Syncope, Urinary Retention, and Neuropathy in a 40-Year-Old

Amanda Kennedy, MD, MPH; Jeffrey Kaplan, MD; Dianna Quan, MD


February 27, 2023


With the clinical combination of a progressive, length-dependent sensorimotor neuropathy; prominent dysautonomia; and gastrointestinal symptoms with progression to significant weight loss, this patient's presentation is most consistent with hereditary amyloidosis due to variant transthyretin (ATTRv). Transthyretin gene sequencing was performed, which showed a V30M mutation.

Transthyretin is a tetrameric protein that functions as a transport protein for thyroxine and retinol (vitamin A).[1] Most transthyretin is produced in the liver, with less than 5% synthesized in the retinal pigment epithelium and choroid plexus.[1,2] Single amino acid substitution mutations in the TTR gene on chromosome 18 destabilize the tetramer into monomers.[3,4,5] These monomers then form amyloid fibrils (ATTR) that deposit into and disrupt tissues.[6] The most frequently involved tissues include the peripheral nerves and heart; however, ocular and leptomeningeal deposition can occur as well.[5]

ATTRv amyloidosis is an autosomal dominant condition with variable penetrance, with over 130 mutations identified.[4,6] The estimated global prevalence of ATTRv amyloidosis is about 10,000 people on the basis of one study; the endemic countries of Portugal, Sweden, and Japan have 43% of cases.[7] The most common mutation is V30M, found in about 75% of patients with ATTRv amyloidosis worldwide; however, the V122I mutation and cardiac phenotype are most common in the United States.[6,8] Patients with V30M mutations typically present at a younger age, with some studies showing average onset around age 30 years. Patients with non-V30M mutations often have a later onset, around age 50-60 years; however, the average age of onset varies by country, with endemic regions having earlier onset than nonendemic regions.[6,9]

Patients typically present with progressive length-dependent sensorimotor peripheral neuropathy or cardiac symptoms due to a restrictive cardiomyopathy, with either the cardiac or neuropathic symptoms predominating.[6] Half of patients who present with neuropathy symptoms eventually have associated cardiomyopathy.


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