Clinical Guidance

Clinical features of hereditary transthyretin amyloidosis (ATTRv amyloidosis) can include peripheral sensorimotor neuropathy and autonomic neuropathy, as well as non-neuropathic changes. Cardiac amyloidosis (e.g., restrictive cardiomyopathy, arrhythmia), leptomeningeal amyloidosis (e.g., transient focal neurologic episodes, intracerebral and/or subarachnoid hemorrhages), ophthalmopathy (e.g., vitreous opacities, glaucoma), and nephropathy are frequently seen in the advanced stage of the disease . Affected individuals can also present with non-neuropathic forms of ATTRv amyloidosis in which polyneuropathy is less evident. Table 2. Hereditary Transthyretin Amyloidosis: Frequency of Select Features Feature | % of Persons w/Feature

Source: GeneReviews — "Hereditary Transthyretin Amyloidosis"

Penetrance

Penetrance for ATTRv amyloidosis is not 100%; an individual with a TTR pathogenic variant may remain symptom-free until late adulthood. The penetrance may vary by pathogenic variant, geographic region, or ethnic group. The penetrance appears to be much higher in individuals in endemic foci than outside of endemic foci . In Portugal, cumulative disease risk in individuals with TTR pathogenic variant is estimated at 80% by age 50 years and 91% by age 70 years, whereas the risk in French heterozygotes is 14% by age 50 years and 50% by age 70 years . In Sweden, the penetrance is much lower: 1.7% by age 30, 5% by age 40, 11% by age 50, 22% by age 60, 36% by age 70, 52% by age 80, and 69% by age 90 years, respectively . Some p.Val50Met homozygotes remain asymptomatic.

Source: GeneReviews — "Hereditary Transthyretin Amyloidosis"

Differential Diagnosis

Genetic disorders. Genes of interest in the differential diagnosis of hereditary transthyretin amyloidosis (ATTRv amyloidosis) are listed in . Note: A total of 35 amyloidogenic proteins including transthyretin (TTR) have been identified in human amyloidoses . Among the hereditary amyloidoses, ATTRv amyloidosis is the most prevalent . Table 3a. Genes of Interest in the Differential Diagnosis of Hereditary Transthyretin Amyloidosis

Source: GeneReviews — "Hereditary Transthyretin Amyloidosis"

Clinical Guidance

Since most individuals with ATTRv amyloidosis have decreased temperature and pain perception, affected individuals should not use local heating appliances, such as hot-water bottles, which can cause low-temperature burn injuries.

Source: GeneReviews — "Hereditary Transthyretin Amyloidosis"

Therapies Under Investigation

Strategies for potential molecular therapies for ATTRv amyloidosis include the following:

• Stabilization of variant transthyretin (TTR). A Phase III clinical trial of a new TTR tetramer stabilizer, acoramidis, showed greater TTR stabilization and clinical benefit in individuals with ATTRv amyloidosis-related cardiomyopathy (see NCT03860935). To date, acoramidis is not FDA approved.

• Gene editing

of TTR. NTLA-2001, a new gene-editing therapy using the CRISPR/Cas9 technology, showed reducuction of serum TTR concentration comparable to gene silencers in a Phase I clinical trial . A Phase III clinical trial of NTLA-2001 is under way (see NCT04601051).

• Disruption of insoluble amyloid fibrils

Source: GeneReviews — "Hereditary Transthyretin Amyloidosis"