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Abstract：
OBJECTIVE: We conducted a presentation on an 84-year-old male patient who has been diagnosed with TTRA81V (p. TTRA101V) hereditary transthyretin cardiac amyloidosis (hATTR-CM). In order to establish its pathogenicity, we extensively investigated the biochemical and biophysical properties of the condition.
RESULTS: Transthyretin amyloid cardiomyopathy (ATTR-CM) is an increasingly acknowledged progressive infiltrative cardiomyopathy that leads to heart failure and potentially fatal arrhythmias. Gaining a comprehensive understanding of the biochemical and biophysical characteristics of genetically mutated TTR proteins serves as the fundamental cornerstone for delivering precise medical care to individuals affected by ATTR. Laboratory assessments indicated a brain natriuretic peptide of 200.12 ng/L (normal range: 0-100 ng/L) and high-sensitivity cardiac troponin I of 0.189 μg/L (normal range: 0-0.1 μg/L). Echocardiography identified left atrial enlargement, symmetrical left ventricular hypertrophy (16 mm septal and 16 mm posterior wall), and a left ventricular ejection fraction of 56%. Cardiac-enhanced magnetic resonance imaging revealed subendocardial late gadolinium enhancement. Tc-99m-PYP nuclear scintigraphy confirmed grade 3 myocardial uptake, showing an increased heart-to-contralateral ratio (H/CL = 2.33). Genetic testing revealed a heterozygous missense mutation in the TTR gene (c.302C>T), resulting in an alanine-to-valine residue change (p. Ala81Val, following the first 20 residues of signal sequence nomenclature). Biochemical analysis of this variant displayed compromised kinetic stability in both the TTRA81V:WT (wild-type) heterozygote protein (half-life, t1/2 = 21 h) and the TTRA81V homozygote protein (t1/2 = 17.5 h). The kinetic stability fell between that of the TTRWT (t1/2 = 42 h) and the early-onset TTRL55P mutation (t1/2 = 4.4 h), indicating the patient\'s late-onset condition. Kinetic stabilizers (Tafamidis, Diflunisal, and AG10) all exhibited the capacity to inhibit TTRA81V acid- and mechanical force-induced fibril formation, albeit less effectively than with TTRWT. Chromatographic assessment of the patient\'s serum TTR tetramers indicated a slightly lower concentration (3.0 μM) before oral administration of Tafamidis compared with the normal range (3.6-7.2 μM).
CONCLUSIONS: We identified a patient with hATTR-CM who possesses a rare TTRA81V mutation solely associated with cardiac complications. The slightly reduced kinetic stability of this mutation indicates its late-onset nature and contributes to the gradual progression of the disease.
RESULTS: Transthyretin amyloid cardiomyopathy (ATTR-CM) is an increasingly acknowledged progressive infiltrative cardiomyopathy that leads to heart failure and potentially fatal arrhythmias. Gaining a comprehensive understanding of the biochemical and biophysical characteristics of genetically mutated TTR proteins serves as the fundamental cornerstone for delivering precise medical care to individuals affected by ATTR. Laboratory assessments indicated a brain natriuretic peptide of 200.12 ng/L (normal range: 0-100 ng/L) and high-sensitivity cardiac troponin I of 0.189 μg/L (normal range: 0-0.1 μg/L). Echocardiography identified left atrial enlargement, symmetrical left ventricular hypertrophy (16 mm septal and 16 mm posterior wall), and a left ventricular ejection fraction of 56%. Cardiac-enhanced magnetic resonance imaging revealed subendocardial late gadolinium enhancement. Tc-99m-PYP nuclear scintigraphy confirmed grade 3 myocardial uptake, showing an increased heart-to-contralateral ratio (H/CL = 2.33). Genetic testing revealed a heterozygous missense mutation in the TTR gene (c.302C>T), resulting in an alanine-to-valine residue change (p. Ala81Val, following the first 20 residues of signal sequence nomenclature). Biochemical analysis of this variant displayed compromised kinetic stability in both the TTRA81V:WT (wild-type) heterozygote protein (half-life, t1/2 = 21 h) and the TTRA81V homozygote protein (t1/2 = 17.5 h). The kinetic stability fell between that of the TTRWT (t1/2 = 42 h) and the early-onset TTRL55P mutation (t1/2 = 4.4 h), indicating the patient\'s late-onset condition. Kinetic stabilizers (Tafamidis, Diflunisal, and AG10) all exhibited the capacity to inhibit TTRA81V acid- and mechanical force-induced fibril formation, albeit less effectively than with TTRWT. Chromatographic assessment of the patient\'s serum TTR tetramers indicated a slightly lower concentration (3.0 μM) before oral administration of Tafamidis compared with the normal range (3.6-7.2 μM).
