Central Nervous System Manifestations Associated with Hereditary Transthyretin Amyloidosis: a Narrative Review

Hereditary transthyretin amyloidosis (ATTRv) is a rare, autosomal dominant, inherited disease caused by variants in the gene encoding the transthyretin (TTR) protein. These variants lead to TTR tetramer destabilization, resulting in the formation and progressive deposition of insoluble amyloid fibrils in various tissues, including those of the central nervous system (CNS). Although previously neglected, the recognition of CNS involvement in ATTRv has become progressively relevant due to prolonged patient survival and the ineffectiveness of the current therapies in addressing CNS synthesis of TTR. The first descriptions of the pathological involvement of the CNS in ATTRv date from the 1960s; however, this topic has not been fully explored. In the present article, the main CNS clinical manifestations of ATTRv, such as transient focal neurological episodes, bleeding complications, leptomeningeal amyloidosis, and cognitive impairment, are reviewed, and the phenotypic variability of this condition is highlighted. A literature review of the PubMed/Medline database was conducted using the following keywords: hereditary amyloidosis, transthyretin amyloidosis, familial amyloidosis, central nervous system, neurological manifestations, leptomeningeal amyloidosis, cognition, and cognitive impairment. Studies published in the last 15 years, including review articles, prospective observational studies, experimental studies and clinical trials, were evaluated. Improving our understanding of CNS involvement in ATTRv will enable the early identification of neurological symptoms in this condition, which will enhance the understanding of the pathophysiological mechanisms and boost the advancement of research, expanding potential treatments and improving the quality of life of these individuals.