transient focal neurologic episodes, intracerebral and/or subarachnoid hemorrhages), ophthalmopathy (e.g., vitreous opacities, glaucoma), and nephropathy are frequently seen in the advanced stage of the disease (see Table 2). Affected individuals can also present with non-neuropathic forms of ATTRv amyloidosis in which polyneuropathy is less evident.

Onset. The disease usually begins earlier in persons from endemic foci in Portugal and Japan. In Japanese individuals from two large endemic foci (Ogawa and Arao) heterozygous for TTR pathogenic variant p.Val50Met, the mean age at onset is 40.1 ± 12.8 years (range: age 22-74 years) [Nakazato 1998]. In persons of Portuguese ancestry with TTR pathogenic variant p.Val50Met, the mean age at onset is 33.5 ± 9.4 years (range: age 17-78 years). In persons of Japanese ancestry with p.Val50Met who are unrelated to the two large endemic foci, the mean age at onset is much later (62.7 ± 6.6 years; range: age 52-80 years) [Misu et al 1999, Ikeda et al 2002]. In 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]. Individuals with pathogenic variant p.Val50Met and early-onset disease have type B amyloid fibrils composed of full-length transthyretin (TTR), whereas individuals with p.Val50Met and late-onset disease have type A amyloid fibrils composed of both full-length TTR and TTR fragments [Ihse et al 2008, Ihse et al 2013].

Neuropathy. The cardinal feature of ATTRv amyloidosis neuropathy is slowly progressive sensorimotor and autonomic neuropathy [Ando et al 2005]. Typically, sensory neuropathy starts in the lower extremities and is followed by motor neuropathy within a few years. The initial symptoms are paresthesia (sense of burning, shooting pain) or hypoesthesia 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. Individuals with TTR pathogenic variants p.Leu78His, p.Leu78Arg, p.Lys90Asn, p.Ile104Ser, p.Ile127Val, and p.Tyr134His tend to develop carpal tunnel syndrome as an initial manifestation [Nakazato 1998, Connors et al 2000, Benson 2001, Hund et al 2001, Connors et al 2003]. Due to sensory neuropathy, trophic ulcers on the lower extremities are common.

Motor neuropathy (muscle atrophy and weakness) of the extremities develops with foot drop, wrist drop, and disability of the hands and fingers. Eventually sensorimotor neuropathy shows a glove-and-stocking distribution.

Autonomic neuropathy may be the presenting manifestation of ATTRv amyloidosis, including orthostatic hypotension, constipation alternating with diarrhea, attacks of nausea and vomiting, delayed gastric emptying, impotence, anhidrosis, and urinary retention or incontinence. Frequently, the autonomic neuropathy produces the most significant morbidity of the disorder. Amyloid deposition in the gastrointestinal tract wall, especially with involvement of the gastrointestinal autonomic nerves, is common [Ikeda et al 1982, Ikeda et al 1983].

Cardiac amyloidosis. Most individuals develop cardiac manifestations after age 50 years. Cardiac manifestations include arrhythmias such as atrioventricular block, sick sinus syndrome, and atrial fibrillation due to amyloid deposition in the heart. Amyloid deposition in the myocardium causes progressive restrictive cardiomyopathy and heart failure, and it is thought that ventricular diastolic dysfunction precedes systolic dysfunction. In some individuals, cardiomyopathy is the predominant feature and peripheral neuropathy is not present.

The typical electrocardiogram shows a pseudoinfarction pattern with prominent Q wave in leads II, III, _aV_F, 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 show a "granular sparkling appearance."

Leptomeningeal amyloidosis / cerebral amyloid angiopathy. Liver transplant and disease-modifying drugs do not affect TTR production in the choroid plexus, and TTR production in the cranial nervous system (CNS) continues in those on therapy. This results in the emergence of CNS manifestations. The most common include transient focal neurologic episodes (TFNEs), in which affected individuals have short, self-limited episodes of focal cortical dysfunction, including hemiparesis, hemisensory disturbance, and motor aphasia. TFNEs are common, particularly in individuals with TTR pathogenic variant p.Val50Met and long-standing disease [Sekijima et al 2016, Taipa et al 2023, Takahashi et al 2023]. Following TFNEs, dementia and intracranial hemorrhage can develop approximately 20 years after the onset of ATTRv amyloidosis [Takahashi et al 2023].

