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Transthyretin (TTR)-related familial amyloidotic cardiomyopathy is a hereditary TTR-related systemic amyloidosis (ATTR) with predominant cardiac involvement resulting from myocardial infiltration of abnormal amyloid protein.
ORPHA:85451Classification level: Disorder
- ATTR cardiomyopathy
- ATTRV122I-related amyloidosis
- TTR-related amyloid cardiomyopathy
- TTR-related cardiac amyloidosis
- Transthyretin amyloid cardiopathy
- Transthyretin-related familial amyloid cardiomyopathy
- Prevalence: Unknown
- Inheritance: Autosomal dominant
- Age of onset: Adult
- ICD-10: E85.4+ I43.1*
- OMIM: 105210
- UMLS: -
- MeSH: -
- GARD: -
- MedDRA: -
Prevalence is unknown. Patients present during adulthood (usually after 30 years of age) with restrictive cardiomyopathy (with varying degrees of chronic heart failure and possible brady/tachyarrhythmias).
ATTR cardiomyopathy is often accompanied by sensorimotor/autonomic polyneuropathy (familial amyloid polyneuropathy; see this term) but in some cases phenotypic expression of ATTR may be exclusively cardiac.
Over 80 pathogenetic mutations in the TTR gene (18q12.1) have been reported so far. The phenotype of ATTR varies depending on the particular TTR mutation, geographic area and the type of aggregation (endemic/non-endemic). Several specific TTR mutations are associated with predominant cardiac involvement. Among these, V122I is particularly common among African-Americans (3.5% of the population) and the L111M mutation, first reported in a Danish kindred, has been associated with exclusive cardiac involvement.
The gold standard for diagnosis of amyloidosis is histological analysis and Congo red staining of biopsy specimens. Detection of TTR mutations 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 magnetic resonance imaging with late enhancement. A family history of neurologic and/or cardiac disease may suggest TTR etiology.
The differential diagnosis should include other infiltrative/storage myocardial diseases, including other types of cardiac amyloidosis, such as AL amyloidosis (see this term). Hypertrophic cardiomyopathy (see this term) should also be included in the differential diagnosis.
ATTR is transmitted as an autosomal dominant trait.
Management and treatment
As the abnormal protein responsible for ATTR is almost exclusively produced by the liver, the only consolidated treatment for ATTR is orthotopic liver transplantation (OLT), which provides a ``surgical gene therapy'' for patients with amyloidotic cardiomyopathy. Combined heart-liver transplantation may also be considered.
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.
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