Clinical characteristics: Hereditary transthyretin amyloidosis (ATTRv amyloidosis) is characterized by a slowly progressive peripheral sensorimotor and/or autonomic neuropathy. Amyloidosis can involve the heart, central nervous system (CNS), eyes, and kidneys. The disease usually begins in the third to fifth decade in persons from endemic foci in Portugal and Japan; onset is later in persons from other areas. Typically, sensory neuropathy starts in the lower extremities with paresthesia and hypesthesia of the feet, followed within a few years by motor neuropathy. In some persons, particularly those with early-onset disease, autonomic neuropathy is the first manifestation of the condition; findings can include orthostatic hypotension, constipation alternating with diarrhea, attacks of nausea and vomiting, delayed gastric emptying, sexual impotence, anhidrosis, and urinary retention or incontinence. Cardiac amyloidosis is mainly characterized by progressive restrictive cardiomyopathy. Individuals with leptomeningeal amyloidosis may have the following CNS findings: dementia, psychosis, visual impairment, headache, seizures, motor paresis, ataxia, myelopathy, hydrocephalus, or intracranial hemorrhage. Ocular involvement includes vitreous opacity, glaucoma, dry eye, and ocular amyloid angiopathy. Mild-to-severe kidney disease can develop.

Diagnosis/testing: The diagnosis of ATTRv amyloidosis is established in a proband with characteristic clinical features, including imaging or histopathology findings of amyloidosis, and a heterozygous pathogenic variant in TTR identified by molecular genetic testing.

Management: Targeted therapies: Pharmacotherapeutics (e.g., gene-silencing therapies, transthyretin tetramer stabilizers) are first-line therapy for all individuals with ATTRv amyloidosis. There is limited indication for orthotopic liver transplantation.

Treatment of manifestations: Pharmacologic treatments for neuropathic pain; surgical release for carpal tunnel syndrome; ankle-foot orthoses and physical therapy for motor neuropathy; standard treatments for autonomic dysfunction and CNS manifestations. In those with sick sinus syndrome or second- or third-degree atrioventricular block, a cardiac pacemaker may be indicated. Vitrectomy for vitreous opacification; surgical treatment for glaucoma; ocular lubrication for dry eye; erythropoietin or intravenous iron for normocytic normochromic anemia; hemodialysis as needed for end-stage kidney disease.

Surveillance: Abdominal wall fat aspiration or gastrointestinal tract biopsy annually to identify disease onset in asymptomatic individuals; systematic neurologic screening at least annually; nerve conduction studies annually; clinical assessment for manifestations of cardiac disease and serum B-type natriuretic peptide levels annually; electrocardiogram and echocardiography at least annually; ^99mTc-PYP myocardial scintigraphy every three to five years; clinical assessment for dementia, psychosis, headache, seizures, motor paresis, and ataxia annually; ophthalmology examination including assessment for glaucoma at least annually; laboratory assessment of kidney function annually; modified body mass index annually; assessment of psychological manifestations as needed.

Agents/circumstances to avoid: Local heating appliances, such as hot-water bottles, which can cause low-temperature burn injuries in those with decreased temperature and pain perception.

Evaluation of relatives at risk: Clarify the genetic status of at-risk relatives by molecular genetic testing for the TTR pathogenic variant(s) in the family in order to identify as early as possible those who would benefit from prompt early diagnosis and treatment.

Genetic counseling: ATTRv amyloidosis is inherited in an autosomal dominant manner. Each child of an individual who is heterozygous for a TTR pathogenic variant has a 50% risk of inheriting the TTR pathogenic variant. All offspring of an individual who has biallelic TTR pathogenic variants will inherit a pathogenic variant. Once the TTR pathogenic variant(s) has been identified in an affected family member, predictive testing for at-risk family members and prenatal/preimplantation genetic testing are possible.