Familial amyloid neuropathy explained

The familial amyloid neuropathies (or familial amyloidotic neuropathies, neuropathic heredofamilial amyloidosis, familial amyloid polyneuropathy) are a rare group of autosomal dominant diseases wherein the autonomic nervous system and/or other nerves are compromised by protein aggregation and/or amyloid fibril formation.^{[1] [2] [3]}

Classification

The aggregation of one precursor protein leads to peripheral neuropathy and/or autonomic nervous system dysfunction. These proteins include: transthyretin (ATTR, the most commonly implicated protein), apolipoprotein A1, and gelsolin.^[4]

Due to the rareness of the other types of familial neuropathies, transthyretin amyloidogenesis-associated polyneuropathy should probably be considered first.^[5]

"FAP-I" and "FAP-II" are associated with transthyretin.^{[1] [6]} (Senile systemic amyloidosis [abbreviated "SSA"] is also associated with transthyretin aggregation.)

"FAP-III" is also known as "Iowa-type", and involves apolipoprotein A1.^[7]

"FAP-IV" is also known as "Finnish-type", and involves gelsolin.^[8]

Fibrinogen, apolipoprotein A1, and lysozyme are associated with a closely related condition, familial visceral amyloidosis.

Diagnosis is confirmed by blood tests, organ biopsies, and tissue biopsies. Genetic testing can also be used to confirm a mutation in the TTR gene. Although some people with a hATTR gene mutation may not experience symptoms.

Treatment

Liver transplantation has proven to be effective for ATTR familial amyloidosis due to Val30Met mutation.^[9]

In 2011 the European Medicines Agency approved tafamidis for this condition.^[10] The FDA rejected the application for marketing approval in the US in 2012 on the basis that the clinical trial data did not show efficacy based on a functional endpoint, and the FDA requested further clinical trials.^[11]

Notes and References

1. Andrade C . A peculiar form of peripheral neuropathy; familiar atypical generalized amyloidosis with special involvement of the peripheral nerves . Brain . 75 . 3 . 408–27 . September 1952 . 12978172 . 10.1093/brain/75.3.408.
2. Kelly JW . Alternative conformations of amyloidogenic proteins govern their behavior . Curr. Opin. Struct. Biol. . 6 . 1 . 11–7 . February 1996 . 8696966 . 10.1016/S0959-440X(96)80089-3.
3. Dobson CM . Protein folding and misfolding . Nature . 426 . 6968 . 884–90 . December 2003 . 14685248 . 10.1038/nature02261 . 2003Natur.426..884D . 1036192 .
4. Ghoshdastider U, Popp D, Burtnick LD, Robinson RC . The expanding superfamily of gelsolin homology domain proteins . Cytoskeleton . 70 . 11 . 775–95 . 2013 . 24155256 . 10.1002/cm.21149 . 205643538 .
5. Delahaye N, Rouzet F, Sarda L . Delahaye N . Impact of liver transplantation on cardiac autonomic denervation in familial amyloid polyneuropathy . Medicine (Baltimore) . 85 . 4 . 229–38 . July 2006 . 16862048 . 10.1097/01.md.0000232559.22098.c3 . 25723585 . etal. free .
6. Web site: Amyloid .
7. Web site: Amyloid .
8. Akiya S, Nishio Y, Ibi K, etal . Lattice corneal dystrophy type II associated with familial amyloid polyneuropathy type IV . Ophthalmology . 103 . 7 . 1106–10 . July 1996 . 8684801 . 10.1016/s0161-6420(96)30560-5.
9. Web site: ATTR Famililial Amyloidosis . BU – Amyloid Treatment & Research Program . dead . https://web.archive.org/web/20080706150949/http://www.bu.edu/amyloid/doctors/features/clinical-attr.html . 2008-07-06 .
10. Said. G. Grippon. S. Kirkpatrick. P. Tafamidis.. Nature Reviews. Drug Discovery. 1 March 2012. 11. 3. 185–6. 10.1038/nrd3675. 22378262. 256746210.
11. News: Grogan. Kevin. FDA rejects Pfizer rare disease drug tafamidis. Pharma Times. 19 June 2012. en.