Double Transthyretin Gene Variants Linked to Increased Severity in Transthyretin Amyloidosis

A case series presented at the 2024 International Symposium on Amyloidosis by researchers from the Instituto Dante Pazzanese de Cardiologia explored the impact of possessing more than 1 pathogenic variant of the transthyretin (TTR) gene on the severity of transthyretin amyloidosis (ATTR). Led by L. Bruscky and colleagues, the study highlights the clinical characteristics and outcomes of patients with dual TTR mutations, providing novel insights into this rare but severe presentation of variant TTR cardiac amyloidosis.

ATTR is a hereditary systemic amyloidosis resulting from genetic variants of the TTR gene. These autosomal dominant conditions cause the precursor protein, TTR, to misfold and aggregate into amyloid fibrils, leading to organ dysfunction. More than 120 TTR mutations have been identified, with V142I and V50M being among the most common. The V142I mutation is notably prevalent among individuals of West African ancestry, with an estimated 3.2% of African American individuals carrying this variant. The diagnosis of ATTR has significant implications for prognosis, genetic counseling, and treatment strategies.

The series aimed to describe the clinical presentation and severity of ATTR in patients with double TTR gene variants (eg, carrying a variant mutation in both TTR alleles). Three cases with double TTR gene variants were presented:

• Patient 1 (P1): A 41-year-old man with dysautonomia, reduced left ventricular ejection fraction, dyspnea (New York Heart Association [NYHA] functional class II), and severe limb pain. PYP-Tc99m scintigraphy showed a heart-to-total-body (HTE/HTD) ratio of 2.22. Symptoms began at age 40.
• Patient 2 (P2): A 67-year-old man with severe bradycardia, syncope requiring a permanent pacemaker, and severe polyneuropathy. PYP-Tc99m scintigraphy showed an HTE/HTD ratio of 2.4. Symptoms began at age 50.
• Patient 3 (P3): A 66-year-old woman with preserved heart function, a pacemaker implanted at age 60, and dyspnea (NYHA I). PYP-Tc99m scintigraphy showed an HTE/HTD ratio of 2. Symptoms began at age 55.

The researchers observed that patients with double TTR gene variants exhibited more severe clinical phenotypes, including mixed cardiomyopathy and polyneuropathy. The onset of symptoms was earlier, and the severity was greater than in those with single variants. The scintigraphy results indicated higher uptake, reflecting more significant amyloid deposition in the heart.

This series of illustrative cases underscores the heightened severity of ATTR in patients with double TTR gene variants, emphasizing the need for early diagnosis and tailored therapeutic approaches. The findings highlight the importance of genetic screening and vigilant monitoring in managing this complex condition, providing a foundation for future research into targeted treatments for patients with multiple pathogenic TTR mutations.

Key Takeaways

• Increased Severity: Patients with double TTR gene variants present with a more severe disease phenotype, including early onset and intense symptoms.
• Clinical Implications: Dual mutations in the TTR gene are associated with mixed cardiomyopathy and polyneuropathy, necessitating more aggressive management.
• Diagnostic Insights: PYP-Tc99m scintigraphy revealed higher uptake ratios in these patients, indicating greater amyloid burden.