TTR Variant p.Ala65Val Causing Early-Onset Hereditary Transthyretin Amyloidosis With Mixed Cardiac and Neuropathic Phenotype

Abstract

Background

Variant transthyretin amyloidosis (ATTRv) remains undercharacterized in Latin America, with limited awareness of its regional mutational diversity.

Case Summary

A 48-year-old Peruvian man presented with syncope, exertional dyspnea, weight loss, and lower extremity paresthesia. Multimodality evaluation demonstrated severe infiltrative cardiomyopathy, small fiber and autonomic neuropathy, and peripheral nerve hypertrophy. Genetic testing identified a heterozygous pathogenic p.Ala65Val transthyretin variant, confirming ATTRv. No transthyretin-targeting therapies are currently accessible in Peru.

Discussion

To our knowledge, only 1 prior case harboring this variant has been reported, in a European patient with a late-onset presentation. Our patient exhibited an early-onset mixed cardiac and neuropathic phenotype, broadening the clinical spectrum of this rare variant.

Take-Home Message

This case highlights the phenotypic diversity of ATTRv and underscores the critical unmet need for disease-modifying therapy access and greater inclusion of Latin American patients in clinical trials.

Visual Summary

Visual Summary.

Multimodality Imaging in a Patient From a High-Altitude Andean Community With Variant Transthyretin Amyloid Cardiomyopathy p.Ala65Val

(A) Geographic location of Yanama within the high-altitude Peruvian Andes. (B) Four-chamber transthoracic echocardiographic view demonstrating severe concentric left ventricular hypertrophy, right ventricular wall thickening, mild biatrial dilatation, interatrial septal thickening, and mitral and tricuspid valve leaflet thickening. (C) Two-dimensional speckle-tracking strain map demonstrating reduced global longitudinal strain of −9.7% with characteristic apical sparing. (D) Technetium-99m pyrophosphate scintigraphy demonstrating Perugini grade 3 cardiac uptake. (E) Follow-up cardiac magnetic resonance demonstrating late gadolinium enhancement in 4-chamber view showing circumferential and transmural left ventricular enhancement with right ventricular involvement. (F) Native T1 mapping and (G) extracellular volume (ECV) fraction are markedly elevated (local reference range for native T1: 958-1,057 ms).

History of Presentation

A 48-year-old man with a recent diagnosis of atrial fibrillation and receiving rivaroxaban and bisoprolol presented to the emergency department with a 6-month history of recurrent syncope and exertional dyspnea on mild effort, as well as a 1-year history of unintentional weight loss and lower extremity paresthesia. On admission, vital signs were notable for hypotension with blood pressure 90/60 mm Hg, heart rate 64 beats/min, respiratory rate 14 breaths/min, and oxygen saturation 98% on room air. Cardiac auscultation revealed irregular heart sounds without murmurs; pulmonary examination was unremarkable.

Past Medical History

The patient was a native resident of Yanama, Yungay, Ancash, a high-altitude community in the Peruvian Andes (Supplemental Figure 1). He reported no family history of structural heart disease; however, his mother had died at an early age from an undetermined cause.

Differential Diagnosis

Common causes of left ventricular hypertrophy (LVH), including hypertensive heart disease, aortic stenosis, and athlete's heart, were considered unlikely based on the clinical presentation and initial investigations. Conventional hypertrophic cardiomyopathy (HCM), cardiac amyloidosis, and genetic systemic disorders were therefore entertained. Among the latter, Fabry disease warranted particular consideration given the patient's age: This X-linked lysosomal storage disorder is well recognized to mimic HCM in adults, typically manifesting in the third to fourth decade with progressive LVH, small-fiber neuropathy, renal involvement, and angiokeratomas. However, no features specific to Fabry disease or other systemic storage disorders were identified. HCM and cardiac amyloidosis remained the leading etiologies, with the presence of sensory neurological symptoms favoring amyloidosis.

Investigations

Laboratory analyses demonstrated hemoglobin 13 g/dL, creatinine 0.8 mg/dL, albumin 4.1 g/dL, 24-hour urinary protein 0.04 g/d, high-sensitivity troponin T 47 ng/L (0-14 pg/mL), and N-terminal pro B–type natriuretic peptide (NT-proBNP) 147 pg/mL (0-125 pg/mL). Chest radiography showed an increased pulmonary vascular pattern with blunting of the costophrenic angles, without parenchymal consolidation (Figure 1). Electrocardiogram revealed low QRS voltage, a pseudo-infarct pattern, and atrial flutter with a controlled ventricular rate (Figure 2A).

Figure 1.

Chest Radiographic Findings

Posteroanterior chest radiograph demonstrating increased pulmonary vascular markings with preserved parenchymal pattern.

