The clinical and biochemical spectrum of hereditary amyloidosis

Familial amyloidosis, once described as a puzzling and highly unusual form of polyneuropathy, is now recognized to be a collection of familial diseases with usually autosomal-dominant inheritance and widespread ethnic distribution. Familial amyloidosis occurs throughout the world and encompasses an extremely broad spectrum of clinical manifestations. In some families, progressive peripheral neuropathy dominates the illness, while in others, renal failure, ocular amyloid deposits, cardiac decompensation, or intracranial hemorrhage is the most significant clinical feature. The Portuguese (type I) and the Iowa (type III) neuropathies characteristically begin with lower limb involvement, while in the Indiana (type II) form, upper limb neuropathy is seen first; in the Japanese families with familial amyloid polyneuropathy, symptoms first become evident around age 40, whereas in the Texas family, onset is in the seventh decade. The prognosis for the different families is highly variable. Current classification of the familial amyloid polyneuropathy syndromes is based on their characteristic clinical presentations, but ongoing biochemical identification of the protein composition of amyloid substance in each form will make a more rational nosology feasible in the near future. To date, no therapy has been shown to arrest or reverse the progressive accumulation of amyloid deposits in most forms of familial amyloidosis. Familial Mediterranean fever is a major exception, and the incidence of amyloidosis associated with this disease has been dramatically reduced by the widespread prophylactic use of colchicine. Technology currently available permits the reliable identification of asymptomatic relatives at risk for developing amyloid neuropathy as well as the prenatal identification of carriers of the mutant transthyretin gene. These strategies can be used in genetic counseling aimed at reducing the continued propagation of the mutant gene.