Hereditary Transthyretin Amyloid Cardiomyopathy with Val142Ile Mutation in Taiwan: A Case Report

Abbreviations

ATTR, Transthyretin amyloidosis

ATTR-CM, Transthyretin amyloid cardiomyopathy

CAD, Coronary artery disease

H/CL, Heart-to-contralateral ratios

hATTR-CM, Hereditary transthyretin amyloid cardiomyopathy

ISR, In-stent restenosis

LV, Left ventricular

POBAS, Percutaneous occlusive balloon angioplasty with stenting

^99mTc PYP, Technetium-99m pyrophosphate

wtATTR-CM, Wild-type ATTR-CM

INTRODUCTION

Cardiac amyloidosis, a rare and severe type of infiltrative cardiomyopathy leading to heart failure, is often misdiagnosed due to limited understanding of the disease. We report a case of an 85-year-old female patient with hereditary transthyretin amyloid cardiomyopathy (hATTR-CM) caused by the Val142Ile (also known as Val122Ile) mutation, previously unreported in Taiwan. The patient, with a history of coronary artery disease (CAD) status post percutaneous occlusive balloon angioplasty with stenting (POBAS), presented with heart failure symptoms. Initial examination revealed septal hypokinesia, which prompted suspicion of in-stent restenosis (ISR). However, this was not supported by cardiac catheterization. Given the patient’s unexplained clinical symptoms and findings from the electrocardiogram and transthoracic echocardiography, cardiac amyloidosis was suspected. Further investigation through blood tests, nuclear scintigraphy, and pathology confirmed a diagnosis of transthyretin amyloid cardiomyopathy (ATTR-CM), with the TTR gene sequencing validating the Val142Ile mutation. Due to its elusive nature, cardiac amyloidosis presents a diagnostic challenge, with key clues often overlooked by physicians. Therefore, it’s imperative to consider this diagnosis when evaluating patients with heart failure symptoms.

CASE

An 85-year-old woman with a history of CAD and heart failure presented with progressive shortness of breath and lower limb edema. Since the age of 81, she had been experiencing episodes of breathlessness lasting 2-3 minutes during walks. At 83, she underwent POBAS on her right coronary and left anterior descending arteries and was concurrently diagnosed with heart failure, New York Heart Association Functional Classification II, with N-terminal pro B-type natriuretic peptide at 4416 pg/mL, and high sensitivity troponin-T at 59.9 ng/L. By 85, she was suffering from acute decompensated heart failure. A 24-hour Holter’s electrocardiogram monitor showed a 7-beat short-run ventricular tachycardia and some episodes of paroxysmal atrial fibrillation. Subsequent examinations, including an electrocardiogram, revealed atrial fibrillation with a heart rate of 88 bpm, a QS pattern in lead III, aVF, V1-3, and relative low voltage (Figure 1A). A chest X-ray showed cardiomegaly with bilateral pleural effusion (Figure 1B). A transthoracic echocardiography revealed a dilated left atrium size of 48 mm, left ventricular (LV) concentric hypertrophy (18/43/15/34 mm), moderate mitral regurgitation, severe tricuspid regurgitation, LV ejection fraction of 50%, and an LV filling pattern suggesting restrictive cardiomyopathy (ratio of E- to A-wave velocities 3.2, deceleration time 306 mSec, E′/med E′: 21, E/lat E′: 11.4) (Figure 1C & 1D). As her symptoms were suggestive of possible ISR, a thallium-201 myocardial perfusion scan was arranged, revealing moderate reversible perfusion defect and septal hypokinesia. However, a repeated coronary angiogram did not show significant ISR. Despite this, the unexplained clinical symptoms and transthoracic echocardiography findings suggested the possibility of restrictive cardiomyopathy, and cardiac amyloidosis was highly suspected. To investigate further, a technetium-99m pyrophosphate (^99mTc PYP) scintigraphy was performed, which revealed heart-to-contralateral ratios (H/CL) of uptake 1.66 and 1.54 at 1 and 3 hours, respectively, and a grade 3 semi-quantitative visual scoring for cardiac retention compared to bone (Figure 1E & 1F). The results of the serum free light chain assay showed free kappa: 38.15 mg/L, free lambda: 22.01 mg/L, kappa/lambda: 1.733, and serum and urine protein immunofixation electrophoresis revealed no monoclonal protein. With these laboratory findings and the results of the ^99mTc PYP scintigraphy, ATTR-CM was suspected. Exon-wide sequencing analysis of the TTR gene confirmed a heterozygous transthyretin p.Val142Ile (V122I) genetic variant, specifically c.424G>A/WT. This finding, along with the endocardial biopsy results, confirmed a diagnosis of hATTR-CM with the Val142Ile mutation. The biopsy showed deposition of amorphous eosinophilic material with apple-green birefringence on Congo red stain and a positive immunohistochemistry stain of transthyretin (Figure 2A-2C). The patient sometimes experienced fingertip numbness. Nerve conduction velocity testing for her bilateral upper and lower limbs revealed nonspecific findings. The patient, the youngest and sole surviving sibling of ten from a pure Hoklo Taiwanese lineage with no history of intermarriage outside the ethnicity, had six children. Only two daughters consented to genetic screening, one of whom tested positive for the Val142Ile mutation. The patient declined tafamidis therapy due to its high cost and was prescribed conservative treatment. However, she developed severe heart failure with a progressively reduced ejection fraction and passed away 1.5 years later after receiving hospice care.

Figure 1.

