Omar F. Abou Ezzeddine, MD, CM, MS, FACC, FHFSA

Common TTR Gene Mutations

 (ATTR) disease is driven by mutations in the 

 gene, which encodes the TRR protein. In the United States, the most common mutations linked to 

 amyloidosis include several specific mutations in the TTR gene. These mutations are associated with a range of disease severities, primarily affecting cardiac and neurological systems. Below are the most common 

 mutation is the most common and most well-known mutation in hATTR amyloidosis, particularly in patients with 

peripheral neuropathy. It is most prevalent in Scandinavian countries but is also seen in the United States.

: This mutation is associated with a more aggressive form of the disease and can result in early-onset ATTR amyloidosis, typically presenting in patients in their 30s to 40s. Patients often experience both 

 symptoms, with neuropathy being one of the most debilitating features.

 mutation is found in a significant number of patients with hATTR amyloidosis, particularly in the African American population. This mutation is more commonly associated with 

 and may present with heart failure symptoms, often without significant peripheral neuropathy.

: It typically manifests in midlife or later and is characterized by 

, which may be misdiagnosed as other forms of heart failure, such as heart failure with preserved ejection fraction (HFpEF).

 mutation is another prevalent mutation in the United States, particularly among African American populations. It is considered one of the most common mutations associated with 

 has been linked to a form of ATTR amyloidosis that is more likely to present as 

, especially in older individuals. This form is often misdiagnosed as HFpEF, and symptoms may emerge after the age of 60.

 mutation is less common but still occurs in a subset of hATTR cases. It is associated with a more progressive form of the disease and tends to cause more severe neuropathy along with cardiomyopathy.

: This mutation typically presents in adulthood and causes both 

 manifestations, similar to the V30M mutation but with more variable progression.

Although the mutations mentioned above are the most common, numerous other rare mutations in the TTR gene can also cause ATTR amyloidosis. These include mutations such as 

, which may result in either cardiac or mixed cardiac-neurological forms of the disease.

 gene mutations in the United States include 

, each of which can lead to different clinical manifestations of hATTR amyloidosis. 

 is known for its early-onset, aggressive disease, whereas 

 is frequently seen in older African American individuals and is associated with cardiac symptoms. Identifying the specific 

 mutation is critical for accurate diagnosis, prognostication, and tailoring of treatment strategies, particularly as new therapies for hATTR amyloidosis become available. Genetic testing plays a key role in the diagnosis and management of these patients.

Videos

Panelists discuss how identifying the most common TTR gene mutations, including V30M, T60A, and V122I, is essential for accurate diagnosis, understanding clinical presentations, and tailoring treatment strategies for hereditary transthyretin amyloidosis in the United States.

The Pathophysiology of ATTR-CM, Differentiating Between wtATTR-CM and hATTR-CM

Summary for Physicians: Pathophysiology of ATTR-CM and the Importance of Differentiating Between wtATTR-CM and hATTR-CM

 (ATTR-CM) is a form of systemic amyloidosis where misfolded transthyretin (TTR) proteins accumulate as amyloid deposits in various organs, primarily in the heart. TTR is a protein responsible for transporting thyroid hormones and retinol-binding proteins, and it is produced mainly in the liver. When TTR undergoes misfolding due to mutations (in hereditary forms) or aging (in wild-type forms), it forms amyloid fibrils that deposit in tissues, leading to organ dysfunction, particularly in the heart.

, the amyloid fibrils accumulate in the myocardium, causing 

. Over time, this amyloid deposition can lead to stiffening of the heart muscle, impairing its ability to contract and relax, which results in reduced cardiac output and symptoms such as shortness of breath, fatigue, and arrhythmias.

Differentiating Between Wild-Type ATTR-CM (wtATTR-CM) and Hereditary ATTR-CM (hATTR-CM)

This form of ATTR-CM occurs due to the accumulation of normal (wild-type) TTR proteins that misfold and form amyloid deposits as people age. It primarily affects older individuals, especially men, and is commonly associated with heart failure with preserved ejection fraction. wtATTR-CM is often seen in patients older than 60 years and may be more prevalent than previously recognized, but it tends to progress more slowly and is often diagnosed later in the disease course.

hATTR-CM results from mutations in the TTR gene, which causes the production of abnormal TTR proteins that are prone to misfolding and amyloid deposition. The mutations may cause a more aggressive form of the disease that can present earlier in life, often in patients aged 30 to 50 years. hATTR-CM is inherited in an autosomal dominant manner, so there may be a family history of the disease. Certain mutations, such as the V30M mutation, are associated with more severe clinical outcomes, including earlier cardiac involvement, neuropathy, and multiorgan dysfunction.

