ATTRV122I amyloidosis (ORPHA:85451)
A rare hereditary Transthyretin (TTR)-related systemic amyloidosis (ATTR) with predominant cardiac involvement resulting from myocardial infiltration of abnormal amyloid protein.
Epidemiology
Global prevalence is unknown. The prevalence of the Val122Ile variant has been estimated to be 3.5% in American population of African descent, corresponding to potentially 1.6 million carriers in the USA. However, the actual penetrance in this population is unknown, with estimates as low as 10%.
Clinical description
Patients present during late adulthood with restrictive cardiomyopathy (with varying degrees of chronic heart failure and possible brady/tachyarrhythmias). Cardiomyopathy may be accompanied by sensorimotor/autonomic polyneuropathy but in many patients carrying this variant the phenotypic expression may remain exclusively cardiac.
Etiology
Several specific TTR mutations are associated with predominant cardiac involvement. Among these, V122I is particularly common among African-Americans (3.5% of the population).
Diagnostic methods
The gold standard for diagnosis of amyloidosis is histological analysis and Congo red staining of biopsy specimens. Detection of the specific TTR mutation allows confirmation of the diagnosis. A high level of diagnostic suspicion of cardiac amyloidosis can be generated by characteristic echocardiographic and ECG findings, and confirmed by bone tracer scintigraphy and/or magnetic resonance imaging with late enhancement. A family history of cardiac disease may suggest hereditary ATTR amyloidosis etiology.
Differential diagnosis
The differential diagnosis should include other infiltrative/storage myocardial diseases, including other types of cardiac amyloidosis, such as AL amyloidosis. Hypertrophic cardiomyopathy should also be included in the differential diagnosis.
Antenatal diagnosis
Considering the late-onset phenotype and the increasing availability of disease-modifying therapies, antenatal diagnosis has a very limited role in this specific condition.
Genetic counseling
Hereditary ATTR amyloidosis is dominantly transmitted. Genetic counseling is generally highly recommended to at-risk patients' relatives, informing them there is a 50% risk of inheritance in siblings and offspring. For the Val122Ile variant in African-Americans, it is particularly important to discuss the low penetrance and possible gender-related variations, with a higher disease rate observed in males over the age of 70. Factors affecting penetrance are still unknown. In general, pre-symptomatic testing is increasingly offered in hereditary ATTR amyloidosis due to emerging disease-modifying therapies.
Management and treatment
Close monitoring of cardiac function and symptoms by an expert cardiologist is recommended. Supportive therapy plays a major role. Disease modifying therapy is available for hereditary V122I amyloidosis. Patient with exclusive cardiomyopathy can be treated with the TTR stabilizer tafamidis at the dose of 61 mg/day. Patients presenting with a mixed phenotype (cardiomyopathy associated with polyneuropathy) are eligible to a gene-silencing treatment, including the RNAi agent patisiran (or vutrisiran, where already available) and the antisense oligonucleotide inotersen.
Prognosis
Prognosis is driven by the severity of cardiomyopathy. A validated prognostic staging system for patients with hereditary ATTRV122I amyloidosis is the NAC staging system, in which survival correlates with NT-proBNP concentration and eGFR at diagnosis.

                            Last update: 
                            May 2023


                            - Expert reviewer(s): 
                            Dr Laura OBICI | RITA*


                                * European Reference Network