Elsevier

The Lancet Neurology

Volume 10, Issue 12, December 2011, Pages 1086-1097
The Lancet Neurology

Review
Familial amyloid polyneuropathy

https://doi.org/10.1016/S1474-4422(11)70246-0Get rights and content

Summary

Familial amyloid polyneuropathies (FAPs) are a group of life-threatening multisystem disorders transmitted as an autosomal dominant trait. Nerve lesions are induced by deposits of amyloid fibrils, most commonly due to mutated transthyretin (TTR). Less often the precursor of amyloidosis is mutant apolipoprotein A-1 or gelsolin. The first identified cause of FAP—the TTR Val30Met mutation—is still the most common of more than 100 amyloidogenic point mutations identified worldwide. The penetrance and age at onset of FAP among people carrying the same mutation vary between countries. The symptomatology and clinical course of FAP can be highly variable. TTR FAP typically causes a nerve length-dependent polyneuropathy that starts in the feet with loss of temperature and pain sensations, along with life-threatening autonomic dysfunction leading to cachexia and death within 10 years on average. TTR is synthesised mainly in the liver, and liver transplantation seems to have a favourable effect on the course of neuropathy, but not on cardiac or eye lesions. Oral administration of tafamidis meglumine, which prevents misfolding and deposition of mutated TTR, is under evaluation in patients with TTR FAP. In future, patients with FAP might benefit from gene therapy; however, genetic counselling is recommended for the prevention of all types of FAP.

Introduction

Amyloidoses are a group of diseases characterised by tissue deposition of insoluble proteins and fibril aggregates oriented in a β-pleated sheet structure that form unbranched amyloid fibrils of 10–12 nm diameter. Amyloidosis can be acquired or hereditary. There are three main types of familial amyloid polyneuropathy (FAP), defined according to the precursor protein of amyloid: transthyretin (TTR), apolipoprotein A-1, and gelsolin. The main features of each type of FAP, and current approaches to diagnosis and treatment, are shown in the table.

TTR FAP is a life-threatening disease transmitted as an autosomal dominant trait. Nerve lesions are induced by deposits of fibril protein caused by mutated TTR (mTTR). TTR FAP typically causes a nerve length-dependent polyneuropathy that starts in the feet with loss of temperature and pain sensations, with autonomic dysfunction leading to death within 10 years on average. Apoliprotein A-1 amyloidosis, also known as the Iowa type, is characterised by the deposition of amyloid in major organs, including the kidneys, liver, and heart. Although a nerve length-dependent polyneuropathy can occur in apolipoprotein A-1 FAP, it is not a prominent feature of the disease. Gelsolin amyloidosis is characterised by cranial and peripheral sensory neuropathy, corneal lattice dystrophy, and cutis laxa. The course of gelsolin amyloid neuropathy is slow and quite benign.

In this Review, we describe the clinical manifestations and recent progress in the genetics and treatment of FAP, with special emphasis on TTR amyloidosis, which is by far the most common and devastating disease in this group.

Section snippets

TTR amyloidosis

Andrade first described FAP in north Portugal in 1952.1 The disease was subsequently reported in Japan (1968)2 and Sweden (1976).3 TTR was identified as the precursor of amyloid in this setting, and was found to be synthesised mainly by the liver.4 The most common pathogenic substitution, Val30Met, was then described and the TTR gene was fully sequenced in 1985.5 In 1990, liver transplantation was undertaken as a therapeutic approach for the treatment of FAP for the first time.6

Two main

Clinical aspects and diagnosis

Originally described in Iowa by van Allen and colleagues in 1969,74 apolipoprotein A-1 amyloidosis is characterised by polysystemic manifestations with onset in the fourth decade of life. The disease predominantly affects the kidney, liver, and gastrointestinal tract. A length-dependent polyneuropathy occurs but is not a prominent feature of the disease. Progression of renal lesions can lead to chronic renal failure, dialysis, and related polyneuropathy. Amyloid deposits, which strongly react

Gelsolin amyloidosis

Hereditary gelsolin amyloidosis (HGA) is an autosomal dominant systemic amyloidosis, first described in 1969 in Finland.80 HGA is characterised by adult onset of slowly progressive neurological deterioration, with corneal lattice dystrophy, cranial neuropathy, and cutis laxa. A mutation in the gelsolin gene leads to the generation of amyloid fibrils that are composed of fragments of gelsolin.81, 82 Most patients with HGA have been reported in Finland.83, 84 The estimated number of Finnish

Conclusion

FAP represents a heterogeneous group of autosomal dominant hereditary disorders characterised by tissue deposition of amyloid fibrils. The most common and by far the most severe form of FAP is caused by mutations in the TTR gene, which is responsible for the FAP that was originally reported in Portugal and that is found worldwide. Many mutations in the TTR gene have been identified, and progress has been made in diagnostic procedures and genetic counselling. Because TTR is secreted mainly by

Search strategy

References for this Review were identified through searches of PubMed from 1950 to September, 2011, with the search terms “amyloidosis”, “familial amyloidosis”, “liver transplantation”, “apolipoprotein A-1”, and “gelsolin”. References were also identified from our own files. Only papers in English were reviewed. The final reference list was based on original publications and practical interest.

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