Importance of Differentiating Between wtATTR-CM and hATTR-CM

: Treatment for wtATTR-CM focuses on symptom management, particularly heart failure treatment, as there are fewer disease-modifying therapies currently available for this form. However, emerging treatments, such as tafamidis, are starting to show promise in slowing disease progression.

: For hATTR-CM, specific disease-modifying treatments are available, such as 

 strategies. These therapies target the misfolded TTR protein directly and can prevent further amyloid deposition, improve cardiac function, and potentially halt disease progression. Early diagnosis and genetic testing are crucial for the timely initiation of these treatments.

 mutation is important not only for treatment but also for 

. Family members may be at risk, and early screening can help identify asymptomatic carriers who may benefit from early treatment.

 tends to have a slower progression, and the patient’s prognosis may be better compared to 

, which can progress rapidly and result in multiorgan damage. Understanding whether the patient has wtATTR-CM or hATTR-CM helps predict disease course and guide clinical decision-making.

 is critical for ensuring the correct diagnosis, appropriate treatment selection, and better management of patient outcomes. Although both forms share similar pathophysiology with TTR amyloid deposits in the heart, the underlying causes, progression, and treatment strategies differ significantly. Early diagnosis of hATTR-CM is particularly important for initiating disease-modifying therapies and providing genetic counseling to at-risk family members.

Panelists discuss how differentiating between wild-type transthyretin amyloid cardiomyopathy (wATTR-CM) and hereditary transthyretin amyloid cardiomyopathy (hATTR-CM) is essential for accurate diagnosis, tailored treatment strategies, and better management of patient outcomes, given their distinct pathophysiologies, disease progression, and treatment options.

Differentiating Between Light Chain and Transthyretin Amyloidosis

Summary for Physicians: The Importance of Differentiating Between Light Chain Amyloidosis and Transthyretin Amyloidosis

 (ATTR amyloidosis) is crucial for proper diagnosis, treatment planning, and patient management. Both are types of systemic amyloidosis but have different etiologies, clinical presentations, and treatment strategies. Here’s why this distinction is important:

Different etiologies and pathophysiologies

: AL amyloidosis results from the production of abnormal immunoglobulin light chains, typically by plasma cell dyscrasias such as multiple myeloma. These misfolded proteins accumulate as amyloid fibrils in organs, most commonly the heart, kidneys, liver, and nervous system.

: ATTR amyloidosis occurs due to the deposition of misfolded transthyretin (TTR) protein, either due to hereditary mutations in the TTR gene (familial ATTR) or age-related amyloid deposition in the absence of a mutation (wild-type ATTR). The affected organs primarily include the heart and nervous system.

: Understanding the underlying cause of amyloidosis is essential for determining the appropriate therapeutic approach. AL amyloidosis requires treatments that address the underlying plasma cell disorder, whereas ATTR amyloidosis requires different disease-modifying therapies targeting the TTR protein.

: Treatment focuses on managing the underlying plasma cell disorder. This often involves chemotherapy, stem cell transplantation, or novel therapies such as immunomodulatory agents (eg, daratumumab, bortezomib). The goal is to reduce or eliminate the production of the abnormal light chains.

: Treatment for ATTR amyloidosis includes therapies such as TTR stabilizers (eg, tafamidis), RNA interference (eg, patisiran, inotersen), and gene silencing. These therapies aim to stabilize the TTR protein and prevent further amyloid deposition.

: Administering the wrong treatment for either condition could lead to suboptimal results or even worsen the patient’s condition. Therefore, accurate diagnosis is critical to ensure the correct therapeutic pathway is pursued.

: AL amyloidosis is often associated with more aggressive disease and a poorer prognosis, particularly if it is diagnosed late. Early intervention is crucial to prevent organ damage and improve survival.

: Although ATTR amyloidosis (especially wild type) tends to have a more indolent course, early intervention with TTR-stabilizing therapies can significantly improve outcomes, particularly for heart failure and neurological symptoms.