CONCLUSIONS: We identified a patient with hATTR-CM who possesses a rare TTRA81V mutation solely associated with cardiac complications. The slightly reduced kinetic stability of this mutation indicates its late-onset nature and contributes to the gradual progression of the disease.
摘要：
目的：我们对一名被诊断为TTRA81V的84岁男性患者进行了介绍（第TTRA101V）遗传性甲状腺素运载蛋白心脏淀粉样变性（hATTR-CM）。为了确立其致病性,我们广泛研究了该条件的生化和生物物理特性。
结果：转甲状腺素蛋白淀粉样心肌病（ATTR-CM）是一种日益公认的进行性浸润性心肌病，可导致心力衰竭和潜在的致命心律失常。全面了解遗传突变的TTR蛋白的生化和生物物理特征是为受ATTR影响的个体提供精确医疗服务的基本基石。实验室评估显示脑钠肽为200.12ng/L（正常范围：0-100ng/L），高敏心肌肌钙蛋白I为0.189μg/L（正常范围：0-0.1μg/L）。超声心动图发现左心房增大，对称左心室肥厚（16毫米间隔和16毫米后壁），左心室射血分数为56%。心脏增强磁共振成像显示心内膜下钆晚期增强。Tc-99m-PYP核闪烁显像证实3级心肌摄取，显示心脏与对侧比率增加（H/CL=2.33）。基因检测揭示了TTR基因的杂合错义突变（c.306C>T），导致丙氨酸到缬氨酸残基的变化(p.Ala81Val,在信号序列命名法的前20个残基之后)。该变体的生化分析在TTRA81V：WT（野生型）杂合子蛋白（半衰期，t1/2=21h）和TTRA81V纯合子蛋白（t1/2=17.5h）。动力学稳定性介于TTRWT（t1/2=42h）和早发性TTRL55P突变（t1/2=4.4h）之间，表明病人的晚发型。动力学稳定剂(Tafamidis，二氟尼酸,和AG10）均表现出抑制TTRA81V酸和机械力诱导的原纤维形成的能力，尽管效果不如TTRWT。患者血清TTR四聚体的色谱评估表明，口服Tafamidis之前的浓度（3.0μM）略低于正常范围（3.6-7.2μM）。
结论：我们确定了1例hATTR-CM患者，该患者具有罕见的TTRA81V突变，仅与心脏并发症相关。该突变的动力学稳定性略微降低表明其迟发性,并有助于疾病的逐渐进展。
结果：转甲状腺素蛋白淀粉样心肌病（ATTR-CM）是一种日益公认的进行性浸润性心肌病，可导致心力衰竭和潜在的致命心律失常。全面了解遗传突变的TTR蛋白的生化和生物物理特征是为受ATTR影响的个体提供精确医疗服务的基本基石。实验室评估显示脑钠肽为200.12ng/L（正常范围：0-100ng/L），高敏心肌肌钙蛋白I为0.189μg/L（正常范围：0-0.1μg/L）。超声心动图发现左心房增大，对称左心室肥厚（16毫米间隔和16毫米后壁），左心室射血分数为56%。心脏增强磁共振成像显示心内膜下钆晚期增强。Tc-99m-PYP核闪烁显像证实3级心肌摄取，显示心脏与对侧比率增加（H/CL=2.33）。基因检测揭示了TTR基因的杂合错义突变（c.306C>T），导致丙氨酸到缬氨酸残基的变化(p.Ala81Val,在信号序列命名法的前20个残基之后)。该变体的生化分析在TTRA81V：WT（野生型）杂合子蛋白（半衰期，t1/2=21h）和TTRA81V纯合子蛋白（t1/2=17.5h）。动力学稳定性介于TTRWT（t1/2=42h）和早发性TTRL55P突变（t1/2=4.4h）之间，表明病人的晚发型。动力学稳定剂(Tafamidis，二氟尼酸,和AG10）均表现出抑制TTRA81V酸和机械力诱导的原纤维形成的能力，尽管效果不如TTRWT。患者血清TTR四聚体的色谱评估表明，口服Tafamidis之前的浓度（3.0μM）略低于正常范围（3.6-7.2μM）。
结论：我们确定了1例hATTR-CM患者，该患者具有罕见的TTRA81V突变，仅与心脏并发症相关。该突变的动力学稳定性略微降低表明其迟发性,并有助于疾病的逐渐进展。
