Hereditary transthyretin amyloidosis (hATTR) is an autosomal dominant polyneuropathy (PN) or mixed PN and cardiomyopathy, caused by mutations in the TTR gene. Silencing TTR gene therapies recently became available. Little is known on the transition phase from an asymptomatic carrier to the status of overt patient.

 We reviewed retrospectively the data of monitoring visits since the genetic test to first symptoms and signs of hATTR. Evaluation included neurological assessments, nerve conduction studies (NCS), small nerve fibers (SNF) neurophysiological tests, EKG, echocardiography, cardiac MRI, biological tests, tissular biopsies, HMPD-Tc⁹⁹ cardiac scintigraphy.

Between 1997 and 2016, 28 asymptomatic carriers were monitored (16 men, 19 ATTR-Val30Met, 13 of Portuguese origin) with a mean age of 39 years-old [range 18-62] at genetic testing. Average time to the overt diagnosis was 6.6±5.3 years [range 1 to 19].

In all cases, sensory, autonomic symptoms and/or impaired neurological examination were the first warning manifestation. Five patients had concomitant bilateral surgery on carpal tunnel syndrome. Together, EKG demonstrated conduction blocks (5 cases) or NCS detected reduced lower limbs sensory nerve action potentials (6 cases) and/or one or a combination of altered SNF tests (16 individuals). Cardiac or renal biomarkers were normal in all cases.

Meantime, 32 biopsies (skin, salivary gland, intestinal, carpal tunnel, nerve) showed amyloid deposits in 12 individuals, including 1 showing entirely normal neurological assessment. Also, HMPD-Tc⁹⁹cardiac scintigraphy was positive in 4 out of 5 individuals, after age 50 years.

Our data give insights on the profile of early markers in hATTR-PN or mixed PN and CM. Useful markers will allow identification of carriers with “latent disease”, candidates for non invasive therapeutics.