{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T19:50:53Z","timestamp":1788378653361,"version":"build-2803163510"},"reference-count":29,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2025,2,6]],"date-time":"2025-02-06T00:00:00Z","timestamp":1738800000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Union-FESR or FSE, PON Research and Innovation 2014\u20132020","award":["DM 1062\/2021"],"award-info":[{"award-number":["DM 1062\/2021"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JPM"],"abstract":"<jats:p>Introduction. Hereditary transthyretin amyloidosis (hATTR) is a rare disorder with a largely variable worldwide prevalence, and it is caused by autosomal dominant mutations in the transthyretin (TTR) gene, leading to cardiological, neurological, or mixed phenotypes. Apart from the Glu89Gln, Phe64Leu, and Thr49Ala variants, recently, other mutations of TTR gene have been reported in Sicily (His90Asn, Val122Ile, Ser77Phe, Val20Ala). With this paper, we describe a novel mutation in the TTR gene, the Glu61Ala variant, which had been previously reported in only one case with a cardiac phenotype, and the clinical findings surrounding it. Materials and Methods. One individual affected by chronic idiopathic polyneuropathy and a major red flag for hATTR underwent genetic testing to look for mutations in the TTR gene. Then, his relatives were subjected to the same test. We assessed the anamnestic profile and conducted general and neurological examination, blood tests, nerve conduction studies (NCS), electrocardiogram, and Sudoscan for each patient. Written informed consent was acquired for every patient. Results. Among 7 patients screened, 5 patients carried the Glu61Ala variant (71%). The mean age was 64.6 \u00b1 10.2 years, whereas the mean age at onset was 59.4 \u00b1 7.9 years. In our study, three patients (60%) showed a mixed phenotype, whereas two of them (40%) showed a neurological phenotype. Discussion. The Glu61Ala variant was reported only in one case with a cardiological phenotype, but our patients showed both neurological and cardiological involvement. Further studies are needed to improve knowledge of this genetic variant.<\/jats:p>","DOI":"10.3390\/jpm15020061","type":"journal-article","created":{"date-parts":[[2025,2,6]],"date-time":"2025-02-06T08:53:41Z","timestamp":1738832021000},"page":"61","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Expanding the Genetic and Clinical Spectrum of Hereditary Transthyretin Amyloidosis: The Glu61Ala Variant"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3027-7863","authenticated-orcid":false,"given":"Christian","family":"Messina","sequence":"first","affiliation":[{"name":"Department of Biomedicine, Neuroscience and Advanced Diagnostics (BiND), University of Palermo, 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salvatore","family":"Gulizia","sequence":"additional","affiliation":[{"name":"Azienda Sanitaria Provinciale di Siracusa (ASP Siracusa), Corso Gelone 17, 96100 Siracusa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9948-9712","authenticated-orcid":false,"given":"Federica","family":"Scalia","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, Neuroscience and Advanced Diagnostics (BiND), University of Palermo, 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5458-7415","authenticated-orcid":false,"given":"Eugenia","family":"Borgione","sequence":"additional","affiliation":[{"name":"Oasi Research Institute-IRCCS, Via Conte Ruggero 73, 94018 Troina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9288-1148","authenticated-orcid":false,"given":"Francesco","family":"Cappello","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, Neuroscience and Advanced Diagnostics (BiND), University of Palermo, 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5875-3126","authenticated-orcid":false,"given":"Filippo","family":"Brighina","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, Neuroscience and Advanced Diagnostics (BiND), University of Palermo, 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9805-1655","authenticated-orcid":false,"given":"Vincenzo","family":"Di Stefano","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, Neuroscience and Advanced Diagnostics (BiND), University of Palermo, 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Poli, L., Labella, B., Cotti Piccinelli, S., Caria, F., Risi, B., Damioli, S., Padovani, A., and