Amyloid deposition is seen in the pial and arachnoid membrane, as well as in the walls of blood vessels in the subarachnoid space. Amyloid in the blood vessels disappears as the vessels penetrate the brain parenchyma. More rarely, a few individuals have developed myelopathy, caused by amyloid deposition in the blood vessel walls in the spinal cord [Dowell et al 2007].

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]. CNS amyloid deposition can also be detected by amyloid PET, using Pittsburgh compound B (PiB) [Sekijima et al 2016].

Ophthalmopathy. Ocular involvement, including vitreous opacity, glaucoma, dry eye, and ocular amyloid angiopathy, is common and occurs in most individuals with TTR pathogenic variant p.Val50Met [Ando et al 1997]. Vitreous opacification has been reported in approximately 20% of individuals with ATTRv amyloidosis. Four of 43 individuals with TTR pathogenic variant p.Val50Met developed vitreous amyloidosis as the first manifestation of ATTRv amyloidosis [Kawaji et al 2004]. In one individual vitreous opacification was the only evidence of ATTRv amyloidosis [Yazaki et al 2002].

Nephropathy. The kidney is consistently involved, with marked deposition of amyloid demonstrated at postmortem examination. Mild-to-severe kidney involvement is usually seen in the advanced stage [Haagsma et al 2004, Lobato et al 2004]. Kidney involvement is preceded by proteinuria. Kidney failure occurs in about one third of individuals of Portuguese descent with early-onset ATTRv amyloidosis caused by TTR pathogenic variant p.Val50Met [Lobato et al 2004]; however, severe kidney dysfunction rarely occurs in individuals with late-onset disease. Anemia with low erythropoietin has been reported in 25% of individuals [Beirão et al 2004].

Other

• Nodular cutaneous amyloidosis has been reported in one individual [Mochizuki et al 2001].
• Shortness of breath induced by diffuse pulmonary amyloid deposition has been reported in two individuals [Yazaki et al 2000].

Prognosis. Sensorimotor and autonomic neuropathy progress over ten to 20 years. Cachexia is a common feature at the late stage of the disease. Affected individuals usually die of cardiac failure, kidney failure, or infection.

Homozygotes / compound heterozygotes. Homozygosity for TTR pathogenic variant p.Val50Met has been reported in at least 19 individuals from 14 families [Tojo et al 2008]. Individuals homozygous and compound heterozygous for other TTR pathogenic variants have also been reported. Individuals with biallelic TTR pathogenic variants have increased penetrance and earlier onset than heterozygotes within the same family [Reddi et al 2014]; amyloid deposition is also more widespread in those with biallelic pathogenic variants than in heterozygotes [Yoshinaga et al 2004]. However, there are some reported homozygous individuals from non-endemic areas with p.Val50Met or p.Val142Ile with disease onset at the same age as heterozygotes [Uchida et al 2015, Micaglio et al 2023].

Genotype-Phenotype Correlations

Despite intensive investigation, few genotype-phenotype correlations have been detected. Most TTR pathogenic variants result in peripheral and autonomic neuropathy; but some pathogenic variants have been associated with phenotypes in which peripheral or autonomic neuropathy is clinically absent or less prominent:

