Journal
NEUROLOGY
Volume 87, Issue 8, Pages 750-751Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1212/WNL.0000000000003018
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Transthyretin (TTR) is an amyloidogenic protein synthesized primarily (>95%) by the liver and, to a lesser extent, by the choroid plexuses and retinal pigment epithelium. Hereditary TTR amyloidosis (ATTR) is a multisystem disorder that may manifest with 3 main clinical phenotypes: familial amyloid polyneuropathy (FAP), familial amyloid cardiomyopathy, and familial leptomeningeal amyloidosis.(1) TTR-FAP is the most common presentation. More than 130 autosomal dominant mutations cause ATTR, with the Val30Met mutation being the most frequent variant worldwide: prevalence of up to 1:1,000 in endemic regions of Portugal, Sweden, and Japan. Highly penetrant endemic Val30Met-FAP occurs in early adulthood (before age 50) and manifests as a progressive motor-sensory neuropathy dominated by the involvement of small fibers and autonomic dysfunction. Untreated patients die 7-12 years from onset due to dysautonomia and cardiomyopathy. In nonendemic areas, Val30Met-TTR and other TTR variants have a later age at onset (after age 60), lower penetrance, greater phenotypical variability, and a 2- to 3-year gap from symptom onset to the definite diagnosis. TTR-familial leptomeningeal amyloidosis and cerebral amyloid angiopathy (CAA) are associated with selected TTR variants that deposit in the media and adventitia of medium-sized and small cerebral arteries and veins of the cortex and leptomeninges. Occasionally, ATTR-Val30Met may also lead to leptomeningeal amyloidosis throughout the natural course of the disease.(2) This CNS ATTR is mainly related to the production of TTR variants by the choroid plexus and manifests with TIA-like episodes, aura-like episodes, ischemic or hemorrhagic brain or spinal cord strokes, epileptic seizures, and dementia.
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