Adult Summary Report

Secondary Findings in Adult Subjects

Non-diagnostic, excludes newborn screening & prenatal testing/screening

• Status (Adult): Passed (Consensus scoring is Complete)
• Curation Status (Adult): Released 2.0.4
• Status (Pediatric): Incomplete (Consensus scoring is Incomplete)
• GENE/GENE PANEL: TTR
• Condition: Hereditary transthyretin-related amyloidosis
• Mode(s) of Inheritance: Autosomal Dominant

Actionability Assertion

• TTR ⇔ 0007100 (familial amyloid neuropathy): Strong Actionability

Actionability Rationale

All experts agreed with the assertion computed according to the rubric.

Final Consensus Scores

Gene Condition Pairs: TTR ⇔ 0007100 (OMIM:105210)

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the Intervention	Total Score
Morbidity and mortality from amyloidosis / Referral to specialist and surveillance for amyloidosis to guide appropriate downstream treatment	2	3C	2B	2	9CB
Morbidity and mortality from cardiac amyloidosis / Referral to specialist and surveillance for amyloidosis to guide appropriate downstream pharmacotherapy treatment (tafamidis)	2	3C	3C	3	11CC

1. What is the nature of the threat to health for an individual carrying a deleterious allele?

Prevalence of the Genetic Condition

Familial transthyretin (TTR) amyloidosis is considered endemic in Portugal, Japan, Sweden, and Brazil. The frequency of familial TTR amyloidosis in northern Portugal is estimated as 1 in 1108. In Europe, the prevalence of familial TTR amyloidosis is estimated as less than 1 in 100,000 individuals. In some areas of Japan, the prevalence of familial TTR amyloidosis is approximately 1 in 1,000,000. The Val50Met variant, the most widely studied variant, is estimated as 1 in 538 in northern Portugal, the largest cluster worldwide. In individuals of northern European origin in the US, the frequency of Val50Met-related familial TTR amyloidosis is estimated as 1 in 100,000. The worldwide prevalence of cardiac TTR amyloidosis is unknown, but it is almost certainly underdiagnosed, particularly in the African American population. [1, 2, 3, 4, 5]

Clinical Features

TTR amyloidosis is characterized by extracellular deposition of amyloid fibrils composed of TTR that accumulate in various organs and tissues. Presence of a disease-causing variant is not considered diagnostic due to variable penetrance; clinical observation and tissue biopsy are required for diagnosis. Clinical features include progressive peripheral sensorimotor and autonomic neuropathies and non-neuropathic cardiomyopathy, nephropathy, vitreous opacities, and central nervous system (CNS) amyloidosis. The spectrum of cardiovascular involvement is wide, ranging from asymptomatic atrioventricular and bundle branch block to severe, rapidly progressive heart failure due to restrictive pathophysiology. The majority of familial TTR amyloidosis cases are neuropathic, but there are several phenotypes:
• TTR amyloid neuropathy, mostly due to the Val50Met variant, includes slowly progressive sensory neuropathy that begins in the lower extremities, followed by motor neuropathy within a few years. Sensory neuropathy progresses to sensory loss, muscle atrophy, and weakness of the extremities. Autonomic neuropathy may occur as the first symptom of the disease and may produce the most significant morbidity. It includes orthostatic hypotension, disturbances of gastrointestinal motility, sexual impotence, anhidrosis, and urinary retention or incontinence. Cachexia is a common feature at the late stage of the disease. Cardiomyopathy, ophthalmopathy, nephropathy, and CNS manifestations are frequent in advanced disease.
• TTR cardiac amyloidosis, associated with specific variants such as Val142Ile and Leu111Met, is characterized by progressive cardiomyopathy. It generally presents with restrictive cardiomyopathy with varying degrees of chronic heart failure and possible brady/ tachyarrhythmias. Polyneuropathy is absent or, if present, less evident.
• Leptomeningeal amyloidosis is a relatively rare subtype associated with CNS findings: dementia, psychosis, visual impairment, headache, seizures, motor paresis, ataxia, myelopathy, hydrocephalus, or intracranial hemorrhage. Polyneuropathy is absent or, if present, less evident. When associated with vitreous amyloid deposits, leptomeningeal amyloidosis is known as familial oculoleptomeningeal amyloidosis (FOLMA). [1, 2, 3, 4, 5, 6]