• A cardiac-dominant phenotype is associated with p.Asp38Asn, p.Val40Ile, p.Pro44Ser, Ala65Ser, p.Ala65Thr, p.His76Arg, p.Gly77Arg, p.Ile88Leu, p.Ala101Thr, p.Ala101Val, p.His108Arg, p.Glu112Lys, p.Arg123Ser, p.Leu131Met, or p.Val142Ile [Nakazato 1998, Benson 2001, Saraiva 2001, Connors et al 2003, Benson & Kincaid 2007]. Peripheral and autonomic neuropathy are absent or less evident in persons with these variants.
• A leptomeningeal-dominant phenotype is associated with p.Leu32Pro, p.Asp38Gly, p.Ala45Thr, p.Val50Gly, p.Ala56Pro, p.Gly73Glu, p.Gly73Ala, p.Phe84Ser, p.Tyr89His, or p.Tyr134Cys [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]. It has been demonstrated that highly destabilizing TTR pathogenic variants induce leptomeningeal amyloidosis [Hammarström et al 2001, Sekijima et al 2003, Sekijima et al 2005].
• A leptomeningeal- and ocular-dominant phenotype are the first and primary manifestations in individuals with TTR pathogenic variants p.Ala45Thr, p.Gly73Arg, p.Gly73Glu, p.Tyr89His, and p.Tyr134Cys [Sousa et al 2021].

The benign TTR variant c.416C>T (p.Thr139Met) has a protective effect on amyloidogenesis in individuals who also have TTR pathogenic variant p.Val50Met [Hammarström et al 2001, Sebastião et al 2001].

Penetrance

Penetrance for ATTRv amyloidosis is not 100%; an individual with a TTR pathogenic variant may remain symptom-free until late adulthood. The penetrance may vary by pathogenic variant, geographic region, or ethnic group.

The penetrance appears to be much higher in individuals in endemic foci than outside of endemic foci [Misu et al 1999]. In Portugal, cumulative disease risk in individuals with TTR pathogenic variant p.Val50Met is estimated at 80% by age 50 years and 91% by age 70 years, whereas the risk in French heterozygotes is 14% by age 50 years 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 years, respectively [Hellman et al 2008].

Some p.Val50Met homozygotes remain asymptomatic.

Nomenclature

Historical protein numbering was based on the mature protein after cleavage of a 20-amino-acid signal sequence (e.g., p.Val50Met would be referred to as Val30Met). Standard nomenclature uses numbering beginning at the Met initiation codon. Variants reported in older literature may use historical nomenclature.

ATTRv amyloidosis-related neuropathy 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)

The abbreviation "ATTRv" refers to hereditary transthyretin-related amyloid protein [Ando et al 2022]; "v" stands for variant and is the recommended abbreviation in the International Society of Amyloidosis (ISA) nomenclature committee [Buxbaum et al 2022].

Prevalence

TTR pathogenic variant p.Val50Met is the most common pathogenic variant in Portugal, Sweden, and Japan; p.Val50Met is also one of the most common pathogenic variants worldwide. The frequency of ATTRv amyloidosis caused by p.Val50Met is estimated at 1:538 in northern Portugal (Povoa do Varzim and Vila do Conde), the largest cluster worldwide of individuals with ATTRv amyloidosis. The frequency of p.Val50Met 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). In individuals of northern European origin in the United States, the frequency of p.Val50Met-related ATTRv amyloidosis is estimated at 1:100,000 [Benson 2001].

The frequency of p.Val142Ile in the African American population is 3.0%-3.9%; most heterozygous individuals develop late-onset cardiac amyloidosis. More than 5% of the population in some areas of West Africa is heterozygous for this variant. The high frequency of p.Val142Ile in the African American population 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 [Akinboboye et al 2020].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with hereditary transthyretin amyloidosis (ATTRv amyloidosis), the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 7 are recommended [Ueda et al 2020, Ando et al 2022].

Agents/Circumstances to Avoid

Since most individuals with ATTRv 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 injuries.

Evaluation of Relatives at Risk

For early diagnosis and treatment. It is appropriate to clarify the genetic status of apparently asymptomatic adult at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures to reduce morbidity and mortality.

For liver donation. In Japan, where liver transplantation from living, related donors is the generally accepted therapy for ATTRv amyloidosis, molecular genetic testing is always performed on asymptomatic adult family members volunteering to be liver donors.

