Enhancing heme synthesis attenuates pathological α-synuclein propagation in vivo.

Hereditary transthyretin (ATTRv) amyloidosis with polyneuropathy (ATTRv-PN) is a rare, autosomal dominant, multisystem disorder caused by pathogenic variants in the () gene [, ], leading to misfolding and aggregation of TTR and subsequent extracellular deposition of amyloid fibrils []. Progressive amyloid accumulation results in a length-dependent sensorimotor and autonomic neuropathy, frequently accompanied by cardiomyopathy and other organ involvement [, –]. If left untreated, ATTRv-PN is associated with substantial morbidity and premature mortality []. Consistently across trials, placebo-treated patients showed rapid disease progression with irreversible loss of neurological function and quality of life [–]. Early diagnosis and timely initiation of disease-modifying therapy are therefore critical to alter the natural history of the disease and to preserve neurological function and quality of life [, –]. In the European Union, six disease-modifying pharmacological agents are currently approved for the treatment of ATTRv-PN, depending on Coutinho disease stages (FAP stages, familial amyloid polyneuropathy) []. In FAP stage 1, patients are fully ambulatory, in stage 2, they use walking aids, and in stage 3, individuals are wheelchair-bound or bedridden [, ]. Currently available treatment options include transthyretin stabilizers (tafamidis [], diflunisal []) as well as gene-silencing approaches, targeting hepatic production (inotersen [], patisiran [], vutrisiran [], eplontersen []). Unprecedented expansion of therapeutic options has transformed patient care and offers individualized strategies tailored to disease stage, phenotype, comorbidities, and patient preference [, ]. However, head-to-head comparisons of the different DMTs are lacking. As a result, clinicians must rely on indirect comparisons across pivotal trials with differing study designs, populations, endpoints, and follow-up durations. Moreover, real-world data remain limited, and long-term comparative effectiveness and safety data are still evolving [, ]. In this context, treatment decisions require careful consideration of the available evidence on efficacy and safety, as well as regulatory status, mode of administration, monitoring requirements, comorbid organ involvement, patient-specific factors, patient preferences, and the peculiarities of the healthcare system.