Natural History

TTR amyloidosis is clinically heterogeneous, with presentation depending on genotype and geographic origin. The age at onset varies between the second and ninth decades of life, with great variations across different populations. Based on age of symptom onset, TTR amyloidosis can be divided into early onset (< 50 years old) and late onset (≥ 50 years old). TTR amyloid neuropathy usually begins in the third to fifth decade (mean age of 33 years) in persons from endemic foci in Portugal and Japan. Onset is later in persons from other areas (e.g., 56 years in Sweden). Even in foci generally considered early-onset, some subgroups of patients experience a later onset. Sensorimotor neuropathy and autonomic neuropathy progress over ten to 20 years, with a mean period of 10 years from onset to death when untreated. Cardiac amyloidosis is usually later onset; most individuals develop cardiac symptoms after age 30 years. Cardiac amyloidosis is four times more common among blacks than whites in individuals in the US older than age 60 years. Homozygous individuals present with a slightly more severe clinical course (higher incidence rate and earlier onset) than heterozygous individuals within the same family. In patients with cardiac-related symptoms, 5-year survival is less than 50%. Major events include progressive heart failure and sudden death due to arrhythmia. Affected individuals usually die of cardiac failure, renal failure, or infection. [1, 2, 3, 4, 5, 6]

2. How effective are interventions for preventing harm?

Patient Management

To establish the extent of disease in an individual diagnosed with familial transthyretin (TTR) amyloidosis, the following evaluations are recommended:
- Gadolinium-enhanced MRI of the brain and spinal cord and amyloid PET imaging to evaluate CNS amyloidosis
- Ophthalmologic evaluation to evaluate for vitreous opacities and glaucoma
- Evaluation of renal function. (Tier 4) [1]

To confirm amyloidosis, demonstration of amyloid deposits via tissue biopsy is essential. Tissue confirmation helps management, especially in oligosymptomatic TTR variant carriers with normal/borderline neurological examination and/or neurophysiological tests. (Tier 2) [2, 5]

At diagnosis, individuals should undergo a complete neurologic assessment which may include electromyographic testing with sympathetic skin response (SSR), quantitative sensory testing, heart rate deep breathing, and other autonomic tests, determined by presenting physical signs. Symptoms and stage of disease progression can be identified by neurologic scales/tests and the modified body mass index (mBMI), a measure of nutritional status and wasting (Tier 2) [2]

TTR requires comprehensive multidisciplinary care to improve patient care and quality of life. Symptomatic treatment should be provided to every patient, as many patients may not have access to anti-amyloid therapy. (Tier 2) [5]

A cardiologist should look for signs of cardiac amyloid involvement. Electrocardiography (ECG), echocardiography, scintigraphy with bone tracers, biomarkers (brain natriuretic peptide [BNP] and troponin I or T) and cardiac magnetic resonance (CMR) imaging usually provide all the necessary information to diagnose infiltrative cardiomyopathy. Holter monitoring may also be recommended. (Tier 2) [2]

A systematic review and meta-analysis assessed diagnostic performance of CMR and nuclear scintigraphy for cardiac amyloidosis. Estimates for sensitivity and specificity of CMR ranged from 79-86% and 92-94%, respectively, depending on tissue used for histopathological reference, while estimates for nuclear scintigraphy ranged from 82-88% and 87-99%, respectively. However, only nuclear scintigraphy was able to reliable differentiate between TTR and immunoglobulin light-chain (AL) amyloidosis (sensitivity: 91-92%; specificity: 89-97%). A second systematic review and meta-analysis estimated the sensitivity and specificity of bone scintigraphy in detecting cardiac TTR amyloidosis as 92% and 95%, respectively. (Tier 1) [7, 8]

