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Transthyretin-type cerebral amyloid angiopathy: a serious complication in post-transplant patients with familial amyloid polyneuropathy
  1. Yoshiki Sekijima1,2
  1. 1Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Matsumoto, Japan
  2. 2Institute for Biomedical Sciences, Shinshu University, Matsumoto, Japan
  1. Correspondence to Dr Yoshiki Sekijima, Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan; sekijima{at}

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Liver transplantation is a well-established treatment for transthyretin (TTR)-type familial amyloid polyneuropathy (TTR-FAP).1 According to data in the Familial Amyloidotic Polyneuropathy World Transplant Registry (, more than 2000 liver transplantations have been performed to date in 19 countries. Transplantation replaces the variant TTR gene with the wild-type gene in the liver, the main source of serum circulating TTR. The serum concentration of variant TTR decreases rapidly, reaching almost zero after the operation. The effects of liver transplantation on neuropathy are evident as its progression is stopped in most patients. However, eye deposition of TTR is not relieved by liver transplantation due to TTR synthesis by the retinal pigment epithelium. Similarly, there is concern regarding TTR deposition in the central nervous system (CNS) after liver transplantation as choroid plexus continues to produce variant TTR. Cerebral amyloid angiopathy (CAA) accompanied by leptomeningeal amyloidosis is observed in TTR-FAP patients with several specific TTR gene mutations, but develops only rarely in FAP patients with Val30Met (ATTR Val30Met FAP),2 the most common mutation found worldwide.

Maia et al3 report a retrospective analysis of 87 consecutive post-transplant ATTR Val30Met FAP patients. They report that 31% of the patients developed CNS disorders, including TIA-like episodes, stroke, focal seizures and aura-like episodes, probably due to TTR-type CAA. CNS disorders occurred on average 14.6 years after the onset of TTR-FAP, which is beyond the average life expectancy (10.9 years) of non-transplanted patients. Fortunately, CNS symptoms were transient in most of these patients.3 However, TTR-type CAA seems to be a serious complication in post-transplant ATTR Val30Met FAP patients, considering the poor prognosis of TTR-FAP patients with specific mutations that induce CNS-dominant amyloidosis. Liver transplantation markedly improved survival in FAP patients. Ironically, however, the prolonged disease duration induced de novo CNS amyloidosis, TTR-type CAA. Serious consideration should be given to this issue, as more than 2000 post-transplant TTR-FAP patients will develop de novo CNS amyloidosis in the very near future.

Recently, two TTR tetramer stabilisers, tafamidis and diflunisal, were shown to inhibit polyneuropathy progression and preserve quality of life in TTR-FAP patients.4 These drugs may correct the de novo CNS amyloidosis if they can efficiently cross the blood–brain barrier. In addition, intraventricular administration of TTR-specific antisense oligonucleotides may reduce the production of TTR in the choroid plexus and halt CNS amyloidosis.5 These newly developed pharmacological agents have the potential to prevent or treat TTR-type CAA. However, further investigations on the pharmacokinetics, safety and efficacy of these molecules are necessary to establish therapeutic strategies for this complication.



  • Competing interests None.

  • Provenance and peer review Commissioned; internally peer reviewed.

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