Hereditary cardiac amyloidosis associated with a rare p.Ala101Val transthyretin mutation: a case description

Introduction

Transthyretin (TTR) amyloidosis (ATTR) is a systemic disorder caused by the extracellular deposition of insoluble amyloid fibrils in the peripheral and autonomic nerves, heart, kidney, gastrointestinal tract, and other organs (1,2). ATTR may be a hereditary form caused by TTR mutations (ATTRv) or an acquired form arising to the deposition of wild-type TTR (ATTRwt) (3). ATTRv is an autosomal dominant disease that typically manifests as either a neuropathic or cardiomyopathic phenotype (4). ATTR-cardiac amyloidosis (ATTR-CA) is being increasingly recognized as a cause of heart failure (HF) and mortality worldwide (5). Here, we report the case of a patient with ATTRv-CA associated with a rare TTR mutation, p.Ala101Val, which represents the first reported case in China.

Case presentation

A 66-year-old Chinese man was admitted to the Heart Center of Qingdao Municipal Hospital with gradually worsening dyspnea for 8 months in August 2023. He had a history of hypertension of more than 20 years but had withdrawn from antihypertensive drugs 6 months prior to his admission to Heart Center of Qingdao Municipal Hospital due to hypotension and had been diagnosed with cerebral embolism due to dizziness in 2019. At that time, after he received medical treatment, his symptoms improved, and he was discharged from the hospital. Additionally, he was diagnosed with hypertrophic cardiomyopathy at that time due to left ventricular wall hypertrophy (12–19 mm) as indicated by transthoracic echocardiography (TTE); both electrocardiography (ECG) and Holter monitoring displayed a sinus rhythm but showed no indication of atrial fibrillation (AF). The patient had no family history of cardiomyopathy. In December 2022, he had paroxysmal palpitations caused by paroxysmal AF, as indicated on ECG, and then underwent radiofrequency ablation. He underwent coronary angiography for multiple vessel lesions in February 2023 and then underwent coronary artery bypass graft surgery. Thereafter, the patient developed persistent dyspnea, lower limb edema, and orthopnea and was referred to Heart Center of Qingdao Municipal Hospital. His blood pressure at admission was 81/51 mmHg, his heart rate was 70 beats per minute, and his respiratory rate was 22 breaths/min. He had slight cyanosis of the lips and mild pretibial edema. Laboratory tests showed an elevation of cardiac troponin I levels (0.316 ng/mL; reference range, 0–0.034 ng/mL) and of brain natriuretic peptide levels (502 pg/mL; reference range, 0–100 pg/mL). ECG indicated a sinus rhythm with a heart rate of 70 beats/min, left axis deviation possibly due to left anterior fascicular block, poor R wave progression, first-degree atrioventricular block by a PQ interval of 220 msec, and intraventricular conduction disturbance by a QRS width of 146 msec but no low voltage (6) (Figure 1). TTE (Figure 2) revealed restrictive/infiltrative cardiomyopathy, showing diffuse thickening of the left ventricular wall with dotted strong echoes inside, mainly in the basal segment of the interventricular septum with a maximum thickness of approximately 16.1 mm; thickening of the right ventricle (approximately 8 mm); thickening of the mitral and aortic valves; left atrial enlargement; severely decreased left ventricular diastolic dysfunction; mildly decreased right ventricular systolic dysfunction (tricuspid annular plane systolic excursion 14 mm); moderate aortic regurgitation; severe mitral regurgitation; and left ventricular ejection fraction (LVEF) of 55%. Therefore, the patient underwent diagnostic testing for cardiac amyloidosis (CA). Light chain amyloidosis (AL) was excluded by serum and urine protein electrophoresis and immunofixation. Noninvasive radionuclide scintigraphy images with technetium-99m stannous pyrophosphate (99mTc-PYP) acquired 1 and 4 hours after the intravenous injection of 740 MBq of the radiotracer revealed myocardial uptake greater than that of bone, considered to be grade 3. Single-photon emission computed tomography-computed tomography fusion images confirmed myocardial tracer uptake, indicating ATTR-CA (Figure 3). The patient received diuretics, dapagliflozin, and a cardiac stimulant but no beta-blockers or angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers (7,8). Subsequently, the patient was started on tafamidis, a TTR stabilizer. The genetic test was performed by Sanger sequencing after genomic DNA was extracted from the peripheral blood of the patient, and the exon and intron regions of related genes were amplified by polymerase chain reaction. The result showed a rare heterozygosity mutation of TTR gene-c.302C>T (p.Ala101Val) (Figure 4), which was evaluated as a pathogenic mutation, indicating that the patient had ATTRv amyloidosis and not hypertrophic cardiomyopathy. Although the patient received tafamidis, his HF progressively worsened, and he died of a cardiac arrest 20 days after admission, 8 months after the onset of HF symptoms. It is worth noting that the patient was admitted to the Department of Rheumatology and Immunology due to bilateral upper arm pain and swelling 3 months before his visiting Heart Center of Qingdao Municipal Hospital, and ultrasound taken at the time indicated thickening of synovium and flexor tendon sheaths in both hands, suggesting that he might have had carpal tunnel syndrome (CTS).

