Three patients of transthyretin amyloidosis in a Japanese family with amyloidogenic transthyretin Thr49Ser (p.Thr69Ser) variant |
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| Affiliation: | 1. Department of Cardiology, Keio University School of Medicine, Tokyo, Japan;2. Division of Diagnostic Pathology, Keio University School of Medicine, Tokyo, Japan;3. Department of Cardiology, Tokyo Dental College Ichikawa General Hospital, Chiba, Japan;4. Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan;5. Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan;1. Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India;2. Department of Pediatrics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India;3. Department of Neuroimaging and Interventional Radiology, STAR Institute of Neurosciences, STAR Hospitals, Hyderabad, India;4. Diagnostics Division, Center for DNA Fingerprinting and Diagnostics, Hyderabad, India;1. Genetics Division, Department of Morphology and Genetics, Universidade Federal de São Paulo, São Paulo, Brazil;2. Medicine Department, Marília University (UNIMAR), Marília, São Paulo, Brazil;3. Division of Child Neurology, Reference Center for Neuromuscular Diseases, Department of Pediatrics, CHR, University of Liège, Belgium;1. Division of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China;2. Department of Cardiology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 22100, China;3. State Key Laboratory in Reproductive Medicine, Centre for Clinical Reproductive Medicine, Nanjing Medical University, Nanjing, 210029, China;1. Department of Obstetrics and Gynaecology, Hannover Medical School, Hannover, Germany;2. Department of Radiation Oncology, Hannover Medical School, Hannover, Germany;3. Department of Medical Genetics, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran;4. Department of Radiology, Norman Bethune College of Medicine, Second Hospital of Jilin University, Changchun, China;5. Genome Analytics Unit, Helmholtz Center for Infection Research, Braunschweig, Germany;6. Radiation Oncology Cancer Research Center, Mashhad University of Medical Sciences, Mashhad, Iran;1. Neurology Department, Coimbra University and Hospital Centre, Portugal;2. Neuropediatrics Department, Coimbra University and Hospital Centre, Portugal;3. Faculty of Medicine of the University of Coimbra, Portugal;1. CHU Grenoble Alpes, Genetic Service, Department of Genetics and Procreation, Grenoble, France;2. CHU Saint Etienne, Genetic Service, Hôpital de Nord, Saint Etienne, France;3. Centre Léon Bérard, Laboratory of Constitutional Genetics for Frequent Cancers HCL-CLB, Lyon, France;4. Centre Léon Bérard, Department of Medicine, Lyon, France;5. Centre Léon Bérard, Cancer Genetics Unit, Department of Public Health, Lyon, France;6. Hôpital Arnaud de Villeneuve, Cellular and Hormonal Biology Service, Montpellier, France;7. CHU Dijon Bourgogne, Genetic and Rare Disease Reference Center for Development Abnormalities in the East Interregion, Children''s Hospital, Dijon, France;8. Centre Georges François Leclerc, Department of Pathology and Tumor Biology, Dijon, France;9. Hôpital Cochin, Genetic and Molecular Biology Service, Paris, France |
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| Abstract: | Transthyretin (TTR)-related hereditary amyloidosis (ATTRv) is a rare autosomal dominant disorder that is caused by pathogenic missense mutation of the TTR gene. As of today, more than 150 TTR gene variants have been reported to occur as causal mutations. Herein, we present three familial patients of ATTRv caused by the Thr49Ser (p.Thr69Ser) variant, including their phenotypes and penetrance.The first patient was a 68-year-old woman with a history of carpal tunnel syndrome, who was referred to our department with heart failure symptoms. Echocardiography, 99mTechnetium (Tc)-pyrophosphate scintigraphy, and myocardial biopsy confirmed her diagnosis as TTR-related amyloidosis. Genetic testing for the TTR gene was performed, which confirmed the presence of a Thr49Ser (p.Thr69Ser) variant. The second patient, a 45-year-old woman, who was the niece of the first patient, presented with dyspnea on exertion. Her clinical manifestations included cardiac symptoms in addition to polyneuropathy. Similarly, myocardial biopsy showed TTR amyloid deposition within cardiac tissues, and TTR gene sequencing detected the presence of a Thr49Ser (p.Thr69Ser) variant. The final patient was a 42-year-old man, who was the nephew of the first patient, presented with numbness in his hands. Abdominal wall fat pad biopsy showed TTR amyloid deposition, and TTR gene sequencing was performed considering the familial history to confirm the presence of Thr49Ser (p.Thr69Ser) variant. No cardiac symptoms or dysfunctions have been observed yet, but imaging has detected TTR amyloid deposition in the heart.The present three patients with Thr49Ser (p.Thr69Ser) variant showed variation in phenotypes including cardiac and neurological manifestations at a fairly young age. In addition, the familial relationship in this report suggested that this variant is highly penetrant. Early genetic diagnosis due to collecting the genetic information from family medical history may be beneficial to improve patient prognosis via early therapeutic intervention. |
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| Keywords: | Transthyretin amyloidosis Thr49Ser (p.Thr69Ser) Familial amyloid polyneuropathy Heart failure |
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