Filosto, M. (2023). Hereditary transthyretin amyloidosis: A comprehensive review with a focus on peripheral neuropathy. Front. Neurol., 14.","DOI":"10.3389\/fneur.2023.1242815"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1002\/mus.26034","article-title":"Estimating the global prevalence of transthyretin familial amyloid polyneuropathy","volume":"57","author":"Schmidt","year":"2018","journal-title":"Muscle Nerve"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"E2403","DOI":"10.1002\/humu.22619","article-title":"Online Registry for Mutations in Hereditary Amyloidosis Including Nomenclature Recommendations","volume":"35","author":"Rowczenio","year":"2014","journal-title":"Hum. Mutat."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"S39","DOI":"10.3233\/JND-150091","article-title":"Transthyretin-Related Familial Amyloid Polyneuropathy (TTR-FAP): A Single-Center Experience in Sicily, an Italian Endemic Area","volume":"2","author":"Mazzeo","year":"2015","journal-title":"J. Neuromuscul. Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"16065","DOI":"10.1111\/ene.16065","article-title":"Genetic screening for hereditary transthyretin amyloidosis with polyneuropathy in western Sicily: Two years of experience in a neurological clinic","volume":"31","author":"Lupica","year":"2024","journal-title":"Eur. J. Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Di Stefano, V., Guaraldi, P., Giglia, F., Cani, I., Pignolo, A., Codeluppi, L., Alonge, P., Canali, E., De Lisi, G., and Florena, A.M. (2024). Successful Treatment with Patisiran in Amyloid Polyneuropathy Harboring His90Asn Mutation in the TTR Gene. Brain Sci., 14.","DOI":"10.3390\/brainsci14060519"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1161\/CIRCULATIONAHA.120.046680","article-title":"Complexities and Pitfalls in Cardiac Amyloidosis","volume":"142","author":"Cuddy","year":"2020","journal-title":"Circulation"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2109","DOI":"10.1007\/s00415-019-09688-0","article-title":"Expert consensus recommendations to improve diagnosis of ATTR amyloidosis with polyneuropathy","volume":"268","author":"Adams","year":"2021","journal-title":"J. Neurol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1684","DOI":"10.1007\/s00415-007-0617-5","article-title":"A brief compound test for assessment of autonomic and sensory-motor dysfunction in familial amyloid polyneuropathy","volume":"254","author":"Denier","year":"2007","journal-title":"J. Neurol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"665","DOI":"10.2340\/16501977-0235","article-title":"Reliability and validity of the Medical Research Council (MRC) scale and a modified scale for testing muscle strength in patients with radial palsy","volume":"40","author":"Posch","year":"2008","journal-title":"J. Rehabil. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"116424","DOI":"10.1016\/j.jns.2019.116424","article-title":"Development of measures of polyneuropathy impairment in hATTR amyloidosis: From NIS to mNIS + 7","volume":"405","author":"Dyck","year":"2019","journal-title":"J. Neurol. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1196","DOI":"10.1016\/j.mayocp.2012.10.013","article-title":"COMPASS 31: A Refined and Abbreviated Composite Autonomic Symptom Score","volume":"87","author":"Sletten","year":"2012","journal-title":"Mayo Clin. Proc."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Vinik, A.I., Nevoret, M.L., and Casellini, C. (2015). The New Age of Sudomotor Function Testing: A Sensitive and Specific Biomarker for Diagnosis, Estimation of Severity, Monitoring Progression, and Regression in Response to Intervention. Front. Endocrinol., 6.","DOI":"10.3389\/fendo.2015.00094"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1056\/NEJMoa2409134","article-title":"Vutrisiran in Patients with Transthyretin Amyloidosis with Cardiomyopathy","volume":"392","author":"Fontana","year":"2024","journal-title":"N.Engl. J. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1759","DOI":"10.1007\/s40120-023-00522-4","article-title":"Impact of Vutrisiran on Quality of Life and Physical Function in Patients with Hereditary Transthyretin-Mediated Amyloidosis with Polyneuropathy","volume":"12","author":"Obici","year":"2023","journal-title":"Neurol. Ther."