YES NO UNKNOWN. Stage I: Rule-Out Dashboard Secondary Findings in Adults ACTIONABILITY PENETRANCE SIGNIFICANCE/BURDEN OF DISEASE NEXT STEPS

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1 Stage I: Rule-Out Dashboard GENE/GENE PANEL: TTR DISORDER: Hereditary transthyretin-related amyloidosis HGNC ID: OMIM ID: ACTIONABILITY PENETRANCE 1. Is there a qualifying resource, such as a practice guideline or systematic review, for the genetic condition? YES 2. Does the practice guideline or systematic review indicate that the result is actionable in one or more of the following ways? Yes No Patient Management Surveillance or Screening 4. Is there at least one known pathogenic variant with at least moderate penetrance ( 40%) or moderate relative risk ( 2) in any population? YES UNKWN SIGNIFICANCE/BURDEN OF DISEASE 5. Is this condition an important health problem? YES Family Management Circumstances to Avoid YES ( 1 of above) NEXT STEPS 6. Are Actionability (Q2-3), Penetrance (Q4), and Significance (Q5) all YES? 3. Is the result actionable in an undiagnosed adult with the genetic condition? YES YES (Proceed to Stage II) (Consult Actionability Working Group) Exception granted, proceed to Stage II Exception not granted, STOP 1

2 Signif/Burden of Condition Stage II: Summary Report GENE/GENE PANEL: TTR DISORDER: Hereditary transthyretin-related amyloidosis Topic Narrative Description of Evidence Ref 1. What is the nature of the threat to health for an individual carrying a deleterious allele? Prevalence of the genetic disorder The frequency of familial transthyretin (TTR) amyloidosis caused by the Val30Met 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 Val30Met-related familial TTR amyloidosis is estimated as 1 in 100,000. In Europe, the prevalence is estimated as less than 1 in 100,000 individuals. In some areas of Japan, the prevalence is approximately 1 in 1,000,000. The worldwide prevalence of cardiac TTR amyloidosis is unknown, but it is almost certainly underdiagnosed, particularly in the African American population. 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 peripheral sensorimotor and autonomic neuropathies and nonneuropathic 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 TTR cases are neuropathic, but there are several manifestations: (1-4) (1-5) Clinical Features (Signs/symptoms) Natural History (Important subgroups & survival/recovery) TTR amyloid neuropathy (familial amyloid polyneuropathy type I; Portuguese-Swedish-Japanese type) is mostly due to the Val30Met variant. This phenotype includes slowly progressive sensory neuropathy 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. Cardiac disease occurs in approximately 50% of individuals, most commonly amyloid cardiomyopathy. Individuals may also have ocular and renal involvement. Cachexia is a common feature at the late stage of the disease. TTR amyloid neuropathy (familial amyloid polyneuropathy type II; Indiana/Swiss or Maryland/ German type) is associated with the Ile84Ser variant and starts in the upper extremities as carpal tunnel syndrome. Sensorimotor neuropathy and autonomic neuropathy are accompanied by visceral involvement. Cardiomyopathy and/or nephropathy are frequent in advanced disease. TTR cardiac amyloidosis is characterized by progressive cardiomyopathy without peripheral neuropathy and is associated with the Val122Il3 variant. It generally presents with restrictive cardiomyopathy with varying degrees of chronic heart failure and possible brady/ tachyarrhythmias. Leptomeningeal amyloidosis is associated with the Asp18Gly variant and 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). TTR amyloidosis is clinically heterogeneous, with the 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. 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. (1-5) 2

3 Stage II: Summary Report Cardiac amyloidosis is usually late onset; most individuals develop cardiac symptoms after age 30 years. Cardiac amyloidosis is four times more common among blacks than whites. Homozygotes present with a slightly more severe clinical course (higher incidence rate and earlier onset) than heterozygotes within the same family. In patients with cardiac-related symptoms, 5-year survival is less than 50%. Affected individuals usually die of cardiac failure, renal failure, or infection. 2. How effective are interventions for preventing the harm? Information on the effectiveness of the recommendations below was not provided unless otherwise stated. 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 to evaluate CNS amyloidosis (Tier 3) Ophthalmologic evaluation (Tier 4) Evaluation of renal function (Tier 4) To confirm amyloidosis, demonstration of amyloid deposits via tissue biopsy is essential. (Tier 2) 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; BMI multiplied by serum albumin level [g/l] to compensate for edema formation), a measure of nutritional status and wasting. (Tier 2) 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 imaging usually provide all the necessary information to diagnose infiltrative cardiomyopathy. Holter monitoring may also be recommended. (Tier 2) (1) Patient Management An implantable cardiac device (ICD) should be considered in patients with hereditary TTRassociated 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). Nonsurvivors more often showed progression of left ventricular wall thickness, higher levels of N-terminal pro-brain natriuretic peptide (NT-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) Pharmacotherapy with TTR stabilizing agents can be prescribed at an early stage (stage 0 or I) of disease in anticipation of liver transplantation or potentially delaying the need for liver transplant. However, there is limited data to support the efficacy and safety of treatment given these agents are still in clinical trials. (Tier 2) 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 (6) 3

