FAMILIAL AMYLOID POLYNEUROPATHY ASSOCIATED WITH TRANSTHYRETIN GLY42 MUTATION - A QUANTITATIVE LIGHT AND ELECTRON-MICROSCOPIC STUDY OF THE PERIPHERAL NERVOUS-SYSTEM

We performed extensive quantitative analyses of the peripheral nervous system (PNS) of two siblings with familial amyloid polyneuropathy (FA P) caused by a transthyretin (TTR) Gly42 mutation. Pronounced amyloid deposition was found in the sympathetic ganglia (SyG), dorsal root gan glia (DRG) and throughout the length of the peripheral nerve fibers wi th some accentuation in the more proximal portion. There was severe ne uronal loss in the SyG and DRG together with nerve fiber depletion in the nerve trunk, while only a small amount of amyloid deposition with mild fiber loss was seen in the spinal roots. Sprouts of regenerating axons were very scanty even in the spinal nerves or roots. A teased fi ber study mainly showed demyelinating fibers, but axonal degeneration was also present throughout peripheral nerves. An electron microscopic study showed fine amyloid fibrils in direct contact with The axoplasm ic membrane of demyelinated axons and destruction of axons in some are as. Amyloid deposition within the PNS in this type of FAP resembled th at in type I FAP (TTR Met30). However, direct axonal damage by amyloid fibrils appeared to be more prominent in our cases than in type I FAP . Lectin histochemistry using Ulex- europaeus agglutinin I demonstrate d preferential depletion of small neurons in the DRG and their primary afferent fibers in the spinal dorsal hem. Primary axonal degeneration and ganglionopathy due to amyloid deposition appear to be the pathoge netic mechanisms for peripheral neuropathy in this type of FAP.