Abstract
We performed extensive quantitative analyses of the peripheral nervous system (PNS) of two siblings with familial amyloid polyneuropathy (FAP) caused by a transthyretin (TTR) Gly42 mutation. Pronounced amyloid deposition was found in the sympathetic ganglia (SyG), dorsal root ganglia (DRG) and throughout the length of the peripheral nerve fibers with some accentuation in the more proximal portion. There was severe neuronal 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 fiber 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 axoplasmic membrane of demyelinated axons and destruction of axons in some areas. Amyloid deposition within the PNS in this type of FAP resembled that 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 demonstrated preferential depletion of small neurons in the DRG and their primary afferent fibers in the spinal dorsal horn. Primary axonal degeneration and ganglionopathy due to amyloid deposition appear to be the pathogenetic mechanisms for peripheral neuropathy in this type of FAP.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Andersson R (1970) Hereditary amyloidosis with polyneuropathy. Acta Med Scand 188:85–94
Andrade C (1952) A peculiar form of peripheral neutropathy: familial atypical generalized amyloidosis with special involvement of the peripheral nerves. Brain 75:408–427
Araki S, Mawatari S, Ohta M, Nakajima A, Kuroiwa Y (1968) Polyneuritic amyloidosis in a Japanese family. Arch Neurol 18: 593–602
Coimbra A, Andrade C (1971) Familial amyloid polyneuropathy: an electron microscope study of the peripheral nerve in five cases. I. Interstitial changes. II. Nerve fiber changes. Brain 94:199–212
Costa PP, Figueria AS, Bravo FR (1978) Amyloid fibril protein related to prealbumin in familial amyloidic polyneuropathy. Proc Natl Acad Sci USA 75:4499–4503
Dwulet FE, Benson MD (1984) Primary structure of an amyloid prealbumin and its plasma precursor in a heredofamilial polyneuropathy of Swedish origin. Proc Natl Acad Sci USA 81:694–698
Dyck PJ, Lambert EH (1969) Dissociated sensation in amyloidosis: compound action potential, quantitative histologic and teased-fiber, and electron microscopic studies of sural nerve biopsies. Arch Neurol 20:490–507
Fisher J, Csillik B (1985) Lectin binding: a genuine marker for transganglionic regulation of human primary sensory neurons. Neurosci Lett 54:263–267
Fujimura H, Lacroix C, Said G (1991) Vulnerability of nerve fibers to ischemia: a quantitative light and electron microscope study. Brain 114:1929–1942
Hanyu N, Ikeda S, Nakadai A, Yanagisawa N, Powell HC (1989) Peripheral nerve pathological findings in familial amyloid polyneuropathy: a correlative study of proximal sciatic nerve and sural nerve lesions. Ann Neurol 25:340–350
Ikeda S, Hanyu N, Hongo M, Yoshioka J, Oguchi H, Yanagisawa N, Kobayashi T, Tsukagoshi H, Ito N, Yokota T (1987) Hereditary generalized amyloidosis with polyneuropathy: clinicopathological study of 65 Japanese patients. Brain 110:315–337
Nakagawa F, Schulte BA, Spicer SS (1986) Lectin cytochemical evaluation of somatosensory neurons and their peripheral and central process in rat and man. Cell Tissue Res 245:579–589
Relly MM, King RHM (1993) Familial amyloid polyneuropathy. Brain Pathol 3:165–176
Saeki Y, Ueno S, Yorifuji S, Sugiyama Y, Ide Y, matsuzawa Y (1991) New mutant gene (transthyretin Arg58) in cases with hereditary polyneuropathy detected by non-isotope method of single-strand conformation polymorphism analysis. Biochem Biophys Res Commun 180:380–385
Said G, Ropert A, Faux N (1984) Length-dependent degeneration of fibers in Portuguese amyloid polyneuropathy: a clinicopathologic study. Neurology 34:1025–1032
Saraiva MTM, Birken S, Costa PP, Goodman DS (1984) Amyloid fibril protein in familial amyloidotic polyneuropathy. Portuguese type: definition of molecular abnormality in transthyretin (prealbumin). J Clin Invest 74:104–119
Skare JC, Saraiva MJM, Alves IL, Skare ID, Milunsky A, Cohen AS, Skinner M (1989) A new mutation causing familial amyloidic polyneuropathy. Biochem Biophys Res Commun 164:1240–1246
Sobue G, Nakao N, Murakami K, Yasuda T, Sahashi K, Mitsuma T, Sasaki H, Sasaki Y, Takahashi A (1990) Type 1 familial amyloid polyneuropathy: a pathological study of the peripheral nervous system. Brain 113:903–919
Sommer C, Schroder JM (1989) Amyloid neuropathy: immunocytochemical localization of intra and extracelluar immunoglobulin light chains. Acta Neuropathol 79:190–199
Staunton H (1991) Familial amyloid polyneuropathies. Handb Clin Neurol 60:89–115
Staunton H, Dervan P, Kale R, Linke RP, Kelly P (1987) Hereditary amyloid polyneuropathy in north-west Ireland. Brain 110:1231–1245
Takahashi N, Ueno S, Uemichi T, Fujimura H, Yorifuji S, Seiichiro T (1992) Amyloid polyneuropathy with transthyretin Arg50 in a Japanese case from Osaka. J Neurol Sci 112:58–64
Tawara S, nakazato M, Kangawa K, Matsuo H, Araki S (1983) Identification of amyloid prealbumin variant in familial amyloidotic polyneuropathy (Japanese type). Biochem Biophys Res Commun 116:880–888
Thomas PK, King RHM (1974) Peripheral nerve changes in amyloid neuropathy. Brain 97:395–406
Toyooka K, Fujimura H, Yoshikawa H, Taniike M, Inui K, Yorifuji S, Tarui S, Okada S, Yanagihara T (1993) Nephrosialidosis: ultrastructural and lectin histochemical study. Acta Neuropathol 86:198–205
Uemichi T, Ueno S, Fujimura H, Umekage T, Yorifuji S, Matsuzawa Y, Tarui S (1992) Familial amyloid polyneuropathy related to transthyretin Gly42 in a Japanese family. Muscle Nerve 15:904–911
Ueno S, Uemichi T, Takahashi N, Soga F, Yorifuji S, Tarui S (1990) Two novel variants of transthyretin identified in Japanese cases with familial amyloid polyneuropathy: transthyretin (Glu42 to Gly) and transthyretin (Ser50 to Arg). Biochem Biophys Res Commun 169:1117–1121
Ueno S, Fujimura H, Yorifuji S, Nakamura Y, Takahashi M, Tarui S, Yanagihara T (1992) Familial amyloid polyneuropathy associated with the transthyretin Cys 114 gene in a Japanese kindred. Brain 115:1275–1289
Wallace MR, Dwulet FE, Conneally PM, Benson MD (1986) Biochemical and molecular genetic characterization of a new variant prealbumin associated with hereditary amyloidosis. J Clin Invest 78:6–12
Yamada M, Hatakeyama S, Tsukagoshi H (1984) Peripheral and autonomic lesions in systemic amyloidosis. Three pathological types of amyloid polyneuropathy. Acta Pathol Jpn 34: 1251–1266
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Toyooka, K., Fujimura, H., Ueno, S. et al. Familial amyloid polyneuropathy associated with transthyretin Gly42 mutation: a quantitative light and electron microscopic study of the peripheral nervous system. Acta Neuropathol 90, 516–525 (1995). https://doi.org/10.1007/BF00294814
Received:
Revised:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00294814