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Transthyretin-associated neuropathic amyloidosis

Pathogenesis and treatment

From the Department of Neurology (Drs. Hund and Grau), University of Heidelberg; Department of Neurology (Dr. Linke), Max Planck Institute for Biochemistry, Martinsried; and Academic Hospital for Internal Medicine Speyererhof (Dr. Willig), Heidelberg, Germany.

Address correspondence and reprint requests to Dr. E. Hund, Department of Neurology, University of Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany; e-mail: ernst_hund{at}med.uni-heidelberg.de

Hereditary amyloidoses form a clinically and genetically heterogeneous group of autosomal dominantly inherited diseases characterized by the deposit of unsoluble protein fibrils in the extracellular matrix. They typically present with polyneuropathy, carpal tunnel syndrome, autonomic insufficiency, and cardiomyopathy and gastrointestinal features, occasionally accompanied by vitreous opacities and renal insufficiency. Other phenotypes are characterized by nephropathy, gastric ulcers, cranial nerve dysfunction, and corneal lattice dystrophy. Rarely, involvement of the leptomeningeal or cerebral structures dominates the clinical picture. The age at onset is as early as 17 and as late as 78 years. The basic constituents of amyloid fibrils are physiologic proteins that have become amyloidogenic through genetically determined conformation changes. Mutated transthyretin (TTR), formerly termed prealbumin, is the most frequent offender in hereditary amyloidosis. Orthotopic liver transplantation (OLT) stops the progression of the disease, which is otherwise invariably fatal, by removing the main production site of the amyloidogenic protein. The indications for OLT and its success depend on the grade of cardiovascular and autonomic dysfunction at the time of surgery, age, comorbidity, and type of mutation. Alternative treatment modalities with drugs stabilizing the native tetrameric conformation of TTR and inhibiting fibril formation are currently being intensively studied.

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