Chance or challenge, spoilt for choice? New recommendations on diagnostic and therapeutic considerations in hereditary transthyretin amyloidosis with polyneuropathy: the German/Austrian position and review of the literature

Hereditary transthyretin amyloidosis is caused by pathogenic variants (ATTR(v)) in the TTR gene. Alongside cardiac dysfunction, the disease typically manifests with a severely progressive sensorimotor and autonomic polyneuropathy. Three different drugs, tafamidis, patisiran, and inotersen, are approved in several countries, including the European Union and the United States of America. By stabilizing the TTR protein or degrading its mRNA, all types of treatment aim at preventing amyloid deposition and stopping the otherwise fatal course. Therefore, it is of utmost importance to recognize both onset and progression of neuropathy as early as possible. To establish recommendations for diagnostic and therapeutic procedures in the follow-up of both pre-symptomatic mutation carriers and patients with manifest ATTR(v) amyloidosis with polyneuropathy, German and Austrian experts elaborated a harmonized position. This paper is further based on a systematic review of the literature. Potential challenges in the early recognition of disease onset and progression are the clinical heterogeneity and the subjectivity of sensory and autonomic symptoms. Progression cannot be defined by a single test or score alone but has to be evaluated considering various disease aspects and their dynamics over time. The first-line therapy should be chosen based on individual symptom constellations and contra-indications. If symptoms worsen, this should promptly implicate to consider optimizing treatment. Due to the rareness and variability of ATTR(v) amyloidosis, the clinical course is most importantly directive in doubtful cases. Therefore, a systematic follow-up at an experienced center is crucial to identify progression and reassure patients and carriers.

Automated summary

Hereditary transthyretin amyloidosis is caused by pathogenic variants in the TTR gene, leading to severe sensorimotor and autonomic polyneuropathy. Three approved drugs aim to prevent amyloid deposition by stabilizing TTR protein or degrading its mRNA. Early recognition of disease onset and progression is essential, with therapy based on individual symptoms and constant monitoring for optimization.