4 Surveillance Family Management Circumstances to Avoid Stage II: Summary Report 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 Val30Met. Organ impairment that occurred before the transplant does not usually reverse. However, long-term observations show clear regression of amyloid deposits and an overall patient survival rate at 5 years of >77% with variant-specific utility survival: 10-year survival rate of 74% for Val30Met versus 44% for non-val30met patients. Some patients continue to have disease progression after transplant. (Tier 2) 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). Genetic testing should be performed on relatives of patients when they are capable of comprehending the medical, social, and psychological ramifications of a positive result. Relatives should be strongly encouraged to undergo genetic testing and, if positive, tissue biopsies. However, for some individuals, including those with a family history of late-onset disease, early genetic testing may produce severe anxiety to which the physician needs to be sensitive. In all cases, genetic counseling and, if necessary, psychological support should be offered to affected family members. (Tier 2) 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) Description of sources of evidence: Tier 1: Evidence from a systematic review, or a meta-analysis or clinical practice guideline clearly based on a systematic review Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources Tier 5: Evidence from a non-systematically identified source 4

5 Stage II: Summary Report GENE/GENE PANEL: TTR DISORDER: Hereditary transthyretin-related amyloidosis Topic Narrative Description of Evidence Ref 3. What is the chance that this threat will materialize? Mode of Inheritance Autosomal dominant Val30Met is the most prevalent TTR variant in the world, focused in Portugal, Sweden, Japan, Brazil, and Majorca. It is believed to have arisen independently in Portugal and Sweden. In endemic areas of northern Sweden, the frequency of Val30Met is 4%. The frequency of heterozygotes is 1.5% in the northern part of Sweden. (Tier 3) Prevalence of Genetic Mutations Families with variants other than Val30Met have also been identified worldwide. (Tier 4) The cardiomyopathy-related Leu111Met and Val122Ile variants are found primarily in Danish and African American populations, respectively. (Tier 4) The frequency of Val122Ile in the African American population is %. More than 5% of the population in some areas of West Africa is heterozygous for this variant. In the US, the frequency of Val122Ile in the white and Hispanic populations is 0.44% and 0.0%, respectively. (Tier 3) Penetrance for familial TTR amyloidosis is not 100%. (Tier 4) (1) Penetrance OR Relative Risk (include high risk racial or ethnic subgroups) Expressivity Within a global longitudinal study on the natural history of TTR amyloidosis, 611 of 885 individuals with a TTR pathogenic variant (Val30Met, Val122Ile, 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) Penetrance may vary by variant, geographic region, or ethnic group. It is generally accepted that penetrance is much higher in individuals in endemic foci than outside. In Portugal, cumulative risk of disease in individuals with the Val30Met 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. (Tier 3) Information on relative risk was not available. Phenotypes are not always uniform, and the same point mutation may have varied phenotypes even within the same family. (Tier 4) 4. What is the nature of the intervention? Nature of Intervention Management includes regular invasive and non-invasive surveillance. Recommendations also include potential pharmacotherapy (with associated side effects), liver transplant, and ICD implantation. Preliminary evidence of pharmacotherapies in clinical trials indicate that these agents are well-tolerated. 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-FAP. 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. 5. Would the underlying risk or condition escape detection prior to harm in the (7) (2, 6) 5

6 Stage II: Summary Report setting 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. (Tier 4) Final Consensus Scores Gene(s) Outcome/intervention pair Severity Likelihood Effectiveness Nature of the Intervention Total Score Severe visceral, neurological, or cardiac 2 3E 2B 0 7EB TTR involvement / Liver transplant Sudden cardiac death / Implantable 3 0D 1B 2 6DB cardiac device To see the scoring key, please go to: Date of Search (MM.DD.YYYY): References 1. Sekijima Y, Yoshida K, Tokuda T, Ikeda S. Familial Transthyretin Amyloidosis. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, et al., editors. GeneReviews(R). Seattle (WA) Ando Y, Coelho T, Berk JL, Cruz MW, Ericzon BG, Ikeda S, et al. Guideline of transthyretin-related hereditary amyloidosis for clinicians. Orphanet J Rare Dis. 2013;8: OrphaNet. ATTRV30M amyloidosis. Orphanet encyclopedia OrphaNet. ATTRV122I amyloidosis. Orphanet encyclopedia Online Mendelian Inheritance in Man (OMIM). Amyloidosis, hereditary, transthyretin-related. Johns Hopkins University, Baltimore, MD; 2986 (Updated 2016). 6. Priori SG, Blomstrom-Lundqvist C, Mazzanti A, Blom N, Borggrefe M, Camm J, et al 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): 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):