By Michael Rubin, MD
Professor of Clinical Neurology, Weill Cornell Medical College
Dr. Rubin reports he is a consultant for Merck Sharp & Dohme Corp.
SYNOPSIS: Wild-type tranthyretin amyloidosis, referred to as “senile” amyloidosis previously, usually occurs in the aging population and affects the peripheral nerves and the heart. Usually, neurological symptoms precede cardiac symptoms.
SOURCE: Yungher FW, Kim A, Boehme A, et al. Peripheral neuropathy symptoms in wild type transthyretin amyloidosis. J Peripher Nerv Syst 2020;25:265-272.
Amyloidosis, the extracellular deposition of fibrillary proteins recognizable by their affinity for Congo red and yellow-green birefringence under polarized light, is classified based on its amyloid protein type. AL amyloidosis, derived from immunoglobulin light chain, is the most common form of systemic amyloidosis in the developed world. AA amyloidosis, derived from serum amyloid A protein and typically associated with chronic underlying inflammation, is the most common form in developing countries. Hereditary amyloidoses constitute 10% of all systemic amyloidoses. ATTRv, caused by the mutation of the transthyretin gene, is its most common form (TTRv, variant), and is associated with neuropathy. Wild type transthyretin amyloid (ATTRwt), formerly called senile systemic amyloidosis, is associated with aging and likely is to become the most common form of cardiac amyloid. It is associated with carpal tunnel syndrome. Is it also associated with polyneuropathy?
A retrospective review of the medical records of 151 consecutive patients with ATTRwt cardiomyopathy, seen in the department of cardiology, was undertaken to determine the presence of neuropathy, and combined with 12 ATTRwt patients, evaluated by the department of neurology at the Columbia University Irving Medical Center in New York. ATTRwt diagnosis was confirmed on biopsy or by nuclear scintigraphy, or both, and all patients were negative for TTR mutations. Data collected from the cardiomyopathy group was comprised of medical history, including date of symptom onset, autonomic symptoms of orthostatic hypotension and positional lightheadedness, and laboratory investigations including A1c, fasting glucose, and serum protein electrophoresis. Paresthesiae in both legs were considered neuropathic symptoms, but hand paresthesiae were not, because of the known association of ATTRwt with carpal tunnel syndrome. Data collected from the neurology group was comprised of medical history, laboratory studies, electrodiagnostic examination, and skin biopsy for epidermal nerve fiber density and analysis.
Autonomic studies were performed in selected neurology patients, comprising heart rate variability and range on cyclic deep breathing, sympathetic analysis of portions of the Valsalva maneuver, and tilt table testing with heart rate and blood pressure monitoring. Statistical analysis included the χ2 or Fisher exact tests, with P < 0.05 set as the level of significance.
All 12 neurology ATTRwt amyloid patients had neuropathy, confirmed by electrodiagnostic studies or skin punch biopsy, of which two had no cardiac symptoms. All were male, with mean age of onset of neurological symptoms at 68.9 years and cardiac symptoms at 74.1 years. Large fiber neuropathy was present in 83.3% (n = 10), carpal tunnel syndrome in 91.7% (n = 11), ulnar neuropathy in 41.7% (n = 5), and lumbar or cervical radiculopathy in 50% and 33.3% (n = 6 and 4, respectively). Prediabetes was present in 41.7% (n = 5) and diabetes in 8.3% (n = 1). Among 151 cardiac ATTRwt amyloid patients, 30.5% (n = 46) had leg paresthesiae, of which 17.9% (n = 7) had diabetes, 34.8% (n = 16) had prediabetes, and 50% (n = 23) had neither diabetes nor prediabetes. No significant difference between those with or without neuropathy was found with respect to the rate of diabetes, age, body mass index, smoking history, or triglyceride levels. Neuropathic symptoms may precede cardiac symptoms in ATTRwt amyloidosis and are seen at a higher rate than believed previously, suggesting a causal relationship between ATTRwt and neuropathy.
Transthyretin (alternatively, prealbumin), a tetrameric protein produced mainly in the liver, transports thyroid hormone and retinol, explaining its name, “trans” for transporter, “thy” for thyroid hormone, and “retin” for retinol. With a destabilizing mutation (ATTRv, variant type) or aging (ATTRwt, wild type), the tetramer dissociates into monomers or oligomers that mis-fold and aggregate into amyloid fibrils. More than 130 amyloidogenic mutations have been identified (ATTRv), which may cause a predominantly cardiomyopathic, neuropathic, or mixed phenotype.
ATTRwt amyloidosis, a cause of cardiac amyloidosis, often is preceded by several years by orthopedic clues, including carpal tunnel syndrome, lumbar spinal stenosis, hip and knee arthroplasty, and biceps tendon rupture. It now appears that neuropathy may be added to this list.1
- Rubin J, Maurer MS. Cardiac amyloidosis: Overlooked, underappreciated, and treatable. Annu Rev Med 2020;71:203-219.