Transthoracic echocardiography demonstrated a left ventricular ejection fraction of 61%, severe concentric LVH (interventricular septum 16 mm, posterior wall 17 mm), global longitudinal strain of −9.7% with apical sparing, right ventricular wall thickening, mild biatrial dilatation, and a small pericardial effusion (Figures 2B and 2C). Cardiac magnetic resonance confirmed the echocardiographic findings and revealed diffuse subendocardial late gadolinium enhancement (Figures 3A to 3C). Serum and urine immunofixation electrophoresis and free light chain assays excluded monoclonal gammopathy. Technetium-99m pyrophosphate scintigraphy demonstrated a visual uptake score of 3 (Figure 3D), consistent with transthyretin amyloidosis.

Figure 2.

Electrocardiographic and Echocardiographic Findings

(A) Electrocardiogram showing low QRS voltage, a pseudo-infarct pattern, and atrial flutter with a controlled ventricular rate. (B) Four-chamber transthoracic echocardiographic view demonstrating severe concentric left ventricular hypertrophy, right ventricular wall thickening, mild biatrial dilatation, interatrial septal thickening, and mitral and tricuspid valve leaflet thickening. (C) Two-dimensional speckle-tracking strain map demonstrating reduced global longitudinal strain (−9.7%) with apical sparing, a pattern characteristic of infiltrative cardiomyopathy.

Figure 3.

Multimodality Imaging Consistent With Transthyretin Amyloid Cardiomyopathy

Cardiac magnetic resonance in 4-chamber (A) and short-axis (B) planes demonstrating severe concentric left ventricular hypertrophy, right ventricular wall thickening, mild biatrial dilatation, interatrial septal thickening, and pericardial effusion. (C) Late gadolinium enhancement sequence in 4-chamber view revealing diffuse pathologic gadolinium deposition with a predominantly subendocardial distribution. (D) Technetium-99m pyrophosphate scintigraphy demonstrating intense biventricular tracer uptake exceeding bone (Perugini grade 3).

Given the presence of sensory symptoms, a comprehensive neurological evaluation was performed. Examination revealed global areflexia and bilateral distal predominant hypoesthesia in 4 limbs. Quantitative sensory testing demonstrated significant hyposensitivity to cold thermal stimuli and heat-nociceptive stimuli in both upper and lower extremities. Additionally, paradoxical heat sensation was elicited in the lower limbs, a phenomenon reflecting aberrant transduction of cold stimuli perceived as warmth, indicative of small fiber dysfunction. Autonomic function testing confirmed neurogenic orthostatic hypotension. The Small Fiber Neuropathy Symptoms Inventory Questionnaire score was 15/39, and the Composite Autonomic Symptom Score was 29, consistent with moderate autonomic dysfunction. Electromyography confirmed a length-dependent sensorimotor axonal polyneuropathy with mild right carpal tunnel syndrome. Nerve ultrasound revealed enlargement of the cross-sectional area of the fibular nerve (25.5 mm²; normal <7.1 mm²) and tibial nerve (3 2.7 mm²; normal <8.43 mm²), consistent with peripheral nerve hypertrophy.

Genetic testing identified a heterozygous pathogenic p.Ala65Val variant in the TTR gene, confirmatory for variant transthyretin amyloidosis (ATTRv). Cascade genetic screening identified the same pathogenic variant in the proband's son, 2 brothers, 1 sister, and 1 maternal uncle; no other younger relatives exhibited cardiac or neurologic involvement at the time of evaluation. The maternal uncle, however, demonstrated evidence of cardiac compromise (Supplemental Figure 2).

Management

Following confirmation of ATTRv cardiomyopathy, the patient was evaluated for disease-modifying therapy. No TTR-stabilizing or gene-silencing agents are currently approved or accessible in Peru. A formal request for compassionate access was submitted to the hospital's administrative authorities; no response had been received at the time of this report. Management was therefore limited to guideline-directed symptomatic therapy, including spironolactone 25 mg daily, as-needed furosemide for peripheral edema, rivaroxaban 20 mg daily, and dapagliflozin 10 mg daily.

Outcome and Follow-Up

At 3 years following diagnosis, and in the absence of disease-modifying therapy, the patient continues regular outpatient follow-up without additional heart failure hospitalizations. However, he has experienced progressive worsening of autonomic symptoms and skeletal muscle weakness, alongside a parallel rise in cardiac biomarkers—high-sensitivity troponin T 47.9 ng/L (reference: 0-14 pg/mL) and NT-proBNP 9,560 pg/mL (reference: 0-125 pg/mL)—consistent with ongoing disease progression. Repeat cardiac magnetic resonance demonstrated transmural late gadolinium enhancement with increased extracellular volume and T1 mapping values, indicating advancing myocardial infiltration; direct quantitative comparison with the index study was not feasible because of the unavailability of postprocessing software at the time of the initial examination (Figure 4).

Figure 4.

Follow-Up Cardiac Magnetic Resonance Demonstrating Disease Progression

Phase-sensitive inversion recovery late gadolinium enhancement images in 4-chamber (A), 2-chamber (B), and 3-chamber (C) views showing circumferential and transmural left ventricular enhancement with right ventricular involvement (Query Amyloid Late Enhancement score 18), indicative of advancing myocardial infiltration. (D) Native T1 mapping and (E) extracellular volume (ECV) fraction are markedly elevated (local reference range for native T1: 958-1,057 ms), consistent with significant interstitial expansion. (F) T2 mapping values remain within normal limits (local reference range: 44-54 ms), arguing against active myocardial edema.