An implantable cardiac device (ICD) should be considered in patients with hereditary TTR-associated cardiac amyloidosis with ventricular arrhythmia (VA) causing hemodynamic instability who are expected to survive 1 year with good functional status. There is currently insufficient data to provide recommendations on primary prophylaxis. Case reports describe successful termination of sustained VA with ICDs. A study of 19 patients with histologically proven cardiac amyloidosis and a history of syncope (n=4), ventricular extra beats (n=10), or both (n=5) received an ICD. During a mean follow-up of 811 +/- 151 days, 2 patients with sustained VAs were successfully treated. Two patients underwent heart transplantation, and 7 died due to electromechanical dissociation (n=6) or glioblastoma (n=1). Non-survivors more often showed progression of left ventricular wall thickness, higher levels of N-terminal proBNP, low-voltage pattern on echocardiogram, and ventricular extra beats more often than in survivors, indicating ICD is not appropriate for all patients. (Tier 2) [9]

Pharmacotherapy with TTR stabilizing agents (tafamidis and diflunisal) can be prescribed at an early stage (stage 0 when patients are asymptomatic with evidence of amyloid deposits or stage I with mild disease and are ambulatory) of disease in anticipation of liver transplantation or potentially delaying the need for liver transplant. (Tier 2) [2, 5]

In a study of untreated (n=1771), liver transplant-treated (n=957), and tafamidis-treated (n=432) cohorts, tafamidis reduced mortality risk 91% compared to no treatment and 63% compared to liver transplant in early-onset disease. Among individuals with late-onset disease, tafamidis reduced mortality risk 82% compared to no treatment. (Tier 3) [1]

Importantly, tafamidis is only FDA approved for TTR cardiac amyloidosis. In a Phase III trial of 441 patients with TTR amyloidosis cardiomyopathy (included hereditary and wild type TTR amyloidosis), tafamidis reduced mortality of all causes (29.5% vs. 42.9%), cardiovascular-related hospitalizations (0.48 per year vs. 0.70 per year), and the rate in decline in functional capacity (6-minute walk test) and increased quality of life compared to placebo. (Tier 3) [1]

Other therapeutic agents include TTR gene silencers. In a Phase III clinical trial of 225 patients, patisiran (approved by the FDA for TTR amyloidosis neuropathy), a small interfering RNA (siRNA) therapeutic agent, showed efficacy in halting peripheral neurologic impairment compared with placebo. In a Phase III clinical trial of 172 patients, inotersen (approved by the FDA for TTR amyloidosis), an anti-sense oligonucleotide (ASO) therapeutic agent, showed efficacy in delaying peripheral neurologic impairment and improved quality of life compared with placebo. (Tier 2) [2, 5]

For individuals with mild (stage I, symptomatic but ambulatory) or moderate disease (stage II, ambulatory with assistance) and a confirmed diagnosis by biopsy, liver transplant is the current standard of care. Since variant TTR is produced largely in the liver, liver transplant should almost completely eliminate production of the variant protein (removes roughly 95%) and halt disease progression outside the brain and eyes. Nerve function rarely improves after successful liver transplantation; however, a lessening of autonomic disturbances may occur. Liver transplant does not effectively prevent cardiomyopathy in most cases and is not recommended for patients with late-stage TTR amyloidosis or leptomeningeal-type amyloidosis. Moreover, cardiac disease may progress even after successful liver transplant, especially in patients with variants other than Val50Met. Organ impairment that occurred before the transplant does not usually reverse. Overall, liver transplant has the best outcomes when performed in young patients whose disease has not become advanced. Long-term observations show clear regression of amyloid deposits and an overall patient survival rate at 5 years of >77%. Outcomes from the Familial Amyloidosis Polyneuropathy World Transplant Registry (FAPWTR) indicate variant-specific utility survival: 10-year survival rate of 74% for Val50Met versus 44% for non-Val50Met patients. Most recent reports from FAPWTR indicate an overall 20-year survival rate of 55%. Since the development of TTR stabilizers, liver transplant rates are decreasing. The role of liver transplant in the era of TTR stabilizer treatment is yet to be defined. (Tier 2) [2, 5]

Surveillance

Individuals should undergo the following assessments every 6 months to monitor disease progression (Tier 2):
• Neurologic assessment and nerve conduction and sensory assessments
• Autonomic function should be assessed by heart rate deep breathing measures
• Echocardiography
• Holter monitoring
• Ophthalmologic testing
• mBMI
• Electrophysiologic evaluation
• Cardiac and renal laboratory measures (plasma brain natriuretic peptide (BNP), NT-proNBP, serum troponin, creatinine clearance, albuminuria). (Tier 2) [2]

