Systemic amyloidosis is comprised of a group of rare disorders characterized by extracellular deposition of amyloid fibrils that can damage a body’s organs, tissues, and nerves. Below we discuss both acquired and inherited types of amyloidosis and, in particular, how it can affect the body’s nervous systems – both peripheral and autonomic.
ACQUIRED TYPES OF AMYLOIDOSIS
Acquired forms of the disease include AL or “light chain” amyloidosis, where increased levels of misfolded light chain proteins lead to amyloid formation and deposition, and “wild type” transthyretin (ATTRwt) amyloidosis where amyloid fibrils deposit slowly over time, typically becoming symptomatic in the elderly.
Acquired forms of the disease tend to predominantly impact the heart and kidneys, however less common or pronounced neuropathic manifestations of the disease may also preside. In the case of AL amyloidosis, although not a prominent symptom, peripheral neuropathy is seen in 15% of patients at disease onset and in about 35% of patients as the disease progresses. In the case of wild type transthyretin amyloidosis some degree of neuropathy is found in approximately 50% of patients.
The two graphics below illustrate the most common organs affecting AL amyloidosis and wild type amyloidosis, including the nervous system.
INHERITED TYPES OF AMYLOIDOSIS
The most prominent inherited form of the disease is hereditary transthyretin amyloidosis (hATTR or ATTRv), which includes over 120 genetic variants. With many of the variants, neuropathic symptoms frequently accompany, or even dominate, over cardiac symptoms. (1)
The graphic below illustrates the most common organs affecting hATTR amyloidosis, including the nervous system.
HOW AMYLOIDOSIS CLINICALLY IMPACTS THE NERVOUS SYSTEM
Amyloidosis can impact the bodies peripheral and/or the autonomic nervous system. When the disease affects both systems it is defined as polyneuropathy.
Peripheral Nervous System
The peripheral nervous system consists of nerves that branch out from the brain and spinal cord to the extremities (periphery) of the body. Sensory nerves carry electrical signals from the extremities towards the brain and motor nerves (afferent nerves) carry signals from the brain to the extremities. The figure below illustrates a basic layout of the system. (2)
The peripheral nervous system includes dorsal root ganglion, which functions to branch sensory and motor nerves from the spine to the periphery of the body. The figure below illustrates a dorsal root ganglion. Amyloid fibrils damage the dorsal root ganglion, often early in disease progression.
Additionally, amyloid deposits in and damages peripheral nerve endoneurium and Schwann cells. The endoneurium is a layer connective tissue around the protective sheath of each nerve fiber in the peripheral nervous system. Schwann cells function to produce the myelin sheath around cell axons. Schwann cell entanglement with amyloid fibrils causes axon degeneration. Both of these processes contribute to nerve damage and can result in symptoms such as numbness in ankles, feet, and hands, and in many cases muscular atrophy, particularly in the legs.
The figure shown below provides an illustrated summation of the production of amyloid fibrils and their impact on both the peripheral and autonomic nervous systems.
Autonomic Nervous System
The autonomic nervous system controls involuntary bodily functions such as regulation of the heart rate, blood pressure, breathing, and digestion, amongst other functions. The system contains sympathetic ganglia, which signal various organs and tissues, contributing to the “fight or flight” response. Amyloid fibrils damage the sympathetic ganglia. (3). Involvement of the autonomic nervous system can lead to symptoms such as compromised heart rate and blood pressure regulation, which can result in chronic orthostatic hypotension, and even syncope (fainting), to name a few.
HEAR FROM AN EXPERT NEUROLOGIST
Patients with ATTR amyloidosis are commonly faced with neurological complications. In this presentation, Dr. Chafic Karam from the University of Pennsylvania goes through four areas: an overview of the neurological systems, how amyloid damages the nerves, neurological signs of ATTR amyloidosis, and how to detect amyloid and diagnose ATTR amyloid neuropathy.
Bibliography
- Neuromuscular Complications of Systemic Amyloidosis, Dina Namiranian, MD, Stefanie Geisler, MD, Department of Neurology, Neuromuscular Division, Washington University School of Medicine in St. Louis, Mo, 2022 Elsevier Inc. The American Journal of Medicine (2022)
- Peripheral nervous system, Adrian Rad. https://www.kenhub.com/en/library/anatomy/the-peripheral-nervous-system
- Peripheral Nerve Fibers-Endoneurium
https://www.elsevier.com/resources/anatomy/peripheral-nerve-fibers/nerve-fascicles/endoneurium/16249
