Genetic Screening for Hereditary Transthyretin Amyloidosis in the Population of Cammarata and San Giovanni Gemini Through Red Flags and Registry Archives

Abstract

Introduction: Hereditary transthyretin amyloidosis (ATTRv) is a severe, multisystemic, autosomal dominant disease with variable penetrance caused by mutations in the TTR gene generating protein misfolding and accumulation of amyloid fibrils. The diagnosis is usually challenging because ATTRv may initially manifest with nonspecific multisystemic symptoms. Conversely, an early diagnosis is needed to start timely appropriate therapy. Hence, screening models have been proposed to improve ATTRv diagnosis. In this study, we propose a genetic screening model based on predefined “red flags” followed by “cascading screening” on first-degree relatives of patients who tested positive. Materials and methods: After obtaining written informed consent, genetic testing on salivary swabs was performed in individuals who met at least two major red flags for ATTRv (age > 65 years old, progressive sensory or sensorimotor neuropathy not responsive to steroids or immunomodulant therapies, recent and unexplained weight loss associated with gastrointestinal signs and symptoms, diagnosis of cardiac amyloidosis, bilateral or relapsing carpal tunnel syndrome, unexplained autonomic dysfunction) or one major flag and two minor flags (family history of neuropathy, ambulation disorders or cardiopathy, sudden cardiac death, a bedridden, wheelchaired patient without specific diagnosis excluding upper motor neuron diseases, infections, juvenile cardiac disease, ocular disorders, lumbar spine stenosis, biceps tendon rupture). Results: In the first screening phase, 29 suspected cases (individuals meeting at least two major red flags or one major red flag and two minor red flags) underwent genetic testing. One patient (3.5%) was diagnosed with hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN), carrying the Phe64Leu mutation. Then, cascade screening allowed for early recognition of two additional individuals (two pre-symptomatic carriers) among two first-degree relatives (100%). The identified patient was a 72-year-old man who had a family history of both cardiopathy, neuropathy, and a diagnosis of juvenile cardiac disease and progressive sensorimotor neuropathy unresponsive to steroids or immunomodulant therapies. Conclusions: ATTRv is a progressive and often fatal disease that should be promptly diagnosed and treated to stop progression and reduce mortality. Systematic screening for ATTRv yielded increased recognition of the disease in our neurological clinic. A focused approach for the screening of ATTRv-PN could lead to an earlier diagnosis and identification of asymptomatic carriers, enabling timely intervention through close clinical monitoring and early treatment initiation at symptom onset.