Circumstances to Avoid

Individuals should not use local heating appliances, such as hot-water bottles, which can cause low-temperature burn injury in those with decreased temperature and pain perception. (Tier 4) [1]

3. What is the chance that this threat will materialize?

Mode of Inheritance

Autosomal Dominant

Prevalence of Genetic Variants

Val50Met is the most prevalent TTR pathogenic variant in the world, focused in Portugal, Sweden, Japan, Brazil, and Majorca. It is believed to have arisen independently in Portugal and Sweden. In a recent review of the literature, Val50Met was observed in 49% of cases. In endemic areas of northern Sweden, the frequency of Val50Met is 4%. The frequency of heterozygotes is 1.5% in the northern part of Sweden. (Tier 3) [1, 2, 5]

Families with variants other than Val50Met have also been identified worldwide. (Tier 4) [1, 2]

The cardiomyopathy-related Leu111Met and Val142Ile variants are found primarily in Danish and African American populations, respectively. (Tier 4) [2]

The frequency of Val142Ile in the African American population is 3.0-3.9%. More than 5% of the population in some areas of West Africa is heterozygous for this variant. In the US, the frequency of Val142Ile in the white and Hispanic populations is 0.44% and 0.0%, respectively. (Tier 3) [1, 2]

Penetrance

Penetrance for familial TTR amyloidosis is not 100%. (Tier 4) [1]

Cardiac disease occurs in approximately 50% of patients. (Tier 3) [2]

Within a global longitudinal study on the natural history of TTR amyloidosis, 611 of 885 (69%) individuals with a TTR pathogenic variant (Val50Met, Val142Ile, Leu111Met, or Glu89Gln) were symptomatic and had received a clinical diagnosis of TTR amyloidosis. Among symptomatic patients, 86.1% reported signs/symptoms of sensory neuropathy, 42.1% had signs/symptoms of cardiac disease. Gastrointestinal manifestations and autonomic neuropathy were recorded in 65.5% and 50.1%, respectively (Tier 5) [10]

Penetrance may vary by variant, geographic region, or ethnic group. In Portugal, cumulative risk of disease in individuals with the Val50Met variant 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. 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. In Brazil, penetrance is 83% by age 63 years. (Tier 3) [1, 2, 5]

In a multi-site, hospital-based study of 3160 symptomatic patients with TTR amyloidosis with the Val50Met variant, 1001 (32%) underwent a liver transplant during a period from first patient observation to December 2016. (Tier 3) [1]

Relative Risk

Information on relative risk was not available for the Adult context.

Expressivity

Phenotypes are not always uniform, and the same point mutation may have varied phenotypes even within the same family. (Tier 4) [2]

4. What is the Nature of the Intervention?

Nature of Intervention

Management includes regular invasive and non-invasive surveillance. Recommendations also include potential pharmacotherapy, liver transplant, and ICD implantation. TTR stabilizing agents are capsules taken once (tafamidis) or twice (diflunisal) daily. Preliminary evidence of these pharmacotherapies in clinical trials indicate they are well-tolerated. However, there are concerns about long-term complications of diflunisal (an NSAID) in the kidneys, heart, and gastrointestinal tract; indeed 57% of patients in the clinical trial who discontinued therapy did so due to gastrointestinal disorders. For TTR gene stabilizers, patisiran is administered intravenously over approximately 80 minutes once every 3 weeks. Inotersen is administered as weekly subcutaneous injections that can be administered at clinical visits or at home by the patient, a trained family member, or a health professional. The overall incidence and types of adverse events were similar in patisiran and placebo groups. The most frequent serious adverse events in the inotersen group were glomerulonephritis (in 3%) and sudden, severe thrombocytopenia (3%), with one death associated with one of the cases of grade 4 thrombocytopenia. Many patients are able to live relatively normal lives after liver transplant. However, in addition to the risks of liver transplant surgery, patients also need to remain on immunosuppressants for the rest of their lives. Cardiac risks and complications constitute major adverse events in patients undergoing orthotopic liver transplant for TTR amyloidosis. Cardiovascular complications account for about 39% of deaths following liver transplant, almost half of which occur within the first 3 months. Implantation of an ICD in 19 patients was complicated by a lead revision because of low sensing (n=1) or frequent discharges due to atrial fibrillation with high ventricular rate response (n=2) over a median of 536 days. None of the patients died of perioperative complications. No other relevant technical complications or device failures occurred during follow-up. [1, 2, 5, 9]

