Central Nervous System Involvement as the Initial Manifestation of Transthyretin Amyloidosis: A Case Report and Literature Review

Abstract

Transthyretin amyloidosis (ATTR), a rare systemic disorder characterized by misfolded transthyretin (TTR) protein aggregation, predominantly affects the heart and peripheral nervous system. Central nervous system (CNS) involvement in ATTR, especially widespread leptomeningeal amyloidosis (LA), is exceedingly rare. Early diagnosis of CNS-predominant ATTR is difficult due to nonspecific symptoms and low awareness. This study adopted a dual-methodology: A single-case analysis of a CNS-predominant hereditary ATTR(CNS-ATTR) patient at a tertiary referral center and a systematic literature review following PRISMA guidelines. PubMed and Embase were systematically searched from the start to March 2025 using controlled vocabulary (MeSH/Emtree terms) and Boolean operators for reported CNS-involved ATTR cases. A systematic review of 79 CNS-ATTR cases revealed universal leptomeningeal enhancement on magnetic resonance imaging (MRI) (77/79, 97%) and cerebrospinal fluid (CSF) protein elevation (66/79, 84%). The index case (p. Gly73Ala) showed diffuse leptomeningeal enhancement, grade 3 PYP uptake, and CSF protein 1.88 g/L. In summary, LA associated with ATTR is extremely scarce. A four-tiered, protocolbased diagnostic algorithm is crucial for patients with unexplained leptomeningeal disorders.