Abstract
Hereditary transthyretin amyloidosis is caused by pathogenic variants (ATTRv) 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 ATTRv 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 ATTRv 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.
Highlights
Hereditary transthyretin amyloidosis was first described by the Portuguese neurologist Andrade in 1952 [1]
Up to 25% of the elderly population (80 years and beyond) are estimated to have systemic amyloid deposits caused by wild-type TTR (ATTRwt) known for its amyloidogenicity even though not associated with mutations in the TTRgene [32]
Performing biopsies is recommended, whenever the cause of neuropathy symptoms is unclear especially in the presence of differential diagnoses such as diabetes or alcohol consumption as well as “refractory” chronic inflammatory demyelinating polyneuropathy (CIDP), which is one of the most frequent misdiagnoses of ATTRvamyloidosis [39, 40]
Summary
Hereditary transthyretin amyloidosis was first described by the Portuguese neurologist Andrade in 1952 [1]. Harmonizing the experience of the German and Austrian centers, it is recommended to monitor progression not focusing on one particular score only, but by repeatedly using a broad clinical approach, including a detailed patient history, clinical examinations, quantitative sensory testing (especially in the early disease phase), NCS (becomes representative within the course of stage 1), examinations of autonomic function (can be disturbed in the early course already), and specific questionnaires on autonomic disturbances, neuropathic pain, disability, and quality of life. From a neurological point of view, the pedestal of every diagnostic work-up (Table 3) contains a detailed patient history, a clinical examination including the different modalities of the NIS score, questionnaires (e.g., R-ODS, COMPASS-31, and Norfolk Quality of Life), as well as NCS If available, examinations, such as quantitative sensory testing (QST), Sudoscan, and sympathetic skin response (SSR), might contribute helpful additional information on small fiber impairment in the very early stage 1, when NCS are still insensitive. These centers are due to forming networks on a national and international basis enabling the low-threshold exchange of knowledge and the participation in clinical trials
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