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Hereditary transthyretin-mediated (hATTR) amyloidosis is an inherited, progressively debilitating, fatal disease caused by a mutation in the transthyretin (TTR) gene. hATTR amyloidosis results in abnormal amyloid accumulation in multiple sites causing sensory, motor and autonomic neuropathies, and cardiac dysfunction. The disease was traditionally divided into polyneuropathy and cardiomyopathy; however, it is now understood that the disease manifests in a heterogenous manner which results in mixed presentations. The objective of this analysis was to describe the frequency of signs and symptoms observed in individuals with hATTR amyloidosis identified through Alnylam Act®. To facilitate earlier diagnosis, Alnylam Pharmaceuticals and Invitae have partnered to offer Alnylam Act®, a no-charge genetic testing and counseling program for individuals suspected of having hATTR amyloidosis. Individuals 18 years and older with a suspected diagnosis or a confirmed family history of hATTR amyloidosis can take part in the Alnylam Act® program. Healthcare professionals must confirm that the individuals meet the eligibility criteria via symptom checklist on the test requisition form. The program offers testing with one of the three options: a comprehensive neuropathies panel, cardiomyopathy comprehensive panel, or transthyretin amyloidosis single-gene TTR test. Descriptive analysis was performed to understand the frequency of signs and symptoms reported in the Alnylam Act® program across various genotypes. From April 2017 to February 2019, 562 individuals with pathogenic TTR mutations were identified through Alnylam Act®. These individuals presented with family history of hATTR amyloidosis (n=204; 36%) and/or the following signs and symptoms: heart disease (n=329; 59%), sensory and/or motor neuropathy (n=164; 29%), bilateral carpal tunnel syndrome (n=110; 20%), and autonomic dysfunction (n=70; 12%). The genotype-phenotype relationships of the most common variants are described in Table 1. The data demonstrates that hATTR amyloidosis manifests in a heterogenous manner irrespective of genotype, with many individuals having overlapping symptomatology. Individuals may develop a wide range of symptoms including but not limited to neuropathy, cardiac, and autonomic dysfunction. This highlights the importance of incorporating a multidisciplinary approach to the diagnosis and management of these individuals . Because of this, hATTR amyloidosis requires a high index of clinical suspicion and recognizing all these multisystem manifestations as clues to the diagnosis. |
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