Discussion

ATTRv remains undercharacterized in Latin America, with limited epidemiologic data and inadequate awareness of its regional mutational diversity. Reporting novel or rare variants from underrepresented populations is essential to expand the known genetic and phenotypic spectrum of this disease. We report a case of early-onset ATTRv amyloidosis caused by the p.Ala65Val variant, manifesting with a mixed cardiac and neuropathic phenotype, thereby extending the recognized spectrum of amyloidogenic TTR mutations.

ATTRv is an autosomal dominant disease with variable age of onset, ethnic clustering, and a broad clinical spectrum encompassing cardiomyopathy, peripheral neuropathy, central nervous system involvement, soft tissue infiltration, nephropathy, and ocular disease.^1,2 Phenotypic expression is largely determined by genotype, alongside other factors influencing disease penetrance. The p.Ala65Val TTR variant identified in our patient was not catalogued as amyloidogenic in the Mutations in Hereditary Amyloidosis database³; however, ClinVar classifies it as pathogenic or likely pathogenic based on a limited number of submitted interpretations.⁴

To our knowledge, only 1 prior case harboring this variant has been reported—a European patient with late-onset ATTRv with mixed cardiac and neuropathic phenotype. In that report, cardiac amyloidosis was incidentally diagnosed on echocardiography performed during preoperative evaluation for lumbar canal stenosis, and tafamidis was initiated. The subsequent emergence of neuropathic symptoms and rapid disease progression despite treatment prompted genetic testing, ultimately identifying the p.Ala65Val mutation.⁵ In contrast, our patient had an early-onset presentation, broadening the known clinical expression of this variant.

Three disease-modifying therapies are currently approved for ATTRv cardiomyopathy: tafamidis, acoramidis, and vutrisiran. However, patients with ATTRv represented only 24%, 10%, and 12% of enrollees in the respective pivotal trials, of whom approximately two-thirds carried the Val142Ile variant.² This narrow representation limits the generalizability of efficacy data to other TTR variants, and differential effectiveness across specific mutations cannot be entirely excluded. Furthermore, because these trials were placebo-controlled rather than head-to-head comparative studies, no direct evidence exists to establish the superiority of 1 agent over another.² In patients with ATTRv cardiomyopathy and concomitant amyloid polyneuropathy, vutrisiran may be the preferred option, given its demonstrated benefit in ATTRv-related polyneuropathy.⁶ Patisiran and inotersen have also shown efficacy in halting—and potentially reversing—neurologic progression in hereditary polyneuropathy; notably, patisiran demonstrated improvement in cardiac indexes and heart failure biomarkers in patients with hereditary polyneuropathy and concomitant cardiomyopathy.⁷

Latin American representation in pivotal clinical trials remains critically insufficient—for example, comprising only 7% of participants in the HELIOS-B trial⁸—reflecting a systemic gap that undermines the applicability of current evidence to this population and perpetuates diagnostic and therapeutic inequities. Beyond underrepresentation in research, access to approved therapies across Latin America is severely constrained by regulatory, economic, and policy barriers. In Peru, for instance, inotersen is the only agent with national regulatory approval, yet it remains unavailable in practice: patients are unable to sustain the financial burden of long-term treatment, and existing health policy frameworks have not yet enabled its evaluation for coverage by the Ministry of Health.⁹

This case expands the known phenotypic spectrum of the rare p.Ala65Val TTR variant, demonstrating that early-onset multisystem ATTRv amyloidosis can occur beyond previously reported populations. It further highlights the urgent need to improve diagnostic awareness, increase Latin American representation in clinical trials, and address the substantial barriers to disease-modifying therapy access in the region.

Take-Home Messages

• •The p.Ala65Val TTR variant can manifest as early-onset ATTRv amyloidosis with a mixed cardiac and neuropathic phenotype, broadening the clinical spectrum of this rare mutation.
• •Limited access to disease-modifying therapies and underrepresentation in clinical trials represent critical unmet needs for ATTRv patients in Latin America.

Funding Support and Author Disclosures

The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Appendix

Supplemental Figures

Supplemental Figure 1. Geographic Location of Patient's Community of Origin

Map depicting the location of Yanama, a high-altitude rural community in the district of Yungay, province of Ancash, Peru, situated in the Peruvian Andes at approximately 3,100 m above sea level. The inset panels illustrate the location of Ancash within the national territory of Peru, and the district of Yungay within the province of Ancash.

Supplemental Figure 2. Pedigree of Proband's Family Demonstrating Segregation of p.Ala65Val TTR Variant

Family pedigree illustrating the results of cascade genetic screening for the heterozygous pathogenic p.Ala65Val variant in the TTR gene. A plus sign (+) denotes confirmed variant carriers; a minus sign (−) denotes individuals who underwent genetic testing and were found not to carry the variant. A diagonal line through a symbol indicates a deceased individual; available cause of death is noted beneath the corresponding symbol. The proband is indicated by an arrow.