Clinical characteristics: Hereditary transthyretin (ATTR) amyloidosis is characterized by a slowly progressive peripheral sensorimotor and/or autonomic neuropathy as well as non-neuropathic changes of cardiomyopathy, nephropathy, vitreous opacities, and CNS amyloidosis. 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 paresthesias and hypesthesias 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 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.
Diagnosis/testing: The diagnosis of hereditary ATTR amyloidosis is established in a proband with characteristic clinical features, amyloid deposits identified on biopsy that bind to anti-TTR antibodies, and identification of a heterozygous pathogenic variant in TTR by molecular genetic testing.
Management: Treatment of manifestations: Orthotopic liver transplantation (OTLX) halts the progression of peripheral and/or autonomic neuropathy; OTLX is recommended in individuals younger than age 60 years with: (1) disease duration less than five years, (2) polyneuropathy restricted to the lower extremities or with autonomic neuropathy alone, and (3) no significant cardiac or renal dysfunction. Additional treatment options include TTR tetramer stabilizers and gene-silencing therapies. Surgery is indicated for carpal tunnel syndrome, vitrectomy for vitreous involvement, and surgical treatment for glaucoma. In those with sick sinus syndrome or second-degree or third-degree AV block, a cardiac pacemaker may be indicated.
Surveillance: Serial nerve conduction studies to monitor polyneuropathy; serial electrocardiogram, echocardiography, and serum B-type natriuretic peptide levels to monitor cardiomyopathy and conduction block; follow modified body mass index to monitor nutritional status.
Agents/circumstances to avoid: Local heating appliances, such as hot-water bottles, which can cause low-temperature burn injury in those with decreased temperature and pain perception.
Evaluation of relatives at risk: If the family-specific pathogenic variant is known, molecular genetic testing ensures early diagnosis and treatment. If the familial variant is not known, clinical evaluations ensure early diagnosis and treatment.
Genetic counseling: Hereditary ATTR amyloidosis is inherited in an autosomal dominant manner. Each child of an affected individual (who is heterozygous for one TTR pathogenic variant) has a 50% chance of inheriting the TTR variant. For affected individuals homozygous for TTR pathogenic variants:
Each sib is at a 50% risk of inheriting one TTR pathogenic variant and a 25% risk of inheriting two TTR pathogenic variants;
All offspring will inherit a pathogenic variant.
Prenatal testing for pregnancies at increased risk is possible if the pathogenic variant has been identified in the family. Requests for prenatal testing for adult-onset conditions that (like hereditary ATTR amyloidosis) do not affect intellect and have some treatment available are not common.
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