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

Therapies Under Investigation

Strategies for potential molecular therapies for ATTRv amyloidosis include the following:

• Stabilization of variant transthyretin (TTR). A Phase III clinical trial of a new TTR tetramer stabilizer, acoramidis, showed greater TTR stabilization and clinical benefit in individuals with ATTRv amyloidosis-related cardiomyopathy [Gillmore et al 2024, Verbeeck et al 2024] (see NCT03860935). To date, acoramidis is not FDA approved.
• Gene editing of TTR. NTLA-2001, a new gene-editing therapy using the CRISPR/Cas9 technology, showed reducuction of serum TTR concentration comparable to gene silencers in a Phase I clinical trial [Gillmore et al 2021]. A Phase III clinical trial of NTLA-2001 is under way (see NCT04601051).
• Disruption of insoluble amyloid fibrils
  • A Phase I clinical trial of NI006, an investigational antibody designed to target and clear the amyloid conformations of both wild type and variant TTR but not physiologically folded TTR, is completed [Garcia-Pavia et al 2023], and a Phase III trial is under way.
  • A Phase II clinical trial of PRX004/NN6019, an investigational antibody designed to target and clear the pathogenic, misfolded forms of the TTR protein found in ATTR without affecting the native, or normal, tetrameric form of the protein, is under way (see NCT05442047).

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

Hereditary transthyretin amyloidosis (ATTRv amyloidosis) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Some individuals diagnosed with ATTRv amyloidosis have an affected parent.
  Note: If an individual diagnosed with ATTRv amyloidosis has biallelic TTR pathogenic variants, both parents may be affected and/or heterozygous for a TTR pathogenic variant.
• A proband with ATTRv amyloidosis may have the disorder as the result of a de novo pathogenic variant. The proportion of individuals with a de novo TTR pathogenic variant is unknown.
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• The family history of some individuals diagnosed with ATTRv amyloidosis 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. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent has the pathogenic variant(s) identified in the proband.

Sibs of a proband. The risk to sibs depends on the genetic status of the parents:

• If one parent of the proband is known to be heterozygous for a TTR pathogenic variant, the risk to sibs of inheriting a TTR pathogenic variant is 50%.
• If both parents of the proband are known to be heterozygous for a TTR pathogenic variant, sibs of the proband have a 50% chance of inheriting one TTR pathogenic variant and a 25% chance of inheriting two TTR pathogenic variants (see Clinical Description, Homozygotes / compound heterozygotes).
• Significant clinical variability may be observed among affected family members, with age of onset differing by ten to 20 years or more.
• If the TTR pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental germline mosaicism [Rahbari et al 2016].
• If the parents have not been tested for the TTR pathogenic variant but are clinically unaffected, sibs of the proband are presumed to be at increased risk for ATTRv amyloidosis because of the possibility of reduced penetrance in a parent or the possibility of parental germline mosaicism.

Offspring of a proband

• Each child of an individual who is heterozygous for a TTR pathogenic variant has a 50% risk of inheriting the TTR pathogenic variant.
• All offspring of an individual who has biallelic TTR pathogenic variants will inherit a TTR pathogenic variant.

Other family members. 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, the parent's 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.

Predictive testing (i.e., testing of asymptomatic at-risk individuals)

• Predictive testing for at-risk relatives is possible once the TTR pathogenic variant(s) have been identified in an affected family member. Such testing is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals.
• Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
• In Japan, where liver transplantation from living, related donors is the generally accepted therapy for ATTRv amyloidosis, molecular genetic testing is always performed on asymptomatic adult family members volunteering to be liver donors.

Predictive testing in minors (i.e., testing of asymptomatic at-risk individuals younger than age 18 years)

• For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, 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.
• For more information, see the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Academy of Pediatrics and American College of Medical Genetics and Genomics policy statement: ethical and policy issues in genetic testing and screening of children.

In a family with an established diagnosis of ATTRv amyloidosis, it is appropriate to consider testing of symptomatic individuals regardless of age.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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.

