Familial Amyloid Polyneuropathy

Abstract

Transthyretin-related familial amyloid polyneuropathy (TTR-FAP) is a life-threatening disease caused by the accumulation of amyloidogenic transthyretin (TTR) protein in tissues. Mutations in TTR gene destabilize TTR protein to misfold from its native tetramer form to amyloidogenic monomer form. In endemic countries, TTR-FAP presents with length-dependent small fiber neuropathy, however in non-endemic countries clinical features can be highly variable. Genetic testing for TTR gene is mandatory for the diagnosis. Demonstrating amyloid deposits in tissues may be necessary for distinguishing symptomatic patients from asymptomatic carriers. Routine follow-up should include a wide range of tests to demonstrate systemic involvement. In recent years, treatment of TTR-FAP has significantly improved with new therapeutic approaches. TTR stabilizers and TTR-gene silencing drugs prevent the progression of the disease. Monoclonal antibodies that target amyloid deposits are currently under development. Early initiation of the treatment is important for better functional outcome.

Keywords: Transthyretin; genetic; hereditary; neuropathy; treatment.

Figure 1

Sural nerve biopsy findings of a patient with Glu89Gln mutation. Note endoneural, perivascular amyloid deposits (arrow); there is a remarked reduction of myelinating fibres (semi-thin section ×40, Thionin staining). (Neuropathology Lab, Neuromuscular Unit of the Istanbul Faculty of Medicine)

Figure 2

Sural nerve biopsy findings of a patient with Glu89Gln mutation. Note endoneural amyloid deposits (arrow) (longitudinal paraffin section ×10, modified Gomori trichrome staining). (Neuropathology Lab, Neuromuscular Unit of the Istanbul Faculty of Medicine)

Figure 3

Diagnostic techniques and diagnostic algorithm of TTR-FAP* TTR-FAP: transthyretin-related familial amyloid polyneuropathy, TTR: transthyretin, NIS: neuropathy impaiment score, FAP: familial amyloid polyneuropathy, PND: polyneuropathy disability, BMI: body-mass intex, NCS: nerve conduction studies, EMG: electromyography, SSR: sympathetic skin response, HRV: heart rate variability, QST: quantitative sensory testing, ECG: electrocardiography, BNP: brain natriuretic peptide, MRI: magnetic resonance imaging. Adapted from.

Figure 4

Current suggested treatment algorithm of TTR-FAP* TTR-FAP: transthyretin-related familial amyloid polyneuropathy, 1= recently approved or on the approval process of United States Food and Drug Administration (FDA) also for Stage 1 disease..Adapted from.