Case Report: Five-year follow-up of leptomeningeal transthyretin amyloidosis (Ala45Thr) with CNS involvement under tolcapone therapy.

BACKGROUND: Transthyretin (TTR) p.Ala45Thr variant is pathogenic, typically associated with cardiomyopathy and peripheral neuropathy. Leptomeningeal and central nervous system (CNS) involvement is rare, and longitudinal treatment data remain limited. METHODS: We conducted a single-patient longitudinal observational study of a patient with genetically confirmed hereditary transthyretin amyloidosis (ATTRv) carrying the TTR p.Ala45Thr variant with CNS involvement. The patient was followed over 5 years using multimodal assessments, including neurological and cognitive testing, cerebrospinal fluid (CSF) analysis, magnetic resonance imaging (MRI), and electrophysiological studies. RESULTS: A 48-year-old woman presented with progressive neurological symptoms beginning at age 37, including gait ataxia, dysarthria, and left hypoesthesia. Family history was notable for early-onset neurological decline in maternal relatives. Baseline MRI showed cerebellar micro-hemorrhages, leptomeningeal enhancement, and a cervical spinal cord lesion (C4-C7). CSF protein was markedly elevated, and genetic testing confirmed the TTR p.Ala45Thr variant. Cardiac and peripheral nerve evaluations were unremarkable. Tolcapone therapy was initiated and titrated to the maximal dose. Over 5 years, follow-up assessments demonstrated progressive neurological and cognitive decline, increased CSF protein levels, and enlargement of the spinal cord lesion, with mild progression of leptomeningeal and ependymal enhancement on MRI. CONCLUSION: This report highlights progressive CNS involvement in Ala45Thr-associated ATTR despite treatment with a CNS-penetrant TTR stabilizer. These findings suggest that disease progression may continue despite TTR stabilization in some patients and underscore the need for early intervention, systematic CNS monitoring, and further development of CNS-targeted therapies.