2Department of Medical Genetic, Eskişehir Osmangazi University, Eskişehir, Türkiye
3Department of Nuclear Medicine, Eskişehir Osmangazi University, Eskişehir, Türkiye
4Department of Internal Medicine, Division of Hematology, Eskişehir Osmangazi University, Eskişehir, Türkiye
5Department of Cardiology, Eskişehir City Hospital, Eskişehir, Türkiye
Introduction
Transthyretin (TTR) cardiac amyloidosis is an increasingly recognized cause of heart failure and mortality worldwide.1,
Case Report
A 70-year-old male patient was admitted to the cardiology outpatient clinic with gradually worsening dyspnea on exertion and lower extremity edema for the last 3 months. The patient’s functional capacity was New York Heart Association class III. It was learned that the patient was diagnosed with bilateral carpal tunnel syndrome 5 years ago. He had no additional chronic disease. There was no medication he used. There is no known cardiac disease in his family. On physical exam, his blood pressure was 115/70, heart rate 72 beats/min with regular rhythm. He had a grade 2/6 systolic murmur and severe pretibial edema. For 3 years, he has also reported paresthesia in the feet and hands.
Electrocardiogram revealed sinus rhythm, right bundle branch block, left anterior hemiblock (
The patient had 2 healthy siblings and 2 children. Pedigree analysis was performed (
Discussion
The phenotype in the patients with the p.Val114Ala variant is characterized by a late-onset predominantly cardiac phenotype with right bundle branch block on ECG and cardiac symptoms and signs of heart failure at diagnosis, along with mild neurological involvement. ATTRm is a rare disease caused by TTR gene mutations. The clinical presentation of ATTRm varies depending on the type of mutation and includes significant heterogeneity, ranging from primarily cardiac, primarily neuropathic, or mixed cardiac and neuropathic disease. Data on cardiac and extra-cardiac manifestations regarding the p.Val114Ala TTR variant are limited. This condition was previously described in a few patients in Germany, Crete, and Austria.4-
Another important point of this case report is that a genetic study was performed covering the entire family. One of the major challenges of genetic screening is that all TTR variants show incomplete penetrance and variable expressivity, and therefore an individual may carry a relevant variant but show no evidence of the associated phenotype. It is difficult to comment on the incomplete penetrance and expressivity in the family members of this case due to the age-dependent manifestation of the disease. However, incomplete penetrance and variable expressivity data can be obtained with long-term follow-up of these cases. The 2023 ACC Expert Consensus Decision Pathway on Cardiac Amyloidosis recommends cascade testing of first-degree relatives. As a result of cascade testing, mutations were detected in 5 cases in the relatives of this case. Phenotypic features of the disease were also evident in one of the siblings and tafamidis was started for this sibling as a result of the diagnostic process.
To the authors’ knowledge, this is the first ATTRm case due to this mutation described in Türkiye. Additionally, it is also a family medical history in which all family members at risk are identified through genetic study, and guideline recommendations are reflected in the diagnostic process. Revealing the clinical manifestations of TTR mutation types is important to ensure early diagnosis of the disease and to increase awareness. Unfortunately, there is a lack of genetic data on TTR variants in Türkiye. It would be valuable to conduct an ATTRm survey to reveal the genetic spectrum in Türkiye.
Artificial intelligence (AI)-assisted technologies (such as Large Language Models [LLM], chatbots, or image creators) were not utilized in the production of this case report.
Footnotes
References
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- Kittleson MM, Ruberg FL, Ambardekar AV. 2023 ACC expert consensus decision pathway on comprehensive multidisciplinary care for the patient with cardiac amyloidosis: a report of the American College of Cardiology solution set oversight committee. J Am Coll Cardiol. 2023;81(11):1076-1126.
- Arbelo E, Protonotarios A, Gimeno JR. 2023 ESC Guidelines for the management of cardiomyopathies. Eur Heart J. 2023;44(37):3503-3626.
- Tzagournissakis M, Foukarakis E, Samonakis D. High hereditary transthyretin-related amyloidosis prevalence in Crete: genetic heterogeneity and distinct phenotypes. Neurol Genet. 2022;8(5):e200013-.
- Kristen AV, Ehlermann P, Helmke B. Transthyretin valine-94-alanine, a novel variant associated with late-onset systemic amyloidosis with cardiac involvement. Amyloid. 2007;14(4):283-287.
- Auer-Grumbach M, Rettl R, Ablasser K. Hereditary ATTR amyloidosis in Austria: prevalence and epidemiological hot spots. J Clin Med. 2020;9(7):2234-.