{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T08:14:47Z","timestamp":1778228087096,"version":"3.51.4"},"reference-count":52,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2019,11,4]],"date-time":"2019-11-04T00:00:00Z","timestamp":1572825600000},"content-version":"vor","delay-in-days":307,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,1,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Familial amyloid polyneuropathy with the substitution of methionine for valine at position 30 in the TTR gene is the most common type of hereditary transthyretin amyloidosis. Although several authors have previously reported a size-dependent fibre loss, predominantly involving unmyelinated and small-diameter myelinated fibres, the mechanisms of nerve fibre loss have not been fully understood. In this study, we establish the morphometric pattern of peripheral neuropathy in patients with familial amyloid polyneuropathy and asymptomatic mutation carriers in the biopsies from our archive and correlated the pathological findings with clinical features. A total of 98 patients with familial amyloid polyneuropathy and 37 asymptomatic mutation carriers (TTR Val30Met mutation), aged between 17 and 84\u2009years, who underwent sural nerve biopsy between 1981 and 2017 at Centro Hospitalar Universit\u00e1rio do Porto were studied. Thirty-one controls were included for comparison. The median age at nerve biopsy was 26.0 [interquartile range = 23.5\u201339.5] years for asymptomatic mutation carriers, 45.0 [35.0\u201360.0] years for patients with familial amyloid polyneuropathy and 44.0 [30.0\u201363.0] years for controls. The median duration between nerve biopsy and symptoms\u2019 onset was 7.0 [3.3\u201311.8] years (range: 1\u201327\u2009years) in the asymptomatic carriers. Most patients were in an earlier disease stage (93% with a polyneuropathy disability scale \u22642). Patients had loss of small and myelinated fibres compared with both asymptomatic carriers and controls (P\u2009&amp;lt;\u20090.001), whereas asymptomatic carriers showed loss of small myelinated fibres when compared with controls (P\u2009&amp;lt;\u20090.05). The loss of myelinated fibres increased with disease progression (P\u2009&amp;lt;\u20090.001), and patients in more advanced clinical stage showed more frequent amyloid deposition in the nerve (P\u2009=\u20090.001). There was a positive correlation between large myelinated fibre density and time to symptoms\u2019 onset in the asymptomatic carriers that developed early-onset form of the disease (r\u2009=\u20090.52, P\u2009&amp;lt;\u20090.01). In addition, asymptomatic carriers with amyloid deposition already present in sural nerve biopsies developed symptoms earlier than those with no amyloid (P\u2009&amp;lt;\u20090.01). In conclusion, this study confirms that the loss of small fibre size is an initial event in familial amyloid polyneuropathy, already present in asymptomatic gene carriers, starting several years before the onset of symptoms. We show for the first time that large myelinated fibres\u2019 loss and amyloid deposition are pathological features that correlate independently with short period to the onset of symptoms for asymptomatic carriers that developed early-onset form of the disease. These findings are therapeutically relevant, as it would allow for a better interpretation of the role of disease-modifying agents in transthyretin familial amyloid polyneuropathy.<\/jats:p>","DOI":"10.1093\/braincomms\/fcz032","type":"journal-article","created":{"date-parts":[[2019,11,4]],"date-time":"2019-11-04T12:56:33Z","timestamp":1572872193000},"source":"Crossref","is-referenced-by-count":23,"title":["Clinicopathological correlations of sural nerve biopsies in TTR Val30Met familial amyloid polyneuropathy"],"prefix":"10.1093","volume":"1","author":[{"given":"Armindo","family":"Fernandes","sequence":"first","affiliation":[{"name":"Institute of Biomedical Sciences Abel Salazar, Universidade do Porto, 4050-313 Porto, Portugal"}]},{"given":"Teresa","family":"Coelho","sequence":"additional","affiliation":[{"name":"Unidade Corino de Andrade, Department of Neurosciences, Centro Hospitalar do Porto, 4099-001 Porto, Portugalu"}]},{"given":"Aurora","family":"Rodrigues","sequence":"additional","affiliation":[{"name":"Neuropathology Unit, Department of Neurosciences, Centro Hospitalar Universit\u00e1rio do Porto, 4099-001 Porto, Portugal"}]},{"given":"Helena","family":"Felgueiras","sequence":"additional","affiliation":[{"name":"Department of Neurology, Centro Hospitalar Vila Nova de Gaia\u2014Espinho, 4434-502 Vila Nova de Gaia, Portugal"}]},{"given":"Pedro","family":"Oliveira","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Sciences Abel Salazar, Universidade do Porto, 4050-313 Porto, Portugal"},{"name":"Epidemiological Research Unit (EPIUnit), Institute of Public Health, Universidade do Porto, 4050-091 Porto, Portugal"}]},{"given":"Ant\u00f3nio","family":"Guimar\u00e3es","sequence":"additional","affiliation":[{"name":"Neuropathology Unit, Department of Neurosciences, Centro Hospitalar Universit\u00e1rio do Porto, 4099-001 Porto, Portugal"}]},{"given":"Manuel","family":"Melo-Pires","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Sciences Abel Salazar, Universidade do Porto, 4050-313 Porto, Portugal"},{"name":"Unidade Corino de Andrade, Department of Neurosciences, Centro Hospitalar do Porto, 4099-001 Porto, Portugalu"},{"name":"Neuropathology Unit, Department of Neurosciences, Centro Hospitalar Universit\u00e1rio do Porto, 4099-001 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9260-0227","authenticated-orcid":false,"given":"Ricardo","family":"Taipa","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Sciences Abel Salazar, Universidade do Porto, 4050-313 Porto, Portugal"},{"name":"Unidade Corino de Andrade, Department of Neurosciences, Centro Hospitalar do Porto, 4099-001 Porto, Portugalu"},{"name":"Neuropathology Unit, Department of Neurosciences, Centro Hospitalar Universit\u00e1rio do Porto, 4099-001 Porto, Portugal"}]}],"member":"286","published-online":{"date-parts":[[2019,11,4]]},"reference":[{"key":"2020081108570049000_fcz032-B1","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1056\/NEJMoa1716153","article-title":"Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis","volume":"379","author":"Adams","year":"2018","journal-title":"N Engl J Med"},{"key":"2020081108570049000_fcz032-B2","doi-asserted-by":"crossref","first-page":"61","DOI":"10.3109\/13506129.2012.685665","article-title":"Regional difference and similarity of familial amyloidosis with polyneuropathy in France","volume":"19","author":"Adams","year":"2012","journal-title":"Amyloid"},{"key":"2020081108570049000_fcz032-B3","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/S0006-291X(02)00465-5","article-title":"Only amyloidogenic intermediates of transthyretin induce apoptosis","volume":"294","author":"Andersson","year":"2002","journal-title":"Biochem Biophys Res Commun"},{"key":"2020081108570049000_fcz032-B4","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1186\/1750-1172-8-31","article-title":"Guideline of transthyretin-related hereditary amyloidosis for clinicians","volume":"8","author":"Ando","year":"2013","journal-title":"Orphanet J Rare Dis"},{"key":"2020081108570049000_fcz032-B5","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1001\/archneur.62.7.1057","article-title":"Transthyretin-related familial amyloidotic polyneuropathy","volume":"62","author":"Ando","year":"2005","journal-title":"Arch Neurol"},{"key":"2020081108570049000_fcz032-B6","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1093\/brain\/75.3.408","article-title":"A peculiar form of peripheral neuropathy; 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