Early skin denervation in hereditary and iatrogenic transthyretin amyloid neuropathy

Objective: To elucidate early skin denervation in hereditary transthyretin (TTR) amyloidosis and iatrogenic TTR amyloidosis. Methods: We investigated intraepidermal nerve fiber density (IENFD) and clinical findings in 32 patients with hereditary TTR amyloidosis, 11 asymptomatic mutation carriers, 6 patients with iatrogenic TTR amyloidosis, and 23 healthy volunteers. Results: IENFD values were reduced in patients with the V30M mutation (1.9 +/- 2.1 per 1 mm), patients with non-V30M mutations (5.8 +/- 3.2 per 1 mm), and patients with iatrogenic TTR amyloidosis (3.5 +/- 1.8 per 1 mm) compared with healthy volunteers (11.8 +/- 3.2 per 1 mm) (p < 0.01). Skin denervation also occurred, even in presymptomatic V30M mutation carriers (5.0 +/- 2.2 per 1 mm). The IENFD was correlated with disease duration (rho = -0.533, p = 0.002) and various peripheral neuropathy parameters such as sensory impairment in the Kumamoto clinical score (rho = -0.575, p = 0.001), heat-pain detection threshold (rho = -0.704, p < 0.001), and sural sensory nerve action potential (rho = 0.481, p = 0.005). TTR amyloid deposits frequently occurred in connective tissues and vessels of the dermal reticular layer in patients with hereditary TTR amyloidosis and those with iatrogenic TTR amyloidosis. Conclusions: Patients with hereditary TTR amyloidosis and those with iatrogenic TTR amyloidosis may show early skin denervation even in the presymptomatic stage. IENFD may thus be useful for early diagnosis and may serve as a biomarker in clinical trials for hereditary and iatrogenic TTR amyloidosis.