: A correct diagnosis of either AL or ATTR amyloidosis will lead to better disease monitoring and prognosis prediction, as well as timely intervention to improve quality of life and survival.

: Diagnosis is confirmed by the detection of light chain protein deposits in tissues, typically using 

. In cases of familial ATTR, genetic testing can reveal specific mutations.

: Accurate diagnostic testing using appropriate tools for each type of amyloidosis is essential for confirming the diagnosis and differentiating between these 2 conditions.

: Differentiating between AL amyloidosis and ATTR amyloidosis is vital for determining the correct treatment, optimizing patient outcomes, and providing an accurate prognosis. Both conditions have distinct underlying causes, therapeutic approaches, and prognoses, making accurate diagnosis and tailored treatment critical for effective management.

Panelists discuss how differentiating between light chain amyloidosis and transthyretin amyloidosis is crucial for accurate diagnosis, appropriate treatment selection, and optimal patient management, given their distinct etiologies, therapeutic approaches, and prognoses.

Increasing Awareness Around ATTR-CM

Summary for Physicians: The Call to Action for ATTR-CM Awareness and Its Classification as a Rare Disease (Brito et al 2023)

The Call to Action for Raising Awareness for ATTR-CM (Brito et al 2023)

: The call to action to raise awareness about 

 (ATTR-CM) stems from the realization that this condition is frequently underdiagnosed or misdiagnosed despite its growing prevalence and devastating impact on patients. ATTR-CM can easily be mistaken for other common cardiac conditions such as heart failure with preserved ejection fraction, which leads to delays in diagnosis and appropriate treatment.

: ATTR-CM is often diagnosed too late, after irreversible damage has occurred. Early recognition is critical, as recent advancements in diagnostic tools (eg, 99mTc-PYP scintigraphy) and disease-modifying therapies (eg, tafamidis, patisiran, and inotersen) can significantly improve patient outcomes when started early.

: The increasing recognition of the disease, especially in the aging population, has prompted the need for greater awareness. Both hereditary (mutated 

 gene) and wild-type ATTR (mostly seen in older adults) contribute to the disease burden. As the population ages, ATTR-CM is expected to be more common than previously recognized.

: Raising awareness among health care providers, especially cardiologists, can lead to faster diagnosis, earlier treatment initiation, and better management, ultimately improving quality of life and survival for affected patients.

 emphasized by Dr Abou Ezzeddine and Brito et al, highlights the importance of increased awareness, faster diagnosis, and early therapeutic intervention to optimize patient outcomes in ATTR-CM.

Is ATTR-CM Still Considered a Rare Disease?

: Although ATTR-CM was historically classified as a rare disease, this is increasingly being questioned, especially with the rise in awareness and the availability of diagnostic tools. It is becoming clear that ATTR-CM is not as rare as once thought, particularly in aging populations.

: Advances in imaging techniques, genetic testing, and biomarker identification have led to increased recognition of ATTR-CM. As more clinicians consider this diagnosis in patients with unexplained heart failure, the number of diagnosed cases grows.

: Wild-type ATTR-CM, which primarily affects older individuals, is much more common than previously acknowledged. This form of the disease is now recognized as a significant cause of heart failure in older populations, suggesting that ATTR-CM may be more prevalent than we once thought, especially in older patients.

: The introduction of diagnostic imaging methods (eg, 99mTc-PYP scintigraphy) and genetic testing has enabled clinicians to detect the disease earlier, even in asymptomatic or mildly symptomatic patients, further contributing to the apparent rise in prevalence.

: ATTR-CM, although still classified as a rare disease by traditional definitions, is likely more common than previously recognized, especially in older populations. With better diagnostic tools and increasing awareness, the condition may no longer be considered rare, and more patients will benefit from timely diagnosis and intervention.

Panelists discuss how increasing recognition of transthyretin amyloid cardiomyopathy (ATTR-CM), fueled by advancements in diagnostic tools and greater awareness, is challenging its classification as a rare disease, particularly in aging populations, and emphasizing the need for earlier diagnosis and intervention.

Omar F. Abou Ezzeddine, MD, CM, MS, FACC, FHFSA

Articles

Common TTR Gene Mutations

The Pathophysiology of ATTR-CM, Differentiating Between wtATTR-CM and hATTR-CM

Differentiating Between Light Chain and Transthyretin Amyloidosis

Increasing Awareness Around ATTR-CM