5. Would the underlying risk or condition escape detection prior to harm in the settting of recommended care?

Chance to Escape Clinical Detection

Given its phenotypic unpredictability and variability, TTR amyloidosis can be difficult to recognize and manage. Misdiagnosis is common, and patients may wait several years before accurate diagnosis, risking additional significant irreversible deterioration. Many patients are erroneously diagnosed with simple carpal tunnel syndrome; progressive symptoms or lack of improvement after surgery often leads to the correct diagnosis. (Tier 4) [2]

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a common misdiagnosis, especially in late-onset patients without a family history. Cardiac TTR amyloidosis is thought to be vastly underdiagnosed, particularly when neurologic involvement is mild or absent. Poor sensitivity and specificity of echocardiography in detecting cardiac amyloidosis may contribute to the substantial misdiagnosis or delay in diagnosing it. (Tier 3) [2, 5, 7]

Date of Search: 08.28.2017 (updated 12.23.2019)

Reference List

1. Y Sekijima, K Yoshida, T Tokuda, S Ikeda. Familial Transthyretin Amyloidosis. 2001 Nov 05 [Updated 2012 Jan 26]. In: MP Adam, HH Ardinger, RA Pagon, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1194

2. Ando Y, Coelho T, Berk JL, Cruz MW, Ericzon BG, Ikeda S, Lewis WD, Obici L, Plante-Bordeneuve V, Rapezzi C, Said G, Salvi F. Guideline of transthyretin-related hereditary amyloidosis for clinicians. Orphanet J Rare Dis. (2013) 8:31.

3. ATTRV30M amyloidosis. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=85447

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5. Pinto MV, Barreira AA, Bulle AS, Freitas MRG, Franca MC Jr, Gondim FAA, Marrone CD, Marques W Jr, Nascimento OJM, Rotta FT, Pupe C, Waddington-Cruz M. Brazilian consensus for diagnosis, management and treatment of transthyretin familial amyloid polyneuropathy. Arq Neuropsiquiatr. (2018) 76(9):609-621.

6. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. AMYLOIDOSIS, HEREDITARY, TRANSTHYRETIN-RELATED. MIM: 105210: 2019 Aug 01. World Wide Web URL: http://omim.org.

7. Brownrigg J, Lorenzini M, Lumley M, Elliott P. Diagnostic performance of imaging investigations in detecting and differentiating cardiac amyloidosis: a systematic review and meta-analysis. ESC Heart Fail. (2019) 6(5):1041-1051.

8. Treglia G, Glaudemans AWJM, Bertagna F, Hazenberg BPC, Erba PA, Giubbini R, Ceriani L, Prior JO, Giovanella L, Slart RHJA. Diagnostic accuracy of bone scintigraphy in the assessment of cardiac transthyretin-related amyloidosis: a bivariate meta-analysis. Eur J Nucl Med Mol Imaging. (2018) 45(11):1945-1955.

9. Priori SG, Blomstrom-Lundqvist C, Mazzanti A, Blom N, Borggrefe M, Camm J, Elliott PM, Fitzsimons D, Hatala R, Hindricks G, Kirchhof P, Kjeldsen K, Kuck KH, Hernandez-Madrid A, Nikolaou N, Norekval TM, Spaulding C, Van Veldhuisen DJ. 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC). Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC). Eur Heart J. (2015) 36(41):2793-867.

10. Coelho T, Maurer MS, Suhr OB. THAOS - The Transthyretin Amyloidosis Outcomes Survey: initial report on clinical manifestations in patients with hereditary and wild-type transthyretin amyloidosis. Curr Med Res Opin. (2013) 29(1):63-76.