The proper management of the patient with hereditary transthyretin amyloidosis with mixed phenotype: recommendations from a group of Italian experts

Hereditary transthyretin amyloidosis (ATTRv) is a progressive systemic disease characterized by extracellular deposition of amyloid fibrils in different organs and tissues, leading to a sensory and motor polyneuropathy, often with the involvement of the autonomic nervous system, and infiltrative cardiomyopathy, with a fatal outcome within 4-15 years from the onset, if not treated. A cardiological phenotype, a neurological phenotype and a mixed phenotype, characterized by a worse outcome, are distinguished. In recent years, drugs acting on the amyloidogenesis process have increased. Consequently, the correct and timely diagnosis of ATTRv plays a central role. At the same time, it is essential to spread the knowledge of this disease and the related phenotype and elaborate recommendations for the correct patients' management, considering the limited literature evidence. These issues were addressed by a group of clinicians with proven experience in the management of ATTRv. The experts carried out a consensus activity through the Nominal Group Technique (NGT). This activity highlighted the importance of the differential diagnosis, placing genetic testing at the center of this process, and the relevance of a multidisciplinary approach to diagnosis and treatment, especially for the correct identification and management of patients with mixed phenotype. It was agreed that the main factors contributing to the definition of prognosis are genotype, neurological stage at diagnosis, cardiac involvement and rate of progression. During follow-up, each patient should undergo a complete evaluation of organ involvement through a multidisciplinary approach, especially useful for promptly verifying the onset of a mixed phenotype.