Journal of Pathology J Pathol 2008; 216: 253–261 Published online 14 July 2008 in Wiley InterScience (www.interscience.wiley.com) DOI: 10.1002/path.2411 Original Paper Amyloid fibril composition is related to the phenotype of hereditary transthyretin V30M amyloidosis E Ihse, 1 A Ybo, 1 OB Suhr, 2 P Lindqvist, 3 C Backman 3 and P Westermark 1 * 1 Department of Genetics and Pathology, Uppsala University, Sweden 2 Department of Internal Medicine, Ume˚ a University, Sweden 3 Department of Clinical Physiology, Ume˚ a University, Sweden *Correspondence to: P Westermark, Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden. E-mail: Per.Westermark@genpat.uu.se No conflicts of interest were declared. Received: 28 May 2008 Revised: 4 July 2008 Accepted: 9 July 2008 Abstract Swedish familial systemic amyloidosis with polyneuropathy (FAP) depends on a mutation leading to a methionine-for-valine substitution in transthyretin. The disease appears with different clinical manifestations, including age of onset and involvement of the heart. Liver transplantation is currently the only curative treatment, but progressive cardiomyopathy may occur post-transplant. Two amyloid deposition patterns have previously been described in the heart. In one, the amyloid consists partially of transthyretin fragments and is weakly stainable by Congo red, while in the other, only full-length molecules are found and the fibrils have a strong affinity for Congo red. The present study aimed to see whether these morphological and biochemical variations have clinical implications. Subcutaneous adipose tissue biopsies were taken from 33 patients with Val30Met FAP and examined by microscopy, electrophoresis and western blot. Clinical data included age, sex, duration of disease and echocardiographic determination of the interventricular septum (IVS) thickness. It was found that fibrils composed of only full-length transthyretin were associated with early age of onset (44.8 ± 12.9 years), no clinical cardiac involvement and a strong affinity for Congo red. In contrast, presence of transthyretin fragments in the amyloid was associated with late age of onset (67.3 ± 7.0 years), signs of cardiac involvement and weak Congo red staining. For each individual, the same molecular type of amyloid was found in different organs. This is the first report showing that variations in clinical appearance of familial ATTR amyloidosis are associated with specific structural differences in the amyloid fibrils, and therefore may have a molecular cause. The molecular type of amyloid can be determined from a subcutaneous fat tissue biopsy. Copyright  2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Keywords: amyloid; transthyretin; fibril; familial; heart; phenotype; age of onset Introduction Familial transthyretin (TTR) amyloidosis is caused by a point mutation in the TTR gene. Over 100 different TTR mutations are known, most of them amyloidogenic [1]. Polyneuropathy and cardiomyopa- thy are the most pronounced clinical manifestations of the amyloidosis. The most common neuropathic form of familial ATTR amyloidosis is caused by a substitution of methionine for valine at position 30 (TTRVal30Met), leading to a fatal disease, familial amyloidotic polyneuropathy (FAP). Apart from neu- ropathy, the disease affects several other organs, most notably the heart, but also the gastrointestinal tract, eyes and kidneys [2]. TTR is a homotetrameric protein, each monomer consisting of 127 amino acid residues. It is a plasma transport protein for thyroxin and indirectly for retinol and is mainly synthesized in the liver. Small amounts are also produced in the choroid plexus, the eye and in the glucagon cells in the islets of Langerhans [11,12]. So far, liver transplantation is the only treatment that has been shown to arrest the progress of the disease [3]. As plasma TTR is almost exclusively synthesized in the liver, the mutant form of TTR is thereby nearly eliminated from the blood plasma [4,5]. However, in some patients, progression of cardiomy- opathy has been seen after transplantation, especially in carriers of non-Val30Met TTR mutations. Lately, progression of cardiomyopathy has also been noted in some Swedish ATTRVal30Met-patients [6]. Why there are discrepancies in the outcome of the transplantation regarding cardiomyopathy between the different muta- tions, and even within the same mutation, has not been elucidated. TTR can also aggregate into amyloid from the wild-type (wt) protein. The wt form is seen in senile Copyright  2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. www.pathsoc.org.uk