(A) The electrocardiogram showed atrial fibrillation, heart rate 88 bpm, left bundle branch block, QS wave in septal and inferior leads. (B) The chest X-ray showed cardiomegaly with bilateral pleural effusion. (C & D) The transthoracic echocardiography revealed dilated left atrium size, left ventricular concentric hypertrophy. (E & F) The ^99mTc PYP scintigraphy showed heart-to-contralateral ratios (H/CL) of uptake 1.66 and 1.54 at 1 and 3 hours, respectively, and a visual score of grade 3 in the planar and single photon emission computed tomography (SPECT)/computed tomography (CT) images, strongly suggestive of transthyretin amyloid cardiomyopathy (ATTR-CM).

Figure 2.

Endocardial biopsy was performed of the right ventricle (A) Hematoxylin and eosin stain showed myocardial tissue with deposition of amorphous eosinophilic material. (B) Congo red stain demonstrates apple green birefringence, compatible with amyloidosis. (C) By using immunohistochemistry, a monoclonal-transthyretin (TTR) antibody from Santa Cruz was employed to confirm the existence of transthyretin in the myocardium. This confirmed the diagnosis of transthyretin amyloid cardiomyopathy (ATTR-CM).

DISCUSSION

Cardiac amyloidosis is caused by the accumulation of misfolded proteins, which form amyloid fibrils in the heart. Most cases are either immunoglobulin light chain amyloidosis or transthyretin amyloidosis (ATTR). ATTR can be either wild-type or hereditary, depending on the presence of a TTR gene mutation.¹ Over 120 mutations, each associated with varied phenotypes, can lead to hATTR-CM. The Val30Met mutation, primarily causing neurological conditions, is the most common and is prevalent in Portugal, Japan, and Sweden.² The Ala97Ser mutation, primarily causing late-onset axonal degeneration, is the dominant pathogenic variant of ATTR in Taiwan.³ The current case involves the Val142Ile mutation, predominantly causing cardiomyopathy, and is prevalent in 3% to 4% of African Americans.² This is the first case reported in Taiwan.

Patients with cardiac amyloidosis frequently present with heart failure with preserved ejection fraction due to restrictive cardiomyopathy, often leading to misdiagnosis given the disease’s rarity and limited understanding.¹ For patients presenting with an unexplained LV thickness of ≥ 12 mm and at least one compatible symptom, ‘red flags’ should be noted for better diagnosis. These may include intolerance to standard heart failure treatments, mismatches between electrocardiographic voltage and LV wall thickness, and existing diagnoses of carpal tunnel syndrome or lumbar spinal stenosis. In addition, autonomic dysfunction, gastrointestinal complaints, or unexplained weight loss warrant further investigation.^1,3,4 In our case, the discrepancy between electrocardiographic voltage and LV wall thickness, along with a pseudo-infarction pattern, steered us towards the underlying condition.

Non-invasive methods are now preferred over traditional endomyocardial biopsy for suspected ATTR-CM. Techniques such as nuclear scintigraphy with ^99mTc PYP, which demonstrate high sensitivity and reasonable specificity, are employed once clonal dyscrasia has been ruled out by serum free light-chain assays, as well as serum and urine protein electrophoresis with immunofixation.^1,4,5 Once ATTR-CM is confirmed, TTR gene sequencing is recommended, as wild-type ATTR-CM (wtATTR-CM) and hATTR-CM cannot be distinguished solely based on the clinical profile. If a TTR mutation is identified, hATTR-CM is diagnosed, triggering a recommendation for genetic counseling.¹ Genetic counseling can assist healthy TTR mutation carriers in understanding the disease, potentially leading to earlier diagnoses through regular follow-ups. Although the clinical penetrance of the p.Val142Ile variant is incomplete in subjects up to 80 years of age, it is likely under-recognized as a cause of heart failure. Typically, it’s recommended that the assessment of penetrance in allele carriers begins approximately 10 years prior to the age of disease onset in affected family members (or other individuals with the same mutation), or as soon as amyloidosis-compatible symptoms develop.⁶ This patient’s 58-year-old daughter, who carries the Val142Ile mutation but currently exhibits no symptoms of heart failure or LV hypertrophy, is engaged in regular outpatient clinic follow-ups.

A review of 62 studies involving around 150,000 subjects found the global prevalence of the Val142Ile mutation causing ATTR-CM is between 0.3% and 1.6%, and between 1.1% and 9.8% among individuals of African descent. This mutation is most observed in males in their 70s or 80s and is associated with high mortality rates (up to 50% within five years of diagnosis). Patients with this mutation typically have lower survival rates and poorer quality of life. Atrial fibrillation is diagnosed in 25%-38% of cases. Early diagnosis and treatment, especially with drugs like tafamidis, can improve patient outcomes.⁷ A recent research suggests that the p.Val142Ile variant, previously attributed primarily to the "African" population and responsible for ATTR, is more prevalent in central Italy due to a founder effect, rather than recent admixture from African populations.⁸ This discovery draws attention to a potential underestimation of the variant’s worldwide prevalence and emphasizes the importance of including TTR in gene panels for clinical genetic testing.

In conclusion, we reported a case of hATTR-CM associated with the Val142Ile mutation, previously unreported in Taiwan. The patient presented with common symptoms of heart failure, and the diagnosis was made through a series of examinations. This case serves as a reminder to consider this diagnosis and to be alert to potential clues when treating heart failure patients. Deciding when to initiate further investigations remains challenging and requires practice and experience.

LEARNING POINTS

The Val142Ile mutation causing hATTR-CM is rare in Taiwan, with cardiac involvement typically being the primary clinical manifestation. Key takeaways from this case include the importance of considering cardiac amyloidosis as a potential diagnosis for patients presenting with heart failure symptoms, regardless of age, history of coronary artery disease, or other comorbidities, especially when subtle clinical hints are present. Comprehensive studies to understand the impact of the mutation on the patient’s heart failure are crucial for future personalized and precision medicine treatment strategies.

DECLARATION OF CONFLICT OF INTEREST

All authors have no conflict of interest to declare.