Effect of Mutation Zygosity and Sex on the Range of Transthyretin Cardiac Amyloidosis Disease Severity in 1 Family

Providers face challenges with clinical vigilance and treatment for transthyretin amyloidosis due to the range of disease severity and phenotypic penetrance of carriers of variant forms.

Protein misfolding contributes to the formation and aggregation of insoluble fibrils that is the basis of the family of disorders called amyloidosis. Tissue architecture and organ function is disrupted by these amyloid deposits. Although there are more than 27 different precursor proteins that have been recognized as amyloidogenic, there are 2 that are particularly clinically significant proteins. These are immunoglobulin light chain and transthyretin (TTR), which have both been associated with cardiac amyloidosis. Two types of cardiac TTR amyloidosis (ATTR) are hereditary or variant (ATTRv) and wild-type ATTR.

When a pathogenic mutation in the TTR gene occurs, ATTRv ensues; this is caused either by a spontaneous or direct result of an autosomal dominant inherited mutation. However, when no mutation of the TTR gene occurs, this conversely results in wild-type ATTR, which is generally related to the aging process and is frequently associated with patients aged ≥70 years.

The cause of ATTRv is an excess of 100 confirmed pathogenic single-point mutations in the TTR gene. Specific mutations have been identified and occur at a rate of approximately 3% to 4% of Americans of African descent. This includes the V122I mutation. Tushak and colleagues describe 3 sibling carriers to highlight the range of challenges providers may face with clinical vigilance and treatment.

The first case involved a 62-year-old African-American male who had been referred for heart failure evaluation. Over the previous year, the patient had reported a history of shortness of breath when climbing a flight of stairs, orthopnea, and lower extremity pitting edema. Multiple hospital admissions for recurring pleural effusion and cough had occurred during this period. Based on laboratory findings, 99mTechnetium-pyrophosphate with single-photon emission computerized tomography imaging was conducted, which revealed an increased uptake in the myocardium with a heart-to-contralateral lung uptake ratio of 1.8. Based on medical history, symptoms, and laboratory findings, the diagnosis of ATTRv was made. Notably, genetic testing had revealed a homozygous V122I mutation. The patient received tafamidis (Vyndamax) therapy, and due to disease progression, he had an isolated heart transplantation 2 years later, after which time, tafamidis therapy was continued.

The second case, a 68-year-old African-American male, was the brother of the first patient, and was referred for screening for ATTRv. Genetic testing revealed the patient to be heterozygous for the V122Imutation. Laboratory analysis was conducted, and the patient was enrolled in a clinical trial for a novel TTR stabilizer. At 3 years post-diagnosis, the patient continued to have minimal cardiovascular symptoms.

The third case, a 64-year-old African-American female, was the sister to both male patients and was being screened based on her brothers’ diagnoses. Although the patient was homozygous for the V122I mutation and reported mild exertional shortness of breath, she denied marked activity limitations. At the time of publication, the patient was currently being monitored and has not received prophylactic treatment, based on a lack of objective evidence of ATTR.

These 3 cases highlight the range of disease severity and phenotypic penetrance based on mutation zygosity and patient sex. More importantly, it is critical for healthcare providers to be aware of subtle and overt clinical signs that may assist with early diagnosis and highlight opportunities for appropriate early treatment. Further research is warranted to help improve surveillance programs, focused on treatment initiation for asymptomatic genotype-positive family members.

Source: Tushak ZJ, Doshi A, Trankle CR, et al. Phenotypic spectrum of transthyretin cardiac amyloidosis in a family: impact of mutation zygosity and sex. JACC CardioOncol. 2021;3:602-605.

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