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1007\/s10072-020-04889-2","article-title":"Hereditary transthyretin amyloidosis overview","volume":"43","author":"Manganelli","year":"2022","journal-title":"Neurol. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1186\/s13023-022-02481-9","article-title":"Clinical phenotypes and genetic features of hereditary transthyretin amyloidosis patients in China","volume":"17","author":"He","year":"2022","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1016\/j.cjco.2022.09.005","article-title":"Genotype-Phenotype Correlation of a Rare Transthyretin Variant Causing Amyloidosis","volume":"4","author":"Chaudhary","year":"2022","journal-title":"CJC Open"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1007\/s40119-023-00344-3","article-title":"Clinical and Genotype Characteristics and Symptom Migration in Patients With Mixed Phenotype Transthyretin Amyloidosis from the Transthyretin Amyloidosis Outcomes Survey","volume":"13","author":"Dispenzieri","year":"2024","journal-title":"Cardiol. Ther."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1007\/s10072-016-2767-7","article-title":"Phenotypic variability of TTR Val122Ile mutation: A Caucasian patient with axonal neuropathy and normal heart","volume":"38","author":"Stancanelli","year":"2017","journal-title":"Neurol. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1090","DOI":"10.1006\/bbrc.1993.1933","article-title":"A Basic Transthyretin Variant (GLU61\u2192LYS) Causes Familial Amyloidotic Polyneuropathy: Protein and DNA Sequencing and PCR-Induced Mutation Restriction Analysis","volume":"194","author":"Shiomi","year":"1993","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1080\/13506120601116625","article-title":"A new transthyretin variant (Glu61Gly) associated with cardiomyopathy","volume":"14","author":"Rosenzweig","year":"2007","journal-title":"Amyloid"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.jns.2018.04.003","article-title":"Two cases of late onset familial amyloid polyneuropathy with a Glu61Lys transthyretin variant","volume":"390","author":"Nakano","year":"2018","journal-title":"J. Neurol. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.jns.2017.08.017","article-title":"Clinical and pathological findings in familial amyloid polyneuropathy caused by a transthyretin E61K mutation","volume":"381","author":"Murakami","year":"2017","journal-title":"J. Neurol. Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/j.jns.2014.07.065","article-title":"First report of a rare mutation in a Polish patient with painful late-onset transthyretin amyloidosis","volume":"346","author":"Hagenacker","year":"2014","journal-title":"J. Neurol. Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1080\/13506120902879335","article-title":"Cardiomyopathy in a Japanese family with the Glu61Lys transthyretin variant: A new phenotype","volume":"16","author":"Noto","year":"2009","journal-title":"Amyloid"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1080\/13506129.2018.1556156","article-title":"Early diagnosis of ATTR amyloidosis through targeted follow-up of identified carriers of TTR gene mutations*","volume":"26","author":"Damy","year":"2019","journal-title":"Amyloid"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Luigetti, M., Vitali, F., Romano, A., Sciarrone, M.A., Guglielmino, V., Ardito, M., Sabino, A., Servidei, S., Piro, G., and Carbone, C. (2024). Emerging multisystem biomarkers in hereditary transthyretin amyloidosis: A pilot study. Sci. Rep., 14.","DOI":"10.1038\/s41598-024-69123-x"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1080\/13506129.2018.1545640","article-title":"Sudoscan in the evaluation and follow-up of patients and carriers with TTR mutations: Experience from an Italian Centre","volume":"25","author":"Luigetti","year":"2018","journal-title":"Amyloid"}],"container-title":["Journal of Personalized Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4426\/15\/2\/61\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:28:02Z","timestamp":1760027282000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4426\/15\/2\/61"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,6]]},"references-count":29,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2025,2]]}},"alternative-id":["jpm15020061"],"URL":"https:\/\/doi.org\/10.3390\/jpm15020061","relation":{},"ISSN":["2075-4426"],"issn-type":[{"value":"2075-4426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,6]]}}}