Early detection of cardiac and skin amyloid deposits among asymptomatic carriers of hereditary pathogenic transthyretin mutation

Abstract

Specific treatments were recently proposed for hereditary transthyretin (ATTRv) amyloidosis. It is essential to screen for disease onset among asymptomatic carriers to trigger treatment as early as possible. We describe their baseline clinical and paraclinical data, as an assessment to detect disease onset. We retrospectively collected data of asymptomatic ATTRv carriers with normal electroneuromyography (ENMG), between March 1st 2015 and January 31st 2019, including symptoms, physical exam, ENMG, cardiac evaluation (multimodal imaging, cardiac denervation), and skin biopsy (amyloid deposition, denervation). We included 130 patients, aged 43.6 years (± 13.5), selected in families of probands with an age of onset of 52.7 years (± 15.7), 41% male, carrying 18 different TTR variants including 65% Val30Met. Cardiac fixation on DPD scintigraphy (11/115) and/or amyloid deposits on skin biopsy (15/95), defining amyloid infiltration, were found in 22/130 patients (16.9%)-amounting to 25% when both were performed. Amyloid infiltration was associated with age ( P = 0.024), age difference < 10 years from proband ( P < 0.001), carpal tunnel syndrome ( P = 0.022), interventricular septum thickness (IVST) > 12 mm ( P < 0.001), late gadolinium enhancement in cMRI ( P p = 0.002), cardiac denervation (MIBG scintigraphy C/M < 1.85 ( P = 0.044). Among patients with a positive DPD scintigraphy, 13% were < 50 years old and had an IVST < 12 mm. Multivariate analysis showed that age difference with proband and IVST were predictors for amyloid infiltration (OR = 1.11, IC [1,04–1,19] and OR = 1,76, IC [1,19–2,60]). Clinical and paraclinical assessment of asymptomatic carriers of ATTRv mutations shows that skin or cardiac amyloid infiltration precedes ENMG abnormalities in up to 25% of patients. This may trigger specific therapies in borderline cases. Prospective follow up of this cohort might help further define criteria for early onset of specific treatments.