Familial amyloid polyneuropathy

Diagnosis

Clinical suspicion arises from a family history of neuropathy and physical findings of neuropathy. Genetic testing identifies mutations in the TTR gene. Nerve conduction studies typically reveal axonal polyneuropathy with greater sensory than motor involvement, and superimposed mononeuropathies such as carpal tunnel syndrome may occur. Electromyography can show chronic denervation and reinnervation.

Autonomic testing, including quantitative sweat testing, may detect autonomic involvement. Biopsy of skin, nerve, or muscle may demonstrate denervation and amyloid deposition reacting to anti-TTR antibodies. Additional testing evaluates heart or kidney involvement.

Treatments

Tafamidis has been approved in Europe for transthyretin familial amyloid polyneuropathy, delaying neurological problems when started early; the FDA's advisory committee rejected it in June 2012, requesting more trials, and the FDA later approved tafamidis for transthyretin-mediated cardiomyopathy but not for this polyneuropathy. In August 2018, the FDA approved patisiran, an siRNA treatment, at an expected cost up to $450,000 per year.

In August 2021, six patients received NTLA-2001, a CRISPR gene editing system, with mild adverse events and decreased serum misfolded transthyretin. Vutrisiran (Amvuttra) was approved in the US in June 2022, in the EU in September 2022, and in Australia in June 2024. Eplontersen (Wainua) was approved in the US in December 2023.

Prognosis

Without liver transplantation, FAP is invariably fatal, usually within a decade. Liver transplantation, a form of gene therapy replacing the liver with one expressing only wild-type TTR, carries about a 10% mortality from the procedure or its complications, and recipients require lifelong immune suppressants. In late 2011, the European Medicines Agency approved tafamidis (Vyndaqel), a transthyretin kinetic stabilizer, based on clinical trial data showing it slowed progression over 36 months and reversed weight loss and muscle wasting.

Epidemiology

The disease is endemic in the Portuguese locations Póvoa de Varzim and Vila do Conde (Caxinas), with over 1000 affected individuals from about 500 families, 70% of whom develop the illness; all analyzed Portuguese families share haplotype I with the Met 30 mutation. In northern Sweden, specifically Skellefteå, 1.5% of the population carries the mutated gene. The disease is somewhat prevalent in Cyprus, where mean age of onset is 46 years and penetrance is estimated at 28%, differing from Portuguese and Swedish populations.

Did You Know?

• The transthyretin protein is a tetramer that must dissociate into misfolded monomers to aggregate into amyloid fibrils.
• Because most patients are heterozygotes, they deposit both mutant and wild type TTR subunits.
• FAP is characterized by systemic deposition of amyloidogenic variants of transthyretin, especially in the peripheral nervous system, causing progressive sensory and motor polyneuropathy.