Prenatal Testing and Preimplantation Genetic Testing

Once the TTR pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing for ATTRv amyloidosis are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. For more information, see the National Society of Genetic Counselors position statement on prenatal testing in adult-onset conditions.

Molecular Pathogenesis

TTR encodes transthyretin (TTR), a protein synthesized predominantly by the liver and secreted into plasma as a tetramer composed of four identical monomers. TTR is also synthesized in the retina and choroid plexus. TTR pathogenic variants reduce the stability of the TTR tetramer and produce a pro-amyloidogenic monomer. The amyloidogenic process occurs in 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 variants in TTR cause significant conformational change in TTR protein molecules, in turn disrupting the stability of the TTR tetramer. Tetramers containing abnormal TTR monomers more easily dissociate into pro-amyloidogenic monomers than do normal TTR tetramers [Sekijima et al 2005].

In vitro amyloidogenicity correlates with protein stability. All abnormal TTR proteins are energetically (thermodynamically and kinetically) less stable than wild type TTR. However, extremely destabilized (highly amyloidogenic in vitro) TTR protein does not result in severe systemic amyloidosis because serum concentrations of TTR are very low due to protein degradation before secretion. The most clinically severe TTR pathogenic variant (p.Leu75Pro), associated with the earliest disease onset, is the most destabilized variant that can be secreted at levels comparable to the wild type, consistent with disease-associated variants being missense rather than nonsense or deletion/duplication. TTR pathogenic variants that are predominantly associated with central nervous system (CNS) amyloidosis result in the least stable TTR protein. The choroid plexus secretes highly destabilized TTR more efficiently than hepatic cells, potentially accounting for CNS-selective amyloid deposition (leptomeningeal amyloidosis) [Hammarström et al 2003, Sekijima et al 2003, Mitsuhashi et al 2005, Sekijima et al 2005].

Mechanism of disease causation. Gain of function

Author History

Shu-ichi Ikeda, MD, PhD; Shinsu University Hospital (2001-2018)
Katsuya Nakamura; MD, PhD (2024-present)
Yoshiki Sekijima, MD, PhD (2006-present)
Takahiko Tokuda, MD, PhD; Kyoto Prefectural University Hospital (2001-2018)
Kunihiro Yoshida, MD, PhD; Shinsu University Hospital (2001-2018)

Revision History

• 30 May 2024 (sw) Comprehensive update posted live
• 20 December 2018 (sw) Comprehensive update posted live
• 26 January 2012 (me) Comprehensive update posted live
• 15 September 2009 (me) Comprehensive update posted live
• 15 March 2006 (me) Comprehensive update posted live
• 9 January 2004 (me) Comprehensive update posted live
• 5 November 2001 (me) Review posted live
• 25 June 2001 (ky) Original submission

Published Guidelines / Consensus Statements

• Adams D, Ando Y, Beirão JM, Coelho T, Gertz MA, Gillmore JD, Hawkins PN, Lousada I, Suhr OB, Merlini G. Expert consensus recommendations to improve diagnosis of ATTR amyloidosis with polyneuropathy. J Neurol. 2021;268:2109-22. [PubMed]
• Ando Y, Adams D, Benson MD, Berk JL, Planté-Bordeneuve V, Coelho T, Conceição I, Ericzon BG, Obici L, Rapezzi C, Sekijima Y, Ueda M, Palladini G, Merlini G. Guidelines and new directions in the therapy and monitoring of ATTRv amyloidosis. Amyloid. 2022;29:143-55. [PubMed]
• Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available online. 2013. Accessed 5-21-24.
• National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available online. 2018. Accessed 5-21-24.

Literature Cited

• Adams D, Lacroix C, Antonini T, Lozeron P, Denier C, Kreib AM, Epelbaum S, Blandin F, Karam V, Azoulay D, Adam R, Castaing D, Samuel D. Symptomatic and proven de novo amyloid polyneuropathy in familial amyloid polyneuropathy domino liver recipients. Amyloid. 2011;18 Suppl 1:174–7. [PubMed: 21838477]
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