Figure 1 ECG of this patient indicating sinus rhythm and left bundle branch block. ECG, electrocardiography.

Figure 2 TTE of this patient showing diffuse thickening of the ventricular wall. TTE, transthoracic echocardiography.

Figure 3 Radionuclide scintigraphy with 99mTc-PYP revealed a myocardial uptake greater than that of bone. 99mTc-PYP, technetium-99m stannous pyrophosphate.

Figure 4 Genetic test showed a mutation of the TTR gene: c.302C>T (as indicated by the red arrow). TTR, transthyretin.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for publication of this article and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

CA is an underdiagnosed cause of HF and is associated with significant morbidity and mortality (9). ATTR, one of the most common types of amyloidosis that can present as ATTRv or ATTRwt results from the misfolding and deposition of TTR and mainly invades the heart and nerves (10). Over 140 TTR mutations have been previously described. In this case, we identified a rare TTR variant c.302C>T (p.Ala101Val), mainly manifesting as CA. It affects a highly conserved amino acid position within a hotspot region in exon 3 of the TTR gene, with several other pathogenic variants in close vicinity (p.Ser97Tyr, p.Ser97Phe, p.Tyr98Phe, p.Lys100Arg, etc.) indicated in the Human Gene Mutation Database (HGMD), all of which are disease-causing mutations. In addition, other mutations at this amino acid site (p.Ala101Ser and pAla101Tyr) have been associated with amyloidosis in the HGMD. Based on this information, the variant was diagnosed as pathogenic.

To date, six patients with amyloidosis carrying this mutation, including ours, have been reported in the literature (11-13). Three patients were briefly mentioned in a research article (11), and the other two and our patient have been described in detail (12,13). The characteristics of the three cases are summarized in Table 1. Our patient (patient 1) first presented with cerebral embolism without any evidence of AF at the time and was misdiagnosed with hypertrophic cardiomyopathy. He developed symptoms of AF, HF, and CTS after 4 years and died 8 months after the onset of HF symptoms. Patient 2 (12), a Chinese male with a family history of neuropathy (mother), presented at age 58 with bilateral CTS. He subsequently developed lumbar spondylosis and painless distal lower limb weakness and numbness at 65 years of age, with sequential development of orthostatic hypotension (OH) and cardiomyopathy within a year. He died of pneumonia at the age of 67 years. Patient 3 (13), a 67-year-old Polish male, presented with progressive HF and permanent AF and significantly decreased LVEF (35%). This patient also had OH, bilateral CTS, and mild symptoms of polyneuropathy. The patient died of stroke at 71 years of age. All three patients were male—two Chinese and one Polish. The age of onset was approximately 60 years. Cardiomyopathy and CTS were present in all three cases. Two of the three patients (patients 1 and 3) developed stroke, and thus stroke may be one of the common clinical phenotypes of the variant. Thromboembolic events have been recognized as one of the most critical complications of ATTR and may also occur in patients with a normal sinus rhythm (14). Although the underlying mechanisms have not yet been fully clarified, cardiac mechanical dysfunction and the prevalence of AF, atrial myopathy, and intracardiac thrombi in patients with ATTR may be contributors. According to a recent report, this variant has most commonly been found in individuals of Polish and Russian descent (15).

In this case, the patient was misdiagnosed with hypertrophic cardiomyopathy when the TTE suggested myocardial hypertrophy, which is highly common in patients with CA, as initial symptoms are often nonspecific, family history can be absent, and the diagnosis of hypertrophic cardiomyopathy is more easily recognized by clinical doctors. Nonetheless, early identification remains important, as there has been a tremendous breakthrough in the specific treatment of ATTR, including with stabilizers, silencers, and degraders of TTR. Tafamidis, a stabilizer that prevents misfolding of the native TTR tetramer, has been recently approved for patients with cardiac involvement, and patients treated earlier in the disease course have demonstrated improved survival. We strongly urge clinicians to increase awareness and vigilance regarding this disease when managing with patients with cardiac hypertrophy. A cardiac pyrophosphate (PYP) scan is a relatively novel and powerful tool with high sensitivity for ATTR-CA. Recent guidelines have emphasized the utility of this approach in the diagnosis of ATTR-CA, and this may downplay the importance of biopsy and make it easier for clinicians to identify ATTR-CA (16).

In conclusion, we report a case of ATTRv-CA associated with a rare TTR mutation p.Ala101Val. We found that 99mTc-PYP scintigraphy is extremely valuable for providing a definitive diagnosis of ATTR-CA. As early disease recognition is critical to deriving the greatest benefit from novel treatments, clinicians should be more aware of this disease and practice vigilance in their daily work.

Acknowledgments

None.

Footnote

Funding: This work was supported by the Qingdao Medical and Health Research Project (No. 2022-WJZD002).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-24-1542/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for publication of this article and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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