Common TTR Gene Mutations

Summary for Physicians: Most Common TTR Gene Mutations in the United States

The transthyretin amyloidosis (ATTR) disease is driven by mutations in the TTR gene, which encodes the TRR protein. In the United States, the most common mutations linked to hereditary ATTR (hATTR) 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 TTR gene mutations in the United States:

V30M (Valine 30 Methionine):

• Prevalence: The V30M mutation is the most common and most well-known mutation in hATTR amyloidosis, particularly in patients with hATTR cardiomyopathy and hATTRperipheral neuropathy. It is most prevalent in Scandinavian countries but is also seen in the United States.
• Clinical presentation: 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 cardiac and neurological symptoms, with neuropathy being one of the most debilitating features.

T60A (Threonine 60 Alanine):

• Prevalence: The T60A 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 cardiac involvement and may present with heart failure symptoms, often without significant peripheral neuropathy.
• Clinical presentation: It typically manifests in midlife or later and is characterized by cardiomyopathy, which may be misdiagnosed as other forms of heart failure, such as heart failure with preserved ejection fraction (HFpEF).

V122I (Valine 122 Isoleucine):

• Prevalence: The V122I 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 wild-type ATTR (often seen in older adults).
• Clinical presentation: V122I has been linked to a form of ATTR amyloidosis that is more likely to present as cardiac amyloidosis, especially in older individuals. This form is often misdiagnosed as HFpEF, and symptoms may emerge after the age of 60.

TTR Phe64Leu (Phenylalanine 64 Leucine):

• Prevalence: The Phe64Leu 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.
• Clinical presentation: This mutation typically presents in adulthood and causes both cardiac and neurological manifestations, similar to the V30M mutation but with more variable progression.

Other mutations:

• 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 A25T, L55P, and Y114C, which may result in either cardiac or mixed cardiac-neurological forms of the disease.

Conclusion:

The most common TTR gene mutations in the United States include V30M, T60A, and V122I, each of which can lead to different clinical manifestations of hATTR amyloidosis. V30M is known for its early-onset, aggressive disease, whereas V122I is frequently seen in older African American individuals and is associated with cardiac symptoms. Identifying the specific TTR 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.