ATTR Epidemiology, Genetics, and Prognostic Factors

Abstract

Transthyretin amyloid cardiomyopathy (ATTR-CM) is an underdiagnosed disease and an underestimated cause of both heart failure and conduction abnormalities. It is characterized by pathologic accumulation of extracellular protein arising from unstable transthyretin (TTR) tetramers, which dissociate into monomers that misfold, aggregate, and form insoluble fibrils that are resistant to proteolysis. Cardiac amyloidosis appears in two distinct forms: hereditary and wild-type. There is considerable heterogeneity in the clinical presentation of ATTR, ranging from primarily cardiac, primarily neuropathic, or mixed cardiac and neuropathic disease. Pathogenic variants in the TTR gene that predominantly involve the heart include Val122Ile, Leu111Met, and Ile68Leu. The wild-type form of ATTR is also predominantly cardiac. Phenotypic heterogeneity is linked to differences among specific pathogenic TTR variants, geography, and the subtype of endemic versus nonendemic disease. Factors contributing to wild-type ATTR are largely unknown, but similar factors likely influence the penetrance of hereditary ATTR. Recognition of ATTR-CM is improving due to the increased use of cardiac scintigraphy as a noninvasive diagnostic tool, and early recognition of cardiac infiltration is crucial to optimize long-term prognosis.

Hereditary transthyretin amyloidosis presenting with spontaneous periorbital purpura: a case report

“… 9 Thr80Ala is the second most common mutation in the USA, and this variant originated in the northern parts of the Republic of Ireland. 8 Symptoms in this cohort of patients typically present between 50 and 60 years of age, with predominantly neurologic and cardiac phenotypes. 1 TTR genetic testing is recommended for all patients with ATTR amyloidosis, particularly given that this has implications for first-degree relatives.…”

“… 7 Another case reported a Glu54Gly mutation in the TTR gene in a patient who had spontaneous periocular bruising. 8 Spontaneous periorbital purpura has not been described with the Thr80Ala mutation to our knowledge.…”

“… 1 Hereditary ATTR amyloidosis has an autosomal dominant pattern of inheritance. 8 The most common pathogenic TTR variant in the USA is the Val142Ile mutation, which occurs in 3.4% of African Americans. 9 Thr80Ala is the second most common mutation in the USA, and this variant originated in the northern parts of the Republic of Ireland.…”

Natural history and survival rate of familial amyloidosis with polyneuropathy: A nationwide databank

“…Hereditary amyloid transthyretin (ATTRv) amyloidosis with polyneuropathy is a rare disease that has attracted attention in recent years due to novel disease-modifying medication and diagnostic tools. 1 This autosomaldominant disease is due to the accumulation of misfolded transthyretin proteins in the peripheral nerves and systemic organs. 2,3 The clinical manifestations of ATTRv amyloidosis are highly variable and are determined by the type of amyloid fibrils, tissue distribution, and amount of amyloid deposited.…”

Prevalence estimation of ATTRv in China based on genetic databases

“…ATTRv is an underdiagnosed disease and the true incidence and prevalence are currently unknown ( Obi et al, 2022 ). Its global prevalence is traditionally and somewhat anecdotally estimated as 5,000 to 10,000 persons but only several countries in Europe and Japan have relatively exact prevalence ( Sousa et al, 1995 ; Kato-Motozaki et al, 2008 ; Dardiotis et al, 2009 ; Ines et al, 2018 ; Lauppe et al, 2021 ).…”