"Red-flag" symptom clusters in transthyretin familial amyloid polyneuropathy

Abstract

Transthyretin familial amyloid polyneuropathy (TTR-FAP) is a rare, progressive, life-threatening, hereditary disorder caused by mutations in the transthyretin gene and characterized by extracellular deposition of transthyretin-derived amyloid fibrils in peripheral and autonomic nerves, heart, and other organs. TTR-FAP is frequently diagnosed late because the disease is difficult to recognize due to phenotypic heterogeneity. Based on published literature and expert opinion, symptom clusters suggesting TTR-FAP are reviewed, and practical guidance to facilitate earlier diagnosis is provided. TTR-FAP should be suspected if progressive peripheral sensory-motor neuropathy is observed in combination with one or more of the following: family history of a neuropathy, autonomic dysfunction, cardiac hypertrophy, gastrointestinal problems, inexplicable weight loss, carpal tunnel syndrome, renal impairment, or ocular involvement. If TTR-FAP is suspected, transthyretin genotyping, confirmation of amyloid in tissue biopsy, large- and small-fiber assessment by nerve conduction studies and autonomic system evaluations, and cardiac testing should be performed.

Keywords: diagnosis; hereditary amyloidosis; transthyretin; transthyretin familial amyloid neuropathy.

Figure 1

Clinical features associated with TTR‐FAP. CNS, central nervous system; GI, gastrointestinal.

Figure 2

Potential “red‐flag” symptom clusters that may warn of a diagnosis of transthyretin familial amyloid polyneuropathy (TTR‐FAP).