Genetics of Familial Amyloid Neuropathies


Familial amyloid polyneuopathies (FAP) are life‐threatening disorders transmitted as an autosomal‐dominant trait. Mutated transthyretin (TTR) is the most common protein precursor of amyloid deposits with more than 100 amyloidogenic mutations identified worldwide. Manifestations of TTR‐related FAP predominantly include a length‐dependent progressive polyneuropathy, myocardiopathy and ocular involvement. Early liver transplantation and tafamidis are currently available to treat these patients. Hereditary gelsolin amyloidosis, which is mainly observed in Finland, is related to mutations of the gelsolin gene. It is characterised by cranial nerve involvement, corneal lattice and abnormal skin laxity, with occasional systemic involvement. Apolipoprotein A1 amyloidosis is a devastating polysystemic disease with predominant kidney and peripheral nerve involvement. No specific treatment is currently available for gelsolin and apoliprotein A1 amyloidosis.

Key Concepts:

  • Protein precursors of amyloid responsible for familial amyloid polyneuropathies include mutated transthyretin, gelsolin and apolipoprotein A1.

  • Amyloids are insoluble substances that cannot be removed from the tissues after deposition.

  • Most of mutated transthyretin is synthesised in the liver.

  • More than 100 amyloidogenic mutations have been identified making DNA testing mandatory.

  • Early liver transplantation dramatically reduces the amount of TTR in the blood.

Keywords: familial amyloid polyneuropathy; transthyretin; gelsolin; apolipoprotein A1; DNA testing; liver transplantation; tafamidis; cardiac amyloidosis; mutations of the transthyretin gene; mutations of the gelsolin gene; mutations of the Apo A1 gene; genetic counselling

Figure 1.

Longitudinal section of a paraffin‐embedded sural nerve biopsy specimen of a patient with TTR‐familial amyloid polyneuropathy. The congophilic endoneurial deposit is characteristic of amyloid (arrow). Congo red staining. Bar: 20 μm. Thickness: 7 μm.

Figure 2.

Electron micrograph of a sural nerve biopsy specimen of a patient with TTR‐familial amyloid polyneuropathyto show endoneurial amyloid fibrils (arrows) in contact with Schwann cell processes. Uranyl acetate and lead citrate staining. Bar: 1 μm.



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Said, Gérard, and Planté‐Bordeneuve, Violaine(Jun 2013) Genetics of Familial Amyloid Neuropathies. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0024633]