Diagnostic Criteria

Suggestive Findings

Hereditary transthyretin amyloidosis (ATTRv amyloidosis) should be suspected in adults with the following clinical, imaging, and histopathology findings and family history. Clinical findings. Slowly progressive sensorimotor and/or autonomic neuropathy that is frequently accompanied by one or more of the following:

• Cardiac conduction blocks

• Cardiomyopathy

• Nephropathy

• Vitreous opacities

• Glaucoma

Imaging findings

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

Management Guidelines

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with hereditary transthyretin amyloidosis (ATTRv amyloidosis), the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 4.

Hereditary Transthyretin Amyloidosis: Recommended Evaluations Following Initial Diagnosis

System/Concern | Evaluation | Comment

Neurologic

| Complete neurologic assessment incl baseline nerve conduction studies |

Cardiac

| Echocardiogram | To evaluate ventricular wall thickness, ventricular septal thickness, diastolic systolic function, longitudinal strain

Electrocardiogram | To evaluate for low voltage in standard limb leads QS pattern in right precordial leads w/ or w/o conduction blocks

Myocardial 99mTc-PYP scintigraphy | To visualize amyloid deposition in heart

CNS | • Gadolinium-enhanced MRI of brain spinal cord

• Amyloid PET imaging using PiB

| To evaluate CNS amyloidosis

Ophthalmologic

| Ophthalmologic eval | To evaluate for vitreous opacities glaucoma

Renal

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"

Surveillance Guidelines

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in are recommended . Table 7. Hereditary Transthyretin Amyloidosis: Recommended Surveillance

Source: GeneReviews — "Hereditary Transthyretin Amyloidosis"