Familial amyloid polyneuropathy: A clinico-pathologic study

Abstract

In familial amyloid polyneuropathy (FAP), destruction of nerve fibres is related to accumulation of mutated transthyretin (mTTR) derived amyloid deposits (AD) in the endoneurium. Liver transplantation (LT), which removes the main source of mTTR, does not prevent deterioration of the clinical condition in all recipients. Material and methodsWe evaluated the distribution of AD in the central and peripheral nervous system in order to better understand the pathophysiology of FAP and the potential role of lesions of nerve blood vessels and of mTTR released by choroid plexuses (CP). Forty nerve biopsy specimens and 3 autopsy cases, including 7 patients who underwent liver transplantation, all from patients with symptomatic FAP and DNA mutation of the TTR gene, were included. ResultsPatients were ranged into three categories:Group 1:Patients with early neuropathic manifestations. Five patients carrying an amyloidogenic mutation closely followed to detect early neuropathic manifestations experienced paresthesiae with stockings temperature and pains deficit in two; uncertain changes in the others. Sensory nerve action potentials (SNAPs) were normal. Biopsy was performed to detect morphological changes as an indication for early therapeutic intervention. Only one patient had decreased MF and unmyelinated fiber (UF) density.Group 2:Patients with marked sensory-motor and dysautonomic polyneuropathy (35 patients). Non dissociated sensory loss prevailed in distal limbs, while sensory defect predominated on temperature and pain sensations in proximal limbs and anterior trunk. Weakness and amyotrophy predominated in distal lower limbs. Fiber loss massively predominated on UF.Group 3:Patients at terminal stage of the disease. All 3 patients had been bedbound for months with flaccid quadriplegia and non dissociated sensory deficit affecting all four limbs, up to proximal thighs, arms and anterior trunk along with severe autonomic dysfunction. There was virtually no surviving nerve fibers in distal nerves. Morphological changesAmyloid predominated around endoneurial capillaries in 37 patients, with occlusion/destruction of endoneurial capillaries in 15 nerves at late stages of the disease. Post-mortem examination showed amyloid in choroid plexuses and perivascular spaces in the brain and around blood vessels penetrating the endoneurium, following arachnoid and connective tissue septae. Destruction of endoneurial blood vessels is a late event in the natural course of FAP. Morphological findings were similar in patients who underwent liver transplantation and in those who did not. The distribution of amyloid in areas communicating with the subarachnoid space suggests that mutated TTR released in the CSF may move to the endoneurial fluid and accumulate in peripheral nerves, accounting for lack of efficacy of liver transplantation in some individuals.